PRINSIP-PRINSIP TOKSIKOLOGI

Dr. dr. Nurdiana, Mkes TOKSIKOLOGI :

mempelajari sifat-sifat racun zat kimia serta keamanannya

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)

terhadap mahluk hidup dan lingkungan

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/kg Normally expressed as milligrams of substance per kilogram of animal body weight

Measures of Toxicity: The Median Lethal Concentration

LC50 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/L Normally expressed as milligrams of substance per liter of air or water (or as ppm)

Percentage of population killed by a given dose

100

75

50

25

LD

50

10

12

14

16
Fig. 16.5, p. 400

Dose (hypothetical units)

Toxicity
LD50 measured in mg/kg of body weight

LD50
Supertoxic Extreme. Toxic Very Toxic Toxic < 0.01 <5 5-50 50-500

(mg)

Examples
dioxin, botulism, mushrooms heroin, nicotine morphine, codeine DDT, H2SO4, Caffeine

Mod. Toxic
Slight. Toxic Non-Toxic

500-5g
5g-15g >15g

aspirin, wood alcohol

ethyl alcohol, soaps water, table sugar

CHRONIC EXPOSURE

Subchronic Exposure
Toxic 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 lifeexpectancy Mice : 18 m 24 m Rats : 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

(walaupun kecil 0,001 %)

risiko reaksi toksik

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.

Osprey Sucker Trout

Silverside

Bay Shrimp
Water Plants

Plankton

ORGANIC DEBRIS

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 Exposure

Any 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

Not all organs are affected equally, greater susceptibility of the target organ, higher concentration of active compound Liver, Kidney Lung, Neurons, Myocardium, Bone marrow

upon the concentration of active compound at the target site for enough time ),

Primary Routes of Exposure: Dermal Exposure

Animal back Exposure of the skin Examination: erithema,edema, corrosive action

Primary Routes of Exposure: Inhalation Exposure

Occurs 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