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General toxicity tests refer to experiments where experimental animals are subjected to different routes and durations of poisoning, and various toxicity endpoints are tested comprehensively. Confused with the general toxicity test is easily confused with the special toxicity test. Special toxicity study refers to mutagenic, carcinogenic, or teratogenic toxicity tests.
What is the significance of the general toxicity study?
- Is the primary basis for understanding the acute toxicity of drugs to the organism, is an essential work in toxicology research;
- Observe the toxic effect spectrum, toxic effect characteristics, and toxic target organs of drugs, and understand the mechanism of drug toxicity;
- Confirmation of the reversibility of damage caused by drug toxicity;
- To study the dose-response (effect) relationship of repeated exposure to the toxic effects of the test substance, from preliminary understanding to determine the dose at which no harmful effects are observed (NOAEL) and the lowest dose at which harmful effects are observed (LOAEL), to provide reference values for establishing safety limits for human exposure;
- Determining the differences in toxic effects of different animal species on the test substance to provide a basis for extrapolation of study results to humans.
The general toxicity tests for Medicilon include:
- Acute toxicity tests.
- Repeated dose toxicity tests (short-term toxicity tests).
- Sub-chronic toxicity tests.
- Chronic toxicity tests.
The subchronic and chronic toxicity tests are also commonly referred to as long-term toxicity tests in the program.
What is a general toxicity study?
General toxicity tests cannot be performed without the contribution of laboratory animals, and the species of non-clinical laboratory animals are divided into rodents (rats, mice, guinea pigs, rabbits) and non-rodents (dogs, monkeys). According to the basic principles of laboratory animal selection, it is desirable, and the laboratory animals should meet the following four points:
（1） Closest to humans in terms of toxic response;
（2） Easy to keep and handle;
（3） Not too long natural life;
（4） Economical and easy to obtain.
Due to their high genetic similarity to humans, short reproductive period, and environmental adaptability, rats are the first choice for non-clinical laboratory animals. Some of the more common laboratory rat species are Sprague-Dawley (SD) and Wistar in rats, Kunming (KM) in mice, ICR (Institute of Cancer Research), NIH, and BALB/C.
Medicilon has rat, canine, and monkey rooms compliant with GLP standards and can undertake non-clinical general toxicity tests on rodents and non-rodents. It has cooperated with MPI in the US, learned and inherited MPI’s quality management system/SOP, implemented comprehensive quality control measures, adopted three-level QC management, applied advanced data management software system, and is experienced in projects.
The most commonly used routes of infection are oral, respiratory, transdermal, and injectable routes.
In addition to common administration routes such as PO and IV, the following characteristic evaluation solutions are also established: Medicilon has also established an inhalation drug delivery platform, ophthalmic drug delivery platform, skin drug delivery platform, sublingual drug delivery platform, evaluation platform for juvenile animals, and integrated evaluation technology platform for antibodies, vaccines, ADCs, CAR-T cell therapies and other bio-innovative drugs that can be tested in aerosol drug toxicology.
Acute Toxicity test
Acute toxicity refers to the health-damaging and lethal effects produced by experimental animals exposed to a certain dose of test article at one time or multiple times within 24 hours in a short period. The observed indicators include general behavioral and appearance changes, gross morphological changes, and mortality effects.
Suppose the toxicity of the test article is low, and a single maximum dose is insufficient to understand acute toxicity’s effects fully. In that case, multiple doses within 24 hours will be used, with no more than three doses and at least 4 hours between each dose. The observation time of acute toxicity differs from the administration time, which is generally 14 days and can be extended to 14 days or more if necessary.
The acute toxicity test generally determines the maximum dose administered, the maximum non-toxic reaction dose, the maximum tolerated dose, the lethal dose, and other reaction doses. The results obtained help find the optimal drug concentration for use.
In recent years, in response to the international call to protect experimental animals and to reduce the avoidable suffering of experimental animals, the 3R principle of “refinement, reduction and replacement” has been proposed as the central idea – acute toxicity substitution test, which can reduce the suffering of experimental animals by optimizing the test method or replacing animal models with tissue models.
Repeat Dose Toxicity Test
The primary objective of a repeated-dose toxicity study is to characterize the adverse toxicological effects that occur with repeated daily administration or exposure to a substance for a specified period up to the life expectancy of the test species (usually 3 weeks to 2 years in animal studies).
Repeated dosing toxicity test should, in principle, set up at least three dose groups of low, medium, and high, as well as a solvent (or excipient) control group, if necessary to set up a blank control group and/or positive control group.
High dose in principle to produce significant toxic reactions in animals, low dose in principle equivalent or higher than the equivalent dose of animal pharmacodynamic dose or clinical use dose, the medium dose should be combined with the mechanism and characteristics of toxic effects between high and low dose set up to examine the dose-response relationship of toxicity.
Subchronic toxicity studies
Subchronic toxicity refers to the toxic effects of a large dose of a foreign compound that the experimental animal is exposed to for multiple days. The so-called larger dose is less than the acute LD50 dose. The test period is generally 90 days. The subchronic toxicity test aims to explore the threshold dose or concentration of subchronic toxicity and the dose level at which no toxic effects are observed during the subchronic test and to find the exposure dose and observation index for the chronic test.
Subchronic toxicity is far more common than one might think. To cite a few famous examples in history: Napoleon died after being banished from captivity after the defeat at Waterloo, the forensic pathologist found that his hair contained more than 13 times the expected level of Kun, and it turned out that the walls in the captivity room were made of wallpaper containing arsenic, the lord of the generation Napoleon died of chronic Kun poisoning in this way. Hundreds of years ago, the lead powder used for makeup whitening was also the culprit that led to the death of many noblemen by poisoning.
This is the accumulation effect of sub-chronic toxicity. When the test product is continuously and repeatedly ingested. The total amount of absorption exceeds the total amount of metabolism. The toxicity will gradually increase in the body, accumulating in the plasma protein, adipose tissue, liver, kidney, bone, and other organs, causing long-term health hazards and, in severe cases, even leading to death.
Since 2008, Medicilon has continued to meet international standards and completed high-quality GLP safety evaluation services, establishing a long-term brand effect. Medicilon can perform systematic evaluation services covering multiple toxicity endpoints and has internationally recognized pathology studies to support our safety evaluation studies.
In addition to research trials, Medicilon’s preclinical pharmacology and toxicology research team is equipped with a professional send format conversion team and has established a send data conversion platform that is fully mature in terms of software, technology, specification, and quality to realize accurate data conversion and provide a suitable environment for electronic data submission. In 2020 alone, it has helped customers complete 14 send data conversion projects, of which three new drug projects have obtained clinical licenses from the FDA.
SEND Format Conversion Platform
Medicilon equipped with a professional send format conversion team, and has established a send data conversion platform that is fully mature in terms of software, technology, specification and quality
