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/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)
 100

Percentage of population killed by a given dose

75

50

25

LD
50

0
2 4 6 8 10 12 14 16
Fig. 16.5, p. 400
Dose (hypothetical units)
 Toxicity
LD50 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 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 life-
expectancy
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 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
 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

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 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