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Transcript of TOXICOLOGY FOR ENGLISH SPEAKING STUDENTS. DEFINITION THE STUDY ABOUT THE NATURE AND MECHANISMS OF...
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TOXICOLOGY
FOR ENGLISH SPEAKING STUDENTS
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DEFINITION THE STUDY ABOUT THE NATURE
AND MECHANISMS OF CHEMICALS´ EFFECTS ON LIVING ORGANISMUS AND OTHER BIOLOGIC SYSTEMS
QUANTITATIVE ASSESSMENT OF THE SEVERITY AND FREQUENCY OF SUCH EFFECTS
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GOALS FOR PREVENTION PROTECTION THE PUBLIC HEALTH PROTECTION THE WORKERS HEALTH PROMOTION DEVELOPMENT OF SAFER
CHEMICALS USED AS DRUGS, FOOD ADDITIVES, PESTICIDES, INDUSTRIAL CHEMICALS
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SORTS OF TOXICOLOGY ANALYTICAL CLINICAL FORENSIC OCCUPATIONAL ENVIRONMENTAL REGULATORY CONVENTIONAL, …
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SCOPES OF TOXICOLOGY MEDICINE: diagnosis, prevention,
treatment FOOD INDUSTRY: additives AGRICULTURE: pesticides, growth
regulators, animal food additives, veterinary drugs
INDUSTRY
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EPIDEMIES OF POISONING POMPEII – VESUVE, SO2
SMOG REDUCTIVE (dust, CO, PAH): Donora, London
SMOG OXIDATIVE (O3, Nox, CO2 hydrocarbons): Los Angeles
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EPIDEMIES - continue MINAMATA, NIIGATA, IRAQ, USA -
METHYLMERCURY ITAI-ITAI - CADMIUM YUSHO, YUCHENG - PCBs MITCHIGAN – PBBs SEVESO – PCDD (TCDD) BHOPALE - METHYLISOCYANATE
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ROUTES OF INTAKE GASTROINTESTINAL TRACT RESPIRATORY TRACT SKIN VAGINA, RECTUM, EAR, EYES PARENTERAL APPLICATION
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BARRIERS MUCOCILLIAL CLEARANCE SKIN FILM (ACID AND FATTY) PLACENTAL CEREBRO-VASCULAR RATE OF ABSORPTION
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TYPES OF UPTAKE PASSIVE DIFUSSION FILTRATION CARRIER-MEDIATED TRANSPORT ENGULFING BY THE CELLS
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BIOTRANSFORMATION The main influencing factor: WATER / LIPO – SOLUBILITY
WATER – SOLUBILE => EXCRETION WITHOUT METABOLISATION
POLARIC = > AFTER CONJUGATION LIPO-SOLUBILE => 2 STEPS
METABOLISM
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Ist STEP /PHASE OXIDATION, REDUCTION,
HYDROLYSIS CATALYTIC MICROSOMAL ENZYMES METABOLITES DEVELOPED BY
OXIDATION ARE BOTH LESS AND MORE ACTIVE THAN THE MATERNAL COMPOUND
DUE TO OXYGEN / FREE RADICALS
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OXIDATIVE BIOTRANSFORMATION MICROSOMAL ENZYMES –
COMPLEX of CYTOCHROM P450 GENETIC DIFFERENCES IN
GENOTYPE – GENETIC POLYMORPHISM
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CYTOCHROM P450 ENVIRONMENTAL INFLUENCE ON
FENOTYPE: SOME DRUGS, DDT, PCBs, PCDDs,
chemicals in VEGETABLES CAN INDUCE THE RELEASE OF
OXIDATIVE ENZYMES P450
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CYTOCHROM P 450 – exampl. CYP 1A1: lungs, placenta PAH CYP 1A2: liver AFLATOXINS, NITROSAMINES CYP 2A6: lungs, liver, … NITROSAMINES, NICOTINECYP 1B1, 2C9,2C19, 2D6, 2E1, 3A…
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2nd STEP / PHASE CONJUGATION: GLUCURONIDES FORMATION: the
most important and common way, Catalyzing enzymes: UDP- GLUCURONYL
TRANSPHERASEs: Aliphatic and aromatic alcohols,
amines, sulfhydryl compounds, …
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2 nd STEP /PHASE GLUTATHIONE FORMATION Enzymes GLUTATHION-S-
TRANSPHERASEs: Polycyclic aromatic hydrocarbons ACETYLATION: enzymes N-
ACETYL TRANSPHERASEs: SLOW/FAST ACETYLATORS
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2nd STEP /PHASE SULPHATES FORMATION –
enzymes SULPHOTRANSPHERASES METHYLATION
GENETIC POLYMORPHISM: „HAPPY“ / „UNHAPPY“ PEOPLE
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EXCRETION OF CHEMICALS URINARY BILIARY EXPIRATED AIR SALIVA EVAPORATION SKIN ADNEXES (HAIR, NAILS) MOTHER´S MILK
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TESTs OF EXPOSURE LEVELS OF THE SUBSTANCE or IT´S
SPECIFIC METABOLITE: CO in the expirated air, cotinice, BaP DNA adducts
LEVELS OF NON-SPECIFIC METABOLITES: urinary glucuronides, thioethers
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TESTs OF EXPOSURE ASSESSMENT OF THE ORGANISM´S
RESPONSE: anemia in the Pb chronic exposure, Chromosomal aberations in the exposure to mutagens
ASSESSMENT OF THE INDIVIDUAL VULNERABILITY: genetic polymorphism in induction of microsomal enzymes, sexual /ethnic /age differences
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SPECTRUM OF EFFECTS LOCAL x SYSTEMIC REVERSIBLE x IRREVERSIBLE IMMEDIATE x DELAYED MORPHOLOGIC x FUNCTIONAL x
BIOCHEMICAL ALLERGIC x IDIOSYNCRATIC
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SPECTRUM OF EFFECTS IRRITATION, INFLAMATION TOXICITY (according to the target
organ): hemato-, hepato-, neuro-, nephro-, cardio-, …
EMBRYOTOXICITY TERRATOGENICITY MUTAGENICITY CARCINOGENICITY
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DIFFICULTIES IN RESEARCH EXTRAPOLATION from the ANIMAL
EXPERIMENTS to the HUMAN REALITY
DOSE – RESPONSE RELATIONSHIP THE (upper) LIMITS FOR THE
PHYSIOLOGIC RESPONSE INTERACTION OF CHEMICALS IN
MIXTURES
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ANTI-CHEMICAL DEFENSE CONTINUAL
EXCHANGE/REPLACEMENT OF DAMAGED CELLS
INDUCTION OF DETOXIFYING BIOTRANSFORMATION
ACTIVE EXCRETION OF HYDRO-SOLUBLE SUBSTANCES
DNA REPAIR
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IS THE NATURE SAFE? DEFENSE HAS DEVELOPED IN THE
EVOLUTION DUE TO EXPOSURE TO NATURAL CHEMICAL COMPOUNDS
ALL SURVIVE PLANTS HAVE DEVELOPED THEIR PROTECTION
AGAINST THEIR NATURAL ENEMIES = NATURAL PESTICIDES
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NATURAL PESTICIDES ARE CHEMICALY SIMILAR TO
THOSE PRODUCED BY INDUSTRY SOME OF THEM ARE STRONG
TOXINS AND CARCINOGENS (botulotoxine, aflatoxine)
PLANTS CAN CHANGE both the CONCENTRATIONS and the SORT
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TOO MANY RHODENT CARCINOGENS There were tested more than 1000 INDUSTRIAL CHEMICALS and 50 NATURAL CHEMICALS In both groups, about 50% are RHODENT CARCINOGENS
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EXPERIMENTAL TESTS The MAXIMAL TOLERATED DOSES,
and their fractions (1/2 ¼) ARE USED WHICH MATHEMATIC MODEL OF
EXTRAPOLATION FOR HUMAN EXPOSURE IS THE BEST?
LINEAR? EXPONENTIAL? DOES THE SAFE TRESHOLD EXISTS?
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EPIDEMIOLOGIC/CLINIC STUDIES ARE ONLY ACCEPTABLE FOR
HUMAN RISK ASSESSMENT = > CHEMICAL ACCIDENTS and
DISASTERS ARE ASSESSED IN LONGITUDINAL PROSPECTIVE STUDIES
Also PROFESSIONAL EXPOSURES are the sources of IMPORTANT DATA
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CARCINOGENS´ CLASSIFICATION CATEGORIES HUMAN / ANIMAL DATA HUMAN C. 1A suffic. suffic./limited PROBABLE 2A limited sufficient POSSIBLE 2B inadeq. Suffic/limited NO-CLASSIF. 3 absent inadeq/absen NOT CARCIN.4 absent negative in 2 species
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CARCINOGENIC EFFECTS OF CHEMICAL SUBSTANCES RISE THE
MAJOR CONCERN OF RESEARCHES: GENOTOXIC THEORY OF
CARCINOGENESIS: INITIATION of DNA MUTAGENIC CHANGES – REPLICATION – PROMOTION – MANIFESTATION
EPIGENETIC (non-mutagenic) THEORY
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WHAT DO WE KNOW? WE CAN MEASURE THE
MUTAGENICITY (Ames´s test) AND RESPONSE (Chromosomal abberations, sister chromatide exchanges, DNA adducts…)
THERE ARE RELATIONSHIPS BETWEEN SHORT-TERM MARKERS and CANCER INCIDENCE
CELLs PROLIFERATION IS IMPORTANT
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WHAT WE DON´T KNOW? WHICH MODEL FOR
EXTRAPOLATION IS THE MOST PRECIOUS ? WHICH IS THE ROLE OF NATURAL
CHEMICALS and CONDITIONS ? WHICH SIGNALS OF RESPONSE ON
EXPOSURE ARE IMPORTANT FOR USE THEM TO ESTABLISH THE ACCEPTABLE LIMITS ?
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POLITICAL POINT OF VIEW: TO KEEP LIMITS IN MORE
DIFFICULT THAN TO ESTABLISH THEM
HOW MANY VULNERABLE PEOPLE WE WILL PROTECT BY THE LIMITS
CAN WE ACCEPT SOME SPECIFIC PROTECTION OF VULNERABLE PART OF POPULATION
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ENVIRONMENTAL HYSTERY VERY OFTEN ENHANCES THE
PUBLIC INTEREST ABOUT LOW-RISK FACTORS (sacharin, DDT, PBCs, Alar, …)
AND OBSCURES / UNDERESTIMATES
THE REAL RISKS (nutrition, smoking, poor hygiene, …)
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ALL CANCER MORTALITY: ATTRIBUTIVE RISK IN LIFE STYLE NUTRITION …………………… 35% SMOKING ……………………… 30% INFECTIOUS AGENTS …….. 10% SEXUAL BEHAVIOUR ………. 7% ALCOHOL ………………………. 4% TOGETHER ……………………. 87%
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ALL CANCER MORTALITY ATTRIBUTIVE RISK IN ENVIRONMENT OCCUPATION …………………… 4% MEDICAL TREATMENT ………. 3% GEOPHYSICAL FACTORS ……. 3% POLLUTED AIR, WATER …….. 2% FOOD ADDITIVES/CONTAM. . <1% TOGETHER ………………………. 13%
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CONCLUSSIONS TOXICOLOGY IS DYNAMIC,
EXCITATING SCIENCE TOXICOLOGY CAN DISCOVER
MANY MYSTERIOUS THINGS IN LIFE
TOXICOLOGY CAN REDUCE HUMAN CHEMOPHOBIA