Toxicology, 1. Fundamentals

Abstract

The article contains sections titled: 1. Introduction 1.1. Definition and Scope 1.2. Fields 1.3. History 1.4. Information Resources 1.5. Terminology of Toxic Effects 1.6. Types of Toxic Effects 1.7. Dose‐Response: a Fundamental Issue in Toxicology 1.7.1. Graphics and Calculations 1.8. Dose‐Response Relationships for Cumulative Effects 1.9. Factors Influencing Dose‐Response 1.9.1. Routes of Exposure 1.9.2. Frequency of Exposure 1.9.3. Species‐Specific Differences in Toxicokinetics 1.9.4. Miscellaneous Factors Influencing the Magnitude of Toxic Responses 1.10. Exposure to Mixtures 2. Absorption, Distribution, Biotransformation and Elimination of Xenobiotics 2.1. Disposition of Xenobiotics 2.2. Absorption 2.2.1. Membranes 2.2.2. Penetration of Membranes by Chemicals 2.2.3. Mechanisms of Transport of Xenobiotics through Membranes 2.2.4. Absorption 2.2.4.1. Dermal Absorption 2.2.4.2. Gastrointestinal Absorption 2.2.4.3. Absorption of Xenobiotics by the Respiratory System 2.3. Distribution of Xenobiotics by Body Fluids 2.4. Storage of Xenobiotics in Organs and Tissues 2.5. Biotransformation 2.5.1. Phase‐I and Phase‐II Reactions 2.5.2. Localization of the Biotransformation Enzymes 2.5.3. Role of Biotransformation in Detoxication and Bioactivation 2.5.4. Phase‐I Enzymes and their Reactions 2.5.4.1. Microsomal Monooxygenases: Cytochrome P450 2.5.4.2. Microsomal Monooxygenases: Flavin‐Dependent Monooxygenases 2.5.4.3. Peroxidative Biotransformation: Prostaglandin‐synthase 2.5.4.4. Nonmicrosomal Oxidations 2.5.4.5. Hydrolytic Enzymes in Phase‐I Biotransformation Reactions 2.5.5. Phase‐II Biotransformation Enzymes and their Reactions 2.5.5.1. UDP‐Glucuronyl Transferases 2.5.5.2. Sulfate Conjugation 2.5.5.3. Methyl Transferases 2.5.5.4. N ‐Acetyl Transferases 2.5.5.5. Amino Acid Conjugation 2.5.5.6. Glutathione Conjugation of Xenobiotics and Mercapturic Acid Excretion 2.5.6. Bioactivation of Xenobiotics 2.5.6.1. Formation of Stable but Toxic Metabolites 2.5.6.2. Biotransformation to Reactive Electrophiles 2.5.6.3. Biotransformation of Xenobiotics to Radicals 2.5.6.4. Formation of Reactive Oxygen Metabolites by Xenobiotics 2.5.6.5. Detoxication and Interactions of Reactive Metabolites with Cellular Macromolecules 2.5.6.6. Interaction of Reactive Intermediates with Cellular Macromolecules 2.5.7. Factors Modifying Biotransformation and Bioactivation 2.5.7.1. Host Factors Affecting Biotransformation 2.5.7.2. Chemical‐Related Factors that Influence Biotransformation 2.5.8. Elimination of Xenobiotics and their Metabolites 2.5.8.1. Renal Excretion 2.5.8.2. Hepatic Excretion 2.5.8.3. Xenobiotic Elimination by the Lungs 2.6. Toxicokinetics 2.6.1. Pharmacokinetic Models 2.6.1.1. One‐Compartment Model 2.6.1.2. Two‐Compartment Model 2.6.2. Physiologically Based Pharmacokinetic Models 3. Mechanisms of Acute and Chronic Toxicity and Mechanisms of Chemical Carcinogenesis 3.1. Biochemical Basis of Toxicology 3.2. Receptor‐Ligand Interactions 3.2.1. Basic Interactions 3.2.2. Interference with Excitable Membrane Functions 3.2.3. Interference of Xenobiotics with Oxygen Transport, Cellular Oxygen Utilization, and Energy Production 3.3. Binding of Xenobiotics to Biomolecules 3.3.1. Binding of Xenobiotics or their Metabolites to Cellular Proteins 3.3.2. Interaction of Xenobiotics or their Metabolites with Lipid Constituents 3.3.3. Interactions of Xenobiotics or their Metabolites with nucleic Acids 3.4. Perturbation of Calcium Homeostasis by Xenobiotics or their Metabolites 3.5. Nonlethal Genetic Alterations in Somatic Cells and Carcinogenesis 3.6. DNA Structure and Function 3.6.1. DNA Structure 3.6.2. Transcription 3.6.3. Translation 3.6.4. Regulation of Gene Expression 3.6.5. DNA Repair 3.7. Molecular Mechanisms of Malignant Transformation and Tumor Formation 3.7.1. Mutations 3.7.2. Causal Link between Mutation and Cancer 3.7.3. Proto‐Oncogenes and Tumor‐Suppressor Genes as Genetic Targets 3.7.4. Genotoxic versus Nongenotoxic Mechanisms of Carcinogenesis 3.8. Mechanisms of Chemically Induced Reproductive and Developmental Toxicity 3.8.1. Embryotoxicity, Teratogenesis, and Transplacental Carcinogenesis 3.8.2. Patterns of Dose‐Response in Teratogenesis, Embryotoxicity, and Embryolethality

Adli Toksikoloji: Temel Kavramlar ve Prensipler

“…Böylelikle güvenilir ilaç-doz ayarlanmasında ve halk sağlığının korunmasında önemli rol oynar (Nordberg & Fowler, 2019). Doz-yanıt ilişki grafikleri genellikle sigmoid (S şeklinde) eğriden oluşurlar (Şekil 2.1) (Dekant & Vamvakas, 2005;Rhomberg vd., 2018).…”

“…Çoğu zaman madde kanda dağılıma uğramaz, geri ekshale edilir (Spoo, 2004). İnhalasyon yolu ile alınan gaz formundaki toksik maddelere örnek olarak karbon monoksit (CO), nitrik oksit, klor, fosgen, sarin, tabun, buhar halindekilere benzen, karbon tetra klorür (CCl 4 ) ve aerosol formunda bulunanlara ise egzoz dumanındaki kurşun, silika, asbestos örnek verilebilir (Dekant & Vamvakas, 2005). Başka bir örnek ise tetrahidrokannabinolün (THC) sigara yoluyla alınmıdır ki bu durumda madde absorpsiyonu akciğerler tarafından en hızlı biçimde gerçekleşir (15 saniye) ve beyine ulaşır (Pillay, 2013 (Spoo, 2004).…”

“…Asetonitrilin CYP450 enzim sistemi ile metabolizasyonu sonucu siyanür oluşmaktadır. Paratiyonun kendinden daha fazla kolin esteraz inhibitör etkisi gösteren paraoksona oksidatif desülfarasyonu da bu tür oluşumlara örnektir (Dekant & Vamvakas, 2005). İyi bilinen bir prodrug olan kodein ise CYP2D6 enzimi ile metabolize olarak morfine dönüşür .…”

“…Streptozotosin ve alloksan ilacı pankreasın β-hücrelerinde toksik etkiler gösterirken, kanamisin ve klorokin ilaçları ise kulakta melanin proteinine bağlanarak toksik etkiler gösterirler. Gözde toksik etkiler gösteren ilaçlar ise klorokin, klorpromazin ve fenotiyazinler olarak sayılabilir (Dekant & Vamvakas, 2005).…”

Toksikolojide Temel Kavramlar

“…Böylelikle güvenilir ilaç-doz ayarlanmasında ve halk sağlığının korunmasında önemli rol oynar (Nordberg & Fowler, 2019). Doz-yanıt ilişki grafikleri genellikle sigmoid (S şeklinde) eğriden oluşurlar (Şekil 2.1) (Dekant & Vamvakas, 2005;Rhomberg vd., 2018).…”