Regulatory Toxicology

'All substances are poisons; there is none which is not a poison. The right dose differentiates a poison'- Paracelsus

Anciently toxicology was known as the ‘Science of Poison,’ now a days it is defined as the study of the effect of chemicals on living organisms and their evaluation as whether these entities are harmful or not or estimating a safe range. For the establishment of safety margins from the adverse effects of chemicals, toxicology depends on a few factors like dosage, route of exposure, dosing regimen, fate of the chemical and their biotransformation. The safety level of chemical is picked by the execution of sets of step wise experiments. Toxicology plays a major part in the drug development process to determine the safe dose and drug response on an exposed organism. It includes four disciplines like biology, chemistry, pharmacology and lastly medicine with an intervention of information technology up to some extent.

In the current scenario toxicology studies are of vast importance in the field of Pharmaceuticals, Agrochemicals, Nutraceuticals and Ayurvedic Products.

Pharmaceutical Toxicology: Most important concern in the pharmaceutical industries are the side effects of their drug or medicine. It is one of the greatest causes of failure in the drug development process. Toxicologists conduct safety studies in accordance with the regulatory guidelines (ICH, OECD) to show regulators that a certain drug is safe to use for its intended indication. The pharmaceutical industry initially conducts efficacy studies before entering safety screening phase of their molecule or biomolecule. This process of screening of a potent test compound is recognized as part of early drug development which was initiated from drug discovery as below:

  • Synthetic chemist designs molecule with the help of computer modelling tools with the inputs of pharmacophores for the intended target.
  • In early screenings these molecules screened through knowledge-based computer models to predict the toxicity (toxophores) in these complex molecular structures.
  • In next step the toxicologist conducts in vitro assays to rule out the possible specific toxicities.
  • Toxicity of the molecule within the body can impact through metabolism also studied by few in vivo assays and can later help during drug candidate selection.
  • Candidate drugs are thoroughly assessed for their toxicity which usually involves animal studies. The studies include deep examination of organs, tissues, blood and urine collected from the exposed animals.
  • Assess specific type of toxicity, specially designed toxicity studies required such as cancer and reproduction toxicity studies. Further investigation by sophisticated studies is performed with more parameters required to establish safety of their candidate drug.
  • Pharma companies demonstrate safety of the drug through toxicity studies data to regulatory authorities for approval of their drug/chemical entity to be used in humans.

Agrochemicals: As the name suggests chemicals used in agriculture commonly include pesticides (insecticides, herbicides, fungicides, nematicides), synthetic fertilizers, natural (manure), hormones, growth enhancers. Over a period, when used for a long time these agrochemicals become pollutants to our ecosystem. Establishment of their safety and risk assessment is equally important as any pharmaceutical drug. In the case of agrochemicals, it is known as ecological risk assessment (ERA). It works first for the protection of ecosystem and second registration of agrochemicals or regulatory purposes (CIBRC).

  • These agrochemicals enter in the organism systemically by oral route, inhalation or by skin absorption.
  • The first step is toxicity assessment, to ensure that chemical is toxic or not. Likewise, pharma drugs there is a need of shot and long-term bioassays to determine the toxicity levels of agrochemicals.
  • Toxicokinetic and toxicodynamic studies are also important to determine the mode of action (MOA) and understand the toxic effect.
  • The toxicity thresholds LD50 (oral) or LC50 (inhalation or contact) can be determined. Traditional medicines are again gaining popularity in medication because these formulations have fewer or no side effects. In present conditions regarding healthcare products and therapeutics, safety establishment is necessary before use or starting the line of treatment.

Ayurvedic Products: In India, general guidelines for safety/toxicity evaluation of ayurvedic formulations issued by Central Council for Research in Ayurvedic Sciences (CCRS), Ministry of AYUSH, Govt, of India, New Delhi for drug development in the field of ayurveda popular as ‘AYUSH’ (Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy).

  • CCRAS have developed three comprehensive and short Guidelines focusing on drug development (Standardization and quality assurance), safety/toxicity and clinical evaluation for ready reference of investors.
  • These guidelines are necessary to practice who (researchers) are working in the field of AYUSH system.
  • Pre-clinical evaluations of toxicity should be performed on animals according to the guidelines suggested by AYUSH.

To conclude, toxicity is an inevitable part of drug development without safety assessment no molecule or drug will step up from pre-clinical to clinical level of therapeutic expansions. We, at Dabur Research Foundation (DRF), have the expertise to undertake the toxicity studies for Pharmaceuticals, Nutraceuticals, Agrochemicals, and Traditional Medicine fields for regulatory submissions.