ACUTE TOXICITY DEFINITION * Acute toxicity is the toxicity produced by a pharmaceutical when it is administered in one or more doses during a period not exceeding 24 hours. ¢ Single escalating doses are given to small grps of animals and the animals are observed for overt effects and mortality. ¢ The LD 50 dose is calculated (the dose req to kill 50% of the population)LO OBJECTIVES ~ * To determine the Median Lethal Dose (LD50) after a single dose administered through one or more routes, one of which is the intended route of administration in humans. © To determine Maximum Tolerated Dose (MTD) and No Observable Effect Level (NOEL). * To identify potential target organs for toxicity, determine reversibility of toxicity, and identify parameters for clinical monitoring. ° To help select doses for repeated-dose toxicitySub acute toxicity studies e Duration 14 days to go days ¢ Test System/Animal System 2 species required. Mice, rats, rabbits, guinea Pigs, dogs. ¢ Dose Administration 3 to 4 doses given by the same routes as previous toxicity> To identify any toxic substance prior to clinical use. > Qualitative and Quantitative assessment of drug use. > Mostly used to examine specific adverse events or specific end points such as cancer, cardiotoxicity, skin/eye irritation. > Different types of dose identification can be done. (MLD, LD) MTD, ED) NOAEL) > Prediction of therapeutic index (LDsy /EDsp )CHRONIC TOXICITY STUDIES :- * Repeated dose study from 6 months to 12 months or even upto 2 years. * Primary goal of these studies is to characterize the toxicological profile of the test compound following repeated administration. this includes identification of potential target organs of toxicity and exposure/response relationships, & may include potential reversibility of toxic effects. . ty conduct of human clinical trials and the approval of a marketing = V7Acute Toxicity Tests * Test Procedures = 96 hours or less (species specific) — Mortality is the measured endpoint — For daphnia mortality determined by immobilization * Advantages — less expensive and time consuming than chronic — endpoint is easy to quantify * Disadvantages — indicates only lethal concentrations — only the effects of fast acting chemicals are exhibitedAcute vs. Chronic Effects * Acute Effects - Caused by a single exposure and result in an immediate health problem. * Chronic Effects - Long-lasting. Can be result of single large dose or repeated smaller doses. — Very difficult to assess specific health effects due to other factorsShort-term Chronic Toxicity Tests * Test Procedures — typically 4-10 days — Mortality, growth, fecundity, reproduction * Advantages — more sensitive than acute, assess parameters other than lethality — may better reflect real world * Limitations — more costly and time intensive than acute — more sensitive to low level contaminationWhat is Acute Toxicity? Acute toxicity occurs when the toxin is administered to an organism in a single, potent dose. The features of acute toxicity are: ¢ Sudden onset ¢ Quickly changing e Usually severe, dependent upon dosage and the specific toxin administered e Relatively short reaction time People with compromised organ function, particularly the organs that help the body process waste, are at exceptionally high risk for acute toxin poisoning. If the body struggles with liver or kidney function, it is much less likely to survive acute toxicity. Acute toxicity usually doesn't persist for very long because the waste removal aspects of the body will either successfully remove the toxin or the organism will die.What is Chronic Toxicity? Chronic toxicity occurs when the toxin is administered in small doses over a period of time. It usually has the following characteristics: ¢ Gradual onset ¢ Slowly changing and slowly harming the organism being harmed e Damage is caused bit-by-bit over time e Persistent and recurrent « Small, repeated doses of the same or similar toxin The timetable for chronic toxicity can be months or even years and come from various sources. Many examples of chronic toxicity include smoking, drug abuse, and long- term use of pharmaceuticals. However, this type of chemical toxicity does not meet the biological definition of a toxin.What is Toxicity? A critical misconception must be cleared up before discussing the toxicity definition. Poisonous substances are toxic when ingested. Venomous creatures inject poison as a form of aggression or self-preservation. A toxic mushroom is poisonous, and a rattlesnake is venomous. Unfortunately, these two words are used interchangeably in everyday speech but have very different meanings scientifically. Both poisonous and venomous species produce toxins, defined in biology as protein-based substances produced by living organisms that can cause harm or disease. Other substances, such as chemicals, are often referred to as toxic. Therefore, toxicity is the extent to which a substance can harm another organism. For example, poison dart frogs in the family Dendrobatidae produce an extremely toxic poison through their skin. This toxin is called batrachotoxin. When injected into the bloodstream or applied to human skin, batrachotoxin can cause involuntary muscle contractions, seizures, and death. The Golden Poison Dart Frog carries enough toxin to kill ten adult men. The two types of toxicity will be discussed in this lesson.