CARCINOGENICITY, CARCINOGENES, CANCER AND FACTORS

CARCINOGENICITY

1. औषध विज्ञान और विष विज्ञान विभाग / Department of Pharmacology and Toxicology Carcinogenicity ( ICH, & OECD Guidelines ) Presented by Manshad Khan M.S.Pharm./2023-25/PT/17

2. Content Introduction Factor influencing carcinogenesis OECD guidelines for carcinogenesis testing References ICH safety guidelines for carcinogenicity studies

3. INTRODUCTION 3 The process by which normal cells are transformed into cancer cells. A carcinogen is a substance that can cause cancer . What happens during tumor cell transformation? Tumors develop in those tissues in which Cellular homeostasis has been disturbed by hyperplastic, dysplastic or regenerative changes. Clinical and experimental data have proved that during the division process, the cell is more susceptible to carcinogenic factors than at rest. Bronchial carcinoma in smokers invariably appears against A dysplastic or metaplastic background of the airways; bone cancer usually occurs at a young age, when physiological osteogenesis is active.

4. FACTORS INFLUENCING CARCINOGENESIS Non-ionizing :- Non-ionizing radiations are electromagnetic, with low penetration, and present a real danger for eyes and skin. This group includes ultraviolet radiation, light radiation and infrared radiation and ionizing radiations. Physical Factors Ultimate carcinogens:-nitrosamines, epoxides, ethylenimines. Procarcinogens:- aminozoic colorants, aromatic hydrocarbons, aflatoxins, aromatic amines and urethane Co-carcinogens :- Chemical factors 4 Ionizing:- Directly ionizing radiations are electrically charged particles: negative charge, electrons, such as beta rays; positive charge, alpha particles. Indirectly ionizing radiations are particles without electric charges: photons, X rays and Gamma rays. Arsenic:-Skin and lung cancer occurs in arsenic workers. Asbestos:-Asbestos induces pulmonary and pleural mesotheliomas in miners and industrial workers Mineral chemical substance:- Biological factors Over 80% of carcinogenic substances are found in the environment and are taken by living beings with air, water and food. Carcinogens in plants- Alkaloid carcinogens:-reserpine, sanguinarine, nicotine, arecoline, acronycine and caffeine. Reserpine, widely used in hypotensive medication, has been proved to be carcinogenic in mice and rats, inducing hepatomas, lymphosarcomas, carcinomas of the adrenal glands.

5. ICH SAFETY GUIDELINES FOR CARCINOGENICITY STUDIES S1 S1A Need for Carcinogenicity Studies of Pharmaceuticals S1B Testing for Carcinogenicity of Pharmaceuticals(Species selection ) S1C(R2) Dose Selection for Carcinogenicity Studies of Pharmaceuticals

6. 5 ICH guidelines :-S1A Need of carcinogenicity of pharmaceuticals Introduction :- The objectives of carcinogenicity studies are to identify a tumorigenic potential in animals and to assess the relevant risk in humans. Results from genotoxicity studies, toxicokinetic, and mechanistic studies can now be routinely applied in preclinical safety assessment. These additional data are important not only in considering whether to perform carcinogenicity studies but for interpreting study outcomes with respect to relevance for human safety. Objective of the guideline: - To define the conditions under which carcinogenicity Studies, should be conducted to avoid the unnecessary use of animals in testing, and To provide consistency in worldwide regulatory assessments of applications. It is Expected that these studies will be performed in a manner that reflects currently Accepted scientific standards .

7. Factors to consider for carcinogenicity testing Carcinogenic potential Not being subjected to long-term carcinogenicity studies. 1yr study may be carried out Certain serious diseases, carcinogenicity testing need not be conducted Single route (similar to human route)

8. Testing for carcinogenicity of pharmaceuticals S1 B Guidance on the need to carry out carcinogenicity studies in both mice and rats, and guidance is also given on alternative testing procedures

9. Guidelines The testing of the carcinogenic potential of a pharmaceutical is developed only after the acquisition of certain key units of information including Results of genetic toxicology Intended patient population, clinical dosage regimen Pharmacodynamics in animals and in humans Repeated-dose toxicology studies . This information should be considered in the design of any further studies for the assessment of carcinogenic potential.

10. For several decades, gold standard” for preclinical evaluations of carcinogenicity is the 2-year bioassay in standard bred rats and mice. The results demonstrate a high degree of concordance with human cancer responses “This study design has been used widely to evaluate the potential carcinogenicity of New drugs, Agricultural chemicals, occupational chemicals, Environmental contaminants, and a wide range of other agents

11. When to perform: in consideration of their extended duration and substantial cost, chronic carcinogenicity studies of nongenotoxic therapeutics are most often performed following the completion of phase I and phase II clinical trials. Some times, in situations where a positive or equivocal result has been obtained in genetic toxicology bioassays, studies to assess potential carcinogenic activity using a 6-month oncogenicity bioassay in genetically engineered mice may be required by regulatory agencies prior to the start of phase I clinical trials. Genetically engineered mice: Insertion of an oncogene or deletion of a tumor suppressor gene from the germ line; It will increase the sensitivity of these animals to carcinogens Completion of a bioassay with a much shorter period of test article exposure.

12. Rat strains Sprague–Dawley rats and derivative strains such as the CD rat, F344 (Fischer) rat, Wistar rat. Mouse strains Include various strains of Swiss or Swiss-derived mice (such as ICR and cd-1 mice) The B6C3F1 hybrid mouse. Experimental animals

13. Dose selection for carcinogenicity studies Of pharmaceuticals - s1c r2 Introduction:- 6 -Traditionally, carcinogenicity studies for chemical agents have relied upon the maximally tolerated dose (MTD) as the standard method for high dose selection. The MTD is generally chosen based on data derived from toxicity studies of 3 months' duration. This document proposes that any one of several approaches could be useful for dose selection, and should provide for a more rational approach to dose selection for carcinogenicity studies for pharmaceuticals. These include:

14. Rational approach to dose selection for carcinogenicity studies for pharmaceuticals

15. General considerations for the conduct of dose-ranging studies Dose-ranging studies should be conducted for both males and females for all strains and species Dose selection is generally determined from 90-day studies. Appropriate dosing schedule and regimen should be based on clinical use and pharmacokinetics considerations. Changes in metabolite profile or alterations in metabolising enzyme activities should be understood to allow for appropriate interpretation of studies.

16. Pharmacokinetic Endpoints in High Dose Selection Pharmacokinetic endpoints, through which the high dose is selected on the basis of (1) Its generation of maximum plasma levels of the test agent (or key metabolite(s)), and/or (2) the generation of a (large multiple 25×) of presumed human plasma levels.

17. Saturation of Absorption in High Dose Selection Saturation of absorption or excretion, based on demonstrations that dose levels in excess of a specific maximum (1) do not increase the quantity of agent entering the systemic circulation or (2) saturate clearance mechanisms, thereby resulting in local accumulation of the test agent or metabolites .

18. Pharmacodynamic Endpoints in High Dose Selection The utility and safety of many pharmaceuticals depend on their pharmacodynamics receptor selectivity.  The high dose selected should produce a pharmacodynamic response in dosed animals However, the dose should not produce disturbances of physiology or homeostasis which would compromise the validity of the study. Examples include hypotension and inhibition of blood clotting (because of the risk of spontaneous bleeding).

19. Limit Dose Appropriate to limit dose for rodent is 1500 mg/kg/day the maximum recommended human dose does not exceed 500 mg/day Data should be provided by comparing exposure of rodents and humans to drug The rodent systemic exposure at 1500 mg/kg/day should be greater by at least an order of magnitude than human exposure

20. OECD Guidelines for Carcinogenicity testing OECD Guidelines for the Testing of Chemicals (TGs) are periodically reviewed in the light of scientific progress, changing assessment practices and animal welfare considerations. The original Test Guideline 453 was adopted in 1981. The majority of chronic toxicity and carcinogenicity studies are carried out in rodent species and this Test Guideline is intended therefore to apply primarily to studies carried out in these species. Should such studies be required in non-rodent species, the principles and procedures outlined may also be applied, with appropriate modifications, OECD/OCDE 453Adopted:25 June 2018

21. Difference between ICH and OECD Guidelines in terms of Carcinogenicity:- The ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) and OECD ( Organisation for Economic Co-operation and Development) guidelines both provide standards and recommendations for carcinogenicity testing, but they have some differences: Scope and Applicability : ICH Guidelines : Primarily focused on pharmaceuticals for human use, these guidelines aim to harmonize regulatory requirements across regions like the United States, Europe, and Japan. OECD Guidelines : More broadly applicable across various industries and sectors, not limited to pharmaceuticals. They cover a wider range of chemicals, including those used in agriculture, industry, and consumer products. Regulatory Acceptance : ICH Guidelines : Often directly adopted by regulatory authorities in member countries, providing a streamlined approach for drug approval processes. OECD Guidelines : While widely respected and influential, adoption by regulatory bodies can vary between countries. They may serve as a reference point rather than a direct regulatory requirement in some cases.

22. Difference between ICH and OECD Guidelines in terms of Carcinogenicity:- 3. Specific Requirements : ICH Guidelines : Tend to be more tailored to the specific needs and characteristics of pharmaceuticals, including considerations like dose selection, duration of studies, and specific endpoints. OECD Guidelines : Offer a broader framework applicable to a wider array of substances, with flexibility for adaptation to different types of chemicals and exposures. 4.Updates and Revisions : ICH Guidelines : Typically undergo periodic updates and revisions driven by advancements in science, changes in regulatory requirements, and feedback from stakeholders. OECD Guidelines : Similarly subject to periodic updates but may have a broader scope of input from member countries and stakeholders outside the pharmaceutical industry. 5.Harmonization vs. Standardization : ICH Guidelines : Aim to harmonize regulatory requirements and facilitate global drug development and registration by minimizing differences between regulatory authorities. OECD Guidelines : Focus on standardizing testing methodologies and approaches to enhance the quality and reliability of data generated across different laboratories and jurisdictions. Conclusion : - B oth the ICH and OECD guidelines address carcinogenicity testing, the former is more tailored to the needs of the pharmaceutical industry and regulatory approval processes, while the latter provides a broader framework applicable to various industries and regulatory contexts.

23. OECD Guidelines for Carcinogenicity testing PRINCIPLE OF THE TEST :- The study design consists of two parallel phases, a chronic phase and a carcinogenicity phase. The test chemical is normally administered by the oral route although testing by the inhalation or dermal route may also be appropriate. For the chronic phase, the test chemical is administered daily in graduated doses to several groups of test animals, one dose level per group, normally for a period of 12 months, although longer or shorter durations may also be chosen depending on regulatory requirements OECD/OCDE 453Adopted:25 June 2018

24. OECD Guidelines for Carcinogenicity Testing OECD/OCDE 453Adopted:25 June 2018 Description of the method:- Procedure:-

25. OECD Guidelines for Carcinogenicity testing OECD/OCDE 453Adopted:25 June 2018 Observations :- Data and Reporting:- Test chemical Test animals Vehicle Test conditions Results:- General Clinical findings Necropsy data Histopathology Conclusion.

26. REFERENCES Ich harmonized tripartite guideline guideline on the need for carcinogenicity studies of pharmaceuticals s1a , current step 4 version. Ich harmonised tripartite guideline testing for carcinogenicity of pharmaceuticals s1b , current step 4 verson. Ich harmonised tripartite guideline dose selection for carcinogenicity studies of pharmaceuticals s1c(r2), current step 4 version, parent guideline. Guidance for industry carcinogenicity study protocol submissionsn http://www.Fda.Gov/cder/guidance/index.Htm 1. OECD (1995), report of the consultation meeting on sub-chronic and chronictoxicity/carcinogenicity testing (rome, 1995), internal working document, environmentdirectorate, OECD, paris.2. Epa (2005). Guidelines for carcinogen risk assessment risk assessment forum U.S.Environmental protection agency washington, Dchttp://cfpub.Epa.Gov/ncea/cfm/recordisplay.Cfm?Deid=116283&cfid=1267360&cftoken=65052793&jsessionid=9830b2c4116e3d8fbbf017414e1a782e7f79tr3. Combes RD, gaunt, I, balls M (2004). A scientific and animal