Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Ecotoxicology • Ecotoxicological study is a multi-step process, involving: – The entry, distribution and fate of pollutants within the environment; – The entry and fate of pollutants in living (biota) organisms within an ecosystem; and – The harmful effects of the chemical pollutants on the constituents (biotic & abiotic) of ecosystems (which include man). Beyond our toxin trail Is the grave deeper than we thought? Transport and fate Toxin emitted Ecosystem effects Community effects Metabolized and/or stored Ingested Contacts human Population effects Reaches an organ Physiological chain of events Toxicology Ecotoxicology • Host defense mechanisms • Individual susceptibility states • Single effects • Cumulative exposure • Bioaccumulation • Bioconcentration (in water) • Biomagnification • Never single effects • Movement between media (air, water) Ecological bases of Ecotoxicology • The basis for determining the effects of contaminants on ecosystem is at organism level • At organism level, response can be: – Acute toxicity causing mortality – Chronically accumulating damage ultimately causing death – Sublethal impairment of various aspects of physiology and morphology – Sublethal behavioral effects – Measurable biochemical changes •At population level, response can be: –Size and dynamics (based on birth rates, death rates, gains, from immigration and losses from emigration) –Cause a reduction or an increase in the natural flowchart of numbers, in the biomass, sex ratio, etc. •At community level, response can be: –species diversity –predator prey relationship, etc •Change in ecosystem –nutrient cycling rates, patterns of nutrient flow, –physical-chemical conditions etc. Assessment of Structural Changes changes in species / population structure - appearance/disappearance of an indicator species - number of individuals of a species - biomass of a species - presence or absence of a species Biomass-a quantitative estimate of the total mass of living plant or animal materials changes in community/ecosystem structure - biomass abundance biotic indices (e.g. trophic types) species richness / diversity dominance food chain length/complexity Chemicals of ecotoxicological interest • They are toxic and in many cases their metabolites are also harmful e.g. DDT & DDE (metabolite of DDT) • They are very stable both chemically and environmentally • Their stability has lead to their persistence and ubiquitous nature in the environment • Almost all chemicals of ecotoxicologigal interest are bioavailable and in most cases undergo bioaccumluation and biomagnification (food chain) Bioavailabiltiy The fraction of a chemical that is in an available form to an organism e.g. fish: food, absorption from water Bioconcentration - where the chemical concentration in an organism exceeds the concentration in the surrounding media (i.e. aquatic environment) as a result of exposure through the respiratory surfaces (i.e. gills/dermal surfaces) - not food! Bioconcentration Factor = conc. in organism conc. in ambient medium (usually water) Bioaccumulation - where the chemical concentration in an organism achieves a level that exceeds that in the water/media as a result of chemical uptake through all routes of exposure. Bioaccumulation factor = Conc. in organism Conc. in food (or ingested water) •Bio-accumulation of Cd is higher than most metals as it is assimilated rapidly and excreted slowly •depends on the rate of excretion Biomagnification - where the chemical concentration in an organism achieves a level that exceeds that in the organism’s diet due to dietary absorption. i.e. higher trophic levels accumulate more chemical Biomagnification Factor = Conc. in predator Conc. in prey Factors that influence bioaccumulation -Environmental persistence -Lipophilicity -Biotransformation Toxic Effects • The biochemical (molecular in nature) or physiological (observed at organ and whole organism levels) changes which adversely affect individual organisms’ birth, growth or mortality rates. • Both biochemical and physiological changes could lead to behavioral (whole organism level) changes. • Toxicant binding: – Reversible vs. Irreversible binding • Irreversible binding (covalent) causes harmful effects. – Types of bonding: – Covalent > ionic > Hydrogen binding > Vanderwaals > hydrophilic • Biochemical responses: – Biochemical response could be protective or nonprotective (may or may not cause harmful effect). • Non-protective biochemical responses have carcinogenic, mutagenic, teratogenic and neurotoxic potentials. • Protective biochemical responses – Monoxygenase (OCs and PAHs) – Induction and binding to metalothionein (Cu, Cd, Zn and Hg) – Binding to blood plasma, bones and hair (Metals and xenobiotics) – Dissolving in fat (organics- e.g. OCs) – Mineralization ( e.g. MeHg to Hg 2+) – Demineralization (As to MeAs) Protective biochemical response • Heavy metals for example can be stored and detoxified by organisms either by binding to specific proteins e.g. metallothioneins (-SH proteins) • In some cases it is mineralized to inorganic form, which is less toxic: e.g. Hg bound to Se is a mineralized Hg (detoxified Hg: MeHg to Hg). On the other hand, the inorganic form, which is more toxic can be methylated to a less toxic form e.g. As. Protective biochemical response PHASE 1 REACTION. • Organic pollutants could also be metabolized and detoxified by Cytochrome P450 enzymes (Microsomal Monoxygenase; MMO). PHASE 2 REACTION • The metabolites undergo conjugation with endogenous molecules e.g. GSH. • For some chemicals the metabolites/conjugated form are more toxic than the parent compound and can lead to cancer formation. Non-protective response – Binding to DNA (DNA adduct) – DNA structural damage (strands break) induced by genotoxic compounds – Binding to SH-Protein (Protein adduct); enzymes and proteins – Neurotoxicity: prolongation of K and Na flow and inhibition of AChE activity in the brain Non-protective response – Mitochondrial Poison (lost of proton gradient) – Inhibition of vitamin K cycle (competition with vit K binding site) – Inhibition of Thyroxine (competition with thyrosine binding site) – Inhibition of ATPase (enzymes for transport of ions e.g. K, Na, Ca) Non-protective response • Environmental estrogens (eg DDT) and androgens (tributhyl Tin) • Endocrine disrupters (binding to endocrine receptors) • Photosystems of Plants (interruption of electron flow) • Plant growth regulation Physiological changes Non-protective biochemical responses lead to Physiological changes which could be observed at organ and organism levels • Organ level: – accumulation of Cd in kidney, which could cause cell death (cytotoxicity), resulting in dysfunction of the kidney – PAHs and Lung cancer • Organism level: – decrease in production (growth and reproduction) – changes in gene frequency – decrease in resources acquisition and uptake Behavioral Changes – Either or both physiological and biochemical effects could lead to behavioral effects at organism level– migration, – intraspecific attraction, – aggregation, – aggression, – predation, – vulnerability, – mating – caring for young ones and avoidance of predator. . Population Changes • Changes in population may come about as a result of direct changes in numbers of individual organism and gene frequency • By indirect means (decrease in population of predators due to toxic chemicals could lead to increase in numbers of its prey). Diclofenac residues as the cause of vulture population decline in Pakistan. Nature. 2004 Feb 12;427(6975):630-3. • Diclofenac causes kidney damage, increased serum uric acid concentrations, visceral gout, and death. • Changes in community structure – change in pyhtoplankton assemblage due to eutrophication – acid rain affecting microorganisms in the soil, aquatic life • Changes in Ecosystem level (earth as an ecosystem) – carbon dioxide increase – ozone depletion What is an Endocrine Disruptor ? “An exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development and/or behavior. “ Mechanisms of endocrine disrupting compounds 1) Binding and activating the estrogen receptor 2) Binding but not activating the estrogen receptor (therefore acting as an anti-estrogen) 3) Binding other receptors 4) Modifying the metabolism of natural hormones 5) Modifying the number of hormone receptors in a cell 6) Modifying the production of natural hormones Hormone regulation and feedback control Estrogen levels depend on Estrodiol sulfate Estrodiol serum-binding proteins -fetoprotein (AFP) Testosterone-estradiol binding globulin Xenoestrogens (ex. DES) 100-fold lower affinity than E2 to these binding protein Bioavailability increased Non-genomic mechanisms of ED action • Compounds of the azole type, such as ketoconazole and the fungicide fenarimol, inhibit CYP isoforms and consequently can also affect steroid synthesis while the nowbanned anti-fouling agent tributyltin and its metabolites, which have strong ED potential, are thought to act by the same mechanism, probably by inhibition of aromatase. Genomic mechanisms of ED action • bind to oestrogen receptors and so act as pseudoestrogens in vivo, giving feminizing effects • tamoxifen and diethylstilbestrol and industrial chemicals (e.g. octylphenol and bisphenol-A • fungicide vinclozolin binds competitively to the androgen receptor, blocking the cellular actions of testosterone on androgen-dependent tissue growth and behaviour patterns • chlordecone, inhibit binding to the oestrogen and progesterone receptors, whereas bisphenol-A can block ligand binding to the thyroid receptor Timing, duration, and amount of exposure. Organization vs. activation Timing, duration, and amount of exposure are each important determinants of the outcome. There are windows of vulnerability during fetal development in which small exposures to endocrine disruptors may have profound effects not observed in adults. Studies of the intrauterine position of mice during fetal development show that slight fluctuations of steroid hormone levels influence genital morphology, timing of puberty, sexual attractiveness, sexual behavior, aggressiveness, and activity level of offspring. Various Classes of EDCs Flame Retardants Fungicides Herbicides Insecticides Metals Pharmaceuticals Phenols Plasticizers Polyaromatic Hydrocarbons Soy Products Surfactants Polybrominated diphenyl ether Vinclozolin Atrazine Methoxychlor Tributyltin Ethynyl Estradiol Bisphenol A Phthalates PCBs, dioxins Genistein Alkylphenol Ethoxylates PBDEs(多溴二苯基醚) • Polybrominated diphenyl ethers (PBDEs) are a class of recalcitrant and bioaccumulative halogenated compounds that have emerged as a major environmental pollutant. PBDEs are used as a flame-retardant and are found in consumer goods such as electrical equipment, construction materials, coatings, textiles and polyurethane foam (furniture padding). Bioavailability of PBDEs Found in animals Increase in fish Increase in whales Sewage sludge PCBs Found in Lake Washington Fish (PBDEs next?) Found in human (breast milk) PBDEs Breast Milk - Sweden (Norén and Mieronyté, 1998) Health Effects of PBDEs Similar to PCBs (Polychlorinated biphenyls) Persistent Bioaccumulative Toxicant No human data Animals studies indicate Changes in thyroid hormone levels Neurobehavioral toxicity Development effects- alters Behavior Impairs memory and learning Delays sexual development Vinclozolin • Vinclozolin is a fungicide that has been shown to cause Leydig cell tumors and atrophy of the accessory sex glands in adult rodents. In addition, exposure of rats during pregnancy causes a pattern of malformations in the male urogenital tract . • Androgen receptor antagonist Atrazine • A chlorotriazine herbicide, is used to control annual grasses and broadleaf weeds. • Suppression of the luteinizing hormone surge during the estrus cycle by atrazine leads to the maintenance of elevated blood levels of 17betaestradiol (E2) and prolactin. • The mechanism for tumor development may include one or more of the following: the induction of aromatase (CYP19) and/or other P450 oxygenases, an antagonist action at the estrogen feedback receptor in the hypothalamus, an agonist action at the mammary gland estrogen receptor or an effect on adrenergic neurons in the hypothalamic-pituitary pathway. 雙酚A Bisphenol-A BPA is used in the manufacture of polycarbonate plastics and epoxy resins from which food and beverage containers and dental materials are made. Perinatal exposure to environmentally relevant BPA doses results in morphological and functional alterations of the male and female genital tract and mammary glands that may predispose the tissue to earlier onset of disease, reduced fertility and mammary and prostate cancer. 聚氯乙烯(PVC)製的嬰兒固齒器、玩具 讓長牙的嬰兒咬玩的固齒器、洗澡玩的軟性玩具、價格不貴的流 行卡通玩具常常是PVC製品,在使用中可能釋出鄰苯二甲酸 (phthalates)這類有致癌性的環境荷爾蒙。 【安全替代品】仔細查看成分標示,凡是嬰幼兒可能放到口中把 玩的玩具一定選購PE(聚乙烯)製品。 苯乙烯 alkylphenol(烷基酚) 攤販、自助餐店、速食店的熱飲杯(裝湯、茶、咖啡)、泡麵的 碗麵及杯麵絕大多數都使用聚苯乙烯(polystyren)的塑膠容器, 簡稱為PS,被國人稱為保麗龍。其原料單体叫苯乙烯,是已知致 癌物,且製造過程所添加的塑化劑alkylphenol(烷基酚)也是 會干擾內分泌的環境荷爾蒙,二者在使用過程很容易溶出到食物 中。 化妝品中的環境荷爾蒙 多數的化妝品、卸妝用清潔用品含有幾類的環境 荷爾蒙: •壬基苯酚乙烯(一種非離子界面活性劑) •鄰苯二甲酸(phthalates) •烷基酚(alkylphenol) Phthalates鄰苯二甲酸酯 •廣泛存在於化粧品、兒童玩具、食品包裝中 。 •香水中可當作溶煤或香料固著劑使用(已禁用)。 •常用於塑膠類製品的塑化劑,可能遇熱溶出。 PVC或PVDC保鮮膜;PVC塑膠手套。 •male infertility •Interfere with cholesterol uptake and androgen biosynthesis Tributyltin (TBT) 三丁基錫是一種有機錫化合物,常被 添加於船舶油漆中,以防止貝類及藻 類附著於船身,由於具有殺菌效果, 所以也可以作為殺菌劑使用 受到三丁基錫或三苯基錫污染的雌岩螺,因生殖孔阻塞受 精卵無法排出,堆積在生殖管道內變紅變黑形成壞死組織, 此時長出陰莖的雄化作用也同時被引發 TBT Yucheng (油症) of Taiwan, 1979 • ~2000 people exposed to PCBcontaminated rice oil • with chloracne, fatigue, skin and nail pigmentation, polyneuropathy, and abnormal liver function • Long-term follow-up study was established for 1st and 2nd generation (prenatal exposed) Likely Kanechlor 500 (a Japanese PCB mixture) Semen Analysis 40 Yucheng men (37-50 yr old) compared with 28 controls • Volume and count: no difference • Oligospermia: 23% vs. 4% • Morphology: 28% vs. 23% abnormal (~18% increase) • Motile sperm: no difference • Speed by CASA: no difference • Chinese hamster oocyte penetration after one re-thaw cycle: 16% vs. 32% (50% drop) (Hsu et al., JAMA 2003) Children Prenatally Exposed • More stillbirth (Yu et al., 2000) • Called Yucheng children • Born with darker skin, nail pigmentation and deformity, and developmental delay (Rogan et al., 1988) • Reduced neurocognitive functioning up to ages of 12 years (Chen et al., 1992) • Behavioral problems (Lai et al., 2002) Penile length (cm)* in Yucheng and Control Boys by Age 9 8 Yucheng Controls 7 6 5 4 3 2 1 0 6 to 7 8 to 9 10 to 11 12 to 13 14 to 15 *Measured by “Blinded” physicians Hormones in prenatal PCB/PCDF-exposed boys and unexposed controls after puberty Sex Hormones Control Yucheng Testosterone (TT, ng/mL) 4.2 ± 2.2 √(TT/E2) 0.5 ± 0.2 > 3.0 ± 2.4 < 48.6 ± 53.9 > 0.3 ± 0.2 Follicle-stimulating hormone (FSH, mIU/mL) √(TT/FSH) 3.4 ± 0.8 < 4.6 ± 2.2 1.1 ± 0.3 0.8 ± 0.5 √(E2/FSH) 2.4 ± 0.8 > < Estradiol (E2, pg/mL) 21.3 ± 13.2 3.1 ± 1.4 No difference: luteinizing hormone prolactin (Hsu et al., JTEH 2005) (一)殺蟲劑或其代謝中間產物:計有26種, (二)殺菌劑:計有9種(佔13%)。 (三)除草劑:亦有9種(佔13%) (四)塑膠之塑化劑:亦有9種,(佔13%)。禁用鄰苯二甲酸鹽 作為玩具塑膠之塑化劑。 (五)醫藥、化工原料合成之中間產品:計有6種。 (六)有機氯化物之污染副產品或菸煙中之芳香族烴計有3種, 其中以戴奧辛夫喃廣布於空氣、土壤、底泥、甚至於食品、乳製 品中最為令人憂心。 (七)熱媒及防火材料:有2種,其中多氯聯苯,惡名昭彰,雖 已禁用多年,但在環境介質中,仍時常檢出。 (八)界面活性劑之代謝分解中間產物:非離子界面活性劑廣用 於各種民生日用清潔劑、乳化劑中 (九)有機錫:計有2種,作為魚網之防腐劑及船上抗腐蝕油漆。 (十)重金屬:計鉛、鎘、汞三種,亦列為內分泌干擾之疑似物 質 EDSTAC Tier 1 Assays Concerned with detecting • • • • • • • Receptor binding assays (ER and AhR) Uterotrophic Hershberger Pubertal female Steroidogenesis Frog metamorphosis Fish reproductive screen EDSTAC Tier 2 dose-response relationship • Mammal development and reproduction • Bird development and reproduction • Mysid shrimp life cycle • Fish reproduction and development • Amphibian development and reproduction Species-dependent sex determination Mammal XY/XX synthesis of testosterone/functional androgen receptors estrogen receptor in the brain Birds WZ/WW The ability to synthesize and recognize 17-estradiol is necessary for female CNS and gonadal sexual development to occur Reptile temperature-dependent sex determination (aromatase related) Temperature-dependent sex determination thermosensitive period (TSP) Temperature determines their sex. A nest temperature of 73.5 degrees would develop males. If it heats up to 83.5, hormones would trigger changes causing the embryonic cells to differentiate as females.