Lecture 1: Principles Of General Toxicology PDF

LECTURE 1 GENERAL PRINCIPLES OF TOXICOLOGY Miss A. Lewis  objectives On completion of this session students should be able to: i. Discuss the general principles of toxicological evaluation of drugs ii. Describe the various characteristics of toxic effects ii...

LECTURE 1 GENERAL PRINCIPLES OF TOXICOLOGY Miss A. Lewis  objectives On completion of this session students should be able to: i. Discuss the general principles of toxicological evaluation of drugs ii. Describe the various characteristics of toxic effects iii.Describe the features of possible interaction between chemicals iv.Explain the principle of the dose-response curve v. Describe the various animal toxicological test used in drug screening vi.Discuss the various phases of drug development  Introduction Paracelsus (1493-1541) Swiss German Philosopher “All substances are poisons: There is none which is not a poison. The right dose differentiates a poison and a remedy”  definitions Toxicology is a multi-disciplinary science used to address a variety of questions related to the nature, effects and detection of poisons. – Examines adverse effects ranging from short term (acute) to long-term (chronic) – Assess the probability of hazards by analyzing adverse effects – Predict effects on individuals, populations and ecosystems Disciplines/branches  Classification of toxic agents Toxic Agent: substance with poisonous/deadly effects Xenobiotic: a foreign chemical substance found in an organism that is not naturally produced by or expected to be present within. Toxin: toxic substances produced by biological systems (produced naturally), such as plants, animals, bacteria and fungi. Toxicant: substances that are produced by or are by-products of human activities. Toxins which are not naturally occurring – Example: Dioxin (2,3-7,8-tetrachlorodibenzo-p-dioxin, TCDD), by- product of certain chlorinated chemicals  Classification of toxic agents CLASSIFICATION EXAMPLES EFFECTS Heavy Metals Lead, Mercury, Cadmium Renal dysfunction, CNS damage, Endocrine damage Solvents and Vapours Carbon monoxide, ozone Tissue damage, etc. inflammation Radioactive Material and Cesium 137, Cobalt 60, Cataract, cancer, DNA Radiation Uranium 238 etc. damage, sterility etc. Pesticides, Herbicides, Organochlorines, Carcinogenic effects etc. Insecticides Organophosphates, Paraquat Plant Toxins Alkaloids, Terpenes, Cell Death, depression of Resins, hypoglycin etc. CNS, Animal Toxins Snake venom etc. Internal bleeding  Classification of toxic agents: subcategories Effects on target organs (Liver, Kidneys, hematopoietic system) Effects (cancer, mutation, liver injury) Chemical Stability or reactivity (explosive, flammable, oxidizer) Chemistry (aromatic amine, halogenated hydrocarbon) Biochemical Mechanism: alkylating agent, sulfhydryl inhibition, methemoglobin producer) Toxic agents: encounters Toxic agents: encounters Toxic agents: encounters Risk, hazard and exposure explained  Characteristics of toxic exposure A toxic response is dependent on the:\ – Chemical and physical properties of the agent – Exposure situation – Metabolism of the agent by the system – Concentration of the active form of the substance at the target site – Susceptibility of the biological system/organism Characteristics of Toxic Exposure: route and site of exposure Approximate decreasing order For example, the water and of effectiveness: lipid solubility characteristics of a chemical affect its – Inhalation absorption across the; – Intraperitoneal – Subcutaneous Rate and site of absorption – Intramuscular (organ) may also determine the – Intradermal rate of metabolism and excretion – Oral of the chemical. – Dermal Characteristics of toxic exposure: duration and frequency The exposure of organisms to toxic agents can be divided into 4 categories Acute- Exposure to a chemical for Subchronic- Repeated less than 24 hours, usually a single exposure for 1-3 months administration, also refers to cases of repeated exposures within the Chronic- Repeated exposure 24 hour period for slightly toxic or for more than 3 months seemingly non-toxic agents Subacute- Repeated exposure to a chemical for 1 month or less Characteristics of toxic exposure: side effects vs. toxic effects Side Effects Toxic Effects Occur at the normal dosage – Adverse effects usually seen at higher levels of the doses drug/substance – Usually irreversible but may be treated – May be related to the main (undesirable but pharmacological action unavoidable) – Bleeding with Warfarin (Coumadin®) – May be unrelated to the main physiological action – Liver toxicity from Paracetamol (Panadol® and Tylenol®)  Spectrum of undesired effects Allergic Reaction Idiosyncratic Reaction Chemical allergy is an immunoadverse determined abnormal logically mediated reaction to a chemical reactivity to a chemical. resulting from previous sensitization to that – Extreme sensitivity to low chemical or to a structurally similar one. doses or extreme Most chemicals and their metabolic products insensitivity to high doses are not sufficiently large to be recognized by the immune system as a foreign substance and thus must first combine with an endogenous protein to form an antigen (or immunogen). A molecule that must combine with an endogenous protein to elicit an allergic reaction is called a hapten. Spectrum of undesired effects: Immediate vs. delayed toxicity Immediate toxic effects can be Delayed toxic effects are those defined as those that occur or that occur after the lapse of develop rapidly after a single some time. administration of a substance. – Carcinogenic effects of chemicals usually have a long latency period, often 20 to 30 years after the initial exposure, before tumors are observed in humans.  Spectrum of undesired effects: reversible vs. irreversible effects If a chemical produces However, injury to the CNS is pathological injury to a tissue, the largely irreversible because ability of that tissue to regenerate differentiated cells of the CNS largely determines whether the cannot divide and be replaced. effect is reversible or irreversible. Carcinogenic and teratogenic Thus, for a tissue such as liver, effects of chemicals, once they which has a high ability to occur, are usually considered regenerate, most injuries are irreversible toxic effects. reversible.  Spectrum of undesired effects: local vs. systemic toxicity Local effects are those that occur at the Systemic effects require site of first contact between the absorption and biological system and the toxic agent. distribution of a toxicant For example, chlorine gas reacts with from its entry point to a lung tissue at the site of contact, distant site, at which causing damage and swelling of the deleterious effects are tissue, with possibly fatal produced. consequences, even though very little of the chemical is absorbed into the bloodstream.  Chemical interaction Chemical interactions are known Chemical interactions can be to occur by a number of increased or decreased in one of mechanisms, such as; four ways; – Alterations in absorption – Additive – Synergistic – Protein binding, and – Potentiation – Antagonistic – The biotransformation and excretion of one or both of the interacting toxic agents. Variations in toxic response: Selective toxicity Selective toxicity means that a chemical produces injury to one kind of living matter without harming another form of life even though the two may exist in intimate contact. – The living matter that is injured is termed the uneconomic form (or undesirable), – The matter protected is called the economic form (or desirable). Selectivity usually resulting from differences in the absorption, biotransformation, or excretion of the toxicant. Variations in toxic response: Species differences There are many reasons for selective toxicity among different species. Even among phylogenetically similar species (e.g. rats, mice, guinea pigs, and hamsters), large differences in response may occur. Identifying the mechanistic basis for species differences in response to chemicals is an important part of toxicology. Variations in toxic response: individual differences Even within a species, large inter-individual differences in response to a chemical can occur because of subtle genetic differences. Hereditary differences in a single gene that occur in more than 1% of the population are referred to as genetic polymorphism.  Dose response relationships What is "Dose"? – The dose of a chemical or physical agent is the amount of that agent that comes into contact with a living organism or some part of a living organism. The type of dose most familiar to the average person is that associated with medicines.  Dose response relationships Response changes as a function of dose Plot of the effect of a chemical based on the dose: – The drug dose is increasing but there is little response. – The drug must reach a desired concentration before the response increases significantly. – Until there is no further response produced Median effective concentration (MEC/ed50 The minimum concentration of a chemical in plasma required to produce the therapeutic effect. It is the dose of the chemical that is therapeutically effective in 50% of the population. It reflects the concentration of chemical at the receptor site to elicit the desired toxicological response. The concentration below the MEC is referred to as the sub-therapeutic level.  Median toxic concentration (mtc/td50) The concentration of chemical in plasma at and above which adverse or unwanted effects are triggered. It is the dose of the chemical that causes a toxic response in 50% of the population. Concentration of chemical above the MTC is said to be in the toxic level. The MTC may also be called the maximum safe concentration (MSC).  Median lethal concentration (ld50) Statistically derived concentration of a substance in an environmental medium expected to kill 50% of organisms in a given population under a defined set of conditions. Measurement of toxicity – therapeutic index (TI)  Therapeutic index (ti) The “Therapeutic Index” also called the “Therapeutic Window” is comparison of the amount of a therapeutic agents that elicits a therapeutic effect to the amount which causes toxicity  The drug development process Drug development is the The drug development process process by which new pharmaceutical drugs are Step 1: Discovery & introduced to the market once development a lead compound has been Step 2: Preclinical research identified through the process Step 3: Clinical research of drug discovery. Step 4: FDA review Step 5: FDA post-marketing safety monitoring.  Descriptive animal toxicity tests Testing for the safety or efficacy of a substance or product accounts for a major use of animals as defined in this assessment, most of which are rats and mice. Of these, probably the largest portion are used in developing drugs. – A significant portion are also used to test other substances— pesticides, industrial chemicals, and consumer products—to assess possible toxicity and to establish conditions under which they can be used safely. Testing methodologies are standardized to control experimental variables, thus allowing results to be easily compared.  Descriptive animal toxicity tests Pharmacokinetics – Pharmacokinetic studies provide information about; The mechanisms of absorption A substance’s distribution among the various body compartments About metabolism and elimination. – They facilitate the interpretation of results from other tests and their extrapolation to humans because the distribution and elimination of a foreign substance will often explain its toxicity or lack thereof.  Animal toxicity tests 2 main principles – Effects produced by a compound in laboratory animals, when properly qualified, are applicable to humans – Exposure of experimental animals to chemicals in high doses is a necessary and valid method of discovering possible hazards in humans.  Descriptive animal toxicity tests Acute Toxicity Testing Skin and Eye Irritation Sensitization Sub-Acute Sub-Chronic Chronic Developmental and Reproductive Toxicity Mutagenicity Oncogenicity Bioassays Neurotoxicity Assessment Immunotoxicity Assessment  Genetic toxicity Genetic toxicity involves the assessment of the deleterious effects of chemicals or physical agents on hereditary material and related genetic processes of living cells. By altering the integrity and function of DNA at the gene or chromosomal level, the damage can lead to heritable mutations ultimately resulting in genetic disorders, congenital defects or cancer.  Genetic toxicity Toxicogenomics tools are Proteomics important for research aimed at – Characterization of most or identifying the mechanisms and all of the proteins expressed mode of action of toxic substances. in a given cell/tissue Genomics Metabonomics – Characterization of a section or all of the genome of an – Characterization of most or organism all of the small molecules in Transcriptomics a cell/ tissue, including – Characterization of most or all substrates, products, and of the mRNAs or transcriptome, co-factors of enzyme expressed in a given cell/tissue reactions.