What is toxicology? toxicology … ………

1. ` • What is toxicology? • toxicology ………… • • Is the study of the harmful effects of chemicals and physical agents on living organisms • • Examines adverse effects ranging from acute to long-term • • Is used to assess the probability of hazards caused by adverse effects • • Is used to predict effects on individuals, populations and ecosystems

2. These adverse effects may occur in many forms, ranging from immediate death to subtle changes not realized until months or years later. They may occur at various levels within the body, such as an organ, a type of cell, or a specific biochemical.

3. Sources of toxic compounds • Synthetic organic compound • 1. Air, water, and food pollutants • Air-CO, oxides of nitrogen, oxides of sulfur, hydrocarbons and particulates • Water-agricultural chemicals including pesticides, herbicides, fugicides, nematocides, rodenticides, fertilizer • Halogenated hydrocarbons- chloroform, dichloroethane, tetrachloride • Clorinated aromatics-PCB, TCDD • Detergents-alkyl benzene sulfonates • Food contaminants-bacterial toxin, mycotoxin, plant alkaloids, animal toxins, pesticide residues, and residues of animal food additives (DES, antibiotics)

4. 2. Chemical additives in food As preservatives-antibacterial, antifungal, or antioxidant To change physical characteristics, taste, color, odor

5. . 3.Chemicals in work placeInorganics-metals and flurides, CO, etc.Organic compounds-aliphatic hydrocarbons (hexene) aromatic hydrocarbons (eg. benzene, toluene) halogenated hydrocarbons alcohols esters organometallics amino compounds 4. Drugs of abuseCNS depressants-ethanol,secobarbitalCNS stimulants-cocaine, methamphatamine, nicotine, caffeine Opioids-heroin, morphine Hallucinogens-PCP, LSD,THC

6. 5.Therapeutic drugs The danger to the individual depends on : the nature of the toxic response the dose necessary to produce the toxic response the relationship between the therapeutic dose and the toxic dose eg, anticancer drugs are carcinogens Diethylstilbestrol (DES) Thalidomide Chloroquinol-SMON-subacute myelo-optic neuropathy Methyldopa, chloropromazine, methotrexate In general, toxic side effects are not common and may occur only in susceptible individuals or populations.

7. 6. Pesticides 7. Solvents 8. Polycyclic aromatic hydrocarbons (PAH)多環芳香 Incomplete combustion of organic materials, in smoke from wood, coal, oil, tobacco, in tar and broiled foods Carcinogens 9. Cosmetics Allergic reactions and contact dermatitis Bromate, cold-wave neutralizer Thioglycolates and tioglycerol-cold-wave lotion and depilatories Sodium hydroxide-hair straighteners

8. Naturally occurring toxins 1. Mycotoxins 2. Microbial toxins 3. Plant toxins 4. Animal toxins Environmental movement of toxicants Bioaccumulation-lipid soluble toxicants Bioamplification DDT (ppm) amplification Water 0.000003 Floating 0.04 13000 Small fish 0.5 170000 Big fish 2 667000 Bird 25 8330000

9. An interdisciplinary field………… Descriptive Toxicology: The science of toxicity testing to provide information for safety evaluation and regulatory requirements. Mechanistic Toxicology: Identification and understanding cellular, biochemical and molecular basis by which chemicals exert toxic effects. Regulatory Toxicology: Determination of risk based on descriptive and mechanistic studies, and developing safety regulations.

10. Clinical Toxicology: Diagnosis and treatment of poisoning; evaluation of methods of detection and intoxication, mechanism of action in humans (human tox, pharmaceutical tox) and animals (veterinary tox). Integrates toxicology, clinical medicine, clinical biochemistry/pharmacology. Occupational Toxicology: Combines occupational medicine and occupational hygeine. Environmental Toxicology: Integrates toxicology with sub-disciplines such as ecology, wildlife and aquatic biology, environmental chemistry.

11. The scope of toxicity • Mechanisms of Toxic Action • 1. Biochemical toxicology • 2. Behavioral toxicology-behavior is the final integrated expression of nervous function • 3. Nutritional toxicology-the effects of diet • 4. Carcinogenesis-cell growth • 5. Teratogenesis-developmental process • 6. Mutagenesis-genetic material • 7. Organ toxicity-organ function

12. B. Measurement of toxicants and toxicity 1. Analytic toxicology 2. Toxicity testing 3. Toxicologic pathology 4. Structure-activity study 5. Biomathematics and statistics 6. Epidemiology C. Applied Toxicology 1. Clinical toxicology 2. Veterinary toxicology 3. Forensic toxicology 4. Environmental toxicology 5. Industrial toxicology

13. D. Chemical use classes • 1. Agricuture chemicals • 2. Clinical drugs • 3. Drugs of abuse • 4. Food additives • 5. Industrial chemicals • 6. Naturally occurring substances- phytotoxin, mycotoxin, inorganic minerals • 7. Combustion products • "Toxin"=refers to toxic substances that are produced naturally • "Toxicant"=substance that is produced by anthropogenic origin

14. E. Regulatory Toxicology 1. Legal aspects-formulation of laws and regulations and their enforcement 2. Risk assessment- the definition of risks, potential risks and risk- benefit equations F. Development of antidotes

16. Toxic Effects • Immediate effect and delayed effect • CO, cyanide • 2. Local effect and systemic effect • target organ • 3. Reversible and irreversible effect • 4. Anaphylactic reaction (allergic reaction) • 5. Idiosyncratic reaction 特異體質反應

17. DoseDose by definition is the amount of a substance administered at one time. However, other parameters are needed to characterize the exposure to xenobiotics.  The most important are the number of doses, frequency, and total time period of the treatment.For example: 650 mg Tylenol as a single dose 500 mg Penicillin every 8 hours for 10 days 10 mg DDT per day for 90 days

18. A common dose measurement is mg/kg body weight. The commonly used time unit is one day and thus, the usual dosage unit is mg/kg/day. Environmental exposure units are expressed as the amount of a xenobiotic in a unit of the media. mg/liter (mg/l) for liquids mg/gram (mg/g) for solids mg/cubic meter (mg/m3) for airOther commonly used dose units for substances in media are parts per million (ppm), parts per billion (ppb) and parts per trillion (ppt).

20. Fractionatinga total dose usually decreases the probability that the total dose will cause toxicity.  The reason for this is that the body often can repair the effect of each subtoxic dose if sufficient time passes before receiving the next dose.  In such a case, the total dose, harmful if received all at once, is non-toxic when administered over a period of time.  For example, 30 mg of strychnine swallowed at one time could be fatal to an adult whereas 3 mg of strychnine swallowed each day for ten days would not be fatal.

21. vinyl chloride, high dose-hepatotoxicant long latent period at lower doses-carcinogen very low dose-no effect aspirin chronic use-deleterious effects on the gastric mucosa fatal dose 0.2-0.5 g/kg metals dietary essentials eg. Iron, copper, magnesium, cobalt, manganese, and zinc toxic at higher dose

24. 1493-1541-Paracelsusdetermined that specific chemicals were actually responsible for the toxicity of a plant or animal poison.  He also documented that the body's response to those chemicals depended on the dose received.  His studies revealed that small doses of a substance might be harmless or beneficial whereas larger doses could be toxic.  This is now known as the dose-response relationship, a major concept of toxicology.  Paracelsus is often quoted for his statement:  "All substances are poisons; there is none which is not a poison.  The right dose differentiates a poison and a remedy."

25. Dose ResponseThe dose-response relationship is a fundamental and essential concept in toxicology.  It correlates exposures and the spectrum of induced effects.  Generally, the higher the dose, the more severe the response.  The dose-response relationship is based on observed data from experimental animal, human clinical, or cell studies.

26. Knowledge of the dose-response relationship: establishes causality that the chemical has in fact induced the observed effects establishes the lowest dose where an induced effect occurs - the threshold effect determines the rate at which injury builds up - the slope for the dose response.

27. Dose Response Individual, or graded, dose-response relationship results from an alteration of a specific biochemical process Quantal dose-response relationship in a population-”all or none” determination of the LD50 LD (lethal dose)50-the dose required to kill 50% of a population of an organism under stated conditions

30. Normal equivalent deviations(NEDs) NED for 50% response is 0 NED for 84.1% response is 1 Probit (probability unit)=NED+5

32. Compounds may also be toxic under some circumstances, but not other, or, perhaps, toxic in combination with another compound but nontoxic alone. The measurement of toxicity is also complex. Toxicity may be acute or chronic, and may vary from one organ to another as well as with the age, sex, diet, physiological condition, or health status of the organism. Even the LD50 values vary markedly from one laboratory to another. LC50 ED50 TD50

37. Descriptive animal toxicity tests • Two main principle • The effects produced by a compound in laboratory animals, when properly qualified, are applicable to humans. • 2. The exposure of experimental animals to toxic agents in high dose is necessary and valid method of discovering possible hazards in human.

38. Descriptive animal toxicity tests • Acute Single dose with effects occurring for a short period of time (usually up to 96 hr) • Acute lethality (die in a 14-day period) • LD50 (Median Lethal Concentration) • Skin & eye irritation • sensitization • Subacute Multiple doses administered for up to 14 days

39. Subchronic Continuous dosing for up to 90 days NOAEL-no observed adverse effect level Chronic Continuous dosing for up to 6 months to 2 years carcinogenic potential • Acute effects do not predict chronic effects • Doses causing chronic effects may not cause acute or sub-acute effects • Chronic effects of a chemical exposure may manifest themselves as a common disease and go unnoticed

40. Course Objectives Understand……. • mechanisms by which chemicals cause cell injury and cell death • the mode of action of specific organic and inorganic chemicals • how to interpret results of in vitro tests for the evaluation of in vivo toxicity • How multiple chemical exposures and other stressors can alter toxicity

41. • What factors influence individual susceptibility • the importance of dose in determining adverse effects of chemicals • what factors influence the target organ dose of a chemical • mechanisms by which chemicals affect specific organ system functions

42. Homework: • Compare graded dose response vs. quantal dose response. • Define the following terms • toxin • toxicant • LD50 • ecotoxicology • bioactivation • detoxification • 3.What are the goals of acute, subacute, subchronic, chronic toxicity?