W. Tassaneeyakul 1 Principles of Toxicology : The Study of Poisons Wongwiwat Tassaneeyakul Department of Toxicology Khon Kaen University

W. Tassaneeyakul2  To know scope and definition of toxicology,  Describe how toxicologist work and manage toxicants,  Understand dose-response relationship and interactions

W. Tassaneeyakul3 August 21 st, 1986, 9:30 pm >1700 people and 3000 dead cow!!!

W. Tassaneeyakul4 Asia's arsenic crisis deepens Another Indian state succumbs to well water poisoning. 15 February 2003 TOM CLARKE Hand-pump wells tap into natural accumulations of arsenic.

W. Tassaneeyakul5 Thalidomide tragedy

W. Tassaneeyakul6 Fixed drug eruption Drug rash SJS

W. Tassaneeyakul7 A villager uses a dip net to remove dead fish from the Bang Pakong river. The fish, bred in floating baskets, died from pollution in the river. _ TAWATCHAI KEMGUMNERD Friday 15 November 2002 BangkokPost

W. Tassaneeyakul8 ตุลาคม 2547 คนงานโรงสีขอนแก่น เสียชีวิตขณะลงไปทำ ความสะอาดท่อส่งข้าว

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10 TOXICOLOGY : The study of the adverse effects of a toxicant on living organisms. Toxicology related closely to Pharmacology, Biochemistry, Molecular biology, Chemistry, Epidemiology, Pathology, Genetics, Public Health, Medicine, etc.

W. Tassaneeyakul11 Hazard – physical situation that can damage: –people –plant –Environment Risk – likelihood of hazard occurring Risk = hazard * probability * consequence

W. Tassaneeyakul12 Source: Muckter, 2003

W. Tassaneeyakul13 1.Toxicant/ Toxin/ Poison/ Hazard  any agent capable of producing a deleterious response in a biological system 2.Adverse/Toxic effects  any unwanted change from an organism’s normal state  dependent upon the concentration of active compound at the target site (receptor)for a sufficient time. 3.Living organism  cellular target sites/ storage depots and enzymes

W. Tassaneeyakul14 COMMON TOXICOLOGY QUESTIONS 1.What is a poison? 2.Where dose it come from? (exposure Q) 3.How does it get into living organism? (exposure Q) 4.What does it do to living organism? (mechanism Q) 5.How can we treat/prevent this toxicity? (clinical Q)

W. Tassaneeyakul15 Routes of Entry: Oral=Ingestion by mouth Dermal=Skin exposure Inhalation=Absorbed by lungs Ocular= Eye exposure

W. Tassaneeyakul16 Why human have to concern with other species toxicology and/or environmental health?

W. Tassaneeyakul17 Classification of Toxic Agents –Target organ/site (e.g., liver, kidney, blood, lung, nerves) –Use (e.g., pesticide, solvent, food additive) –Effects (e.g., cancer, mutation, liver injury) –Labeling requirements (e.g., explosive, flammable, oxidizer) –Poisoning potential (e.g., very or slightly toxic)

W. Tassaneeyakul18 “ Allein die Dosis macht, da ß ein Ding kein Gift ist. ” ( “ Dose determines toxicity ” ) Dose-Response Relationship

W. Tassaneeyakul19 All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy. Paracelsus ( ) THE DOSE MAKES THE POISON

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W. Tassaneeyakul21 Change from normal state could be on the molecular, cellular, organ, or organism level--the symptoms Graded vs. Quantal degrees of the same damage vs. all or none What is a Response?

W. Tassaneeyakul22 Dose-response EFFECT linear, no threshold non-linear, threshold Dose

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W. Tassaneeyakul26 LD 50 Comparison

W. Tassaneeyakul27 Toxicity rating or class Probable lethal oral dose for human Dosage for average adult 1. Practically nontoxic > 15 g/kg more than 1 quart (>0.94 L) 2. Slightly toxic 5-15 g/kgbetween pint and quart ( L) 3. Moderately toxic g/kgbetween ounce and pint (28 mL-0.47L) 4. Very toxic mg/kgbetween teaspoon and ounce (5-28 mL) 5. Extremely toxic 5-50 mg/kgbetween 7 drops and teaspoon 6. Supertoxic < 5 mg/kga taste (less than 7 drops)

W. Tassaneeyakul28 THE DOSE-RESPONSE RELATIONSHIP The dose-response relationship (from C.D. Klaassen, Casarett and Doull ’ s Toxicology, 5th ed., New York: McGraw-Hill, 1996).

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W. Tassaneeyakul31 Acute vs. Chronic Allergic (hypersensitivity) Idiosyncratic (e.g. G6PD def.) Local vs. Systemic Reversible vs. Irreversible Type of Toxic Response

W. Tassaneeyakul32 Acute Toxicity: (short-term exposure)

W. Tassaneeyakul33 Chronic Toxicity: (repeated exposures)

W. Tassaneeyakul34  Carcinogens: –Cause cancer  Mutagens: –Cause mutations in an organism’s genetic material  Teratogens: –cause birth defects in offspring following exposure of a pregnant female Examples: Chronic Effects

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W. Tassaneeyakul36 Drug rash

W. Tassaneeyakul37 Dose-response relationship: LEAD decreased erythrocyte delta-ALAD activity increased zinc protoporphyrin anemia CNS effects decreased peripheral nerve conductivity Nervous paralysis, lead colics Adapted from Elinder C-G et al., Biologisk monitoring av metaller hos människa. Arbetsmiljöfonden, Uppsala, 1991

W. Tassaneeyakul38 Additive : 2+2 = 4 Synergism : 2+3 = 10 Potentiation :0+3= 5 Antagonism :2+(-2)= 0 Chemical antagonism Dispositional antagonism Functional antagonism Pharmacological antagonism Toxicity Interactions

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W. Tassaneeyakul40 Synergist / Synergism: Synergism is increased activity (toxicity) resulting from the effect of one chemical on another. LD 50 DDT =250 mg/kg LD 50 synergist=1,000 mg/kg LD 50 DDT + synergist=50 mg/kg

W. Tassaneeyakul41 Source: van den Brandt et al. 2002

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W. Tassaneeyakul45 Source: “A Primer on Toxics”

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W. Tassaneeyakul47 Conclusion  What is toxicology ?  Toxicity, poison, hazard, risk ?  Why dose-response study is so important in toxicology?  How can we classify type of toxicity ?  Why people response differently to toxicant ?

W. Tassaneeyakul48 สรรพสิ่งทั่วถ้วนล้วนมีพิษพึงพินิจตรองไตร่ให้ถ้วนถี่ คุณ ประโยชน์ อีก โทษ ไซร้ล้วนมากมี ต่างกันที่ ขนาด ใช้ให้สังวรณ์ วงศ์วิวัฒน์ ทัศนียกุล THE DOSE MAKES THE POISON