Transcript 劑量與毒性
Introduction to Toxicology • Toxicology (毒物學) can be defined as that branch of science that deals with poisons, and a poison can be defined as any substance that causes a harmful (有害的) effect when administered (施藥), either by accident or design, to a living organism. • Poison is a quantitative (量) concept (概念), almost any substance being harmful at some doses but, at the same time, being without harmful effect at some lower dose (劑量). Between these two limits there is a range of possible effects, from subtle (微微的) longterm chronic (慢性) toxicity to immediate lethality (致命性). • Vinyl chloride (氯乙烯) may be taken as an example. It is a potent hepatotoxicant (肝毒劑) at high doses, a carcinogen with a long latent (潛伏的) period at lower doses, and apparently without effect at very low doses. • Clinical drugs are even more poignant examples. Aspirin (acetylsalicylic acid，乙醯 水楊酸), for example, is a relatively safe drug at recommended doses and is taken by millions of people worldwide. At the same time, chronic use can cause deleterious effects on the gastric mucosa (胃粘膜), and it is fatal at a dose of about 0.2 to 0.5 g/kg. • The importance of dose is well illustrated by metals (金屬) that are essential in the diet but are toxic at higher doses. Thus iron (鐵), copper (銅), magnesium (鎂), cobalt (鈷), manganese (錳), and zinc (鋅) can be present in the diet at too low a level (deficiency), at an appropriate level (maintenance), or at too high a level (toxic). • Even medications often found at a pharmacy or grocery store shelves have a dose at which toxicity occurs. • For example, Vitamin C (as well as some of the other compounds in citrus fruit) will cause diarrhea (腹瀉), stomach upset (反胃), and even vomiting (嘔吐), if ingested in extremely large amounts. • While this might be toxicity, no one would suggest that vitamin C should never be used for therapeutic benefit. • All substances have what is termed an LD50 (半 數致死劑量). This is the dose that, when administered to a large group of animals (or humans), will cause lethality (death) in 50% of that group. • If the LD50 is less than the average therapeutic (治療的) dose, then toxicity occurs before therapeutic effects and the substance should be avoided (避免). • If the LD50 is much greater than the therapeutic dose, then the substance is very safe and can be administered to a patient in large amounts without fear of toxicity. Units used to measure chemicals in the environment • ppm: parts per million 1 cent in $ 10, 000 ppb: parts per billion 1 cent in $ 10, 000, 000 ppt: parts per trillion 1 cent in $ 10, 000, 000, 000 Important Relationship • For water at STP (standard temperature [0℃] and pressure [15psi]) • 1cc = 1ml = 1g • 1 liter of water = 1 kg • 1 mg / kg = 1 ppm • 1 mm3 / liter = 1 ppm • 1 mg / liter = 1 ppm Measures of Toxicity • Toxicity of chemicals is determined in the laboratory. • The normal procedure is to expose test animals by ingestion, application to the skin, by inhalation (呼吸), gavage (胃管), or some other method which introduces the test item into the body. • Toxicity is measured as clinical “endpoints ( 試驗終點指標)” which include: • Mortality (death) (死亡) • Teratogenecity (birth defects) (致畸性) • Carcinogenicity (cancer) (致癌性) • Mutagenecity (DNA damage) (致突變性) The Median Lethal Dosage (LD50 and LC50) • LD50 • The dose of a chemical which produces death in 50% of a population of test animals to which it is administered by a specified method. • Normally expressed as mg/kg (milligrams of substance per kilogram of animal body weight) • LC50 • The concentration of a chemical in air or water which produces death in 50% of an exposed population of test animals in a specified time frame. • Normally expressed as mg/kg (milligrams of substance per liter of air or water [or as ppm])# Routes of exposure (暴露途徑) • There are three primary routes by which organisms are exposed to certain material (solvents, pesticides, )： • Oral (口服) ：Taken in through the mouth and passes through gastrointestinal tract. • Dermal (皮膚)：Most common route of human exposure. • Inhalation (呼吸)：Breathed into the lungs through nose or mouth.# Duration of Exposure (持續暴露時間) • Three terms are commonly used to describe the duration of doses： • Acute (急毒性)：Application of a short-term [generally less than a day] dosing. • Chronic (慢性)：Repeated exposure to a chemical in doses regularly applied to organism for a time greater than half of its life-expectancy. • Subchronic (亞慢性)： • Toxic symptoms are expressed after repeated applications for a timeframe less than half the life expectancy of the organism – but more often than a single dose or multiple doses applied for only a short time. • The less you need to cause a toxic effect, the more toxic the substance is. Thus, an LD50 of 15 mg/kg is more toxic than is one of 250 mg/kg. • Organisms can’t differentiate between “natural” and “synthetic” chemicals. • “synthetic (合成)” does not mean toxic or poisonous. • “natural (天然)” does not mean safe or even low risk. • Chemicals must evaluated in their biological context of behavior in organisms. • Mode of action, not source, is the concern and informed the users of pesticides. • Most herbicides act on biological pathways (代謝途徑) not present in humans.# Insecticides (殺蟲劑) • • • • • TCDD (Dioxin) Parathion (巴拉松) Nicotine (尼古丁) Carbaryl (加保利) Malathion (馬拉松) 0.1 mg/kg 13.0 mg/kg 50.0 mg/kg 270.0 mg/kg 370.0 mg/kg Herbicides (除草劑) • • • • • • • Paraquat (巴拉刈) 2,4-D (二四地) 2,4-DP (N/A) Triclopyr (三氯比) Dicamba (N/A) Hexazinone (N/A) Glyphosate (嘉磷塞) 95 mg/kg 375 mg/kg 532 mg/kg 630 mg/kg 755 mg/kg 1,690 mg/kg 4,320 mg/kg Highly Toxic (劇毒) • • • • Botulinus toxin (肉毒) Dioxin (戴奧辛) Parathion Nicotine 0.00001 mg/kg 0.1 mg/kg 13.0 mg/kg 50.0 mg/kg Moderately Toxic (中等毒) • • • • • Paraquat Caffeine Carbaryl Marathion 2,4-D 95 mg/kg 200 mg/kg 270 mg/kg 370 mg/kg 375 mg/kg Are all substances toxic? • • • • All are toxic to some degree. Sugar has an LD50 of 30,000 mg/kg. Ethanol has an LD50 of 13,700 mg/kg. Even water has a recognized LD50 of slightly > 80,000 mg/kg. • All materials should be treated with care and proper respect!!!