Efek Toksik

Kuliah Toksikologi Industri

Fatma Lestari
Outline
› Definisi
› Mekanisme Toksisitas
› Tahapan Mekanisme Efek Toksik
› Faktor-faktor yang berpengaruh
› Spektrum Efek Toksik
› Contoh Kasus Toksikan di Industri
Tujuan Pemelajaran
› Mahasiswa mampu menjelaskan kembali mekanisme &
tahapan toksisitas
› Mahasiswa mampu menjelaskan kembali faktor-faktor yang
memengaruhi efek toksik
› Mahasiswa mampu menjelaskan pelbagai spektrum efek
toksik
› Mahasiswa mampu menjelaskan pelbagai kasus toksisitas di
Industri
Definisi
› Toksikodinamika adalah ilmu yang mempelajari bagaimana
terjadinya efek atau perubahan dalam tubuh yang ditimbulkan
oleh toksikan, termasuk proses biokimia dan fisiologik pada
molekul dan jaringan target organ, seperti proses mengikat,
mengaktifkan atau menghambat reseptor.
› Efek toksik adalah efek yang merugikan yang ditimbulkan oleh
toksikan
 Tipe-tipe Aksi Toksik

Menutup
Intereferensi Uncouple Reaksi Inhibisi Transfer
Transpor Oksigen
sistem enzim Biokimia Oksigen
pada Hemoglobin

Immunosuppresi
Sintesis Metabolit Penghilangan Ko- Interferensi
dan
Toksik faktor logam fungsi Selular
Hipersensitisasi

Toksisitas pada Sekuestrasi /

Iritasi Jaringan
sel deposit toksikan

William E. Luttrell, Warren W. Jederberg, Kenneth R. Still. Toxicology Principles for the Industrial Hygienist.
Mekanisme Toksisitas
& contoh Toksikan
Industri

William E. Luttrell, Warren W. Jederberg, Kenneth R. Still. Toxicology

Principles for the Industrial Hygienist.
 Toxicant

Tahapan Mekanisme Efek Toksik 1

Delivery

Tahap 1: “DELIVERY” atau PERGERAKAN TOKSIKAN

Dari lokasi kontak pajanan menuju Target
2a 2b
Interaction Alteration
with target of biological
molecule environment

Tahap 2— Reaksi Toksikan dengan molekul target

T
Cellular
3
O
Tahap 3— Disfungsi seluler, resultan toksisitas,
kerusakan
dysfunction,
injury X
I FIG
in t

C toxi
orm
4
I
by t
In a p p r o p r i a t e
Tahap 4— Perbaikan tidak sesuai & Adaptasi r e p a ir a n d
a d a p t a t io n T par
site
Y the

Curtis D. Klaasen, John B. Watkins III. Casarett & Doull’s. Essentials of Toxicology. 2015 FIGURE 3 –1 Potential stag es in the deve lopme nt o toxicity Me
a ter chemical exposure.
Por
 Exposure site
Skin, GI tract, respiratory tract,
injection/bite site, placenta

Toxicant

D Presystemic
Absorption
E elimination
Distribution L Distribution
toward target I away from target
Reabsorption V Excretion
E
Toxication R Detoxication
Y

n
cal
ent
Tahap 1: “DELIVERY” atau
PERGERAKAN TOKSIKAN Dari
Ultimate
toxicant lokasi kontak pajanan menuju
T Target molecule
(Protein, lipid, nucleic acid
Lokasi Target
O macromolecular complex)

X
Target site

I FIGURE 3–2 The process o toxicant delivery is the rst step

in the development o toxicity. Delivery—that is, movement o the

C toxicant rom the site o exposure to the site o its action in an active
orm—is promoted by the processes listed on the le t and opposed
Curtis D. Klaasen, John B. Watkins III. Casarett & Doull’s. Essentials of Toxicology. 2015

by the events indicated on the right.

 Toxicant

Tahap 2: Reaksi Toksikan dengan

Molekul Target 1

Delivery

MOLEKUL TARGET JENIS REAKSI

› DNA › Ikatan Non-kovalen
› Protein › Ikatan Kovalen 2a
Interaction
2b
Alteration

› Membran › Penghilangan Hidrogen with target

molecule
of biological
environment

› Transfer Elektron
EFEK TOKSIKAN PADA › Reaksi Enzimatik
TARGET MOLEKUL T
› Disfungsi Target Molekul EFEK TOKSIK TANPA REAKSI Cellular
3
O
› Destruksi Target Molekul DENGAN MOLEKUL TARGET
dysfunction,
injury X
› Pembentukan I FI
in
Neoantigen › Mendorong peningkatan ion H+ C to
o
› Merusak dinding membrane sel 4
I
by

› Merusak larutan transmembrane In a p p r o p r i a t e

› Menempati ruang atau titik

r e p a ir a n d
a d a p t a t io n T pa
tertentu Y sit
th

Curtis D. Klaasen, John B. Watkins III. Casarett & Doull’s. Essentials of Toxicology. 2015 FIGURE 3–1 Po tential stages in the development o toxicity M
a te r chemical exposure.
Po
 Toxicant
Tahap 3— Disfungsi, efek toksik &
kerusakan sel
28 UNIT 1 Genera Princip es o oxico ogy 1

Delivery

The target molecule The e ect

as determinant of the e ect
Dysregulation Inappropriate
of gene • Cell division neoplasia, teratogenesis
expression • Apoptosis tissue involution, teratogenesis
• Protein synthesis e.g., peroxisome proliferation
2a 2b
Cell regulation Interaction Alteration
(signaling) with target of biological
molecule environment
Dysregulation For example, Inappropriate neuromuscular activity
of ongoing • Tremor, convulsion, spasm, cardiac arrythmia
cell function • Narcosis, paralysis, paresthesia
Role of
the target T
molecule
Impaired
internal
Impaired
• ATP synthesis Cellular
3
O
maintenance • Ca 2+ regulation
• Protein synthesis
Cell
injury/death
dysfunction,
injury X
Cell
maintenance
• Microtubular function
• Membrane function I FI
in

C to
or
4
I
Impaired by
Impaired function of integrated systems
external • Hemostasis bleeding In a p p r o p r i a t e
maintenance r e p a ir a n d
a d a p t a t io n T pa

FIGURE 3–6 The third step in the development o toxicity: alteration o the regulatory or maintenance unction o the cell. Y sit
th

Curtis D. Klaasen, John B. Watkins III. Casarett & Doull’s. Essentials of Toxicology. 2015 FIGURE 3–1 Pote ntial stag es in the development o toxicity M
a te r che mical exposure.
expression may occur at e ements that are direct y responsib e Po
 1 2 3 4 5 4 6 7 8

IL-6 TNF IL-1 EGF ECM EGF PGF2α TSH TGF-β

PRL TGF-α TGF-α NE FSH Ligands
EPO IGF IGF 5-HT LH
UV
Membrane
+P +P –P PLC G G AC re ceptors
PTP
SOCS As
PI3K FAK ROS
Ras GAP SHR DAG + IP cAMP
3
+P PIP 3 +P +P PMA
PTEN FA FB1
–P +P
JAK PTP Akt Src Raf PKC PKA
MMS –P STAU
+P +P
+P PTP +P Pb 2+
+P
+P
ROS IKK MEK Ca 2+ Smad
+P MC-LR
OKA +P
I B CALY
+P
–P
NF- B PP2A ERK CaMK

+P I B +P +P +P
† Signal-
STAT3 * NF- B * c-FOS c-JUN c-Myc Egr1 CREB Smad
activated
Curtis D. Klaasen, John B. Watkins transcription
III. Casarett & Doull’s. Essentials of C/EBP * c-Myc ATF-2 Elk-1 SAP1 FoxM1 c-Myc
factors
Toxicology. 2015

* Mediators of acute phase

protein expression
Cell cycle progression Cell cycle arrest
† Mediates ECM formation
mitosis apoptosis
in ECM-producing cells

FIGURE 3–7 Signal-transduction pathways rom cell membrane receptors to signal-activated nuclear transcription actors that
inf uence transcription o genes involved in cell-cycle regulation. The symbols o cell membrane receptors are numbered 1 to 8 and some
 (PARP). As part o the repair strategy, activated PARP trans Mitochondrial DNA Death receptor
ers mu tip e ADP ribose moieties rom NAD+ to nuc ear insult damage stimulation
Mekanisme Disfungsi Sel proteins and PARP itse . Because consumption o NAD+
severe y compromises A P synthesis (see Figure 3–8) and
CHAPTER 3 Mechanisms o oxicity 37
resynthesis o NAD+ consumes A P, a ce u ar energy ↓ATP ↑Ca2+ p53 stabilization C-8 activation
de cit occurs as a major consequence o DNA damage
by ONOO− . Mitochondrial
insult

↑RO(N)S Bax, Puma, Noxa Bid

d
n
a
g

D
d
li

a
Mit o ch o n d ria l Pe rm e a b ilit y Tra n sit io n (MPT) a n d t h e

N ag
s

m
a

A e
ti r
u pt h

F
n
im c e a t
la o
o
e

Fa
D

Wo rst Ou t co me : Ne crosis Mitochondria Ca2+ uptake,

s
s t re

decreased mitochondriaCyt cmembrane potentia , generation o MPT/MOMP

F
A

x
D

a
D

t -B id B c l-2
ROS and RNS, depBidetion o A P, and consequences o the pri

B
P
C
-8
Cyt c, Smac, AIF release
F

Fas
mary metabo ic disorders (e.g., accumu ation o inorganic
N

T
T

T
F

R
1

F
D
re

A
D
c

phosphate, ree atty acids, and

ATP
ysophosphatides) are a con
P
D

Cyt c Bax p53

C
-8

Apaf-1

sidered as causative actors o an abrupt increase in the mito

PC-9
In a few In more In all
chondria inner membrane permeabi ity, termed MP . T is mitochondria mitochondria mitochondria
is be ieved to be caused by the opening o a proteinaceous
pore that spans both C-8 mitochondria C-9 membranes
Initia tor ca spa ses and is per
meab e to so utes o 1500 Da. T is opening permits ree in ux Autophagy of Caspase ATP
mitochondria activation depletion
into the matrix PC-6 space oPC-3 protons,PC-7 causing rapid and comp ete
dissipation o the membrane potentia , cessation o A P syn
thesis, and the C-6 osmotic C-3in ux o water C-7 E causing
ector ca spa sesmitochondria Cell
swe ing. Ca accumu ated in the matrix space e uxes
2+ Apoptosis Necrosis
survival
through the pore, Hydrolysis of ooding
speci c cellular theproteins
cytop asm. Such mitochondria
are not on y incapab e o synthesizing A P, but a so even
(e.g., PARP, ICAD, α -fodrin, actin, lamins, FAK, SERBP)
FIGURE 3–9 “Decision plan” on the ate o injured cell.
waste the remaining sources because Curtis depo arization
D. Klaasen, o III.the
John B. Watkins See the text or details. MOMP = mitochondrial outer membrane
Casarett & Doull’s. Essentials of Toxicology.
inner membrane orces Apoptosis the A P synthase 2015 to operate in the permeabilization; MPT = mitochondrial permeability transition;
reverse mode, asmitochondrial
an A Pase, hydro yzing Aor TNFP.receptor-1
T en stimulation.
g yco ysis Puma = p53-upregulated modulator o apoptosis; RO(N)S = reactive
FIGURE 3–10 Apoptotic pathways initiated by insult, nuclear DNA insult, and Fas The
oxygen or nitrogen species.
may become compromised by the insu cient A P supp y to
gure is a simpli ed scheme o three pathways to apoptosis. (1) Mitochondrial insult ultimately opens the permeability transition pore spanning
 Toxicant

Tahap 4: Perbaikan 1

Delivery

PERBAIKAN MOLEKULAR PERBAIKAN DITINGKAT SEL

› Protein repair › Autophagy

› Renegerasi kerusakan
› Lipid repair
2a 2b
Alteration
Akson Interaction
of biological

› DNA repair
with target
molecule environment

T
PERBAIKAN JARINGAN (TISSUE) 3
O
Cellular
› Apoptosis dysfunction,
injury X
› Proliferasi: regenerasi jaringan I F

›
in
Penggantian Matriks Ekstraselular C to

›
o
Reaksi Samping Cidera Jaringan 4
I
by
In a p p r o p r i a t e
r e p a ir a n d
a d a p t a t io n T pa

Y si
th

FIGURE 3–1 Potential stages in the deve lopment o toxicity M

a ter chemical exposure.
Po
 HS Keap1 Keap1 SH
Electrophiles Oxidants
Tahap 4: Adaptasi – Ekspresi HS Ub Ub SH
Nrf2
Gen
› Enzim mendetoksifikasi
HS Keap1 Keap1 S
xenobiotic
E S S
› Enzim mengeliminasi radikal
bebas
sMaf Nrf2
› Protein mendetoksifikasi Genes
komponen darah EpRE

› Enzim dalam proses

homeostasis GSH NQO1 SOD1 HO-1 GCL Mrp2 Trx
AR Catalase ferritin GGT Mrp3 TrxR
› Mengeluarkan xenobiotik EH1 GPX2 Mrp4 proteosome
CES Srx1
dan metabolitnya keluar dari GST GR
sel UGT

› Perbaikan protein &

penghilangan protein Xenobiotic
–
O2• , HOOH Heme GSH Export Protein
detoxication detoxication detoxication, synthesis, from cells repair,
iron turnover removal
sequestration
Curtis D. Klaasen, John B. Watkins
III. Casarett & Doull’s. Essentials of FIGURE 3–11 Signaling by Keap1/Nr 2 mediates the electrophile stress response. Normally NF-E2-related actor 2 (Nr 2) is kept
Toxicology. 2015 inactive and at a low intracellular level by interacting with Keap1 that promotes its proteasomal degradation by ubiquitination. Electrophile
covalently bind to, whereas oxidants oxidize the reactive thiol groups o Keap1, causing Keap1 to release Nr 2. Alternatively, Nr 2 release m
ollow its phosphorylation by protein kinases. A ter being released rom Keap1, the active Nr 2 accumulates in the cell, translocates into the
Tahap 4: Efek toksik dari proses perbaikan &
adaptasi yang tidak wajar
› Nekrosis jaringan adalah
bentuk cidera sel yang
mengakibatkan kematian
prematur sel-sel
pada jaringan hidup
› Fibrosis adalah proses
pembentukan jaringan fibrin
› Karsinogenesis adalah proses
pembentukan kanker dari
karsinogen
Curtis D. Klaasen, John B. Watkins
III. Casarett & Doull’s. Essentials of
Toxicology. 2015
Faktor-faktor yang mempengaruhi Efek Toksik
› Sifat fisik & aktivitas kimia dalam › Metabolisme
tubuh › Distribusi dalam tubuh
› Dosis & hubungan dosis-waktu › Ekskresi
› Rute pajanan › Kondisi Kesehatan seseorang
› Spesies › Status gizi
› Usia › Adanya bahan kimia lain dalam tubuh
› Jenis kelamin
› Kemudahan toksikan diabsorpsi
 Spektrum Efek Toksik
Klasifikasi Spektrum Efek Toksik
Lokasi Efek lokal/sistemik/target organ
Tingkat Efek bertingkat /kuantal
Waktu Efek akut/kronik
Waktu Efek segera/tertunda
Kepulihan Efek berpulih/nirpulih
Sel/Molekular Efek selular/molekular
Alergi Efek alergik/idiosinkrasi
Hipersensitivitas
berpulih Efek
tersebut tergantung dari waktu hipersensitivitas/idiosinkrasi
paruh serta kadar toksikan yang kontak atau masuk ke
dalam Karsinogen
tubuh. Sedangkan efek toksik Efek karsinogenik/genotoksik
dikatakan nirpulih apabila efek yang timbul tidak hilang
Pertumbuhan
walaupun Mengganggu
antara tubuh dengan toksikan pertumbuhan
sudah tidak terjadi interaksi samajanin
sekali (menetap di
dalam tubuh).

Mekanisme Efek Alergi Toksikan

Gambar 6.1 Efek Alergi Sumber: ToxTutor. https://toxtutor.nlm.nih.gov/
Lokasi Efek Lokal Efek Sistemik

• Terjadi pada lokasi kontak • Terjadi pada beberapa

pajanan
• Xylen menyebabkan
penghilangan lapisan lemak
pada kulit
• Asam Sulfat menyebabkan
iritasi kulit/mata/luka bakar
kulit
• Tumpahan aldehid pada
mata
lokasi/titik/sistem
• Xylen menyebabkan
kerusakan pada sistem
syaraf pusat & hati
• Kadmium menyebabkan
kerusakan ginjal
• Timbal menyebabkan
kerusakan ginjal
Jenis-jenis efek lokal

C. Winder. Occupational Toxicology. 2nd Ed. 2005

 Efek Lokal

C. Winder. Occupational Toxicology. 2nd Ed. 2005

Video – Nitrogen Asfiksiasi
Valero Refinery Asphyxiation Incident
Accident: Valero Refinery Asphyxiation Incident
Location: Location: Delaware City, DE
Accident Occured On: 11/05/2005 
Final Report Released On: 11/02/2006
Accident Type: Confined Space / Asphyxiation
Investigation Status: The CSB issue a case study report and a safety video
based on this incident at a news conference in Newark, Delaware, on
November 2, 2006. 
Two contract employees were overcome and fatally injured by nitrogen as
they performed maintenance work near a 24-inch opening on the top of a
reactor. One of the workers died attempting rescue.
 When gathering toxicity information it becomes clear that much more acute toxi
data exist for oral exposures than for other routes, such as inhalational or dermal. T
can be limiting when preparing information about chemicals for which the lik
Toxicant Acute Toxicity Chronic Toxic Effects
Efek Toksik Sistemik exposure route is via the lungs or the skin. Some extrapolation across routes can
undertaken, however,
Ethanol as CNS determined by Winder
depression and Agrawal (1995) w
Liver cirrhosis

› Acute Toxicity comprehensively compared acute toxicity by different routes of administration. Table

Gastrointestinal
shows comparative classifications
Arsenic
damagefor acute toxicity for the three major routes
Skin/liver cancer

› Subchronic Toxicity exposure.

› Chronic Toxicity Table Sumber:

2.3 Duration of exposure
ToxTutor. https://toxtutor.nlm.nih.gov/

› Carcinogenicity Nature of exposure Example

Acute or single Accident
› Developmental Toxicity Major spill
Maintenance in enclosed space
› Genetic Toxicity (somatic cells)  Subchronic or short-term repeated Worker on process for e.g. >1 year
Chronic or long-term repeated Worker on process for e.g. 20 years
Exposure to pollution
Pesticide in food
Contaminant in drinking water

C. Winder. Occupational Toxicology. 2nd Ed. 2005

Toksisitas pada Organ Spesifik
› Hematotoksisitas toksisitas darah atau
kardiovaskular
› Dermatotoksisitas (Toksisitas dermal)
› Okulotoksisitas (Toksisitas okular/mata)
› Hepatotoksisitas (toksisitas hati)
› Immunotoksitas (toksisitas sistem
imun)
› Neurotoksisitas (toksisitas sistem
syaraf)
› Toksisitas reproduktif
› Toksisitas sistem pernafasan
› Toksisitas Genetik
› Nefrotoksisitas (toksisitas ginjal)
Kasus Toksikan di Industri
› Terjadi kebocoran toksikan disebuah industri
› Gas berwarna kuning kehijauan
› Bau: menyengat, seperti di kolam renang
› Kerapatan uap : >1
› Efek Toksik:
– Iritasi mata, mata membengkak, keluar air mata, penglihatan terganggu,
kehilangan penglihatan
– Iritasi tenggorokan
– dizziness, agitation, unresponsive, headache, spasms/seizures
› Dampak: 140 cidera, 11.000 masyarakat mengungsi
› Perusahaan merasa tidak memiliki produk tsb
Efek Toksik Kritikal pada TLV-ACGIH
 Video: Mixed Connection

The release
occurred during a
routine chemical
delivery when two
incompatible
chemicals – sulfuric
acid and sodium
hypochlorite –
were inadvertently
mixed, forming the
toxic cloud. 
Terima kasih