An improved method for toxicological profiling of chemical substances

Abstract

Toxicity profiling is an integral part of the drug discovery pipeline. The 3Rs principle—Replacement, Reduction, and Refinement, is considered a golden rule in determining the most appropriate approach for toxicity studies. The acute toxicity study with proper estimate of median lethal dose (LD₅₀) is usually an initial procedure for the determination of most suitable test doses for preclinical toxicological and pharmacological profiling. Several methods, which have been devised to determine the LD₅₀, are faced with the challenge of using a large number of animals and time constraints. Despite the inherent advantage of the newer OECD Test Guidelines, the increasing concerns among toxicologists, the regulatory authorities and the general public, on the need to adhere to 3Rs principle, necessitated the need for an improved approach. Such an approach should not only minimize the time and number of animals required, but also take into cognizance animal welfare, and give accurate, comparable, and reproducible results across laboratories. While taking advantage of the inherent merits of the existing methods, here is presented the mathematical basis and evaluation of an improved method for toxicity profiling of test substances and estimation of LD₅₀. The method makes use of the generated Table of values for the selection of appropriate test doses. Our proposed method has capacities to optimize the time and number of animal use, ensure more reliable and reproducible results across laboratories, allow for easy selection of doses for subsequent toxicity profiling, and be adaptable to other biological screening beyond toxicity studies.

Keywords:

• Median lethal dose
• toxicity profiling
• acute toxicity
• safety
• toxicological agents

Authors contributions

MOD: Conceptualization, Project Administration, and Writing (Original draft); MOD, IAO, MAA and GO: Validation. All authors contributed equally to Data Acquisition and Analysis, Writing (Reviewing and editing), and approved the final submission.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data supporting this manuscript have been supplied with the manuscript and bundled with the accompany installable Python-based software package.

Data deposition

The Excel package and Python-based software for the generation of Table of Values (ToV) and LD₅₀ computation are freely available for download using Zenodo (https://doi.org/10.5281/zenodo.10514422).

Geolocation information

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