Toxicology()

(modern Toxicology )
/

(descriptive toxicology)(mechanistic toxicology)

(regulatory toxicology)

3Rs

(xenobiotics)

toxicity

toxic effect

(poisoning)

(poison)

adverse effect

non-adverse effect

spectrum of toxic effects

dose

graded response

quantal response

dose-effect relationship -graded doseresponse relationship

-dose-response relationship -quantal doseresponse relationship
---
-

selective toxicity

1
2
3
4

(target organ)

biomarker

LD100 LC100

median lethal doseLD50

LD50

LD50
MLDLD01 MLCLC01

LD0LC0

lowest observed adverse effect level

LOAEL

no observed adverse effect level NOAEL

lowest observed effect level LOEL

no observed effect level NOEL

threshold

safety limit value

toxic effect zone

acute toxic effect zone, Zac

Zac=LD50/Limac
Zac

chronic toxic effect zone,Zch

Zch= Limac /Limch
Zch Limac Limch

2.
3.

S
50%
S
S S
S

4.-

3.

1
2 3 4
/ 5 6 7
8
123
456

4.
:
.
4

.
.

5.

* *

( ( (
) )

()

(50)

(
)

6.
1. absolute lethal dose/concentrationLD100/LC100
2. minimal lethal
dose/concentrationMLD, LD01/MLC, LC01
3. maximal non-lethal dose/
concentrationLD0/LC0 4.
median lethal dose/concentrationLD50/LC50
5. threshold dose LOAEL
minimal
effect dose acute
threshold dose subchronic threshold dose chronic
threshold dose6. maximal-no effect doseNOAEL

7.. 1. acute toxic effect zone Zac

Zac=LD50/LimacZac
2. chronic
toxic effect zoneZchZch=Limac/Limch Zch

8.NOEL,NOAEL,LOEL,LOAEL ?
NOAEL LOAEL NOEL
LOEL
9.

ADME (Absorption) (Distribution) (Metabolism)(Excretion)

biotransport ADME

biotransformation

(passive transport)
simple diffusion)

(filtration)
eg:

.
absorption
first pass elimination

(mg/L)(mg/L)
6

accumulation
CO (1) DDT (2)

storage depot
DDT

1. blood-brain barrier 2.
placental barrier 3. blood-testis-barrier 4. blood-ocular barrier

enterohepatic circulation

95%

phase biotransformation
phase biotransformationconjugation

P450 microsomal mixed function

oxidaseMFOmonoxygenase

P450 b5NADPH- P450 NADH-
b5 3 P-450
genetic polymorphism 1%

enzyme induction

enzyme repression:

1.
7

1 2

2.
absorption
1

2

3
/
4
distribution)
ml/min 100g
redistribution target organs
depot excretion)
:1.
2.
3.
4.

3.

/
4.

/

10 m 0.1 m
0.52 m

/ 1

4 ;

5.

a) 5 m
b) 2m5m
c) 0.52 m
d) 0.1 m

, 0.1~10 m
6.

7
1

1
9

2 ZnCdHgPb
3PCB

4PbSiBa Ca F-
OH-90%
2

8.

9.
60kDa

10.
(enterohepatic circulation)

11.

2
3/

10

12.
bioinformation
metabolite

1metabolic detoxication
2metabolic activation
bioactivation


13. genetic
polymorphism 1. 2.
3.

14.

15.

-OH-NH2-SH-COOH
1
2
3

()
(conjugation)
1.

2.

3.

11

4.
5.
6.

16.
P450 microsomal mixed function
oxidaseMFOmonoxygenase
P-450
(1)(2)(3)
(S-N-I-) N- (4)(O-S-N- Si-) (5)
(6) (7)
17.
18 P450

19. II

1 II
()
2
12

20. II

12
1.UDPGA

2. PAPS

3.

4.

5.

6.
21
22
enzyme induction

enzyme repression:
1.
2.

22. 5
23.

13

24.

(Mechanisms of Toxicity)

toxication)
electrophiles)

free radicals)
;

detoxication)

(ultimate toxicant DNA

adducts

1
toxication

2 (,4 )
DNA

1. 2. 3. 4.

3
metabolic activationbioactivation

4(5 )
1

2
3
4

14

5
5

DNA DNA DNA
DNA

1
2 3 DNA

lipid/water partition coefficients
/
DDT
/

blood/gas partition coefficient

<2

1.

2.
I

II
III
3. .

4.(5 )
joint action
15

1 2

synergistic effect

potentiation joint action

antagonistic joint action

acute toxicity:
24 14

1 LD50
LD50
2

1.( LD50 )
20%( 5-7) 5
2000mg/kg 5
14
2.3R
3.


(accumulation)

material accumulation

16

functional accumulation

1430

1/10

:()

(1)
(2)
(3)
(4) -() NOAEL
LOAEL
(5)

() 15g
100g








2.

30 10g/100g
90 8g/100g 5g/100g

17

2-6h
1h 8h

6h

3
3 LD50

( NOAEL)
2-4
(1)28 LD50
10%-20%() 3
(2) LD50

(/) 100g
/(/)100

a)

5-6
18

b)

6 1-2
46 8

1-2

2
10%

3
GLP
4
SOP

(heredity):

(mutation)
(mutagenesis)

1
19

gene mutation
a) (basepair substitution)
b) (frameshift mutation)
chromosome aberration
c) (chromatid-type aberration)
d) (chromosome aberration)

e) (aneuploidy and polyloid)

2 DNA
a)
(alkylating agent) DNA
DNA
O-6 GC AT

N-7 DNA
AP

b) DNA
(1) DNA
(4-6) DNA
(2)DNA DNA adducts

(3) DNA-(DNA-Protein crosslinksDPC)

3

()

()

i.

(genetic endpoint)
20

4
1 DNA ()

( ) (Ames )

(Salmonella typhimurium)
(E. Coli)
()
Salmonella typhimuriumhis

()
()
(S9)
( )
() : (Micronucleus MN)
12O13

DNA

(Micronucleus test MNT)

DNA
( )
5.

6.

A
21

B S9 S9 9000g
(MFO)

A
B DNA
C

()()

8
(chemical carcinogenesis)
(chemical carcinogen)
(direct acting carcinogen):
(indirect acting carcinogen):

(procarcinogen)
(proximate carcinogen)
(ultimate carcinogen)
1.

1
2

5
6

22

1
2

-
()

()

promoted cell population)

-

/

/


2

DNA DPC
DNA

3DNA DNA
DNA
DNA
DNA DNA

DNA

4IARC()()
20021 2
3 (497 )
23

4 (1 )
5

(malformation):

(terate):
(teratogenicity) (teratogenic effect)

(teratogen):

(embryotoxicity)

(developmental toxicity)()
:
:
:
:
:

1 1
preimplantation loss
2
critical period1
2 3 3

-1-a.
b.
c.
24

2
(maternal toxicity)

3

()

5
FDA
--- -

1
23
4

regulatory toxicology:

safety

safety evaluation

hazard

risk()

1
25

hazard identification

Hazard Characterization
- dose-response
relationship assessment 2
exposure assessment

dose
exposure scenario

Risk Characterization

()
----
LD50 LC50,,
,
----
,

----

, LOAEL NOAEL,
,
----
,,
, NOAEL LOAEL,,

1.
26

2.
3. 3R
4

(risk assessment)
(risk)

,
~
~

6 mutagenesis biomarker of

susceptibilityLD50ultimate toxicant
6

3 TAT ~~

27