Concepts and Terminology

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Concepts and Terminology. Toxicology Is the study of poisons, including their chemical properties and biological effects. Toxicant an alternative term for poison. Toxin: A poison that originates from biological processes - PowerPoint PPT Presentation

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Concepts and Terminology

Concepts and Terminology

Toxicology Is the study of poisons, including their chemical properties and biological effects. Toxicant an alternative term for poison.Toxin: A poison that originates from biological processes also called a biotoxin. Examples; Mycotoxins (fungal toxins) and zootoxins (animal toxins). Many plants are also known to be toxic when consumed by specific types of animals. Toxicity: The quantity or amount of a poison that causes a toxic effect. Toxicosis: A disease state that results from exposure to a poison.

Toxicology versus pharmacology

Pharmacology is the study of chemicals (drugs) used at doses to achieve therapeutic (beneficial) effects on an organism. Toxicology is the study of chemicals (toxicants) that produce a harmful (detrimental) effect on an organism. Dose: The amount of toxicant that is received per animal. Dosage: The amount of toxicant per unit of animal mass or weight. It can also be expressed as the amount of toxicant per unit of mass or weight per unit of time. For examples, a dog could receive a dosage of chemical at the rate of 2 mg/kg/day. When conducting traditional acute, subacute, subchronic, or chronic studies, the length and frequency of exposure are also noted. For examples, rats may receive a chemical dosage of 2.5 mg/kg/day for 2 years.

Route of exposure: The most common routes of exposure are inhalation, oral, and dermal, with some variations for each. Less frequently used routes of exposure include rectal, sublingual, subcutaneous, and intramuscular.Threshold dose: The highest dose of a toxicant at which toxic effects are not observed.Lethal dose (LD) or median lethal dose (MLD) (LD50): The dose that will kill 50% of a group of animals during some period of observation in acute toxicity study.Lethal concentration (LC) or minimal toxic dose: is the lowest concentration of a chemical or drug in a matrix (usually feed or water) that causes death.Effective dose (ED).The dose of drug or toxicant or therapeutic agent that produces some desired effect in 50% of a population.

Therapeutic index (TI). Defined by the equation : TI = LD50 ED50 the TI is a unitless estimate that characterizes the relative safety of a drug or chemical. The larger the TI, the more safe a chemical is relative to another with a smaller TI. For example, if chemical X has an LD50 of 1000 mg/kg and an ED50 of 10 mg/kg, the TI would be 100 (the mg/kg units cancel). Compare this to chemical Y, which has an LD50 of 50 mg/kg and an ED50 of 40 mg/kg. The TI of chemical Y is 1.25, a much less safe chemical when compared with chemical X.

Standard safety margin (SSM) or margin of safety (MoS).

Defined by the equation: LD1 SSM = ED99 the SSM, like the TI, is a unitless estimate that characterizes the relative safety of a drug or chemical, but much more conservative data are used. The larger the SSM, the more safe the chemical tends to be relative to other chemicals with smaller SSMs.

Exposure duration. The length of time an animal is exposed to a drug or chemical. In general, there are four subgroups: - Acute: Exposure to a single or multiple doses during a 24-hour period. The LD50 is often determined during acute exposure studies. - Subacute: Exposure to multiple doses of a toxicant for greater than 24 hours but for as long as 30 days. - Subchronic: Exposure lasting from 1 to 3 months. - Chronic: Exposure for 3 months or longer. Hazard (risk): a chemical or drug will cause harm under certain conditions.

Toxic effect : damage effect to certain biological system or process caused by poison or drug in high dose.

Side effect : secondary predicted undesired effect that accompanied the therapeutic effect.

Adverse effect: unpredicted undesired effect caused by drug used at recommended dose ex. Allergy of penicillin.

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 doseresponse relationships exist, depending on the numbers of subjects and doses tested.

Graded DoseResponse The graded doseresponse describes the relationship of an individual test subject or system to increasing and/or continuous doses of a chemical.

Graded doseresponse curve for caffeine HCl chloramphenicol HCl() atropine sulfate , and phenol

Quantal DoseResponse The quantal doseresponse is determined by the distribution of responses to increasing doses in animals 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. A typical quantal doseresponse curve is illustrated in Figure by the LD50 (lethal dose 50%) distribution.

Quantal doseresponse curve showing experimental derivation and graphicestimation of LD50 Three general assumptions must be considered when evaluating the dose-response relationship:1. The chemical interacts with a molecular or receptor site to produce a response.2. The production of the response, or the degree of response, is correlated to the concentration of the chemical at that receptor site.3. The concentration of the chemical at the receptor site is related to the dose of chemical received. Toxicokinetics

Toxicant Exposure

Entrance to Body Ingestion Skin InhalationAbsorption into Blood Stream and Distribution to Body Tissues and Organs Toxicity Storage Excretion Metabolism

xenobiotic (foreign compound): they are substance which not enter any biological process or used as a source of energy or nutrition such as heavy mental

Absorption Defines how much of a chemical passes into the body over a period of time. Different routes of exposure produce different absorption patterns, which can vary both within a species (intraspecies variation) and between different species (interspecies variation). For a xenobiotic to exert a toxic effect, it must reach its site of actions. It must reach to the body by crossing any number of body membranes (e.g., skin, lung, gastrointestinal tract, and red blood cell membranes). Composition of these membranes varies, resulting in various levels of resistance to penetration. For example, the skin more resistance to penetration than the lung alveolar surface.

Absorption can be described in terms of bioavailability (F), which is the quantity or percentage portion of the total chemical that is absorbed and available to be processed (DME) by the animal. In the case of intravenous administration, F = 100% because all of the xenobiotic enters the animal. Inhalation, oral, and dermal are the three usual routes of exposure to xenobiotics.Inhalation (pulmonary) Inhalation exposure to chemicals occurs when the chemical is dissolved in the ambient air inhaled by the animal. The chemical first reaches the nasal passages, when some absorption can take place before it enters the trachea, bronchi, and finally the alveoli, the chemical can cross the very thin alveolar wall and enter the blood

Oral (gastrointestinal) Chemicals can enter the gastrointestinal tract in either contaminated food or water sources. Depending on the physicochemical properties of the chemical. For example, some chemicals are unstable in the stomachs acidic environment and can be destroyed to varying degrees, resulting in decreased absorption. On the other chemicals are readily absorbed from the stomach and enter the small intestine, absorption through the intestinal mucosa and then into the blood. Portal circulation delivers them to the liver, a major metabolic organ of the body. Dermal (percutaneous) Three key events must occur for percutaneous absorption to take place.First, the chemical must be soluble in the vehicle (solvent) that is applied to the skin. Second, it must be able to penetrate the thick keratin layer of the epidermis. Third, it must make its way through the lower cells of the epidermis and into a blood vessel.

Xenobiotics can pass through body membranes by either passive transport or active transport.

1. Passive transport. Passive transport requires no energy expenditure on the bodys part to transport the xenobiotic across a cell membrane. Passive transport occurs via two mechanisms: simple diffusion and filtration. a. Simple diffusion. Simple diffusion depends on both the lipid solubility and the size of the molecule. In biological matrices, most xenobiotics exist in a solution as either an ionized or un-ionized form. Un-ionized (uncharged) molecules have greater lipid solubility than the ionized forms. Xenobiotic will penetrate a body membrane, three facts must be known: (1) whether the xenobiotic is a weak acid or a weak base(2) the pH of the biological matrix (3) the association constant of the xenobiotic (or pKa, the pH at which 50% of the xenobiotic is ionized and 50% is un-ionized). Once this information is known, the Henderson-Hasselbalch equation for either a weak acid or a weak base can be applied.For a weak acid: [un-ionized] pKa pH = log [ionized]For a weak base: [ionized] pKa pH = log [un-ionized] T