Principles of Animal toxicology

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B.CHAKRAPANI M.PHARM(PHD) DEPARTMENT OF PHARMACOLOGY: 

B.CHAKRAPANI M.PHARM(PHD) DEPARTMENT OF PHARMACOLOGY Toxicology 1 WWW.REVOLUTIONPHARMD.COM

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WHAT IS AN LD50?: 

WHAT IS AN LD50? “LD50” is an abbreviation for “Lethal Dose 50%”, sometimes also referred to as the “Median Lethal Dose” (Figure 1). Although the LD50 is no longer the preferred measure for assessing the acute toxicity of single doses of a substance, for historical reasons it is probably still the most commonly cited measure. The 3 WWW.REVOLUTIONPHARMD.COM

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the amount that can be expected to cause death in half (i.e. 50%) of a group of a particular animal species, usually rats or mice, when entering the animal’s body by a particular route. For example, if the substance is swallowed, the figure is an ‘oral LD50’ whereas if it’s absorbed through the skin, it’s a ‘dermal LD50’. LD50 figures are derived by mathematical calculation from the results of tests on animals and hence cannot be regarded as biologically precise values. In general, the amounts of a substance required to kill animals from different species are approximately related to the animals’ body weights. Therefore, LD50 figures are usually reported in units of milligrams of the substance per kilogram body weight for the animal species concerned. 4 WWW.REVOLUTIONPHARMD.COM

Toxicology: 

Toxicology The study of the adverse effects of a toxicant on living organisms. Toxicant (Poison): Any agent capable of producing a deleterious response in a biological system. “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy.” Paracelsus (1493-1541). 5 WWW.REVOLUTIONPHARMD.COM

General principles involved in animal toxicology: 

General principles involved in animal toxicology Toxicology (from the Greek words τοξικός - toxicos "poisonous" and logos ) 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 Acute toxicity of a drug can be determined by the calculation of LD 50 , i.e .,the dose that will kill 50% of animals of a particular species . 6 WWW.REVOLUTIONPHARMD.COM

An approximate LD50 can be initially determined as a pilot study by a so called ‘stair case method ‘ using a small number of animals (2 each dose ) and increasing the doses of the drug . Five doses can be chosen for determination of LD 50 starting from no death to 100% mortality: 

An approximate LD50 can be initially determined as a pilot study by a so called ‘stair case method ‘ using a small number of animals (2 each dose ) and increasing the doses of the drug . Five doses can be chosen for determination of LD 50 starting from no death to 100% mortality The shape, size, and solubility of the toxicant will determine how easily it enters the body, how it will distribute within the body, and the rate of its excretion from the body. 7 WWW.REVOLUTIONPHARMD.COM

General: 

General Humans live in a chemical environment and inhale, ingest, or absorb from the skin many of these chemicals. Toxicology is concerned with the deleterious effects of these chemical agents on all living systems. In the biomedical area, however, the toxicologist is primarily concerned with adverse effects in humans resulting from exposure to drugs and other chemicals as well as the demonstration of safety or hazard associated with their use. 8 WWW.REVOLUTIONPHARMD.COM

Occupational Toxicology: 

Occupational Toxicology Occupational toxicology deals with the chemicals found in the workplace. The major emphasis of occupational toxicology is to identify the agents of concern, define the conditions leading to their safe use, and prevent absorption of harmful amounts. Guidelines have been elaborated to establish safe ambient air concentrations for many chemicals found in the workplace. The American Conference of Governmental Industrial Hygienists periodically prepares lists of recommended threshold limit values (TLVs) for about 600 such chemicals ( Doull , 2001). These guidelines are reevaluated as new information becomes available. 9 WWW.REVOLUTIONPHARMD.COM

Environmental Toxicology: 

Environmental Toxicology Environmental toxicology deals with the potentially deleterious impact of chemicals, present as pollutants of the environment, to living organisms. The term environment includes all the surroundings of an individual organism, but particularly the air, soil, and water. While humans are considered a target species of particular interest, other terrestrial and aquatic species are of considerable importance as potential biologic targets. Air pollution is a product of industrialization, technologic development, and increased urbanization. Humans may also be exposed to chemicals used in the agricultural environment as pesticides or in food processing that may persist as residues or ingredients in food products. 10 WWW.REVOLUTIONPHARMD.COM

Ecotoxicology: 

Ecotoxicology Ecotoxicology is concerned with the toxic effects of chemical and physical agents on populations and communities of living organisms within defined ecosystems; it includes the transfer pathways of those agents and their interactions with the environment. 11 WWW.REVOLUTIONPHARMD.COM

Toxicologic Terms & Definitions: 

Toxicologic Terms & Definitions Hazard & Risk Hazard is the ability of a chemical agent to cause injury in a given situation or setting; the conditions of use and exposure are primary considerations. To assess hazard, one needs to have knowledge about both the inherent toxicity of the substance and the amounts to which individuals are liable to be exposed. Humans can safely use potentially toxic substances when the necessary conditions minimizing absorption are established and respected. 12 WWW.REVOLUTIONPHARMD.COM

Risk: 

Risk Risk is defined as the expected frequency of the occurrence of an undesirable effect arising from exposure to a chemical or physical agent. Estimation of risk makes use of dose-response data and extrapolation from the observed relationships to the expected responses at doses occurring in actual exposure situations. The quality and suitability of the biologic data used in such estimates are major limiting factors. 13 WWW.REVOLUTIONPHARMD.COM

Routes of Exposure: 

Routes of Exposure The route of entry for chemicals into the body differs in different exposure situations. In the industrial setting, inhalation is the major route of entry. The transdermal route is also quite important, but oral ingestion is a relatively minor route. Consequently, preventive measures are largely designed to eliminate absorption by inhalation or by topical contact. Atmospheric pollutants gain entry by inhalation, whereas for pollutants of water and soil, oral ingestion is the principal route of exposure for humans. 14 WWW.REVOLUTIONPHARMD.COM

Duration of Exposure: 

Duration of Exposure Toxic reactions may differ qualitatively depending on the duration of the exposure. A single exposure—or multiple exposures occurring over 1 or 2 days—represents acute exposure. Multiple exposures continuing over a longer period of time represent a chronic exposure. In the occupational setting, both acute (e.g, accidental discharge) and chronic (e.g, repetitive handling of a chemical) exposures may occur, whereas with chemicals found in the environment (e.g, pollutants in ground water), chronic exposure is more likely. 15 WWW.REVOLUTIONPHARMD.COM

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Toxicology: The study of the adverse effects of a toxicant on living organisms . Toxicant (Poison): Any agent capable of producing a deleterious response in a biological system. “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy.” Paracelsus (1493-1541) The shape, size, and solubility of the toxicant will determine how easily it enters the body, how it will distribute within the body, and the rate of its excretion from the body. Dose: The amount of chemical entering the body. This is usually given as milligrams of chemical per kilogram of body weight (mg/kg) so that dose can be compared across specimens. How much, how often (duration and frequency), and how the dose is administered are all important parameters. 16 WWW.REVOLUTIONPHARMD.COM

What is an LD50?: 

What is an LD50? “LD50” is an abbreviation for “Lethal Dose 50%.” It is sometimes also referred to as the “Median Lethal Dose”. Although the LD50 is no longer the only measure available for assessing the acute toxicity of single doses of a substance, for historical reasons it is probably still the most commonly cited measure. The LD50 for a particular substance is essentially the amount that can be expected to cause death in half (i.e. 50%) of a group of some particular animal species, usually rats or mice, when entering the animal’s body by a particular route. 17 WWW.REVOLUTIONPHARMD.COM

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Adverse Effect (Response): Any change from an organism’s normal state that is irreversible at least for a period of time. Producing an adverse effect depends on the concentration of the active compound at the target site. A description of the dose and the conditions of exposure must accompany a description of the adverse effect due to a chemical. An effect or response can be graded (variations of the degree of damage) or quantal (all or none; i.e., mortality or tumor development). Living Organism: The species, strain, individual genetic variation, gender, age, health conditions, nutrition, and previous and concurrent exposures can affect how an organism responds to a chemical exposure. Risk Assessment: Quantitative estimate on the potential effects of various types of chemical exposure on human health. RISK= HAZARD + EXPOSURE 18 WWW.REVOLUTIONPHARMD.COM

Treatment: 

Treatment Acute Exposure In addition to intensive supportive care, prompt chelation with oral or intravenous unithiol, intramuscular dimercaprol, or oral succimer may be of value in diminishing nephrotoxicity after acute exposure to inorganic mercury salts. Vigorous hydration may help to maintain urine output, but if acute renal failure ensues, days to weeks of hemodialysis may be necessary. Because the efficacy of chelation declines with time since exposure, treatment should not be delayed until the onset of oliguria or other major systemic effects. 19 WWW.REVOLUTIONPHARMD.COM

Chronic Exposure: 

Chronic Exposure Unithiol and succimer increase urine mercury excretion following acute or chronic elemental mercury inhalation, but the impact of such treatment on clinical outcome is unknown. Dimercaprol has been shown to redistribute mercury to the central nervous system from other tissue sites, and since the brain is a key target organ, dimercaprol should not be used in treatment of exposure to elemental or organic mercury. Limited data suggest that succimer, unithiol, and N-acetyl-L- cysteine (NAC) may enhance body clearance of methylmercury . 20 WWW.REVOLUTIONPHARMD.COM

Pharmacology of Chelators: 

Pharmacology of Chelators Chelating agents are drugs used to prevent or reverse the toxic effects of a heavy metal on an enzyme or other cellular target, or to accelerate the elimination of the metal from the body. Chelating agents are usually flexible molecules with two or more electronegative groups that form stable coordinate-covalent bonds with a cationic metal atom. 21 WWW.REVOLUTIONPHARMD.COM

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Route and Site of Exposure Ingestion (gastrointestinal tract) Inhalation (lungs) Dermal / topical (skin) Parenteral (intravenous--iv, intramuscular—im, intraperitoneal—ip) Typical Effectiveness of Route of Exposure iv > inhalation > ip > im > ingestion > topical 22 WWW.REVOLUTIONPHARMD.COM

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Major Routes of Chemical Entry Ingestion – via the gastro-intestinal [GI] tract Inhalation – via the lungs Dermal – via the skin Other Parenteral (non-intestinal) routes: Intravenous (IV) – direct injection into a vein Intraperitoneal (IP) – injection into the peritoneal cavity Subcutaneous (SC) – injection between the skin and the muscle Intramuscular (IM) – injection directly into the muscle Intradermal – injection into the dermis Occupational Exposures – Inhalation, Dermal 23 WWW.REVOLUTIONPHARMD.COM