This book focuses on the principles, methods, and interpretation involved in establishing the safety, risk, and hazard assessment of small molecules. It presents the regulatory requirements for risk and hazard identification as per the guidelines of the Organization for Economic Cooperation and Development (OECD), Paris, and the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use ICH and Schedule ‘Y’, India. It serves as reference material for undergraduate and postgraduate pharmacy degree students as well as senior researchers to learn about the principles, methods, and interpretations of systemic dosage (acute and repeated dose) and genotoxicity ( in vitro and in vivo ), special toxicological investigations such as reproductive and developmental toxicology, carcinogenicity, and toxicokinetics using animal models or in vitro methods, as applicable. This book is the first of its kind in providing information on the principles and methods of implementation of Good Laboratory Practice based on the guidelines of OECD. It includes detailed chapters about the regulatory requirements and guidelines in pharmaceutical products and agrochemicals. It also describes the infrastructure needed for preclinical studies, including in vivo and in vitro facilities.

lgli/Saravana Babu Chidambaram, Mohamed Essa, M. Walid Qoronfleh - Introduction to Toxicological Screening Methods and Good Laboratory Practice (2022, Springer).pdf

lgrsnf/372.pdf

zlib/no-category/Saravana Babu Chidambaram, Mohamed Essa, M. Walid Qoronfleh/Introduction to Toxicological Screening Methods and Good Laboratory Practice_19197320.pdf

PRECLINICAL TOXICOLOGY : principles, methods and interpretations

Chidambaram, Saravana Babu, Essa, M. Mohamed, Qoronfleh, M. Walid

Chidambaram Saravana Babu, Mohamed Essa, M. Walid Qoronfleh

Singapore, Singapore

1st ed. 2022, 2022

2, 20220211

S.l, 2022

producers:
Adobe PDF Library 10.0.1

Foreword
Foreword
Foreword
Preface
Acknowledgement
Contents
1: Introduction to Toxicology
1.1 Definition
1.2 History
1.3 Types of Toxicology (Barile 2019)
1.3.1 Descriptive Toxicology
1.3.2 Mechanistic Toxicology
1.3.3 Clinical Toxicology
1.3.4 Forensic Toxicology
1.3.5 Regulatory Toxicology
1.4 Standard, Test Guidelines and Regulatory Bodies
1.4.1 Standards
1.4.2 Test Guidelines (TG)
1.5 Organisation for Economic Co-operation and Development (OECD)
1.5.1 Organisational Structure
1.5.2 The Council
1.5.3 The Secretariat
1.5.4 The Committees
1.5.5 Functions of OECD
1.5.6 OECD Guidelines for Testing for Chemicals
1.6 International Conference on Harmonisation (ICH) (ICH Guidelines for Pharmaceuticals: Pharmaceutical Guidelines n.d.)
1.6.1 History
1.6.2 ICH Organisational Structure and Functions
1.6.2.1 ICH Steering Committee
1.6.2.2 ICH Coordinators
1.6.2.3 ICH Secretariat
1.6.2.4 ICH Working Group
1.6.3 ICH Guidelines (ICH Official web site: ICH n.d.)
1.7 Environmental Protection Agency (EPA)
1.7.1 EPA Organization Structure (Fig. 1.3)
1.7.2 Functions
1.7.3 EPA Health Effects Test Guidelines
1.8 Central Drugs Standard Control Organisation
1.8.1 CDSCO Organisation System
1.8.2 Location of CDSCO and Associated Offices
1.8.3 Functions of CDSCO
1.9 Functions of State Licensing Authority
1.10 Schedule Y (Schedule Y(amended version) - CDSCO n.d.)
1.10.1 Scope
1.10.2 Non-Clinical Toxicity studies as per the Schedule-Y (Appendix-III)
1.10.2.1 Systemic Toxicity Studies (Schedule Y(amended version) - CDSCO n.d.)
1.10.2.2 Local Toxicity
1.10.2.3 Parenteral Drugs
1.10.2.4 Ocular Toxicity Studies
1.10.2.5 Inhalational Toxicity Studies
1.10.2.6 Allergenicity/Hypersensitivity
1.10.2.7 Genotoxicity
1.10.2.8 Carcinogenicity
References
2: Laboratory Animal Models
2.1 Definition
2.2 Types of Animal Models
2.3 History
2.4 Future of Animal Study
2.5 Animal Ethics
2.6 India
2.7 Functions of CPCSEA
2.8 Institutional Animals Ethics Committee (IAEC)
2.9 Composition of IAEC
2.10 Functions of IAEC
2.11 Laboratory Animals
2.11.1 Inbred Strain
2.11.2 F1 Hybrid
2.11.3 Outbred Strain
2.11.4 Stock Vs. Strain
2.11.5 Transgenic Animals
2.11.6 Selection of an Animal Model
2.11.7 Experiment Designing
2.11.8 Disease Models (Schønecker 2014)
2.12 Number of Animals per Group
2.13 Randomisation
2.14 Control Groups
2.14.1 Pilot Study
2.15 Physiological, Clinical Parameters of Laboratory Animal Models
2.15.1 Physiological Parameters
2.15.2 Blood Clinical Chemistry
2.15.3 Haematology
2.15.4 Serum Electrolytes
References
3: Toxicological Screening Methods
3.1 Acute Oral Toxicity
3.1.1 Purpose
3.1.2 Definition
3.1.3 Principle
3.1.4 Procedure
3.1.5 Interpretation
3.2 Acute Oral Toxicity: Step-Up and Step-Down Procedure
3.2.1 Purpose
3.2.2 Definition
3.2.3 Principle
3.2.4 Interpretation
3.3 Acute Eye Irritation/Corrosion in Rabbit
3.3.1 Purpose
3.3.2 Principle
3.3.3 Procedure: (OECD GLP n.d.)
3.3.4 Grading of Ocular Lesions: (Table 3.1, 3.2, 3.3, and 3.4)
3.3.5 Interpretation
3.4 Acute Dermal Irritation/Corrosion
3.4.1 Purpose
3.4.2 Definitions
3.4.2.1 Dermal Irritation
3.4.2.2 Dermal Corrosion
3.4.3 Principle
3.4.4 Procedure: (OECD GLP n.d.)
3.4.5 Grading of Skin Reactions (Test No. 404 n.d.) (Tables 3.6, 3.7, and 3.8)
3.4.6 Interpretation
3.5 Acute Dermal Toxicity
3.5.1 Purpose
3.5.2 Definition
3.5.3 Principle
3.5.4 Interpretation
3.6 Skin Sensitization Test (Guinea-Pig Maximization Test Method)
3.6.1 Purpose
3.6.2 Definition
3.6.3 Principle
3.6.4 Steady-State Experiment
3.6.4.1 Preparation of Test System
3.6.4.2 Pre-test
3.6.4.3 Main Study
3.6.4.4 Preparation of Injection Sites
3.6.5 Day-0/Intradermal injection
3.6.5.1 Control Group
3.6.5.2 Treated Group
3.6.5.3 Epidermal Application
3.6.5.4 Challenge Dose
3.6.5.5 Second Challenge
3.6.5.6 Observations
3.6.5.7 Skin Reactions
3.6.5.8 Readings and Scoring
3.6.5.9 Rating of Allergenicity
3.6.5.10 Necropsy
3.6.5.11 Histopathology
3.6.6 Interpretation
3.7 Acute Inhalation Toxicity
3.7.1 Preamble
3.7.2 Purpose
3.7.3 Definition
3.7.4 Principle
3.7.5 Traditional Protocol
3.7.6 Concentration x Time (C x T) Protocol
3.7.7 Interpretation
3.8 28/90 Day Repeated Oral Toxicity
3.8.1 Purpose
3.8.2 Definition
3.8.3 Principle
3.8.4 Observation
3.8.5 Data Interpretation
3.9 28-Day Inhalation Toxicity Study
3.9.1 Purpose
3.9.2 Definition
3.9.3 Principle
3.9.4 Observations
3.9.5 Data Interpretation
3.10 Neurotoxicity
3.10.1 Purpose
3.10.2 Definition
3.10.3 Principle
3.10.4 Observations: (Research 2020)
3.10.5 Data Interpretation
3.11 Carcinogenicity
3.11.1 Definition
3.11.2 Principle
3.11.3 Observation
3.11.4 Data Interpretation
3.12 Reproduction and Developmental Toxicity
3.12.1 Purpose
3.12.2 Definition
3.13 Fertility and Reproductive Performance Study (Segment I)
3.13.1 Purpose
3.13.2 Principle
3.13.3 Observations
3.13.4 Interpretation
3.14 Prenatal Developmental Toxicity Study (Segment II)
3.14.1 Purpose
3.14.2 Definition
3.14.3 Principle
3.14.4 Observations
3.14.5 Maternal Endpoints
3.14.5.1 Foetal Endpoints
3.14.6 Interpretation
3.15 Extended One-Generation Reproductive Toxicity Study (EOGRTS) (Segment III)
3.15.1 Purpose
3.15.2 Principle
3.15.3 Steady State Experiment
3.15.3.1 Cohort-1A: Reproductive toxicity Assessment
3.15.3.2 Cohort-1B: Reproductive performance Assessment
3.15.3.3 Cohort-2: Neurotoxicity Assessment
3.15.3.4 Cohort-3: Immunotoxicity Assessment
3.15.4 Data Interpretation
3.16 Bacterial Reverse Mutation Test
3.16.1 Purpose
3.16.2 Definition
3.16.3 Principle
3.16.4 Study State Experiment
3.16.5 Data and Reporting
3.16.6 Interpretation
3.17 In Vivo Mammalian Erythrocyte Micronucleus Test
3.17.1 Purpose
3.17.2 Definition
3.17.3 Principle
3.17.4 Interpretation of Result
3.18 In Vitro Chromosomal Aberration Test
3.18.1 Purpose
3.18.2 Definition
3.18.3 Principle
3.18.3.1 Study State Experiment (Test No. 473 n.d., p. 473)
3.18.3.2 Experimental Design
3.18.3.3 Microscopic Analysis
3.18.3.4 Data Analysis
3.18.4 Interpretation
References
4: Toxicokinetics
4.1 Purpose
4.2 Definition
4.3 Toxicokinetics in Various Systemic Toxicological Studies
4.4 Toxicokinetics Models
4.5 Orders of Kinetics
4.6 Factors Influencing Toxicokinetics
4.7 Study State Experiment (Test No. 417 n.d.)
4.8 Measurement of Parameters
4.9 Conclusion
References
5: Safety Pharmacology
5.1 Purpose
5.2 Definition
5.2.1 ICH Test Guidelines for Non-clinical Safety Studies
5.2.2 Safety Pharmacology Tiers
5.2.3 Major Organ Systems Studied in Safety Pharmacology Are
5.2.4 Follow-Up and Supplemental Safety Pharmacology Studies
5.3 Cardiovascular Safety System (Champeroux et al. 2013)
5.3.1 Blood Pressure and Heart Rate Measurement
5.3.1.1 Procedure
5.3.2 Electrocardiogram
5.3.3 In-Vivo Telemetry Method
5.3.3.1 Procedure
Internal Jacketed
External Jacketed
5.3.4 In-Vitro hERG Assay
5.3.4.1 Purpose
5.3.4.2 Procedure
5.3.4.3 Interpretation
5.4 Central Nervous System Safety Pharmacology
5.4.1 Core Battery Tests (Porsolt et al. 2002)
5.4.1.1 Irwin Test
5.4.2 CNS Follows Up Studies: (Barile 2019)
5.4.2.1 Behavioural pharmacology
5.4.2.2 Learning and Memory
5.4.2.3 Visual Assessment of Rodents
5.4.2.4 Auditory Function Evaluation
5.5 Respiratory System Safety Pharmacology
5.5.1 Invasive Methods
5.5.1.1 Whole-Body Plethysmography
5.5.1.2 Blood Profile Analysis
5.6 Renal System Safety Pharmacology
5.6.1 Assessment of Glomerular Filtration Rate
5.6.1.1 Procedure
5.6.2 Evaluation of Tubular Function by Micropunctures
5.6.2.1 Procedure
5.6.3 Diuretic Activity in Rats (Lipschitz Test)
5.6.3.1 Procedure
5.7 Gastrointestinal (GI) Safety Pharmacology
5.7.1 Gastric Acid Secretion in Anesthetized Stomach-Lumen Perfused Rats
5.7.1.1 Procedure
5.7.2 Effect of the Test Item on Serum Gastrin Levels
5.7.2.1 Procedure
5.7.3 Bile Secretion in a Mouse Model
5.7.3.1 Purpose
5.7.3.2 Procedure
5.7.4 Bile Duct and Duodenum Cannulation Method
5.7.5 Exocrine Pancreatic Secretion in Anesthetized Rats
5.7.5.1 Purpose
5.7.5.2 Procedure
5.7.6 Gastrointestinal Injury
5.7.6.1 Purpose
5.7.6.2 Procedure
5.7.7 Gastric Ulceration: Pylorus Ligation Model in Rats
5.7.7.1 Purpose
5.7.7.2 Procedure
References
6: Good Laboratory Practice
6.1 Definition
6.2 History
6.3 OECD Principles of Good Laboratory Practice
6.4 Scope of OECD GLP Principles
6.5 National GLP Compliance Monitoring Authority (NGCMA), Government of India
6.6 Responsibilities of GLP Personnel
6.7 Test System and Test Item Characterization
6.7.1 Test System
6.7.2 Test Item and Reference Item
6.8 OECD Documents
References

2022-02-15