Ecotoxicology Toxicology Uptake and distribution of xenobiotics.
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Transcript of Ecotoxicology Toxicology Uptake and distribution of xenobiotics.
![Page 1: Ecotoxicology Toxicology Uptake and distribution of xenobiotics.](https://reader035.fdocuments.us/reader035/viewer/2022062408/56649e865503460f94b89fbd/html5/thumbnails/1.jpg)
Ecotoxicology
ToxicologyUptake and distribution
of xenobiotics
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pH = 6.4[conc. 4]
Ca++
+ + + + + +
- - - - - - - -
pH=7.4[conc. 2]
Functions of the biological membrane
Maintain homeostasisSelective uptake and excretion
Excitability
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The biological membrane
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The lipophilic route
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Phospholipid
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Passage of chemicals through the membrane depends on:
SizeFat solubility
Resemblance with endogenous molecules
The passage takes place through:
Passive diffusion through the phospholipidsThrough water and ion channels
Active transport through channelsEndocytosis
Passive diffusion most important toxicologically
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The diffusion rate increases with the water-octanol distribution coefficient (Kow)
n-octanol
Water
Kow<1 1 >1 >>1
1:5 1:1 5:1 21:1
][
octanol][
conc
concKow
water
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1 10 102
103
104
105
106
107
108
109
Solubility in water (nM)
10
102
103
104
105
106
107
n-octanol:waterDistribution coefficient
2,2',4,4',5,5'-PCB
DDT2,2',4,5,5'-PCB
DDE4,4'-PCB
ParathionNaphtalen
Benzen
Toluen
Chloroform
p-dichlorbenzen
Chlorbenzen
Benzoic acid
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KowD
iffu
sio
n r
ate
O and N increase hydrophilic characteristics
Alkyl groups increase lipophilic characteristics
mnemonic rule: compound lipophilic if
4>+ONC
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Ionization
AH A- + H+
BOH B+ + OH-
+- +
-
pH dependentWater
+-
+-
+-
+-
+-
+-
+-
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The diffusion follows the concentration gradient given by Fick’s law
CAPdtdn
P = Permeability constant (mol/cm2)
A = Area
ΔC = Concentration difference
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COO-
NH3+
COO-
NH3+
COOH
NH2
COOH
NH2
+ H+ + H+
H++ + H+
1
1
1
1
100
1000
2512
251
Stomach pH 2
COO-
NH3+
COO-
NH3+
COOH
NH2
COOH
NH2
+ H+ + H+
H++ + H+
1 1
11
100
10
2512
251
Intestine pH 6 Plasma pH 7.4
Plasma pH 7.4
Uptake of Benzoic acid og Aniline
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The hydrophilic route
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Channel for divalent cation
2+
2+2+
2+
2+2+
2+
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Pyrethroides’ effect on excitable membranes
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Cadmium passes the Ca++ channel
Cd++ [0,97 Å] Ca++ [0,99 Å]
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Endocytosis
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H +
H + lysosome
receptor
coated vesikel
iron - transferrin complex
Endocytosis of iron
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Uptake, distribution and excretionof xenobiotics
Alimentary canal Respiratory surfaces Skin
Faeces
Bile
Secretory structures
Secretions
Lungs/gills
Alveoli
Air/water
Liver
Blood and
lymph
Kidney
Bladder
Urine
Extra-cellular fluid
Organs
Soft
tissue
Hard
tissue
Fat
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Enterohepatic circulation
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1 2 3 4 5Day no
2.5
2.0
1.5
1.0
0.5
Pp
m H
g (
Hg
++
)
1 2 3 4 5 6 7 8Day no
90
60
30
Pp
m H
g (
MeH
g)
1 2 3 4 5 6 7 8Day no
120
60
40
Wei
gh
t (m
g)
1 2 3 4 5 6 7 8Day no
120
60
40
Wei
gh
t (m
g)
Mercury uptake in maggots
10 ppm
1.0 ppm
0.1 ppm
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Air route
Alimentary channel
Blood / haemolymphe
Bronchioler / T
racheoles
Bronchi / T
rachea
Nose and pharynx
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HydrofileLipofile
The skin
Wet skin: Increases penetration by a factor 3Soap and other detergents: Increased penetration of hydrophilic compoundsOrganic solvents: Irreversible degradation of corneum
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Xenobiotics are distributed in tissue fluids
Plasma: 4% of body weightExtracell. fluid: 13% -Intracell. fluid: 41% -
Intracellularfluid
Extracellularfluid
Pla
sm
a Lipophilic compoundsHydrophilic compounds
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Plasma - protein linkage
K1
K2
The organism’sothercompartments
ondissociati2
1 KK
K
High Kdiss loosely boundLow Kdiss tightly bound
Low affinity and high capacity toxicological most important
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DoseBlood sample
Compartment of distribution
(mg/l)ionconcentrat Plasma
(mg)DoseVD
”Apparent compartment of distribution” VD
VD low: high depositing in organs
VD high: low depositing in organs
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Depositing to organs
Co
nc
.
Time
1. order
Co
nc
.
Time
0. order
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Brodie-Gillette’s box model
Bound
Free
Bound
Free
Bound
Free
Metabolites
Excretion
Absorption
Target site
Depot
Metabolism
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Excretory organs
Nephridia in earthworm
Vertebrate kidney
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Nephridium of an invertebrate
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Excretion
CK
on
c.
Tid
1. order
Co
nc
.
Tid
0. order
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Ckdt
dCe
0 10 20 30 40 50
Time (days)
30
50
100
% dioxin remainingIn body
T½ = 30,5 days
eee
t0
k
0,693
k
ln2
k
lnClnCT½