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TOXICOLOGY FOR
PREVENTION
MAIN TASKS IN PRIMARY
PREVENTION https://is.muni.cz/el/1411/podzim2012/VLPL9X1a/seminar-
30-31.qwarp
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TOPICS in RESEARCH
DISCOVERY of HAZARDS
MEASUREMENT of EXPOSURE
IDENTIFICATION THE RISK
WAYS of CONTROL
ACTION
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HAZARD
CHARACTERISTIC PROPERTIES OF
CHEMICAL(s)
AND THEIR MIXTURES
(BOTH NATURAL AND INDUSTRIAL)
TO CAUSE DAMAGES OF HEALTH
ACCUTE, CHRONICAL, LATE
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DISCOVERY OF
HAZARDS
MATHEMATIC MODELS
IN VITRO EXPERIMENTS
ANIMAL EXPERIMENTS
CLINICAL STUDIES
EPIDEMIOLOGICAL STUDIES
ETHIC RULES
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PROBLEMS
CHOICE THE „RIGHT“ ANIMALS FOR
EXPERIMENS (thalidomid – Contergan,
DDT, sacharin, …)
MOTIVATION of VOLUNTEERS for
PARTICIPATION IN CLINICAL and
EPIDEMIOLOGIC STUDIES (smokers,
catastrophes)
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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?
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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, …
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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
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EXPOSURE
THE DOSE WHICH REACHES
THE TARGET ORGAN
IS CRUCIAL FOR THE EFFECT OF
CHEMICAL
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EVALUATION
OF EXTERNAL EXPOSURE =
INTAKE
IS THE MOST EXACT STEP:
ANALYSIS OF AIR, FOOD, WATER,
DRUGS, COSMETICS and
CALCULATION OF USUAL DAILY
INTAKE
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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
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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
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METABOLISM
NO – HYDROSOLUBLE CHEMICALS
CONJUGATION – POLAR CHEM.
TWO-STEPS METABOLISM:
- 1st: REDUCTION, HYDROLYSIS,
OXIDATION
- 2nd: CONJUGATION (sulfids,
glucuronides,…)
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ENZYMES
1 st phase: CYTOCHROM P 450
(CYP … - CYP1A1) =>
ACTIVATION due to FREE RADICALS
2nd phase: TRANSFERASES
DE-ACTIVATION, QUICK EXCRETION
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GENETIC
POLYMORPHISM
THE INDIVIDUAL ABILITY OF
RELEASE OF EACH ENZYME IS
HEREDITARY DETERMINATED
CAN BE SLIGHTLY MODIFICATED BY
SOME CHEMICALS
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„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
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THE PREVENTIVE TASK
TO IDENTIFICATE THE MORE
VULNERABLE PERSONS, and
TO PROTECT THEM FROM THE
EXPOSURE
ARE IN SOME ETHICAL CONFLICTS
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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
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RISK
DEFINITION THE HEALTH DAMAGES
CAUSED BY EXPOSURE:
THE EXACT EVALUATION OF
BIOLOGICAL EXPOSURE IS
EXTREMELY DIFFICULT
INTER- and INTRA- INDIVIDUAL
DIFFERENCES
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BIOLOGIC TESTS of
EXPOSURE
SPECIFIC: MATERNAL CHEMICAL or
its SPECIFIC METABOLITES
NON-SPECIFIC:
- CONJUGATES
- REACTION OF THE BODY
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BIOLOGIC MATERIALS:
URINE, FAECES, EXPIRATED AIR
BLOOD, SALIVA, HAIR, 1st DENTICE
FOLLICULAR FLUID, EJACULATE,
BREAST MILK
BONES, FAT, TISSUES
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EVALUATION of
CHEMICALS
ACCORDING TO LD 50:
- INERT
- HARMFUL
- POISONS
- EXTREMELY HARMFUL POISONS
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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
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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
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THE „ZERO“ EXPOSURE
IS NOT REALISTIC
EVEN AT THE BEGINNING OF THE
EVOLUTION, HISTORIC „PEOPLE“
VERE EXPOSED TO THOUSANDS
CHEMICALS (through air, food, water)
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NATURAL PESTICIDES
ARE IN ALL FRUITS, VEGETABLES
and OTHER PLANT SOURCES OF
NUTRITION
PLANTS CAN CHANGE THEIR
CONCENTRATIONS, and even
THEIR SORTS
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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
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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
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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
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PROTECTION - continue
-METABOLIC TRANSFORMATION
-QUICK EXCRETION OF
HYDROSOLUBLE COMPOUNDS
-DNA REPAIR
-BARRIERS (hematoencephalic,
placental)
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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
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IN DEVELOPED
COUNTRIES
THE MOST IMPORTANT SOURCE OF
CHILDREN´ EXPOSURE TO
HARMFUL CHEMICALS IS
ENVIRONMENTAL TOBACCO SMOKE
(SECONDHAND and THIRDHAND
SMOKING at homes /cars)
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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
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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
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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
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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
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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