Industrial Toxicology

1. Industrial Toxicology BASIC PRINCIPLES Sho’im Hidayat

2. INTRODUCTION What is Toxicology ? - Traditional : the science of poisons - The study of adverse health effects of chemicals or physical agents on living organism What is Industrialtoxicology ? Industrial toxicoloy is the science of poisons whereby is used, produced or byproduced in industry

3. History : Ancient time (1500 BC): Have recognized the use of plants and animal poisons extracts for hunting or warfare : hemlock, opium, arrow poisons, certain metal With time : Poisons become widely used and with great sophistication Victims : Socrates, Cleopatra, Claudius Renaissance & Enlightenment : Fundamental concept of toxicology began to take place (Paracelcus, 1500 AD and Orfila, 1800 AD)

4. Paracelcus : • Specific chemical actually responsible for toxicity of the plant and animal poison • His famous statement : dose–response relationship All substance are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy. Orfila : • Often referred as founder of toxicology • Prepared a systematic correlation between chemical and biological properties of poisons • Demonstrates effect of poison in specific organ by autopsy

5. Basic Toxicology Terminology There are varies in terminology : toxicant toxin poison toxic agent toxic substance toxic chemical

7. Toxic agent : Anything can produce an adverse biological effect(chemical : cyanide; physical : radiation; biological: snake venom) Not included : infected by microorganism Biological toxin : Chemical excreted by microorganism which is the basis of toxicity Ex : tetanus toxin (neurotoxin), produced by Clostridium tetani

8. Toxic material : Doesn’t consist of an exact chemical Ex : asbestos (fiber and other chemical) Organic toxin : Substance originally derived from living organism (named organic) Contain carbon, large molecule Inorganic toxin : Specific chemical not derived from living organism (mineral) Generally small molecule, consist of few atoms

9. Xenobiotic : Foreign substance taken in to the body xeno = foreign Xenobiotics may produce : - beneficial effects (such as pharmaceuticals) - toxic effect (such as lead)

10. Systemic toxin : Effects is in the entire body or many organs rather than a specific organ Ex : potassium cyanide, it effects virtually every cell and organ Organ toxin : Effects only in specific cell or organ (target organ or target tissue), not producing damage to the body as a whole Ex : Benzene blood forming tissue Lead CNS, kidney, hematopoietic system)

11. DOSE and DOSE-RESPONSE Dose : The amount of a substance administered at one time Parameter needed : number of dose, frequency, total time period Ex : - 650 mg Tylenol as single dose - 500 mg Penicillin every 8 hours for 10 days - 10 mg DDT per day for 90 days

12. Type of Doses

13. Dose Unit : mg/kg/day

14. Environmental exposure unit are expressed as the amount of a xenobiotic in a unit of the media Examples : • mg/liter (mg/l) for liquid • mg/gram (mg/g) for solids • mg/cubic meter (mg/m3) for air Smaller unit : µg/ml; ppm; ppb; ppt

15. Dose Response Relationship Correlates : exposure and spectrum of effects In general, higher dose more severe the response (Based on observed data from animal, human clinic or cell study) Knowladge of dose-response relationship : • Establish causality • Establisth the lowest dose where the induce effect occur • Determines the rate which the injury build-up (slope)

18. Dose-response curve : sigmoid

19. The point at which toxicity first appear  threshold dose level • At that point  the ability of the body to detoxify a xenobiotic or repair toxic injury has been exeeded. • For most organs there is a reserve capacity so that loss of some organ function does not cause decreased performance • For example, the development of cirrhosis in the liver may not result in a clinical effect until over 50% of the liver has been replaced by fibrous tissue.

20. Threshold :

21. Shape and slope important for predicting the toxicity of substance • Some / every substance may has a different type of the curve

22. Dose estimates of toxic effect : LD50 LD50  20 mg/kg, rat, oral, 5%

23. Effective doses (ED) :Indicate the effectiveness of a substance

24. Toxic doses (TDs) :Indicates doses that cause adverse toxic effects

26. Therapeutic Index (TI) : compare the therapeutically effective dose to the toxic dose

28. NOAEL and LOAELNo Observed Adverse Effect LevelLow Observed Adverse Effect Level

29. TOXIC EFFECTS Toxicity : complex process; dose is the most important influencing factor Xenobiotic : - originally toxic - after metabolized Toxicity : - adverse cellular - biochemical - macromolecular change

30. Examples : • Cell replacement, such as fibrosis • Damage to an enzym system • Disruption of protein synthesis • Production of reactive chemicals in cell • DNA damage

31. Indirectly : • Modification of an essential biochemical function • Interference with nutrition • Alteration of physiological mechanisme

32. Factors influencing toxicity : • Form and innate chemical activity • Dosage, especially dose-time relationship • Exposure route • Species • Age • Sex • Ability to be absorbed • Metabolisme • Distribution within the body • Excretion • Presence of other chemicals

33. Form Examples : - methyl mercury – mercury vapour (element) - Cr3+ - Cr6+ Innate Examples : HCN cytohrome oxidase hypoxia Nicotin cholinergic receptor paralysis Dosage Toxicant :Acute toxicity :Chronic toxicity : Ethanol CNS depressant liver cirrhosis Arsenic GIT damage skin / liver damage

34. Exposure Route : • Ingested chemicals : intestine liver distributed • Inhaled chemicals : blood circulation whole body Liver : the most active organ for chemicals inactivation Frequenly : diff. target organ for diff. exp. route

35. Selective toxicity : Differences in toxicity between two species - an insectcide is lethal to insect, not to human - antibiotics lethal for microorganisme, nontoxic to human Age : - parathion is more toxic to young animals - nitrosamines are more carcinogenis to newborne or young animals

36. Sex : - male rats 10 x more sensitive to liver damage from DDT - female rats 2x more sensitive to parathion Ability to be absorbed : - ethanol is readily absorbed from GIT but poorly absorbed through the skin - organic mercury is readily absorbed from GIT, but inorganic mercury is not

37. Metabolism = biotransformation Is a major factor in determining toxicity - detoxification (bioinactivation) : process by which a xenobiotic is converted to a less toxic form water soluble - bioactivation : process by which a xnobiotic may be converted to more reactive or toxic form. Distribution : Determine the sites where toxicity occur. Depend on how the lipid-solubility

38. Excretion : Another major factor affecting the toxicity Excretory organ : kidney, GIT, lung. Sometime also : sweat, tears, milk Presence of other chemicals Antagonism, additivity, potentiation, synergism

39. SYSTEMIC EFFECTS Toxic effects occur at multiple sites, including : - acute toxicity - subchronic toxicity - chronic toxicity - carcinogenicity - developmental toxicity - genetic toxicity (somatic cells)

40. Acute toxicity • occurs almost immediatly (h / d) after exposure • Usually single dose at large dose • Examples : Methyl isocyanat accident in Bophal India • Subchronic toxicity • Results from repeated exposure for several weeks or months • Chronic toxicity • Represents cumulative damage to specific organ system and takes many months or years to become a recognizible clinical disease • Ex : cirrhosis in alcoholics, chronis bronchitis in long-term cigarrete smokers, pulmonary fibrosis in coal miners

41. Carcinogenicity • Complex multistages of abnormal cell growth and differentiation • Need : initiator, promoter • Mutation  results initial neoplastic transformation of cellular gene • Developmental toxicity • An adverse effect on developing embryo or fetus • Involving : embryolethality, embryotoxicity, terratogenicity

42. Genetic toxicity • Results from damage to DNA and altered genetic expression  mutagenesis • 3 types of genetic change : gene mutation, chromosome abberation, aneploidy / polyploidy

43. Organ specific toxicity Type of organ specific toxic effect are : - blood / cardiovasculer toxicity - dermal / occular toxicity - genetic (germ cell) toxicity - hepatotoxicity - immunotoxicity - nephrotoxicity - reproductive toxicity - respiratory toxicity

44. Blood & cardiovascular toxicity • Toxicity on circulating blood, bone marrow, heart • Ex : - hypoxia do to monoxide - decrease leucocyte do to chloramphenocol - leukemia do to benzene • Dermal and eye toxicity • Results from direct contact or internal distribution to the skin • Ex : dermal irritation, dermal corrosion, hypersensitivity, skin cancer

45. Hepatotoxicity • Toxicity to the liver, bile dict and gall bladder

46. Immunotoxicity • Toxicity of the immune system • Forms : hypersensitivity (allergic & autoimmunity), immunodeficiency, uncontrolled proliferation (leukemia & lymphoma), • Ex : contact dermatitis, systemic lupus erytematosus (SLE) • Nephrotoxicity • Succeptibility factor of kidney : high volume blood flow & filtrates amount of toxin • Forms : decrease excrete body waste, inability to maintain body fluid, decrease to synthesis hormon erythropoietin

47. Neurotoxicity • Damage cell of CNS & PNS • Types : • Neuropathy (neuron injury) • Axonopathy (axon injury) • Demyelination (loss of axon insulation) • Interference with neurotransmitter • Reproductive toxicity • Male and female • Effects : • Impotency / decrease of libido • Infertility • Interupted pregnancy • Infant death / childhood mortality • Childhood cancer, etc

48. Respiratory toxicity • Upper and lower respiratory tract • Forms : • Pulmonary irritation • Asthma bronchitis • Reactive airways disease • Emphysema • Allergic alveolitis • Fibrotic lung disease • Pnumoconiosis • Lung cancer

49. INTERACTION Type of interaction :