新编THECARCINOGENICITYOFDIETHYLNITROSAMINE二乙基亚硝胺的致癌性课件

1、新编THECARCINOGENICITYOFDIETHYLNITROSAMINE二乙基亚硝胺的致癌性新编THECARCINOGENICITYOFDIETHYLN“Sola Dosis Facit Venenum” Only Dose Determines The PoisonParacelsus (1493-1541) argued that the toxicity of a chemical is determined only by the dose, i.e. by the amount of exposure to the substance. But is this really

2、the case?In chemical carcinogenesis, the carcinogenic dose decreases with the exposure levelThe dose of neonicotinoid insecticides that kills arthropods decreases with the exposure level“Sola Dosis Facit Venenum” OnChemical Carcinogenicity is a Process Measured in Units of TimeChemical Carcinogenici

3、ty is a Liver Carcinogenesis with Diethylnitrosamine in Rats: Latent Period Inversely Related to Exposure LevelLiver Carcinogenesis with DietLiver Carcinogenesis with Diethylnitrosamine in Rats: Carcinogenic Dose Proportional to Exposure LevelLiver Carcinogenesis with DietLiver Carcinogenesis with D

4、iethylnitrosamine in Rats: Latent Period Inversely Related to Exposure Level Carcinogenic Dose Proportional to Exposure LevelLiver Carcinogenesis with DietDoseResponse Characteristics are Determined by the Nature of Receptor Binding and the Effect of Receptor BindingDoseResponse Characteristics Chem

5、ical Carcinogenesis: Irreversible Receptor Binding and an Irreversible EffectIrreversible Receptor Binding:Carcinogens form strong covalent bonds with DNA that lead to mutation and inactivation of tumor-suppressor genes Irreversible Effect:Inactivated tumor-suppressor genes fully autonomously initia

6、te a cascade of further mutations accelerating the carcinogenic process Chemical Carcinogenesis: IrreChemical Carcinogenesis: Irreversible Receptor Binding and an Irreversible EffectIrreversible Receptor Binding:Covalent binding to DNAIrreversible Effect Inactivation of tumor-suppressor genesThe Eff

7、ect is Reinforced by Exposure TimeInactivated tumor-suppressor genes accelerate carcinogenesisReceptor binding CR will be proportional to the integral of compound concentration C (at the site of action) over time t:CR C dtEffect E will be proportional to the integral of receptor binding CR over time

8、 t: E CR dtEffect E will be proportional to the double integral of compound concentration C (at the site of action) over time t:E C dtChemical Carcinogenesis: IrreThe Effect of a Carcinogen is Reinforced by Exposure Time:Receptor Binding & Effect of Receptor Binding are IrreversibleThe Effect of a C

9、arcinogen is No Safe Level of Exposure Risk Assessment of Chemical CarcinogensIf “one hit” could cause a mutation and eventually result in cancer then any exposure level could be associated with a finite cancer probabilityUnder such circumstances, a mathematical model would be required to determine

10、a “virtually” safe dose, a dose associated with an insignificantly small cancer risk No Safe Level of Exposure RThe Toxicity of Neonicotinoid Insecticides to Arthropods is Also Reinforced by Exposure TimeThe Toxicity of Neonicotinoid The Toxicity of the Neonicotinoid Insecticides Imidacloprid and Th

11、iacloprid to ArthropodsEffect (Time to50% mortality)Versus Imidacloprid Concentration (Cypridopsis and Daphnia) orThiacloprid Concentration(other species). Concentrations for Sympetrumand Simulium species are in g/L;for other species in mg/L. The Toxicity of the NeonicotinLethal Effect of Imidaclopr

12、id on Cypridopsis vidua Latent Period Inversely Related to Exposure LevelLethal Effect of Imidacloprid Lethal Effect of Imidacloprid on Cypridopsis viduaLethal Dose is Proportional to Exposure LevelLethal Effect of Imidacloprid Irreversible Receptor Binding of ImidaclopridImidacloprid acts on severa

13、l types of post-synaptic nicotinic acetylcholine receptors in the nervous system.In insects, these receptors are located only within the central nervous system. Following binding to the nicotinic receptor, nerve impulses are spontaneously discharged at first, followed by failure of the neuron to pro

14、pagate any signal. Sustained activation of the receptor results from the inability of acetylcholinesterases to break down the pesticide.This binding process is irreversibleNicotinic Acetylcholine Receptors (nAChRs)Irreversible Receptor Binding Irreversible Effects of Imidacloprid on Honey Bees: Abno

15、rmal Foraging BehaviorUnder normal circumstances of flying between the beehive and the feeding site, the time interval between two successive visits to the same feeding site was consistently within 300 s (T 300 s).Honey bees that showed normal foraging behavior and regularly visited the feeding site

16、 with T 300 s) when the concentration was beyond 50 g/liter Ratio of behavioral abnormality (T 300 s)Irreversible Effects of ImidacImidacloprid is Persistent in Soil and Prone to LeachingImidacloprid has the potential to leach to ground water. In addition, high solubility and mobility are concerns f

17、or transport to surface water by dissolved runoff.Imidacloprids ability to move in soil has been demonstrated by a variety of studiesPersistence of imidacloprid: The shortest half-life (the amount of time required for half of an applied pesticide to break down or move away from the test site) was 10

18、7 days in turf-covered soil in Georgia.The longest half-life was in Minnesota where the imidacloprid concentration in cornfield soil did not decline for one year after treatment. Imidacloprid is Persistent in Surface Water Pollution with Imidacloprid in HollandMTR = maximumtolerable risk limitSurfac

19、e Water Pollution with IMassive Surface Water Pollution with Imidacloprid in Western Parts of the Netherlands with Intensive AgricultureMassive Surface Water PollutioEffect of Imidacloprid Pollution of Dutch Surface Water on Non-Target Diptera (Flies and Midges) AbundanceEffect of Imidacloprid Pollu

20、tiDay Butterflies are Rapidly Declining in the NetherlandsDay Butterflies are Rapidly DThe Decline to Extinction of Corn Bunting (blue) and Ortolan Bunting (green) in Less Than 20 YearsThe Decline to Extinction of CThe Neonicotinoid Insecticides: ConclusionsNeonicotinoids bind irreversibly to critic

21、al receptors in the central nervous system of insects and cause irreversibe effects.The damage is cumulative, and with every exposure more receptors are blocked. In fact, there may not be a safe level of exposure. Neonicotinoids account for worker bees neglecting to provide food for eggs and larvae,

22、 and for a breakdown of the bees navigational abilities. Bees, the number one insect pollinator on the planet, are dying at an alarming rate. Neonicotinoids are prone to leach from soils and contaminate ground and surface water. Not only are they water soluble and mobile in soil, they are also quite

23、 persistent in soil and water. Imidacloprid pollutes Dutch surface water. Ground and surface water contamination with persistent insecticides that cause irreversible damage to non-target insects is an environmental disaster in the making. The imidacloprid pollution of surface water in Western Dutch

24、provinces with intensive agriculture has already been associated with insect decline and a dramatic decline of common grassland birds The Neonicotinoid InsecticideReferencesDruckrey, H., Kpfmller, K., 1949. Dosis und Wirkung. Beitrge zur theoretischen Pharmakologie. Editio Cantor GmbH, Freiburg im BreisgauDruckrey, H., Schildbach, A., Schmaehl, D., Preussmann, R., Iv