Toxicology Unveiled- Exploring the Science, Applications, and Significance of Adverse Substance Effects

1. Toxicology Unveiled: Exploring the Science, Applications, and Significance of Adverse Substance Effects Toxicology has been defined as the study of the adverse effects of xenobiotics (such as drugs, pesticides, cosmetics, flavorings, fragrances, food additives, industrial chemicals and environmental pollutants) in living organism and thus is a borrowing science that has evolved from ancient poisoners. Toxicology is a multifaceted discipline that overlaps chemistry, biology, medicine and pharmacology. From the days of the ancient past when Pedanius Dioscorides, a Greek physician, made the first attempt to classify plants according to their toxic and therapeutic effects, a lot has changed. The science of toxicology is defined as the observational and data-gathering phase, whereas the art of toxicology consists of the utilization of the data to predict outcomes of exposure in human and animal population. Safety pharmacology, pharmacokinetic, and toxicology studies provide nonclinical data that allow regulators to assess whether your product is reasonably safe for initial testing in humans. Successful nonclinical strategies leverage smart product design and planning to identify the right studies and outline an optimized plan to de-risk critical early-stage milestones. A Brief Overview of Toxicology Primarily, toxicity assessment depends on identifying the adverse impact of a substance that depends on two main factors that influence toxicity as it relates to the exposure situation for a specific chemical are the route of exposure such as ingestion, inhalation, dermal contact and injections, and the duration, and frequency of exposure. In addition, dose-response curves are used to derive dose estimates of chemical substances like Lethal Dose 50%, Effective Doses (Eds), Toxic Doses (TDs), No Observed (adverse) Effect Level (NO(A)EL) and Lowest Observed (adverse) Effect Level (LO(A)EL). Applications of Toxicology Toxicology provides critical information and knowledge that can be used by regulatory agencies, decision makers, and others to put programs and policies in place to limit our exposures to these substances, thereby preventing or reducing the likelihood that a disease or other negative health outcome would occur. In drug discovery and drug development, compounds are screened and evaluate for the toxicity ADME properties. These toxicity endpoints are essential to determine the Maximum Page 1 of 4

2. Tolerated Dose (MTD), Maximum Feasible Dose (MFD), Limit Dose (1000mg/kg), exposure saturation, and dose providing a 50-fold margin of exposure. The most common of these, the maximum tolerated dose, is defined as the highest dose of a drug that does not cause unacceptable side effects or overt toxicity in a specific period of time. At the core of safety assessment, general toxicology studies are key to proving your product (such as veterinary, chemical (agrochemical, industrial chemical, consumer products, cosmetics) and device development) is safe to bring to market. Non Clinical Toxicological Studies General Toxicology General toxicology studies are required for determine the product duration, severity and toxic metabolite effects in animals, and also to identify the potential human health hazards and environmental toxicants. These toxicology studies act as bridge in between animal to human, in order to provide dose selection, determine the adverse effects and dose selection for product research studies and clinical trials. Primary aim of these studies to support data for regulatory submission like Investigational New Drug (IND) and New Drug Application (NDA) application. In addition, acute single dose toxicity testing is used to help define and characterize the intrinsic toxicity of new test items and provide data for establishing acute exposure to that substance. Information generated in acute studies along with dose range finding assessments is used to guide the design and selection of dose levels for subsequent sub-chronic and chronic toxicity studies. Developmental and Reproductive Toxicology (DART) Development and reproductive toxicology (DART) studies are required for most non-oncology programs between Investigational New Drug (IND) and New Drug Application (NDA) application. Their aim is crucial for assessing the potential impact of chemicals on male and female fertility (Segment-I), embryo-fetal development (Segment-II), pre-and post-natal development (Segment-II), including fertility, sexual maturation, and reproductive organs, parturition, lactation and teratology hence ensuring the safety of pharmaceuticals, consumer products, and environmental chemicals. Juvenile toxicity studies are performed on case-by- case basis to determined the products effects on neonate to paediatric population. Genetic toxicology A genotoxin is a substance or radiations that permanently alters deoxyribonucleic acid (DNA) (mutagenicity) or alters a cell’s ability to regulate DNA structure and content. Mutation or damage to DNA may or may not permanently change its content or structure, depending on Page 2 of 4

3. several factors, including DNA repair, metabolism, apoptosis, and oxidative stress defence mechanisms. In eukaryotic organisms, damage to genetic material of somatic cell can lead to malignancy (cancer) whereas genetic damage to germ cells can result in heritable mutations that induce birth defects. These studies evaluate various endpoints, such as gene mutations, chromosomal aberrations, and DNA damage. Determining the genotoxic potential of substances is critical in assessing their potential long-term effects, including carcinogenicity. Carcinogenicity Carcinogen is chemical substance or a mixture of chemical substances which induce cancer or increase its incidence. Oncogenicity studies are both time consuming and expensive, and are usually only done when there is reason to suspect that a chemical may be carcinogenic, or when there may be wide spread, long term exposures to humans (e.g., widely used food additives, drinking water contaminants, or pharmaceuticals that are likely to be administered repeatedly for long periods of time). The identification of the carcinogenic properties of a chemical, resulting in an increased incidence of neoplasms, increased proportion of malignant neoplasms or a reduction in the time to appearance of neoplasms. Local Toxicity Local toxicity is mainly evaluated potential effects of a drug or test substance on the contact site or application on the skin or eyes. The mainly focus on effects like skin irritation/corrosion, eye irritation/corrosion and injection site reaction (e.g., intradermal, subcutaneous and intravenous etc.). Toxicokinetic Toxicokinetic (TK) studies are determined the chemical substance information on its absorption, distribution, biotransformation (i.e., metabolism) and excretion, to aid in relating concentration or dose to the observed toxicity, and to aid in understanding its mechanism of toxicity. Toxicokinetic data can contribute to the assessment of the adequacy and relevance of animal toxicity data for extrapolation to human hazard and/or risk assessment. Other toxicity studies Neurotoxicity Neurotoxicity or a neurotoxic effect is defined as an adverse change in the chemistry, structure or function of the nervous system following exposure to a chemical or physical agent. Page 3 of 4

4. Immunotoxicity Immunotoxicity is an evaluation of potential adverse effects of human pharmaceuticals on the immune system should be incorporated into standard drug development. Biocompatibility studies Biocompatibility (ISO-10993) is the most commonly used term to describe appropriate biological requirements of a biomaterial or biomaterials used in a medical device. Biocompatibility has also been described as the ability of a material to perform with an appropriate host response in a specific application. Conclusion Advancement in toxicology has propelled many significant innovations in drug discovery and drug development, research, reproductive sciences, medical device testing, different product development, and so forth. Although toxicology is an elaborate branch of science with supporting to clinical research and regulatory applications, finding the right infrastructure for toxicology services in India is imperative for precision and maximum efficiency. Page 4 of 4