basic toxicology
TRANSCRIPT
PRINSIP-PRINSIP TOKSIKOLOGI Dr. dr. Nurdiana, Mkes
TOKSIKOLOGI : mempelajari sifat-sifat racun zat kimia serta keamanannya terhadap mahluk hidup dan lingkungan
What is a Poison? All substances are poisons;
there is none that is not a poison. The right dose differentiates a poison and a remedy.
Paracelsus (1493-1541)
Xenobiotik ( Xeno = asing ) zat kimia baru uji toksisitas
UJI TOKSISITAS : AKUT
KRONIS
ACUTE EXPOSURE
- DOSIS BAHAN KIMIA TUNGGAL ATAU DL WAKTU PENDEK (PADA UMUMNYA KURANG DARI SATU HARI)-HEWAN COBA : TIKUS, MENCIT, JANTAN ATAU BETINA
-Pemeriksaan : kematian hewan coba dalam kurun waktu 14 hari.(weight, behavioral, lethargy, food consumption etc)
- Information: LD50,target organ, reversibility, dose-response
Measures of Toxicity:The Median Lethal Dose
LD50
The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered by any of
a variety of methods
mg/kgNormally expressed as milligrams of substance
per kilogram of animal body weight
Measures of Toxicity:The Median Lethal
ConcentrationLC50
The concentration of a chemical in an environment (generally air or water) which
produces death in 50% of an exposed population of test animals in a specified time
frame
mg/LNormally expressed as milligrams of substance
per liter of air or water (or as ppm)
Fig. 16.5, p. 400
100
75
50
25
02 4 6 8 10 12 14 16
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Dose (hypothetical units)
LD50
ToxicityLD50 measured in mg/kg of body weightLD50 measured in mg/kg of body weight
LD50 (mg) Examples
Supertoxic < 0.01 dioxin, botulism, mushrooms
Extreme. Toxic <5 heroin, nicotine
Very Toxic 5-50 morphine, codeine
Toxic 50-500 DDT, H2SO4, Caffeine
Mod. Toxic 500-5g aspirin, wood alcohol
Slight. Toxic 5g-15g ethyl alcohol, soaps
Non-Toxic >15g water, table sugar
CHRONIC EXPOSURE
Subchronic ExposureToxic symptoms are expressed after
repeated applications for a timeframe less than half the life expectancy of the organism (90 days)
Examination: body weight, food consumtion, respiratory and cardiovascular distress, motor and behavioral abnormalities etc
At the end of the 90-day blood and organ collected for analysis
Chronic Exposure
Expression of toxic symptoms only after repeated exposure to a chemical in doses regularly applied to the organism for a time greater than half of its life-expectancy
Mice : 18 m – 24 mRats : 2-2.5 y
Pemeriksaan toksisitas tergantung tujuan dan lama penggunaan :
obat cacing penggunaan cepat perlu data toksisitas akut
obat hipertensi, obat kontrasepsi penggunaan lama/kronik perlu data karsinogenisitas, teratogenisitas
Uji toksikologi zat kimia :
-farmakokinetik ADME
-farmakodinamik EFEK YG PALING MENONJOL
Contoh :
penggunaan obat baru risiko reaksi toksik (walaupun kecil 0,001 %)FDA zat x harus diberikan pd 15 000 org utk melihat manifestasi reaksi tdk dikehendaki
Frekuensi kejadian dipengaruhi :
Umur sex, ras, kehamilan, kelainan gen
MENILAI KEAMANAN ZAT KIMIA
Zat kimia yg baru disintesis dan mau digunakan
uji toksisitas.
NEL
( No Effect Level )
Jumlah atau konsentrasi suatu zat kimia yg ditemukan melalui penelitian atau observasi yg tidak menimbulkan kelainan buruk, perubahan morfologi atau fs organ, pertumbuhan, perkembangan, maupun mengurangi lama hidup hewan coba.
ADI
acceptable daily intake
Dosis suatu zat kimia terbesar yang dinyatakan dalam satuan mg/kg BB/hari yg dapat diberikan setiap hari seumur hidup dan dapt diperkirakan tidak menimbulkan efek kesehatan yg buruk pada manusia, berdasarkan pengetahuan yg ada waktu itu
NEL/100 = ADI (mg/kg BB/hari)
MPC : maximal permissible concentration
konsentrasi zat kimia yg diperbolehkan berada dalam makanan tertentu
ADI x Berat badan (kg)MPC = -------------------------- = ……. ppm
faktor makanan (kg)
Faktor makanan : konsumsi rata2 suatu makanan tertentu dlm kg/orang/hr
Area toksikologi khusus yang penting utk kedokteran :
Forensic toxicology kombinasi kimia analitik dan toksikologi dasar yang memperhatikan aspek medikolegal
Clinical toxicology fokus pada penyakit yang disebabkan atau secara unik berhubungan dengan substansi toksik
Toksikologi di tempat kerja (occupational toxicology)
- berhub dg bhn kimia disekitar tempat kerja
- terutama identifikasi “agent”
- kondisi tempat kerja aman, absorbsi bahan kimia berlebih dapat dicegah
- guideline konsentrasi bahan kimia di udara yang pasti aman (establish) ada daftar bahan kimia yg direkomendasikan memenuhi threshold limit values (TLVs). Guideline selalu di evaluasi new information
TOKSIKOLOGI LINGKUNGAN
- berhubungan dg dampak kimia sbg polutan di lingkungan organisme hidup udara, tanah, air, dll
- target utama manusia, spesias lain target biologik potensial
Polusi udara produk industri
pengembangan teknologi
peningkatan urbanisasi
Polusi tanah dan air pestisida
Pengolahan makanan residu bahan kimia pada produk makanan
Ecotoxicology toksikologi ekosistem
Bioaccumulation = the accumulation of a contaminant or toxin in or on an organism from all sources (e.g., food, water, air).
Biomagnification = the increase in concentration of toxin as it passes through successive levels of the food web
Food Web = A summary of the feeding relationships within an ecological
community.
ORGANIC DEBRIS
Osprey
Water Plants
Sucker
Bay Shrimp
Trout
Plankton
Silverside
Measures of Toxicity
• Toxicity of chemicals is determined in the laboratory
• The normal procedure is to expose test animals– By ingestion, application to the skin, by
inhalation, gavage, or some other method which introduces the material into the body, or
– By placing the test material in the water or air of the test animals’ environment
Measures of Toxicity
• Toxicity is measured as clinical “endpoints” which include :– Mortality (death)– Reproductive tox
(teratogenesis,reproduction performance,perinatal and postnatal tox)
– Carcinogenicity (ability to cause cancer), and,
– Mutagenicity (ability to cause heritible change in the DNA)
What is a Response?
• Response (symptoms) could be on the molecular, cellular, organ, or organism level
(interference w/receptor,membrane function,cellular energy production, biomolc, calsium homeostasis etc)
• Local vs. Systemic • Reversible vs. Irreversible• Immediate vs. Delayed• Graded vs. Quantal degrees of the same damage vs. all or none
Primary Routes of Exposure
There are three primary routes by which organisms are exposed to
pesticides
Oral
Dermal
Inhalation
Primary Routes of Exposure:
Oral ExposureAny exposure which occurs when the chemical is taken in through the mouth and passes through the gastrointestinal tract
ADME (target organ adverse effect is dependent upon the concentration of active
compound at the target site for enough time ), • Not all organs are affected equally, – greater susceptibility of the target organ, – higher concentration of active compound• Liver, • Kidney • Lung, • Neurons, • Myocardium, Bone marrow
Primary Routes of Exposure:
Dermal ExposureAnimal backExposure of the skin Examination: erithema,edema, corrosive action
Primary Routes of Exposure:
Inhalation ExposureOccurs when a chemical is breathed into
the lungs through the nose or mouth
Significant route of exposure for aquatic organisms
Not of toxicological concern until it crosses from the lung into the body (unless the chemical is corrosive)
UJI TOKSISITAS
Sebelum menguji suatu bahan telah ada :
Data identifikasi, sifat zat kimia dan rencana penggunaan
Hal-hal yang harus di : - bahan yang diuji
persiapkan - dosis
- hewan coba
- cara pemberian
- lama pemberian
- efek yang diamati organ, laboratorium
hasil
- pengunaan
-