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toxicology Bhatt Laxit K 1 st Year M.Pharm Shree Devi College Of Pharmacy 1 Dept. Of Pharmacology

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INTRODUCTION Toxicology is a branch of biology , chemistry , and medicine concerned with the study of the adverse effects of chemicals on living organisms. It is the study of symptoms, mechanisms, treatments and detection of poisoning , especially the poisoning of people.[1] 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.[2] Dept. Of Pharmacology 3

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Toxicity itself can rarely, if ever, be defined as a single molecular event but is, rather, a cascade of events starting with exposure, proceeding through distribution and metabolism, and ending with interaction with cellular macromolecules (usually DNA or protein) and the expression of a toxic end point. This sequence may be mitigated by excretion and repair.[2] The right dose differentiates a poison from a remedy. Dept. Of Pharmacology 4

Scope of toxicology:

Scope of toxicology 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. 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.[2] The Toxicology Discipline conducts both qualitative and quantitative analyses. Qualitative analyses are intended to identify particular substances in a specimen. Quantitative analyses are intended to both identify particular substances and to establish how much is present. [3] Dept. Of Pharmacology 5

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Because toxicological findings are used in Court, analyses are conducted according to strict practices and methods which are legally defensible. These practices and methods meet the standards established by the, American Society of Crime Lab Directors Laboratory Accreditation Board (ASCLD/LAB). All submitted specimens are maintained under chain-of-custody in a secure environment intended to preserve the material for the intended analyses.[3] Dept. Of Pharmacology 6


DOSE – RESPONSE RELATIONSHIPS Toxicity is a relative event that depends not only on the toxic properties of the chemical and the dose administered but also on individual and interspecific variation in the metabolic processing of the chemical. The first recognition of the relationship between the dose of a compound and the response elicited has been attributed to Paracelsus. A dose–response relationship is said to exist when changes in dose produces consistent, nonrandom changes in effect, either in the magnitude of effect or in the percent of individuals responding at a particular level of effect. For example, the number of animals dying increases as the dose of strychnine is increased. [5] Dept. Of Pharmacology 7

The Basic Components of Tests Generating Dose–Response Data :-:

The Basic Components of Tests Generating Dose–Response Data :- 1. The selection of a test organism 2. The selection of a response to measure (and the method for measuring that response) 3. An exposure period 4. The test duration (observation period) 5. A series of doses to test [5] Dept. Of Pharmacology 8

Ideal drc:

Ideal drc Dept. Of Pharmacology 9


HOW DOSE–RESPONSE DATA CAN BE USED Dosages are often described as lethal doses (LD), where the response being measured is mortality; toxic doses (TD), where the response is a serious adverse effect other than lethality; and sentinel doses (SD), where the response being measured is a non- or minimally-adverse effect. Sentinel effects (e.g., minor irritation, headaches, drowsiness) serve as a warning that greater exposure may result in more serious effects. [5] Dept. Of Pharmacology 10

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Dose–response data allow the toxicologist to make several useful comparisons or calculations. As Figure shows, comparisons of the LD50 doses of toxicants A, B, and C indicate the potency (toxicity relative to the dose used) of each chemical. Knowing this difference in potency may allow comparisons among chemicals to determine which is the least toxic per unit of dose (least potent), and therefore the safest of the chemicals for a given dose. This type of comparison may be particularly informative when there is familiarity with at least one of the substances being compared. In this way, the relative human risk or safety of a specific exposure may be approximated by comparing the relative potency of the unknown chemical to the familiar one, and in this manner one may approximate a safe exposure level for humans to the new chemical. [5] Dept. Of Pharmacology 11

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Factors affecting toxicology:

Factors affecting toxicology The toxicity of a substance depends on the following: Form and innate chemical activity Dosage, especially dose-time relationship Exposure route Species Age Sex Absorption Metabolism Distribution Excretion Presence of other chemicals [4] Dept. Of Pharmacology 13

Form and innate chemical activity :

Form and innate chemical activity The form of a substance may have a profound impact on its toxicity especially for metallic elements.  For example, the toxicity of mercury vapor differs greatly from methyl mercury.  Another example is chromium.  Cr 3+ is relatively nontoxic whereas Cr 6+ causes skin or nasal corrosion and lung cancer. The innate chemical activity of substances also varies greatly.  Some can quickly damage cells causing immediate cell death.  Others slowly interfere only with a cell's function. For example: Hydrogen cyanide binds to cytochrome oxidase resulting in cellular hypoxia and rapid death. Nicotine binds to cholinergic receptors in the CNS altering nerve conduction and inducing gradual onset of paralysis. [4] Dept. Of Pharmacology 14


Dosage The dosage is the most important and critical factor in determining if a substance will be an acute or a chronic toxicant. Virtually all chemicals can be acute toxicants if sufficiently large doses are administered. Often the toxic mechanisms and target organs are different for acute and chronic toxicity. [4] Dept. Of Pharmacology 15

Exposure route :

Exposure route Exposure route is important in determining toxicity.  Some chemicals may be highly toxic by one route but not by others.  Two major reasons are differences in absorption and distribution within the body. For example: ingested chemicals, when absorbed from the intestine, distribute first to the liver and may be immediately detoxified inhaled toxicants immediately enter the general blood circulation and can distribute throughout the body prior to being detoxified by the liver. Frequently there are different target organs for different routes of exposure. [4] Dept. Of Pharmacology 16


species Selective toxicity refers to species differences in toxicity between two species simultaneously exposed. This is the basis for the effectiveness of pesticides and drugs. Examples are: an insecticide is lethal to insects but relatively nontoxic to animals. Antibiotics are selectively toxic to microorganisms while virtually nontoxic to humans. [4] Dept. Of Pharmacology 17


age Age may be important in determining the response to toxicants. Some chemicals are more toxic to infants or the elderly than to young adults. For example: parathion is more toxic to young animals, Nitrosamines are more carcinogenic to newborn or young animals. [4] Dept. Of Pharmacology 18


sex Although uncommon, toxic responses can vary depending on sex . Examples are: male rats are 10 times more sensitive than females to liver damage from DDT. Female rats are twice as sensitive to parathion as male rats. [4] Dept. Of Pharmacology 19


ABSORPTION The ability to be absorbed is essential for systemic toxicity to occur. Some chemicals are readily absorbed and others poorly absorbed. For example, nearly all alcohols are readily absorbed when ingested, whereas there is virtually no absorption for most polymers. The rates and extent of absorption may vary greatly depending on the form of the chemical and the route of exposure. For example: ethanol is readily absorbed from the gastrointestinal tract but poorly absorbed through the skin organic. Mercury is readily absorbed from the gastrointestinal tract; inorganic lead sulfate is not. [4] Dept. Of Pharmacology 20


DISTRIBUTION The distribution of toxicants and toxic metabolites throughout the body ultimately determines the sites where toxicity occurs. A major determinant of whether or not a toxicant will damage cells is its lipid solubility. If a toxicant is lipid-soluble it readily penetrates cell membranes. Many toxicants are stored in the body.  Fat tissue, liver, kidney, and bone are the most common storage depots.  Blood serves as the main avenue for distribution.  Lymph also distributes some materials. [4] Dept. Of Pharmacology 21


METABOLISM Metabolism , also known as biotransformation, is a major factor in determining toxicity. The products of metabolism are known as metabolites. There are two types of metabolism - detoxification and bioactivation . Detoxification is the process by which a xenobiotic is converted to a less toxic form.  This is a natural defense mechanism of the organism.  Generally the detoxification process converts lipid-soluble compounds to polar compounds. Bioactivation is the process by which a xenobiotic may be converted to more reactive or toxic forms. [4] Dept. Of Pharmacology 22


EXCRETION The site and rate of excretion is another major factor affecting the toxicity of a xenobiotic. The kidney is the primary excretory organ, followed by the gastrointestinal tract, and the lungs (for gases) . Xenobiotics may also be excreted in sweat, tears, and milk. A large volume of  blood serum is filtered through the kidney. Lipid-soluble toxicants are reabsorbed and concentrated in kidney cells. Impaired kidney function causes slower elimination of toxicants and increases their toxic potential. [4] Dept. Of Pharmacology 23

presence of other chemicals:

presence of other chemicals The presence of other chemicals may decrease toxicity (antagonism) , add to toxicity (additivity) , or increase toxicity (synergism or potentiation) of some xenobiotics. For  example: alcohol may enhance the effect of many antihistamines and sedatives . Antidotes function by antagonizing the toxicity of a poison (atropine counteracts poisoning by organophosphate insecticides). [4] Dept. Of Pharmacology 24


reference A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson ISBN 0-471-26508-X Principles Of Toxicology - Environmental And Industrial Applications. Second Edition. Edited by Phillip L. Williams, Robert C. James, Stephen M. Roberts. Page 3 – 35. Dept. Of Pharmacology 25

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