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Methods of Toxicological Assessment

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 Feb 17, 2020 |  10:30 pm |  1445



Toxicology is a branch of science that deals with toxins and poisons and their effects and treatment. Toxicological screening is very important for the development of new drugs and for the extension of the therapeutic potential of existing molecules. The US Food and Drug Administration (FDA) states that it is essential to screen new molecules for pharmacological activity and toxicity potential in animals (Parasuraman, 2011). The toxic effects of chemicals, food substances, pharmaceuticals, etc., have attained great significance in the 21st century. This brief review focuses on the historical importance of toxicological screening and alternative and specific methods using various experimental animal models. Toxicity tests are mostly used to examine specific adverse events or specific end points such as cancer, cardiotoxicity, and skin/eye irritation. Toxicity testing also helps calculate the No Observed Adverse Effect Level (NOAEL) dose and is helpful for clinical studies (Setzer and Kimmel, 2013).

1.2    History Of Toxicity Studies

The history of toxicity studies begins with Paracelsus (1493–1541), who determined specific chemicals responsible for the observed toxicity of plants and animals. He demonstrated the harmless and beneficial effects of toxins and proved dose-response relationships for the effects of drugs (Parasuraman, 2011). Paracelsus, who was a physician, alchemist, and astrologer, is widely regarded as the father of toxicology. The following statement of his is often quoted: “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” Mathieu Orfila (1787–1853), a Spanish physician, determined the relationship between poisons and their biological properties and demonstrated specific organ damage caused by toxins. Orfila is referred to as the father of modern toxicology. Toxicological screening methods and toxicological research on individual substances developed in the mid-1900s, and environmental toxicological studies developed in the mid-20th century (Hunter, 2018).

The use of animals in toxicity studies began in 1920, when J. W. Trevan proposed the use of the 50% lethal dose (LD50) test to determine the lethal dose of individual chemicals. After the introduction of LD50, a FDA scientist John Draize developed a method for testing eye and skin irritation using rabbits, and this method was widely accepted for testing the effects of chemicals and pharmaceuticals on the eye and skin. Later, the US National Cancer Institute (NCI) developed a test to identify carcinogenic chemicals through the daily dosing of rats and mice for 2 years. In the early 1960s, thousands of babies were born with debilitating birth defects caused by thalidomide. After this, all the regulatory agencies concentrated on determining the toxicity profiles of all pharmaceutical substances available for regular patient use and made mandatory the submission of toxicity profiles of investigational new drugs (IND). In the late 1980s, the Organisation for Economic Co-operation and Development (OECD) and the International Conference on Harmonization (ICH) brought out the guidelines for toxicity testing of pharmaceutical substances (Parasuraman, 2011). 


3.1    Acute Toxicity Testing

Acute toxicity testing is carried out to determine the effect of a single dose on a particular animal species. In general, it is recommended that acute toxicity testing be carried out with two different animal species (one rodent and one non-rodent). In acute toxicological testing, the investigational product is administered at different dose levels, and the effect is observed for 14 days. All mortalities caused by the investigational product during the experimental period are recorded and morphological, biochemical, pathological, and histological changes in the dead animals are investigated. Acute toxicity testing permits the 50% lethal dose (LD50) of the investigational product to be determined. The LD50 was used as an indicator of acute toxicity previously. The determination of the LD50 involves large numbers of animals, and the mortality ratio is high (Parasuraman, 2011). 


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