Evaluating the toxicity of a substance is essential to assess the risk of any harmful side-effects, including the likelihood of carcinogenic effects and even death. Preclinical toxicity trials must therefore be carried out before any drug is released onto the market for commercial and medical use. This article will provide an overview of this subject.

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Toxicity: an overview

All chemical substances have the potential to cause harm to a whole organism or a part of that organism. The degree of damage the substance causes is its toxicity. The degree of toxicity a substance has on cells is referred to as cytotoxicity, and there are terms that refer to damage to specific organs such as hepatotoxicity (damage to the liver).

Toxicants are dose-dependent. Highly toxic substances such as snake or spider venom have no detectable toxic effect if taken at a small enough dose. Conversely, water, which we need to live and drink every day, can cause intoxication if consumed at too high a dose. Four types of toxic entities exist: biological, chemical, physical, and radiation.

Chemical toxicants include inorganic compounds such as heavy metals and acids, medications, and organic compounds such as methyl alcohol. Biological toxicants include disease-causing microorganisms (more generally referred to as pathogens) and non-living substances secreted by the organism (toxins and venoms). Physical toxicants include asbestos fibers and coal dust. Radioactive toxicants are substances such as radium which cause ionizing radiation.

Pathway of administration, time of exposure, number of exposures, which physical form the toxicant has, and an individual’s overall health and genetic makeup can all influence a substance’s toxicity. Therefore, studies on the toxic potential of a new drug or chemical must take these factors into consideration.

The importance of preclinical trials

Preclinical trials are vitally important for drug safety. Before testing in humans, the toxicity of a substance must be established, usually in animal studies. There are two types of preclinical research; in vivo and in vitro. Good laboratory practice must be followed by research teams and regulations set down by organizations such as the FDA must be adhered to.

Preclinical studies are typically small, but they must provide detailed information on dosing and toxicity levels. After the testing has been concluded findings are reviewed, and a decision is made on whether a drug should be tested in human subjects. Studies need to show good oversight of quality assurance before drugs are approved for human testing.

Preclinical toxicity studies

The development of a new pharmaceutical is a stepwise process. Evaluation of animal safety information must be performed before a drug is authorized for human testing. Pre-clinical studies on toxicity aim to elucidate information including the characterization of toxic effects on target organs, dose dependence, how effects relate to exposure pathways, and potential reversibility of those effects.

This information is important as it helps researchers estimate the initial safe starting dose for human trials. Parameters for clinical monitoring of any side effects which may develop can be identified as well. Preclinical studies must be adequate to characterize the potential toxic effects under the conditions of the subsequent clinical trial.

Toxicity is evaluated in preclinical studies in different ways. Single-dose (acute) toxicity studies are carried out in two mammalian species prior to human studies. An acceptable alternative to the single-dose design is a dose-escalation study.

Repeated dose toxicity studies are also carried out. These can vary in duration, relative to the duration, scale, and therapeutic indication of the proposed clinical trial. In principle, the study should involve one rodent and one nonrodent-species and must last the same duration or longer than the clinical trial.

Preclinical toxicity studies must establish data related to risks including genotoxicity and reproductive damage potential for the pharmaceutical under study before it is allowed to be used in clinical human trials. Additional studies may be needed if previous clinical or preclinical studies of related products have indicated special safety concerns that may be relevant.

New paradigms of drug toxicity measurement

Linear drug toxicity models including the therapeutic index (TI), pharmacodynamic (PD) profiles, and ligand efficiency indices (LEI) are widely used in drug discovery and development. Despite this, challenges remain in predicting drug toxicity at various stages.

Studies have attempted to develop improved models of measurement for drug toxicity. One such study published in Issue 2 of Toxicology Research proposed the Drug Toxicity Index (DTI).

This simple model was developed by the team using 711 oral drugs and redefines drug toxicity as functions of pharmacodynamic (PD), pharmacokinetic (PK) and physicochemical parameters. DTI has been used to predict network meta-analysis on relative toxicity within and across 8 different therapeutic areas and may be able to reduce future instances of failure in drug discovery.

Other studies attempting to improve toxicity studies and clinical outcomes for patients include research published as part of the National Cancer Institute’s Moonshot research initiative in the United Kingdom. In December 2020, a team led by Gillian Gresham proposed and illustrated alternative approaches to toxicity evaluation to provide improvements in the analysis and reporting of treatment toxicity.

In conclusion

Preclinical trials are essential for drug discovery and toxicology studies are an important part of these trials. Establishing the relative toxicity of a new drug is essential to provide the best clinical outcome for patients and discover safety issues and side-effects. New indexes for toxicity measurement are being developed, and the future will see improved preclinical toxicity studies on new target drugs for development for the market.

Further Reading

• All Preclinical Testing Content
• In Vitro vs In Vivo Preclinical Studies

Written by

Reginald Davey

Reg Davey is a freelance copywriter and editor based in Nottingham in the United Kingdom. Writing for News Medical represents the coming together of various interests and fields he has been interested and involved in over the years, including Microbiology, Biomedical Sciences, and Environmental Science.