2. chapter principle of toxicology

Toxicology

1. Bule Hora University College of Health and Medical Sciences Department Of Pharmacy TOXICOLOGY For 4 th year Medical Laboratoy Students 4/15/2021 Basic Principles of toxicology 1 By:Aliyi G.( B.Pharm

2. General Principles of Toxicology CHAPTER TWO 4/15/2021 2 Basic Principles of toxicology

3. Objectives 4/15/2021 Basic Principles of toxicology 3 At the end of this chapter, students will be able to: Discuss basic principles of toxicology Discuss t oxicity parameters: the chemical form, routes and sites of exposure, duration and frequency of exposure (acute, sub acute, chronic), Dose- response effects. Discuss t ypes of toxic reactions Discuss variation in toxic responses .

4. Outline 4/15/2021 Basic Principles of toxicology 4 Basic principles of toxicology Toxicity parameters: the chemical form, routes and sites of exposure, duration and frequency of exposure (acute, sub acute, chronic), Dose- response effects. Types of toxic reactions Variation in toxic responses .

5. Principles of toxicology 4/15/2021 Basic Principles of toxicology 5 Toxicant (Poison) any agent capable of producing a deleterious response in a biological system. Paracelsus (1493-1541) once said "All substances are poisons; there is none which is not a poison The right dose differentiates a poison from a treatment’’ It is not easy to distinguish toxic from non toxic substances.

6. Principles of toxicology cont’d 4/15/2021 Basic Principles of toxicology 6 therapeutic effect toxic effect increasing dose “All things are poison and nothing is without poison, only the dose permits something not to be poisonous The dose makes the poison ”

7. Exposure 4/15/2021 Basic Principles of toxicology 7 The concentration of chemical involved and frequency of its interaction with people. • Degree of exposure = Determined during risk assessment • Excessive Exposure = The amount of exposure that lead to injury or adverse effects . e.g . Median Lethal Dose (LD50) of Ethanol is & 7000 mg/kg, it means that by ingesting 7000 mg/kg Ethanol , half of the rat population in the experiment died LD50 : Refers to the dose of a substance that displays toxicity in that it kills 50% of a test population .

8. Exposure cont’d,… 4/15/2021 Basic Principles of toxicology 8 Adverse effects = abnormal , undesirable harmful change following exposure. • Reversible change • Irreversible Change Injury depends on = property of chemical + nature of exposure + health & developmental state of the person.

9. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 9 Routes and Sites of Exposure Ingestions (gastrointestinal tract) account for 79% of exposures 7% Skin (topical, percutaneous, or dermal) 6% Eye (ophthalmologic) 5% lungs ( inhalation) 3% bites 0.3% injection intravenous, intramuscular, intraperitoneal

10. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 10 Injection (intravenous route) . Toxic agents generally produce the greatest effect and the most rapid response when given directly into the bloodstream. Typical Effectiveness of Route of Exposure: iv > inhale > ip > Sc > im > ingest > topical

11. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 11 Skin direct and prolonged contact of the skin with the substance. • Chemicals that can penetrate healthy intact skin – aniline, hydrogen cyanide, organophosphate , etc .

12. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 12 Lung (Inhalation ) Occupational exposure to toxic agents most frequently results from breathing contaminated air . Depends on Size & Shape of particles • Size – effective aerodynamic diameter • Shape – dust, microorganism Rate of physical work • Advice to avoid physical activity during haze.

13. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 13 Ingestion • Mostly we can control (unlike airborne ). • Airborne particle also can be ingested. • Depends on • Concentration • Time The route of administration can influence the toxicity of agents …. how ????????????????

14. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 14 Duration and frequency exposure Exposure of experimental animals to chemicals is divided into four categories. • Single exposure : Acute exposure - less than 24 hours • Repeated exposures are classified as: • Subacute - repeated for up to 30 days • Subchronic - repeated for 30-90 days • Chronic -repeated for over 90 days

15. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 15 For many agents, the toxic effects that follow a single exposure are quite different from those produced by repeated exposure. E.g …Benzene Acute exposure results in CNS depression. Repeated exposure results in bone marrow toxicity, increased risk of leukemia.

16. Exposure cont’d ,… 4/15/2021 Basic Principles of toxicology 16 Chronic toxic effects may occur if The chemical accumulates in the biological system (rate of absorption exceeds the rate of biotransformation and/or excretion) It produces irreversible toxic effects There is insufficient time for the system to recover from the toxic damage within the exposure frequency interval .

17. 4/15/2021 Basic Principles of toxicology 17 For many agents, the toxic effects that follow a single exposure are quite different from those produced by repeated exposure E.g … Benzene Acute exposure results in CNS depression Repeated exposure results in bone marrow toxicity, increased risk of leukemia

18. Dose - response effects 4/15/2021 Basic Principles of toxicology 18 A key principle in toxicology is the Dose Dose-response relationship There is a graded dose-response relationship in individuals, and A quantal dose-response relationship in the population

19. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 19 Dose is the actual amount of chemical entering the body , usually per unit body mass of a toxicant to which an organism is exposed. This is usually given as mg of chemical/kg of body weight = mg/kg.

20. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 20 Response is the effect on an organism resulting from exposure to a toxicant . Change from normal state could be on the molecular, cellular, organ, or organism level => the symptoms. Local vs. Systemic Reversible vs. Irreversible Immediate vs. Delayed Graded vs. Quantal degrees of the same damage vs. all or none .

21. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 21 A response occurs is dependent on The chemical and physical properties of the agent The exposure situation How the agent is metabolized by the system The overall susceptibility of the biological system or subject

22. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 22 Dose-response Relationship s is a relationship between exposure and response, that can be established by measuring the response relative to an increasing dose. This relationship is important in determining the toxicity of a particular substance. It relies on the concept that a dose or a time of exposure (to a chemical, drug, or toxic substance), will cause an effect (response) on the exposed organism.

23. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 23 Usually, the larger or more intense the dose, the greater the response or the effect. This is the meaning behind the statement “ the dose makes the poison.”

24. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 24 For most toxicants, at very low amounts, there will be no detectable effect of the chemical (NOAEL: no observed adverse effect level) As the dose of a toxicant increases, so does the response, either in terms of the proportion of the population responding or in terms of the severity of the graded responses . In the middle range of doses, the amount of damage will increase as the dose increases.

25. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 25 In the Larger amounts of chemical will cause increasingly more severe biological responses until a maximum level of damage is reached. Additional toxic effects may also appear along with increased doses, dose - effect relationships .

26. Dose-Response Relationship: As the dose of a toxicant increases, so does the response . 2 3 4 1 DOSE RESPONSE 0-1 NOAEL 2-3 Linear Range 4 Maximum Response DOSE DETERMINES THE BIOLOGICAL RESPONSE 4/15/2021 Basic Principles of toxicology 26

27. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 27 There are two types of dose–response relationships: The individual dose–response relationship Which describes the response of an individual organism to varying doses of a chemical Often referred to as a “ graded ” response because the measured effect is continuous over a range of doses A quantal dose–response relationship Which characterizes the distribution of responses to different doses in a population of individual organisms

28. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 28 Graded or Individual Dose–Response Relationships Response of an individual organism to varying doses of a chemical (also called“graded ” response because effect is continuous over a dose range) ( e.g.enzyme activity, blood pressure). Characterized by a dose related increase in the severity of the response The dose relatedness of the response often results from an alteration of a specific biochemical process.

29. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 29 Dose Mg/kg Response

30. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 30 Quantal Dose–Response Relationships Quantal or “all or none”— in nature; that is, at any given dose, an individual in the population is classified as either a “responder” or a “non responder ” The quantal dose-response is the more important one, used to determine the median lethal dose ( LDm ) and judge what percentage of the population is affected by a dose increase and comes closest to a classification of whether something is safe or toxic. 

31. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 31 Diagram of a quantal dose–response relationship

32. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 32 Threshold dose Given the idea of a dose-response, there should be a dose or exposure level below which the harmful or adverse effects of a substance are not seen in a population. That dose is referred to as the ‘threshold dose’. This dose is also referred to as the no observed adverse effect level (NOAEL), or the no effect level (NEL). These terms are often used by toxicologists when discussing the relationship between exposure and dose.

33. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 33 For chronic effects, the determination of a threshold value is very difficult This is especially for substances causing cancer ( carcinogens), no safe level of exposure exists, since any exposure could result in cancer.

34. Dose - response effects cont’d,… 4/15/2021 Basic Principles of toxicology 34

35. Toxicity 4/15/2021 Basic Principles of toxicology 35 Def.: Describes the degree to which a substance is poisonous or can cause injury. The toxicity depends on a variety of factors: dose, duration and route of exposure, shape and structure of the chemical itself, and individual human factors.

36. Toxicity cont’d 4/15/2021 Basic Principles of toxicology 36 Different xenobiotics cause many types of toxicity by a variety of mechanisms. So, we have to take an idea about : - Different types of toxic agents -Different type of toxicity -Different mechanisms of toxic response.

37. Toxicity cont’d 4/15/2021 Basic Principles of toxicology 37 Toxic Agents Toxic agent: is anything that can produce an adverse biological effect. -The most common terms used to describe a toxic agent are toxicant, toxin, poison .

38. Toxicity cont’d 4/15/2021 Basic Principles of toxicology 38 Toxic Agents are classified : 1-According to their nature: 1- Chemicals : as alcohols, phenols & heavy metals… 2- Physical : as radiation & heat. 2- Bilogical : Snake & scorpion venoms .

39. Toxicity cont’d 4/15/2021 Basic Principles of toxicology 39 2-According to their effect: i-Systemic toxicant: is one that affects the entire body or many organs rather than a specific site. E.g.: potassium cyanide is a systemic toxicant it affects virtually every cell and organ in the body by interfering with the cell's ability to utilize oxygen .

40. Toxicity cont’d 4/15/2021 Basic Principles of toxicology 40 ii-Target organs toxicant: affect only specific tissues or organs while not producing damage to the body as a whole. Examples: -Arsenic& paracetamol are hepatotoxic . -Digitalis& antimony are cardiotoxic . -Mercury & gentamycin are nepherotoxic . -Lead is also a specific organ toxin; however, it has three target organs ( central nervous system, kidney, and hematopoietic system) .

41. Types of Toxicity 4/15/2021 Basic Principles of toxicology 41 1-Systemic Toxicity : Toxicity may occur at multiple sites. This is referred as systemic toxicity. The following are types of systemic toxicity:- a-Acute Toxicity: It occurs almost immediately (hours/days) after an exposure to single dose or a series of doses received within a 24 hour period. Death is a major concern in cases of acute exposures. Examples are: -In 1989, 5,000 people died and 30,000 were permanently disabled due to exposure to methyl isocyanate from an industrial accident in Bhopal, India.

42. Types of Toxicity Cont’d 4/15/2021 Basic Principles of toxicology 42 b- Subchronic Toxicity (reversible ) It results from repeated exposure for several weeks or months. This is a common human exposure pattern for some pharmaceuticals and environmental agents. Examples are: -Ingestion of coumadin tablets (blood thinners) for several weeks as a treatment for venous thrombosis can cause internal bleeding. -Workplace exposure to lead over a period of several weeks can result in anemia .

43. Types of Toxicity Cont’d 4/15/2021 Basic Principles of toxicology 43 c-Chronic Toxicity (irreversible) : It is a cumulative damage to specific organ or system and it takes many months or years to become a recognizable clinical disease. This damage is so severe that the organ can no longer function normally (irreversible) and a variety of chronic toxic effects may result. Examples are: -Cirrhosis in alcoholics who have ingested ethanol for several years -Chronic bronchitis in long-term cigarette smokers -Pulmonary fibrosis in coal mineral (black lung disease).

44. Types of Toxicity Cont’d 4/15/2021 Basic Principles of toxicology 44 d-Carcinogenicity: Carcinogenicity is a complex multistage process of abnormal cell growth and differentiation which can lead to cancer. e-Developmental Toxicity: Developmental Toxicity result from toxicant exposure to either parent before conception or to the mother and her developing embryo-fetus. f-Genetic Toxicity: Genetic Toxicity results from damage to DNA and altered genetic expression. This process is known as mutagenesis. The genetic change is referred to as a mutation and the agent causing the change as a mutagen .

45. Types of Toxicity Cont’d 4/15/2021 Basic Principles of toxicology 45 2- Organ Specific Toxicity : Blood and Cardiovascular Toxicity Hypoxia due to carbon monoxide binding of hemoglobin preventing transport of oxygen Hepatotoxicity CCl4 causes lipid peroxidation in liver & lead to liver necrosis . Nephrotoxicity Mercury & gentamycin are nepherotoxic . Neurotoxicity Organophosphorus compounds (insecticides)………damage to sensory fibers.

46. Types of Toxicity Cont’d 4/15/2021 Basic Principles of toxicology 46 Respiratory Toxicity Aluminum …..emphysema…… inflated lung …….fibrosis( aluminosis ). Dermal Toxicity D ermal irritation due to skin exposure to gasoline D ermal corrosion due to skin exposure to sodium hydroxide S kin cancer due to ingestion of arsenic or skin exposure to UV light. Eye Toxicity A cids and strong alkalis may cause severe corneal corrosion C orticosteroids may cause cataracts. M ethanol (wood alcohol) may damage the optic nerve leading to blindness.

47. Types of Toxicity Cont’d 4/15/2021 Basic Principles of toxicology 47 Mechanisms of Toxic Effects Adverse effects can occur at the level of the molecule, cell, organ, or organism Molecular level : chemical can interact with: Proteins / Lipids / DNA. Cellular level : chemical can • interfere with receptor-ligand binding • interfere with membrane function • interfere with cellular energy production • bind to biomolecules

48. Variation in toxic responses 4/15/2021 Basic Principles of toxicology 48 Selective Toxicity Means that a chemical produces injury to one kind of living matter without harming another form of life event though the two may exist in intimate contact. Living matter that is injured is termed the uneconomic form (or undesirable) and the matter protected is called the economic form (or desirable).

49. Variation … 4/15/2021 Basic Principles of toxicology 49 Drugs and other chemical agents used for selective toxic purposes are selective for one of two reasons. The chemical is equitoxic to both economic and uneconomic cells but is accumulated mainly by uneconomic cells or It reacts fairly specifically with a cytological or a biochemical feature that is absent from or does not play an important role in the economic form.

50. Variation …… 4/15/2021 Basic Principles of toxicology 50 Species Differences Both quantitative and qualitative differences in response to toxic substances may occur among different species Identifying the mechanistic basis for species differences in response to chemicals is an important part of toxicology because Only through understanding of these differences can the relevance of animal data to human response be verified.

51. Variation …. 4/15/2021 Basic Principles of toxicology 51 Individual Differences in Response Even within a species, large inter individual differences in response to a chemical can occur because of subtle genetic differences. G enetic polymorphism Hereditary differences in a single gene that occur in more than 1 percent of the population. Genetic polymorphism in physiologically important genes may also be responsible for interindividual differences in toxic responses .

52. Variation …. 4/15/2021 Basic Principles of toxicology 52 In humans, there is evidence that possessing one mutated copy of a tumor suppressor gene greatly increases the risk of developing certain cancers.

53. 4/15/2021 Basic Principles of toxicology 53 Thank You!!