Principles of Toxicology : The Study of Poisons

Wongwiwat Tassaneeyakul Department of Toxicology Khon Kaen University [email protected]

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To know scope and definition of toxicology,

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Describe how toxicologist work and manage toxicants,

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Understand dose-response relationship and interactions

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August 21 st , 1986, 9:30 pm

>1700 people and 3000 dead cow!!!

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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.

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Thalidomide tragedy

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Fixed drug eruption Drug rash

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SJS

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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

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ตุลาคม 2547 คนงานโรงสีขอนแก่น เสียชีวิตขณะลงไปท า ความสะอาดท่อส่งข้าว

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TOXICOLOGY

adverse effects : The study of the of a toxicant on living organisms .

Toxicology related closely to

Pharmacology , Biochemistry, Molecular biology , Chemistry , Epidemiology, Pathology , Genetics , Public Health, Medicine , etc.

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Hazard – physical situation that can damage:

– –

people plant

–

Environment Risk – likelihood of hazard occurring Risk = hazard * probability * consequence

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Source: Muckter, 2003

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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. Tassaneeyakul 13

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)

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Routes of Entry:

Oral Dermal Inhalation Ocular = = = Ingestion by mouth Skin exposure Absorbed by lungs = Eye exposure W. Tassaneeyakul 15

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

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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. Tassaneeyakul 17

Dose-Response Relationship

“ Allein die Dosis macht, da ß ein Ding kein Gift ist.

”

( “ Dose determines toxicity ” )

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

Paracelsus (1493- 1541) W. Tassaneeyakul 19

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What is a Response?

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

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Dose-response

EFFECT

linear, no threshold non-linear, threshold

Dose

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LD

50

Comparison

Chemical Ethyl Alcohol Sodium Chloride Ferrous Sulfate Morphine Sulfate Strychnine Sulfate Nicotine Black Widow Curare Rattle Snake Dioxin (TCDD) Botulinum toxin LD 50 (mg/kg) 10,000 4,000 1,500 900 150 1 0.55 0.50 0.24 0.001 0.0001 W. Tassaneeyakul 26

Toxicity rating or class 1. Practically nontoxic 2. Slightly toxic 3. Moderately toxic 4. Very toxic 5. Extremely toxic 6. Supertoxic Probable lethal oral dose for human > 15 g/kg Dosage for average adult more than 1 quart (>0.94 L) 5-15 g/kg 0.5-5 g/kg 50-500 mg/kg 5-50 mg/kg between pint and quart (0.47 0.94L) between ounce and pint (28 mL-0.47L) between teaspoon and ounce (5-28 mL) between 7 drops and teaspoon < 5 mg/kg a taste (less than 7 drops)

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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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Type of Toxic Response

Acute vs. Chronic Allergic (hypersensitivity) Idiosyncratic (e.g. G6PD def.) Local vs. Systemic Reversible vs. Irreversible

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Acute Toxicity:

(short-term exposure) Threshold Concentration

SYMPTOMS TIME: Minut es or Hours

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Chronic Toxicity:

x (repeated exposures)

Threshold concent rat ion SYMPTOMS

x x x x x x x

TIME: Weeks, mont hs, years

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Examples: Chronic Effects

 Carcinogens: –

Cause cancer

 Mutagens: –

Cause mutations in an organism’s genetic material

 Teratogens: –

cause birth defects in offspring following exposure of a pregnant female

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Drug rash

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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. Tassaneeyakul 37

Toxicity Interactions

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

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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 =

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Source: van den Brandt et al. 2002

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Source: “A Primer on Toxics”

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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. Tassaneeyakul 47

THE DOSE MAKES THE POISON สรรพสิ่งท ั่วถ้วนล้วนมีพิษ พึงพินิจตรองไตร่ให้ถ้วนถี่ คุณ ประโยชน์ อีก โทษ ไซร้ล้วนมากมี ต่างก ันที่ ขนาด ใช้ให้ส ังวรณ์

วงศ์วิวัฒน์ ทัศนียกุล W. Tassaneeyakul 48