The Significance of LD50 and ED50 in Drug Toxicology Studies

 The LD50 and ED50 are vital to research indicators in drug toxicity studies to assess drug safety and efficacy. Toxicology is a science that studies the effects and mechanisms of damage to biological systems and ecosystems by exogenous factors such as chemical, physical and biological factors, as well as the prevention, diagnosis, and treatment of poisoning. 

Drug toxicology is the science of studying the damaging effects of drugs on the organism. LD50 and ED50 are indicators of toxicology research, and understanding these parameters is crucial to ensure the safety and efficacy of drugs and regulatory compliance. This blog will provide a comprehensive overview of LD50 and ED50, their significance in drug toxicology, and how they are measured and interpreted.

LD50 refers to the dose at which half of the test animal samples die, while ED50 is the dose at which half are effective. The safety index of a drug TI = LD50/ ED50. The higher the value, the safer it is. The therapeutic index is generally obtained from animal tests, and a new drug with a TI greater than five can be considered for the study's next step.

1.  LD50

The LD50 is the dose at which half of the test animals die. It is an essential indicator of the acute toxicity of a drug and the strength of its effect, as well as a critical parameter for evaluating the merits of a drug. As an indicator of toxicological research, the greater the LD50 value indicates that the toxicity is less, that is, the higher the drug's safety.

LD50 is a value calculated by mathematical processing of test results, and the results vary significantly between test conditions, test institutions, and research centers for the same drug. A mouse model of stable fungal infection has been developed by some researchers [1]. The method used healthy 6~8 weeks old BALB/c female mice weighing 16~18g, selected for intravenous and intranasal administration. Death observation was performed daily for 26~31d, and the half lethality of mice was calculated.

The results were that all mice in the high dose group (2×10^7) of mice administered with Candida albicans via tail vein died, four mice in the medium dose group (2×10^6) died, and no mice in the low dose group (2×10^5) died. No mice in the high and low doses of the nasal feeding administration group died, indicating that the death of mice with high and low doses and routes of administration were directly related to the appearance of death in mice. It demonstrates that when using mice for experiments on fungal infections, nasal administration is chosen whenever possible.

Other researchers have studied the alkaloid of Thermopsis lanceolate's toxicity mice as test animals to determine the LD50 of its alkaloid fraction [2]. The method was used to study the toxicity of the chloroform-extracted fraction of lanceolate xanthophyll by extracting the plant with ethanol at a volume fraction of 95% combined with ultrasound, using mice as test animals. The test measured the LD50 of the extracted fraction of lanceolate xanthophyll as 127.04 mg/kg with 95% confidence limits of 115.41-139.72 mg/kg. It was found that the results of this test differed significantly from the reported data, which may be related to the test method, the actual concentration of the extracted solution, and other factors. 

The LD50 can evaluate the substance's acute toxicity but does not reflect the chronic toxicity and carcinogenicity of the essence. There is uncertainty in the LD50 due to biological uncertainty, animal quality differences, test conditions, and subject preparation.

Due to LD50 uncertainty, there may be risks if the LD50 value is used as a reference for subsequent non-clinical or clinical dose design for precise calculation. Therefore, it is not scientific to affirm or deny a chemical by LD50 alone, and it is not a good indicator to evaluate the toxicity of a substance. Medicilon offers toxicology study services and can perform GLP services, including acute toxicity tests, long-term toxicity tests, local skin irritation, immunotoxicity, and toxicokinetics tests.

2.  ED50

ED50, or half effective dose, is an essential indicator of toxicology research, referring to the quantity required for an exogenous chemical to cause a 50% change in a hand of the organism, and refers to the dose that makes the general animal produce a drug effect, the smaller the value, the better.

Some researchers have investigated the half-effective dose of intravenous ginseng injection in rats with cardiogenic shock. The method was 64 SD rats, randomly divided into a blank control group, a model group, and six dose administration groups (1.25, 2.5, 5, 10, 20, and 25 ml/kg). The rat cardiogenic shock model was replicated by ligating the left coronary artery in all groups except the blank control group [3]. After successful modeling, real-time blood pressure values (MAP) and heart rate (HR) were recorded using a polysomnographic recorder, and blood was taken from the apical part of the heart at the end of the experiment to determine serum endothelin-1 (ET-1) and nitric oxide content (NO). The Sigmoidal dose-response model was selected using GraphPadPrism 5.0 software to regress the dose on the values of each index to obtain the half-effective dose ED50.

It was found that the ED50 obtained from blood pressure values was more scientifically reasonable, with blood pressure corresponding to ED50=5.727 ml/kg, ED5%=3.368 ml/kg, and ED95%=9.738 ml/kg.

The therapeutic index (TI) refers to the ratio of LD50/ED50, a standard index used to evaluate the safety of drugs in test animals before they are used in patients. When the therapeutic index of a new drug is greater than 5, it can be considered for the following preclinical and experimental study; otherwise, toxicity and slope of the dose-response curve at the maximum practical amount need to be considered.

[1] Establishment of fungal models for different routes of infection in mice and determination of LD50 [J].

[2] Determination of the LD50 of an alkaloid of Thermopsis lanceolate's in mice [J].

[3] Determination of ED50 of Ginseng injection against cardiogenic shock in rats[J].