TOXICOLOGY FOR
PREVENTION
MAIN TASKS IN PRIMARY
PREVENTION
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, …
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