農(nóng)藥藥理學(xué)總論2015

1、農(nóng)藥藥理學(xué)Pesticide Pharmacology朱福興 天惠樓 206Tel: 13098844428zhufuxing@mail.hzau.edu.cn 2015-9,1,Pesticide toxicologyPesticide environmental toxicologyPesticide bioassayPesticide chemicalBi

2、o-pesticide (microbial and botanical pesticides)Pesticide synthesis and processingPesticide (residue) analysis,2,Pesticide,According to a new technical market research report, GLOBAL MARKETS FOR BIOPESTICIDES (CHM029D)

3、, from BCC Research (www.bccresearch.com), the global pesticide market was valued at $37.5 billion in 2011 and should reach $46.1 billion in 2012. Total market value is expected to reach $65.3 billion in 2017 after incre

4、asing at a five-year compound annual growth rate (CAGR) of 7.2%.,3,Pesticide Market,The market for pesticides can be broken down into two segments: synthetic pesticides and bio-pesticides.As a segment, synthetic pestici

5、des should total $44 billion in 2012 and $61.5 billion in 2017, a CAGR of 7%.Bio-pesticides are expected to total $2.1 billion in 2012, and surpass $3.7 billion in 2017, a CAGR of 12%.,4,Pesticide Market,GLOBAL MARKET S

6、HARE FOR SYNTHETIC AND BIOPESTICIDES BY REGION, 2012 AND 2017 (%),5,6,1. Basic Concepts,1.1 Pesticide:Under the USA Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) pesticide are defined as including:,7,1.1

7、 Pesticide,(1)any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest (insect, rodent, nematode, fungus, weed, other forms of terrestrial or aquatic plant or animal l

8、ife or viruses, bacteria, or other micro-organisms, which the Administrator declares to be a pest),,8,1.1 Pesticide,(2) any substance or mixture of substances intended for use as a plant regulator, defoliant or desicca

9、nt. (USA),9,1.1 Pesticide,Pesticides are intentionally designed to be toxic to plant, animal, or microbial pests—e.g., weeds, rodents, bacteria, fungi, and insects.,1.2 Pharmacology,藥理學(xué)(Pharmacology)：研究藥物的來源、性質(zhì)、化學(xué)、作用及

10、應(yīng)用的科學(xué)，包括藥物動力學(xué)，藥效學(xué)，藥物治療學(xué)和毒理學(xué)。Pharmacology: the science dealing with the preparation, use, and the effects of drugs. (Webster Encyclopedia ),10,1.2 Pharmacology,Pharmacology is the study of how drugs interact with livin

11、g organisms to produce a change in function. The field encompasses drug composition and properties, interactions, toxicology, therapy, and medical applications and antipathogenic capabilities.,11,1.3 Toxicology,Toxicolo

12、gy 毒理學(xué)：Toxicology is the scientific study of the harmful effects of chemicals on living organisms: humans, animals, microorganism and plants.,12,1.3 Toxicology,Toxicology is one of the oldest branches of pharmacology.

13、Toxicology is that branch of medical science that deals with the nature, properties, effects, and the detection of poisons.,13,1.3 Toxicology,Toxicology derived from Greek word, τοξιχον.The definition of Toxicology inc

14、ludes:(1) uptake, excretion, and metabolism of poisons. What the organism does with the substance is Toxicokinetics(毒物代謝動力學(xué)).,14,1.3 Toxicology,(2) the symptoms and how they develop (Toxicodynamics毒效動力學(xué), what the toxic

15、ant do to the organisms.)(3) Toxicology also includes the legislation enforced to protect the environment and human health, and the risk assessments necessary for this purpose.,15,1.3 Toxicology,Toxicology: Environme

16、ntal Toxicology Ecological Toxicology (Ecotoxicology) Chemical Toxicology Veterinary Toxicology Molecular Toxicology,16,1.3 Toxicology,The Swiss physician Paracelsus (帕拉塞爾蘇斯,1493-1541), the father of toxicology,

17、 believed that relationship between dose and response to be inseparable. His citations is found in the first chapter of almost all textbooks of toxicology or pharmacology.,17,1.3 Toxicology,“All substances are poisons;

18、there is none which is not a poison. The right dose differentiates a poison from a remedy”.,18,1.3 Toxicology,“Arndt-Schulz law” stated that “for every substance, small doses stimulate, moderate doses inhibit and large

19、doses kill” (and this findings could be generalized to all organisms and all toxic agents).,19,1.4 Pesticide Toxicology,農(nóng)藥毒理學(xué)（Pesticide Toxicology）：是研究農(nóng)藥的毒殺作用的一門科學(xué)，包括作用機(jī)理、環(huán)境及生物的生理狀態(tài)對毒殺作用的影響，以及農(nóng)藥對整個生態(tài)系統(tǒng)的影響。,20,1.4 Pest

20、icide Toxicology,Pesticide toxicology is the study of the adverse effects of pesticides on living organisms. Enzymes and receptors (i.e., proteins) are the primary, if not sole, targets of pesticides designed to control

21、insects, weeds, fungi, bacteria, etc. Proteins are also the major targets of pesticides causing adverse effects on nontarget species such as humans and wildlife.,21,1.4 Pesticide Toxicology,The biological effects of maj

22、or classes pesticides, including: toxicity to non-target organisms, persistence and fate in the environment, biotransformation, and ecological consequences, the mechanism of action on target species.,22,1.4 Pesticide To

23、xicology,Effects of chemicals on animals are determined by the chemical structure of the pesticide, its action mechanism, and the fate of the chemical within the animal.,23,1.4 Pesticide Toxicology,Species-Specific: Pe

24、sticide effects often vary with the species of animals studied.Individual-Specific: Individual animals within a species can exhibit dissimilar responses to the same pesticide. Toxic effects can vary with the size, sex,

25、age and general heath of the test animals.,24,1.4 Pesticide Toxicology,Pesticide toxicology include:(1) Elucidation of the mechanisms of action of pesticide (mode of action).(2) Biotransformation of pesticide(3) Meta

26、bolic fate in various organisms (Metabolism of Pesticides), penetration, excretion(4) Provide an understanding of differential toxicities.,25,1.4 Pesticide Toxicology,(5)Chemical composition of insecticides, fungicides

27、, herbicide, and their effects in plant and animal tissues.  (6)Pesticide environmental ecological toxicology. Toxicity to fauna and flora including domesticated animals and wildlife. Environmental transport and fa

28、te, adsorption, absorption, distribution and pharmacokinetics.,26,1.4 Pesticide Toxicology,(7) Toxicity to mammals. Acute and chronic toxicity in humans. Risk assessment, developmental and reproductive toxicology, carci

29、nogenicity, genotoxicity, immunotoxicity, neurotoxicology, irritant dermatitis syndrome, allergic contact dermatitis.,27,1.4 Pesticide Toxicology,Toxicity 毒性：主要是對高等動物和非靶標(biāo)生物而言；毒力：指對靶標(biāo)生物而言。,28,2.1 Classification of pes

30、ticides according to the target organism,29,2.2 Pesticide classification according to mode of action,Anticholinesterase (cholinesterase inhibitor)Chitin synthesis inhibitorEcdysone agonist Juvenile hormone analogues (

31、Insect growth regulators)GABA blocker (γ-amino butyric acid inhibitor),30,2.2 Pesticide classification according to mode of action,AnticoagulantGlutamine synthetase inhibitorSteroid demethylation (ergosterol麥角固醇bios

32、ynthesis) inhibitorProtoporphyrinogen oxidase inhibitor(原卟啉原氧化酶抑制劑)RNA-polymerase inhibitor,31,2.2 Pesticide classification according to mode of action,Thiol (硫醇) reactantProtein synthesis inhibitorPhotosynthetic e

33、lectron transport inhibitorMitochondrial respiration inhibitor,32,2.3 Classification according to the type of biomolecule,(1)Enzyme inhibitorsThe toxicant may react with an enzyme or a transport protein and inhibit i

34、ts normal function.,33,(1)Enzyme inhibitors,Enzymes may be inhibited by a compound that has a similar, but not identical structure as the true substrate; instead of being processed, it blocks the enzyme.,34,(1)Enzyme inh

35、ibitors,Typical toxicants of this kind are the carbamates and the organophosphorus insecticides that inhibit the enzyme acetyl cholinesterase. Some extremely ef?cient herbicides that inhibit enzymes important for amino a

36、cid synthesis in plants, e.g., glyphosate and glufosinate草銨膦 , are other good examples in this category.,35,(2) Disturbance of the chemical signal systems,Organisms use chemicals to transmit messages at all levels of org

37、anization, and there are a variety of substances that interfere with the normal functioning of these systems.,36,(2) Disturbance of the chemical signal systems,Toxicants, which disturb signal systems, are very often extr

38、emely potent, and often more selective than the other categories of poisons.,37,(2) Disturbance of the chemical signal systems,These toxicants may act by imitating the true signal substances, and thus transmit a signal t

39、oo strongly, too long lasting, or at a wrong time. Such poisons are called agonists. Agonist: nicotineAntagonist(拮抗劑): succinylcholin丁二酰膽堿,38,(2) Disturbance of the chemical signal systems,A typical agonist is nicotine

40、, which gives signals similar to acetylcholine in the nervous system, but is not eliminated by acetylcholinesterase after having given the signal. Other quite different agonists are the herbicide 2,4-D that mimic the pl

41、ant hormone auxin(植物生長素).,39,(2) Disturbance of the chemical signal systems,Some agonists act at intracellular signal systems. One of the strongest man-made toxicants, dioxin (二噁英), is a good example. It activates the so

42、-called Ah receptor (芳香烴受體) in vertebrates, inducing several enzymes such as CYP1A1.,40,dioxin (二噁英),Dioxins are environmental pollutants. They belong to the so-called “dirty dozen” - a group of dangerous chemicals known

43、 as persistent organic pollutants (POPs). Dioxins are of concern because of their highly toxic potential. Experiments have shown they affect a number of organs and systems.,41,dioxin (二噁英),Once dioxins enter the body, th

44、ey last a long time because of their chemical stability and their ability to be absorbed by fat tissue, where they are then stored in the body. Their half-life in the body is estimated to be 7 to 11 years. In the environ

45、ment, dioxins tend to accumulate in the food chain. The higher an animal is in the food chain, the higher the concentration of dioxins.,42,dioxin (二噁英),Dioxins are mainly by-products of industrial processes but can also

46、result from natural processes, such as volcanic eruptions and forest fires. Dioxins are unwanted by-products of a wide range of manufacturing processes including smelting, chlorine bleaching of paper pulp and the manufac

47、turing of some herbicides and pesticides.,43,dioxin (二噁英),More than 90% of human exposure is through food, mainly meat and dairy products, fish and shellfish. Many national authorities have programes in place to monitor

48、the food supply.Dioxins are highly toxic and can cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer.,44,dioxin (二噁英),Short-term exposure of humans to h

49、igh levels of dioxins may result in skin lesions, such as chloracne (氯痤瘡) and patchy darkening of the skin, and altered liver function. Long-term exposure is linked to impairment of the immune system, the developing nerv

50、ous system, the endocrine system and reproductive functions.Chronic exposure of animals to dioxins has resulted in several types of cancer.,45,dioxin (二噁英),Due to the omnipresence of dioxins, all people have background

51、exposure, which is not expected to affect human health. However, due to the highly toxic potential, efforts need to be undertaken to reduce current background exposure.Prevention or reduction of human exposure is best d

52、one via source-directed measures, i.e. strict control of industrial processes to reduce formation of dioxins.,46,dioxin (二噁英),In late 2008, Ireland recalled many tons of pork meat and pork products when up to 200 times t

53、he safe limit of dioxins were detected in samples of pork. This led to one of the largest food recalls related to a chemical contamination. Risk assessments performed by Ireland indicated no public health concern. The co

54、ntamination was also traced back to contaminated feed.,47,dioxin (二噁英),In 1999, high levels of dioxins were found in poultry and eggs from Belgium. Subsequently, dioxin-contaminated animal-based food (poultry, eggs, pork

55、), were detected in several other countries. The cause was traced to animal feed contaminated with illegally disposed PCB-based waste industrial oil.,48,(2) Disturbance of the chemical signal systems,An antagonist blocks

56、 the receptor site for the true signal substance. A typical antagonist is succinylcholin(琥珀酰膽堿), which blocks the contact between the nerve and the muscle ?bers by reacting with the acetylcholine receptor, preventing ace

57、tylcholine from transmitting the signal.,49,(2) Disturbance of the chemical signal systems,Signals given unintentionally by prey or a parasite host, which attract the preying or parasitizing animal, are important. A good

58、 example is CO2 released by humans, which attracts mosquitoes. The mosquito repellent blocks the receptors in the scent organ of mosquitoes.,50,(3) Toxicants that generate very reactive molecules that destroy cellular c

59、omponents,Most redox reactions involve exchange of two electrons. However, quite a few substances can be oxidized or reduced by one-electron transfer, and reactive intermediates can be formed. Oxygen is very often involv

60、ed in such reactions.,51,(3) Toxicants that generate very reactive molecules that destroy cellular components,The classical example of a free radical-producing poison is the herbicide paraquat, which steals an electron

61、from the electron transport chain in mitochondria or chloroplasts and delivers it to molecular oxygen.,52,(3) Toxicants that generate very reactive molecules that destroy cellular components,The superoxide anion (O2-) p

62、roduced may react with hydrogen superoxide (過氧化氫H2O2) in a reaction called the Fenton reaction, producing hydroxyl radicals(羥基自由基, OH).,53,(3) Toxicants that generate very reactive molecules that destroy cellular compon

63、ents,This radical is extremely aggressive, attacking the ?rst molecule it meets, no matter what it is. A chain reaction is started and many biomolecules can be destroyed by just one hydroxyl radical. Because one paraqua

64、t molecule can produce many superoxide anions, it is not dif?cult to understand that this substance is toxic.,54,(3) Toxicants that generate very reactive molecules that destroy cellular components,Cupic ion (Cu2++) can

65、 take up one electron to make the cuprous cation (Cu+) and give this electron to oxygen, producing the superoxide anion (O2-).Free radical producers are seldom selective poisons. They work as an avalanche that destroys

66、membranes, nucleic acids, and other cell structures.,55,(3) Toxicants that generate very reactive molecules that destroy cellular components,Fortunately, the organisms have a strong defense system developed during some

67、billion years of aerobic life.Catalase (CAT，過氧化氫酶)Peroxidase (POD, 過氧化物酶)Superoxide dismutase (SOD,超氧化物歧化酶),56,(4) Toxicants that dissolve in lipophilic membranes and disturb their physical structure,,57,(4) Toxicant

68、s that dissolve in lipophilic membranes and disturb their physical structure,Lipophilic substances with low reactivity may dissolve in the cell membranes and change their physical characteristics. Alcohols, petrol, arom