ecotoxicology toxicology uptake and distribution of xenobiotics
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Ecotoxicology
ToxicologyUptake and distribution
of xenobiotics
pH = 6.4[conc. 4]
Ca++
+ + + + + +
- - - - - - - -
pH=7.4[conc. 2]
Functions of the biological membrane
Maintain homeostasisSelective uptake and excretion
Excitability
The biological membrane
The lipophilic route
Phospholipid
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
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
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
KowD
iffu
sio
n r
ate
O and N increase hydrophilic characteristics
Alkyl groups increase lipophilic characteristics
mnemonic rule: compound lipophilic if
4>+ONC
Ionization
AH A- + H+
BOH B+ + OH-
+- +
-
pH dependentWater
+-
+-
+-
+-
+-
+-
+-
The diffusion follows the concentration gradient given by Fick’s law
CAPdtdn
P = Permeability constant (mol/cm2)
A = Area
ΔC = Concentration difference
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
The hydrophilic route
Channel for divalent cation
2+
2+2+
2+
2+2+
2+
Pyrethroides’ effect on excitable membranes
Cadmium passes the Ca++ channel
Cd++ [0,97 Å] Ca++ [0,99 Å]
Endocytosis
H +
H + lysosome
receptor
coated vesikel
iron - transferrin complex
Endocytosis of iron
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
Enterohepatic circulation
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
Air route
Alimentary channel
Blood / haemolymphe
Bronchioler / T
racheoles
Bronchi / T
rachea
Nose and pharynx
HydrofileLipofile
The skin
Wet skin: Increases penetration by a factor 3Soap and other detergents: Increased penetration of hydrophilic compoundsOrganic solvents: Irreversible degradation of corneum
Xenobiotics are distributed in tissue fluids
Plasma: 4% of body weightExtracell. fluid: 13% -Intracell. fluid: 41% -
Intracellularfluid
Extracellularfluid
Pla
sm
a Lipophilic compoundsHydrophilic compounds
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
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
Depositing to organs
Co
nc
.
Time
1. order
Co
nc
.
Time
0. order
Brodie-Gillette’s box model
Bound
Free
Bound
Free
Bound
Free
Metabolites
Excretion
Absorption
Target site
Depot
Metabolism
Excretory organs
Nephridia in earthworm
Vertebrate kidney
Nephridium of an invertebrate
Excretion
CK
on
c.
Tid
1. order
Co
nc
.
Tid
0. order
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
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