Importance of Studying Adverse Effects of High Doses of Drugs Using Toxicology Studies

This chapter highlights the requirements for conducting an adverse effect study involving laboratory animals. Though this study is not required for Ayurvedic formulations, we are conducting these studies to follow the requirements in order to make the medicinal formulation acceptable by modern medical practitioners. The maximum tolerance limit for the formulation needs to be tested in toxicology studies using a rat and a rabbit model under the ‘New Drugs and Clinical Trials Rules,’ Ministry of Health and Family Welfare, Government of India, and the ‘Organization for Economic Co-operation and Development (OECD)’ guidelines. These two animals are the species accepted by regulatory agencies for conducting safety and toxicity studies. The acute toxic class method is a stepwise procedure using 3 animals of a single-sex per step. Depending on the mortality and/or the moribund status of the animals, on average, 2-4 steps may be necessary to allow judgement on the acute toxicity of the test substance. This procedure is reproducible, uses very few animals, and can rank substances based on their toxicity. The acute toxic class method is based on biometric evaluations with fixed doses, adequately separated to enable a substance to be ranked for classification purposes and hazard assessment. The objective is to determine the possible health hazards of the formulation after repeated daily oral administration for 28 consecutive days. In a second set, the animals were allowed to recover for a further 14 days after a 28-day drug administration to test for reversibility, persistence, or delayed occurrence of toxic effects. The study will provide information on major toxic effects, target organs, if any, and determine the No-Observed- AdverseEffect-Level (NOAEL) of the Ayurvedic formulation. We tested Coronil and Divya Swasari Vati in both rats and rabbits. Preliminary studies showed that either formulation did not show any toxic effects for 28-day administration followed by a 14- day recovery period. We will present data obtained in the toxicity studies in an appropriate forum once the study is completed. This chapter mentions the protocols and standard procedures to be followed while conducting such studies. This is critical since the clearance for clinical studies is based on these toxicological observations, as is described in the next chapter.

Keywords: Acute toxicological study, Sub-acute toxicological study, NOAEL, New Drugs and Clinical Trials Rules, Organization for Economic Co-operation and Development’ (OECD) guidelines.