Toxicology and Measures of Toxicity
T
o
x
i
c
o
l
ogy
is
t
he
study
of the
adver
s
e
effects
o
f chemicals
on
living
organism
s
.
Xenobiotic
- man-made substance and/or produced by plants,
animals, or bacteria but not normally found in the body.
A
t
o
x
i
c
o
l
ogist
is trained
person
to
examine
the
nature
of th
o
se
effec
t
s (in
c
luding
their
cel
l
ular,
biochemi
c
al,
and
m
o
lecul
a
r
mechani
s
ms
of ac
t
ion)
found in the body.
*
P
o
i
s
o
n
o
u
s
s
u
b
s
t
a
n
c
e
s
a
r
e
p
r
o
d
u
c
e
d
b
y
p
l
a
n
t
s
,
a
n
i
m
a
l
s
,
o
r
b
a
c
t
e
r
i
a
.
P
h
y
t
o
t
o
x
i
n
s
Z
o
o
t
o
x
i
n
s
B
a
c
t
e
r
i
o
t
o
x
i
n
s
Mea
s
u
r
es
of
T
o
xicity
The
normal
p
r
o
c
ed
u
r
e
is
t
o
e
x
po
s
e
t
est
ani
m
als
By
in
g
es
t
ion
applicat
i
on
t
o
the
skin
By
placing
the
t
est
ma
t
e
r
ial
in
the
w
a
t
er
or
air
of
the
t
est
animals’
e
n
v
i
r
o
n
ment
te
s
ting
Lab animals
–
Rat
s
,
mi
c
e,
d
o
g
s
, mo
n
k
e
y
s
e
t
c
• Sa
f
ety
in
e
x
per
i
mental
an
i
mals
does
n
o
t
ne
c
essari
l
y i
n
dica
t
e
the
same
in
human
s
.
–
E
x
ample:
Thalid
o
mide
a
h
u
man
t
e
r
a
t
o
g
en
sh
o
ws
t
o
xic
i
ty(caused
shor
t
eni
n
g
or
c
om
p
le
t
e
absen
c
e
of
limbs)
at doses
as
l
o
w
as
0.
5
-1
mg/
k
g
and
has
l
i
t
tle
or
no
ef
f
ect
in
mi
c
e or
r
ats
at
doses
as
hi
g
h
as
4000
mg/
k
g
.
Mea
s
u
r
es
of
T
o
xicity
M
ortali
t
y
(dea
t
h)
T
e
r
a
t
o
g
e
n
icity
(ability
t
o
cause
bir
t
h
d
e
f
ects)
Ca
r
cino
g
e
n
icity
(ability
t
o
cause
can
c
er),
a
n
d,
M
uta
g
eni
c
ity
(
ability
t
o
ca
u
se
heritable
c
h
an
g
e
in
the
D
N
A
)
M
e
a
s
u
r
e
s
o
f
T
o
x
i
c
i
t
y
:
L
D
5
0
T
h
e
a
m
o
u
n
t
(
d
o
s
e
)
o
f
a
c
h
e
m
i
c
a
l
w
h
i
c
h
p
r
o
d
u
c
e
s
d
e
a
t
h
i
n
5
0
%
o
f
a
p
o
p
u
l
a
t
i
o
n
o
f
t
e
s
t
a
n
i
m
a
l
s
t
o
w
h
i
c
h
i
t
i
s
a
d
m
i
n
i
s
t
e
r
e
d
b
y
a
n
y
o
f
a
v
a
r
i
e
t
y
o
f
m
e
t
h
o
d
s
m
g
/
k
g
N
o
r
m
a
l
l
y
e
x
p
r
e
s
s
e
d
a
s
m
i
l
l
i
g
r
a
m
s
o
f
s
u
b
s
t
a
n
c
e
p
e
r
k
i
l
o
g
r
a
m
o
f
a
n
i
m
a
l
b
o
d
y
w
e
i
g
h
t
T
h
e
M
e
d
i
a
n
L
e
t
h
a
l
C
o
n
c
e
n
t
r
a
t
i
o
n
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C
5
0
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h
e
c
o
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e
n
t
r
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t
i
o
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o
f
a
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h
e
m
i
c
a
l
i
n
a
n
e
n
v
i
r
o
n
m
e
n
t
(
g
e
n
e
r
a
l
l
y
a
i
r
o
r
w
a
t
e
r
)
w
h
i
c
h
p
r
o
d
u
c
e
s
d
e
a
t
h
i
n
5
0
%
o
f
a
n
e
x
p
o
s
e
d
p
o
p
u
l
a
t
i
o
n
o
f
t
e
s
t
a
n
i
m
a
l
s
i
n
a
s
p
e
c
i
f
i
e
d
t
i
m
e
f
r
a
m
e
m
g
/
L
N
o
r
m
a
l
l
y
e
x
p
r
e
s
s
e
d
a
s
m
i
l
l
i
g
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m
s
o
f
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u
b
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e
p
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r
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i
t
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r
o
f
a
i
r
o
r
w
a
t
e
r
(
o
r
a
s
p
p
m
)
T
h
e
e
x
p
o
s
u
r
e
E
x
p
o
s
u
r
e
,
l
i
k
e
m
a
n
y
o
f
t
h
e
t
e
r
m
s
i
n
t
o
x
i
c
o
l
o
g
y
,
h
a
s
s
e
v
e
r
a
l
d
i
f
f
e
r
e
n
t
a
s
p
e
c
t
s
,
t
h
e
m
o
s
t
i
m
p
o
r
t
a
n
t
o
f
w
h
i
c
h
a
r
e
1
)
r
o
u
t
e
o
f
e
x
p
o
s
u
r
e
,
2
)
f
r
e
q
u
e
n
c
y
o
f
e
x
p
o
s
u
r
e
3
)
d
u
r
a
t
i
o
n
o
f
e
x
p
o
s
u
r
e
R
ou
t
es
and si
t
e
of Exp
o
su
r
e
An
a
g
ent
e
x
erts
its
ef
f
ects
w
hen
it
en
t
ers
or
c
omes
i
n
t
o
c
o
n
tact
with
the
bo
d
y
,
or
in
other
w
o
r
d
s
,
w
hen
an
i
n
d
i
vidual
has
been
e
x
p
o
sed
t
o
it.
1) O
r
al
⇒
GI
t
r
act
2)
I
nhalati
o
n
⇒
L
u
ngs
3)
T
o
p
ical,
pe
r
cu
t
ane
o
u
s
,
or
dermal
⇒
Skin
4) Oc
u
la
r
,
c
o
n
j
u
nct
i
v
a,
c
or
n
ea
⇒
E
y
es
5) O
t
her
r
ou
t
es
⇒
I
P
,
SC,
IM,
I
D
,
I
V
…
.
.
Durati
o
n
and Frequency of
Exposure
T
ox
i
colog
i
sts
usually
divide
t
he
e
x
posure
of e
x
per
i
m
e
ntal
a
n
i
m
als
to c
h
e
m
icals
into
four
categor
i
es:
Acute
e
x
posure
is
def
i
ned
as exposure
to a
c
h
em
i
c
a
l
for
less
than 24
h
Subacu
t
e
ex
p
osure
re
f
ers to
repeat
e
d
e
xposure
to a
c
hem
i
cal for 1 month
or less
Subchronic
for
1
to 3 mont
h
s
Chronic
for more
t
h
an 3
months
D
o
s
e
r
e
s
p
o
n
s
e
T
h
e
c
h
a
r
a
c
t
e
r
i
s
t
i
c
s
o
f
e
x
p
o
s
u
r
e
a
n
d
t
h
e
s
p
e
c
t
r
u
m
o
f
e
f
f
e
c
t
s
c
o
m
e
t
o
g
e
t
h
e
r
i
n
a
c
o
r
r
e
l
a
t
i
v
e
r
e
l
a
t
i
o
n
s
h
i
p
c
u
s
t
o
m
a
r
i
l
y
r
e
f
e
r
r
e
d
t
o
a
s
t
h
e
d
o
s
e
-
r
e
s
p
o
n
s
e
r
e
l
a
t
i
o
n
s
h
i
p
T
w
o
t
y
p
e
s
I
n
d
i
v
i
d
u
a
l
t
o
v
a
r
y
i
n
g
d
o
s
e
s
o
f
a
c
h
e
m
i
c
a
l
,
R
e
s
p
o
n
s
e
o
f
a
n
i
n
d
i
v
i
d
u
a
l
o
r
g
a
n
i
s
m
t
o
v
a
r
y
i
n
g
d
o
s
e
s
o
f
a
c
h
e
m
i
c
a
l
P
o
p
u
l
a
t
i
o
n
o
f
i
n
d
i
v
i
d
u
a
l
s
Dose response
The
c
h
ara
c
t
e
ri
s
tics
of e
x
posure
a
n
d
the
spectrum
of ef
f
ects
come together
in a
correlative
relationship
c
u
stomarily re
f
err
e
d
t
o
as the
d
o
s
e
-
resp
o
nse
re
l
ationship
T
wo
types
In
d
iv
id
ual
to
varying
d
oses
of
a
ch
e
mi
c
al,
R
e
s
p
onse
of
an
indi
v
idu
a
l
organism
to
vary
i
ng dos
e
s of a chemi
c
al
Popu
l
a
t
ion
of
indiv
i
duals
d
o
s
e
-
r
e
s
p
o
n
s
e
r
e
l
a
t
i
o
n
s
h
i
p
d
o
s
e
-
r
e
s
p
o
n
s
e
r
e
l
a
t
i
o
n
s
h
i
p
LD50 values are the standard for
comparison of acute toxicity
between chemical compounds and
between species
T
D
5
0
–
M
e
d
i
a
n
T
o
x
i
c
D
o
s
e
E
D
5
0
–
M
e
d
i
a
n
E
f
f
e
c
t
i
v
e
D
o
s
e
L
C
5
0
–
M
e
d
i
a
n
L
e
t
h
a
l
Concentration
Dos
e-
Resp
o
nse Curve?
N
O
AEL
V
al
u
e
–
No
Obs
e
rved
Adverse
Ef
f
ect
Lev
e
l,
T
h
e h
i
g
h
est dose
of
a
ch
emi
c
al that,
i
n
a
g
i
v
en tox
i
c
ity
test,
c
a
u
ses
n
o obser
v
able
e
f
f
e
c
t
in
test a
n
imals
T
h
e
NO
A
EL
for the
m
ost
sensi
t
ive
test species
and the
m
ost
sensi
t
ive
in
d
i
c
a
t
or of to
x
i
c
i
t
y
is
us
u
ally e
m
p
l
oyed
for reg
u
latory
p
u
r
p
oses
LOAEL
V
al
u
e
–
Lowest
Obs
e
rved
Adverse
Ef
f
ect
Lev
e
l,
T
h
e l
o
west
dose
of a
c
h
e
m
i
c
al
that,
i
n
a
g
i
ven toxi
c
ity
test,
does
ca
u
se
an
observable
ef
f
ect
in test
a
n
imals
w
h
a
t
C
a
n
B
e
L
e
a
r
n
e
d
F
r
o
m
A
D
o
s
e
-
R
e
s
p
o
n
s
e
C
u
r
v
e
T
O
X
I
C
I
T
Y
R
A
T
I
N
G
F
O
R
H
U
M
A
N
S
(
7
0
K
G
B
O
D
Y
W
E
I
G
H
T
)
Toxicology is the study of the adverse effects of chemicals on living organisms, involving xenobiotics and poisonous substances. Toxicologists examine the nature of these effects, testing in lab animals for measures of toxicity such as mortality, teratogenicity, carcinogenicity, and mutagenicity. Key measures include LD50 and LC50, assessing the lethal effects of chemicals. Exposure, determined by route, frequency, and duration, plays a critical role in toxicology studies.
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Presentation Transcript
Toxicology is the study of the adverse effects of chemicals on living organisms. Xenobiotic - man-made substance and/or produced by plants, animals, or bacteria but not normally found in the body. A toxicologist is trained person to examine the nature of those effects (includingtheir cellular,biochemical,and molecular mechanismsof action)
found in the body. * Poisonous substances are produced by plants, animals, or bacteria. Phytotoxins Zootoxins Bacteriotoxins
Measures of Toxicity Thenormal procedureis toexposetestanimals By ingestion application totheskin Byplacing thetest material in thewaterorairof the test animals environment
testing Lab animals Rats, mice,dogs, monkeysetc Safety inexperimentalanimalsdoes notnecessarily indicatethe same in humans. Example: Thalidomidea human teratogenshows toxicity(caused shortening orcompleteabsenceof limbs) at dosesas lowas 0.5-1 mg/kg and has littleornoeffectin mice orratsatdosesas highas 4000 mg/kg.
Measures of T oxicity Mortality(death) Teratogenicity(abilitytocausebirthdefects) Carcinogenicity(abilitytocausecancer),and, Mutagenicity(abilitytocause heritablechangein theDNA)
Measures of Toxicity: LD50 The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered byanyof avarietyof methods mg/kg Normallyexpressedas milligramsof substanceper kilogramof animal bodyweight
The Median Lethal Concentration LC50 Theconcentrationof achemical inanenvironment (generallyairorwater) which producesdeath in 50%of anexposed populationof testanimals ina specified timeframe mg/L Normallyexpressedas milligramsof substanceper literof airorwater(orasppm)
Theexposure Exposure, like manyof theterms intoxicology, hasseveral differentaspects, the most importantof whichare 1) routeof exposure, 2) frequencyof exposure 3) durationof exposure
Routes and site of Exposure Anagentexerts itseffectswhen itentersorcomes into contactwith the body, orinotherwords, whenan individual has beenexposed to it. 1) Oral GI tract 2) Inhalation Lungs 3) Topical, percutaneous,ordermal Skin 4) Ocular, conjunctiva, cornea Eyes 5) Otherroutes IP , SC, IM, ID, IV ..
Duration and Frequency of Exposure Toxicologists usually divide the exposure of experimental animals to chemicals into four categories: Acute exposure is defined as exposure to a chemical for less than 24 h Subacute exposure refers to repeated exposure to a chemical for 1 month or less Subchronic for 1 to 3 months Chronic for more than 3 months
Dose response The characteristics of exposure and the spectrum of effects Dose response The characteristics of exposure and the spectrum of effects come together in a correlative relationship come together in a correlative relationship customarily referred to as the dose-response relationship Two types Individual to varyingdosesof a chemical,Responseof an individual organism to varying doses of a chemical Populationof individuals customarily referred to as the dose-responserelationship Two types Individualto varyingdosesof a chemical,Responseof an individualorganism to varying doses of a chemical Populationof individuals
LD50 values are the standard for comparison of acute toxicity between chemical compounds and between species TD50 Median Toxic Dose ED50 Median Effective Dose LC50 Median Lethal Concentration
Dose-Response Curve? NOAEL Value No Observed Adverse Effect Level, The highest dose of a chemical that, in a given toxicity test, causes no observable effect in test animals The NOAEL for the most sensitive test species and the most sensitive indicator of toxicity is usually employed for regulatory purposes LOAEL Value Lowest Observed Adverse Effect Level, The lowest dose of a chemical that, in a given toxicity test, does cause an observable effect in test animals
