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Organic substances poisoning – PCBs, dioxins, PAHs, cyanotoxins Lecture No. 6 Copyright © Prof. MVDr. Zdeňka Svobodová, DrSc., Mgr. Zuzana Široká, PhD.

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Presentation on theme: "Organic substances poisoning – PCBs, dioxins, PAHs, cyanotoxins Lecture No. 6 Copyright © Prof. MVDr. Zdeňka Svobodová, DrSc., Mgr. Zuzana Široká, PhD."— Presentation transcript:

1 Organic substances poisoning – PCBs, dioxins, PAHs, cyanotoxins Lecture No. 6 Copyright © Prof. MVDr. Zdeňka Svobodová, DrSc., Mgr. Zuzana Široká, PhD.

2 Polychlorinated dibenzodioxins – PCDD (dioxins), polychlorinated dibenzofurans – PCDF Global pollutants Not produced intentionally but by-products of anthropogenic activity, only minority created in environment (bacterial function etc.) One of the most toxic chemicals, belong to POPs PCDDs and PCDFs are polychlorinated planar molecules. We know 75 congeners of PCDDs and 135 PCDFs. Only 17 of them are of toxicological importance Most toxic is 2,3,7,8-TCDD, standard for comparison of effect: TEF = EC50 of TCDD/EC50 of assessed congener

3 Sources: - industrial processes involving chlorine, chemical and pesticide manufacturing and pulp and paper bleaching - originate in thermic reactions, where chlorine is involved (e.g. PCB combustion at temperatures bellow 1400°C, PVC combustion etc.) - originate in municipal waste water contaminated by chlorphenols – due to biosynthesis mediated by microbial peroxidases Fat-soluble, stable, mainly not volatile (the more chlorines, the less volatility), perzistent and acummulated Half life in soil is ten and more years, in sediments even more In mammals most of them are not metabolized, only slowly excreted by bile and faeces. They go to milk, eggs, embryos. If metabolized, then slowly epoxide is formed, then hydroxylation, conjugation and excretion by bile. Bentic organisms are not able to excrete dioxins et all, they are source of them for food chain

4 Mechanism of action: -Aryl-hydrocarbon receptor (Ah receptor, AhR) and activation of cytochrome P450 1A1 (CYP1A1) -Mammals have AhR1, birds have AhR2, fish have both -Ah receptor is a transcription factor activated by ligand, is connected with 2 molecules of heat shock proteins HSP90, and several other molecules. The whole complex is located in cytoplasm, thus available only for liposoluble substances which cross cell membrane - After substance binds to AhR, the whole complex goes to nucleus, it is connected to Ah nuclear translocator (ARNT), where it binds to DNA parts called AhR-responsive elements (XRE). mRNA and proteosynthesis is influenced, main result is the induction of CYP1A1 production – massive free radical release. Dioxins are surprisingly not metabolized by this activated cytochrome. Also testosterone synthesis is inhibited,, estrogen receptors are down-regulated, phosphorylation of amino-acids appears. - Some effects are not mediated via AhR, e.g. inflammatory effects of dioxins.

5 Chronic effects of dioxins and dibenzofurans on organisms are the same as in PCB – carcinogens, birth defects, inability to maintain pregnancy, decreased fertility, reduced sperm counts, endometriosis, diabetes, learning disabilities, immune system suppression, lung problems, skin disorders, lowered testosterone levels etc. Also high acute toxicity – Agent Orange, Victor Yuschenko, Seveso industrial catastrophe (chloracne, malignities, health problems in offspring)

6 PCBs Polychlorinated biphenyls 1-10 chlorines on biphenyl nucleus 209 derivates (congeners) Toxic congeners - 77, 81, 126, 169 – coplanar, chlorine in non-ortho position – minor congeners (so called dioxin-like PCBs) Indicator congeners – seven - 28, 52, 101, 118, 138, 153, 180 – majority Termostable, photostable, chemically inert Manufacturing started in 1929, lasted till late 1970´s Massively used: Closed systems: transformators, cooling liquids, hydraulic liquids Opened systems: flame retardants, in inks, adhesives, paints and dyes, as plasticisers etc.

7 Later assessed in huge amounts in environment, in Japan disease from oil – Yusho-Yusho (acute toxicity) Since 1980’s banned, classified as persistent organic pollutants - POPs Big problems in cattle breeding – PCBs as a part of paints used in silos, on pounds – poisonings, PCBs in milk Also high concentrations in aquatic organisms found till these days – deposition in sediments – incorporation to food chain Absorbed both orally and via skin Very lipophilic, acummulate in fatty tissues Metabolism is very slow, cytochrome P450 1A is involved - oxidation and hydroxylation. Later conjugation with glucuronate or sulphate Excreted via faeces and/or urine This metabolism is extremely slow in fish –affects the rest of food chain

8 Chronic exposition is very dangerous: Most effects are caused via AhR pathway (dioxin-like PCBs): - potential carcinogens – act via interaction with Ah receptor (AhR). Activated receptor induces enzyme synthesis – most important is cytochrome P450. Increased activity of cytochromes causes an increase in free oxygen radicals production – these facilitate the emergence of tumours - dermatotoxic (hyperplasia, hyperkeratosis, chloracne) - influences balance of steroid hormones - fasten their conversion to less efficient metabolites – disturbances in reproduction, xenoestrogenic effects (atrophy of testes, decrease in amount and mobility of sperms) - other hormonal imbalances (affected function of thyroid gland) - immunotoxic, immunosuppressive (atrophy of lymphatic tissue, leucocytopaenia, lymphocytopaenia, suppression of antibody production) Some effects not mediated via AhR and are seen in all PCBs: - induction of CYP 2 and 3 families, activation of pregnane-X- receptor, neurotoxicity - imbalance in dopamine and serotonine in CNS during brain development, imbalance in Ca 2+ ions homeostasis in CNS

9 PAHs Polycyclic aromatic hydrocarbons Formed during the incomplete burning of coal, oil and gas, garbage, tobacco Some PAHs are manufactured, others are found in coal tar, crude oil, creosote, and roofing tar. A few are used in medicines or to make dyes, plastics, and pesticides. Enter the air mostly as releases from volcanoes, forest fires, burning coal, automobile exhaust, industry 16 so called priority PAHs (have negative eefects on mammals and fish) – indicators of environment contamination (e.g. naphthalene, fluorene, fenanthrene, anthracene, benzo(a)pyrene). Not persistent in bodies and in air: - broken down by sunlight within a few weeks, metabolized by liver Problem: insoluble in water – deposition in sediments, persistence

10 Enter organisms via inhalation, GIT resorption or skin In vertebrates metabolised in liver by cytochrome P450 – carcinogenic epoxydiol, then conjugation. No deposition in body, excreted in bile as 1-hydroxypyrene (biomarker) Low metabolism in invertebrates – source of acummulation in food chain Act via Ah receptor Carcinogenic, mutagenic, teratogenic, genotoxic, reproductive problems - especially reactive metabolites! Some of them endocrine disruptors, immunotoxic, hepatotoxic, phototoxic etc.

11 Cyanotoxins Toxins produces by cyanobacteria (blue-green algae - photosynthetic-planktonic bacteria) These bacteria form waterbloom on water surface – in hot period of year, in lack of oxygen, eutrophication increases its growth Normally not released into water actively Released after death of cells – in massive death they are not decomposed by water bacteria - toxic effect Anatoxin, microcystin, saxitoxin etc. Acute poisonings are not common, but may be seen in cattle and sheep, water birds with no other source of water

12 Most of them are dermatotoxic, embryotoxic, immunotoxic Neurotoxic (anatoxin – similar effect to organophosphates, aphanotoxin – similar to pyrethroids) Hepatotoxic – microcystin + nodularin – disturb phosphorylation of proteins – liver failure Microcystin Anatoxin-a(s)

13 More info: htm _Txt_PAH.htm http://www-

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