TOXICOLOGY FOR PREVENTION MAIN TASKS IN PRIMARY PREVENTION https://is.muni.cz/el/1411/podzim2012/VLPL9X1a/seminar-30-31.qwarp TOPICS in RESEARCH * DISCOVERY of HAZARDS * MEASUREMENT of EXPOSURE * IDENTIFICATION THE RISK * WAYS of CONTROL * ACTION HAZARD * CHARACTERISTIC PROPERTIES OF CHEMICAL(s) * AND THEIR MIXTURES * (BOTH NATURAL AND INDUSTRIAL) * TO CAUSE DAMAGES OF HEALTH * ACCUTE, CHRONICAL, LATE DISCOVERY OF HAZARDS * MATHEMATIC MODELS * IN VITRO EXPERIMENTS * ANIMAL EXPERIMENTS * CLINICAL STUDIES * EPIDEMIOLOGICAL STUDIES * ETHIC RULES PROBLEMS * CHOICE THE „RIGHT“ ANIMALS FOR EXPERIMENS (thalidomid – Contergan, DDT, sacharin, …) * MOTIVATION of VOLUNTEERS for PARTICIPATION IN CLINICAL and EPIDEMIOLOGIC STUDIES (smokers, catastrophes) PROBLEMS continue * EXTRAPOLATION OF RESULTS OBTAINED IN EXPERIMENTS (high levels of exposure doses) * TO HUMAN EXPOSED TO LOW DOSES * IS THE LINEAR MODEL REALY RIGHT? * Does the „SAFE TRESHOLD“ exist? PROBLEMS continue * TO ESTABLISH THE DOSE-EFFECT RELATIONSHIPS IS CRUCIAL * MANY CHEMICALS HAVE DIFFERENT (even oposite) EFFECTS IN LOW AND HIGH LEVELS (narcotics´excitation phase) * HORMESE (U or J curve): vitamins, minerals, alcohol, radioactivity, … l SAFE LIMITS * ARE DEPENDED DIRECTLY ON THE DOSE-RESPONSE CURVE * THE VERY LOW LIMITS: -MAY BE HARMFUL (in the case of „hormese“), and -ARE VERY EXPENSIVE EXPOSURE * THE DOSE WHICH REACHES * * THE TARGET ORGAN * * IS CRUCIAL FOR THE EFFECT OF CHEMICAL EVALUATION * OF EXTERNAL EXPOSURE = * INTAKE * IS THE MOST EXACT STEP: * ANALYSIS OF AIR, FOOD, WATER, DRUGS, COSMETICS and * CALCULATION OF USUAL DAILY INTAKE NEXT STEPS of EXPOSURE: UPTAKE * UPTAKE = RATE of RESORPTION in DIFFERENT WAYS of INTAKE * Heavy metals: 1-10 % in GIT but • 50-70% in lungs * LACK OF KNOWLEDGES ABOUT RATES • • • METABOLISM * MANY CHEMICALS ARE ACTIVATED BY THE 1st PHASE OF METABOLISM (oxidation – free radicals) * INDIVIDUAL DIFFERENCES due to * GENETIC POLYMORPHISMS * in production of MICROSOMAL ENZYMES METABOLISM * NO – HYDROSOLUBLE CHEMICALS * CONJUGATION – POLAR CHEM. * TWO-STEPS METABOLISM: -1st: REDUCTION, HYDROLYSIS, • OXIDATION -2nd: CONJUGATION (sulfids, • glucuronides,…) ENZYMES * 1 st phase: CYTOCHROM P 450 • (CYP … - CYP1A1) => ACTIVATION due to FREE RADICALS • * 2nd phase: TRANSFERASES • DE-ACTIVATION, QUICK EXCRETION • GENETIC POLYMORPHISM * THE INDIVIDUAL ABILITY OF RELEASE OF EACH ENZYME IS HEREDITARY DETERMINATED • * CAN BE SLIGHTLY MODIFICATED BY SOME CHEMICALS „HAPPY and UNHAPPY“ * People with LOW CYP…(s) AND HIGH TRANSFERASES =☻ * People with HIGH CYP(s) and LOW TRANSFERASES = produce many free radicals which cannot be conjucated and excreted * MAJORITY of people have MIXED VULNERABILITY THE PREVENTIVE TASK * TO IDENTIFICATE THE MORE VULNERABLE PERSONS, and * TO PROTECT THEM FROM THE EXPOSURE * ARE IN SOME ETHICAL CONFLICTS FINAL EXPOSURE: * ONLY PART OF ENVIRONMENTAL CHEMICALS ARE INTAKEN * ONLY PART OF THEM ARE UPTAKEN * ONLY PART ARE ACTIVATED * ONLY PART REACHES THE TARGET ORGAN RISK * DEFINITION THE HEALTH DAMAGES CAUSED BY EXPOSURE: * THE EXACT EVALUATION OF BIOLOGICAL EXPOSURE IS EXTREMELY DIFFICULT * INTER- and INTRA- INDIVIDUAL DIFFERENCES BIOLOGIC TESTS of EXPOSURE * SPECIFIC: MATERNAL CHEMICAL or its SPECIFIC METABOLITES * NON-SPECIFIC: -CONJUGATES -REACTION OF THE BODY • BIOLOGIC MATERIALS: * URINE, FAECES, EXPIRATED AIR * BLOOD, SALIVA, HAIR, 1st DENTICE * FOLLICULAR FLUID, EJACULATE, BREAST MILK * BONES, FAT, TISSUES EVALUATION of CHEMICALS * ACCORDING TO LD 50: -INERT -HARMFUL -POISONS •- EXTREMELY HARMFUL POISONS - CARCINOGENS / TERRATOGENS * 1A - EVIDENT HUMAN C / T * 1B - HIGHLY PROBABLE HUMAN C/T * 2 - PROBABLE C/T * 3 - POSSIBLE C/T * 4 - NON-PROBABLE C/T CARCINOGENS / TERRATOGENT * 73 CARCINOGENS CLASS 1A+B * 67 of them IN CIGARETTE SMOKE * 1A TERRATOGENS: alcohol, smoking, nicotine, organic mercury, thalidomid * 1B : cadmium, lead, heroin, coccain THE „ZERO“ EXPOSURE * IS NOT REALISTIC * EVEN AT THE BEGINNING OF THE EVOLUTION, HISTORIC „PEOPLE“ VERE EXPOSED TO THOUSANDS CHEMICALS (through air, food, water) NATURAL PESTICIDES * ARE IN ALL FRUITS, VEGETABLES and OTHER PLANT SOURCES OF NUTRITION * PLANTS CAN CHANGE THEIR CONCENTRATIONS, and even * THEIR SORTS CHEMICAL STRUCTURE * OF „NATURAL PESTICIDES“ IS SIMILAR / THE SAME, * AS FOR „INDUSTRIAL PESTICIDES“ * IN EXPERIMENTS, 50 % of both NATURAL AND INDUSTRIAL CHEMICALS ARE RHODENT CARCINOGENS DAILY INTAKE: * INDUSTRIAL PESTICIDES…..0.09 mg * NATURAL PESTICIDES…1500 mg * NO KNOWLEDGE ABOUT THE HEALTH EFFECTS OF NAT.PESTIC. * PROTECTIVE EFFECT OF FRUIT and VEGETABLES INTAKE IS ACCEPTED • HUMAN PROTECTION: * EXPOSURE DURING THE EVOLUTION => * DEVELOPMENT OF NON-SPECIFIC PROTECTION: •-MUCOCILLIAL TRANSPORT OF DUST •-RATE OF UPTAKE •-CONTINUAL EXCHANGES THE SURFACE LAYERS OF SKIN / MUCOUS MEMBRANES PROTECTION - continue •-METABOLIC TRANSFORMATION •-QUICK EXCRETION OF HYDROSOLUBLE COMPOUNDS •-DNA REPAIR •-BARRIERS (hematoencephalic, placental) CHILD x ADULT DIFFERENCES * HIGHER LEVEL OF INTAKE: water, food, inspirated air per kg/weight * HIGHER RATE OF UPTAKE in GIT * LOWER ACTIVITY OF ENZYMES * HIGHER VULNERABILITY TO EFFECTS * LONGER CUMULATIVE TIME IN DEVELOPED COUNTRIES * THE MOST IMPORTANT SOURCE OF CHILDREN´ EXPOSURE TO HARMFUL CHEMICALS IS * ENVIRONMENTAL TOBACCO SMOKE • (SECONDHAND and THIRDHAND SMOKING at homes /cars) WAYS FOR CONTROL * LEVEL of ACCEPTABLE DAILY INTAKE (ADI) = WHO * MAXIMAL LIMITS FOR WATER, FOOD, AIR (occupational, ambient) = * NATIONAL LAWS and NORMS * WORLD-WIDE COOPERATION ACTION * SETTING THE PRIORITIES = WHICH RISK IS THE MOST IMPORTANT? * DISCUSION ABOUT RISKS – journalists, VIP persons * TO CONVICE POLITICIANS to preferent interest about public health against their individual profit * CONCLUSIONS: * MORE THAN 10.000.000 CHEMICALS WERE IDENTIFICATED * WE ARE IN DIALY/ OFTEN CONTACT WITH 500.000 CHEMICALS * WE HAVE QUITE GOOD MEDICAL INFORMATIONS ABOUT 1.000 CHEMICALS CONCLUSIONS: * WE HAVE MANY OPEN PROBLEMS IN TOXICOLOGY * WE ALLOW TO CONFUSE PEOPLE WITH UNCORRECT INFORMATIONS * WE UNDERESTIMATE THE MAIN TOXICOLOGIC RISK FOR HEALTH = SMOKING PREVENTIVE TOXICOLOGY in the FUTURE * BASIC RESEARCH IN EVALUATION OF EXPOSURE AND EFFECTS * METHODS FOR SEEKING THE VULNERABLE PEOPLE esp. CHILDREN * WAYS OF PROTECTION OF VULNERABLE PEOPLE/CHILDREN