Ecotoxicology
Toxicology
Uptake and distribution
of xenobiotics
Functions of the biological membrane
Maintain homeostasis
Selective uptake and excretion
Excitability
Ca ++
pH=7.4
[conc. 2]
pH = 6.4
[conc. 4]
++++++
--------
The biological membrane
The lipophilic route
Phospholipid
Passage of chemicals through the membrane depends on:
Size
Fat solubility
Resemblance with endogenous molecules
The passage takes place through:
Passive diffusion through the phospholipids
Through water and ion channels
Active transport through channels
Endocytosis
Passive diffusion most important toxicologically
The diffusion rate increases with the
water-octanol distribution coefficient (Kow)
Kow
<1
1
>1
>>1
Kow =
n-octanol
Water
1:5
1:1
5:1
21:1
[conc] octanol
[conc] water
n-octanol:water
Distribution coefficient
7
10
2,2',4,4',5,5'-PCB
2,2',4,5,5'-PCB
6
DDT
10
DDE
4,4'-PCB
5
10
4
10
Parathion
Naphtalen
p-dichlorbenzen
Chlorbenzen
3
10
Toluen
2
Chloroform
Benzen
10
Benzoic acid
10
1
10
2
10
3
10
4
10
5
10
6
10
Solubility in water (nM)
7
10
8
10
9
10
Diffusion rate
Kow
O and N increase hydrophilic characteristics
Alkyl groups increase lipophilic characteristics
mnemonic rule: compound lipophilic if
C
4
>
N +O
Ionization
AH
A- + H +
BOH
B+ + OHpH dependent
Water
+
-
The diffusion follows the concentration gradient given by Fick’s law
dn = -P A D C
dt
P = Permeability constant (mol/cm2)
A = Area
ΔC = Concentration difference
Uptake of Benzoic acid og Aniline
Plasma pH 7.4
Stomach pH 2
COOH
COO-
100
+ H+
1
NH2
NH3+
H++
1000
Intestine pH 6
COO100
+ H+
1
2512
NH2
COOH
COOH
+ H+
NH3+
+ H+
251
1
Plasma pH 7.4
NH2
H++
1
1
1
NH3+
COO-
COOH
10
COO-
1
2512
NH3+
NH2
251
+ H+
1
+ H+
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
Endocytosis of iron
iron - transferrin complex
receptor
coated vesikel
H+
H+
lysosome
Uptake, distribution and excretion
of xenobiotics
Alimentary canal
Respiratory surfaces
Skin
Liver
Bile
Kidney
Bladder
Faeces
Urine
Blood
and
lymph
Lungs/gills
Organs
Secretory structures
Alveoli
Air/water
Fat
Extra-cellular fluid
Secretions
Soft
Hard
tissue
tissue
Enterohepatic circulation
Mercury uptake in maggots
120
10 ppm
Weight (mg)
Ppm Hg (Hg++)
2.5
2.0
1.5
1.0
1.0 ppm
0.1 ppm
0.5
1
2
3
Day no
40
4
5
1
2
3
4 5 6
Day no
7
8
1
2
3
4 5 6
Day no
7
8
120
Weight (mg)
90
Ppm Hg (MeHg)
60
60
30
60
40
1
2
3
4 5 6
Day no
7
8
Air route
Blood / haemolymphe
Nose and pharynx
Bronchi / Trachea
Bronchioler / Tracheoles
Alimentary channel
The skin
Hydrofile
Wet skin:
Soap and other detergents:
Organic solvents:
Lipofile
Increases penetration by a factor 3
Increased penetration of hydrophilic compounds
Irreversible degradation of corneum
Xenobiotics are distributed in tissue fluids
Plasma
Extracellular
fluid
Plasma:
Extracell. fluid:
Intracell. fluid:
Intracellular
fluid
4% of body weight
13%
41%
-
Lipophilic compounds
Hydrophilic compounds
Plasma - protein linkage
K1
The organism’s
other
compartments
K2
K1
= K dissociation
K2
High Kdiss
Low Kdiss
loosely bound
tightly bound
Low affinity and high capacity toxicological most important
Compartment of distribution
Dose
Blood sample
”Apparent compartment of distribution” VD
Dose (mg)
VD =
Plasma concentrat ion (mg/l)
VD low: high depositing in organs
VD high: low depositing in organs
Depositing to organs
Conc.
1. order
Time
Conc.
0. order
Time
Brodie-Gillette’s box model
Absorption
Target site
Bound
Bound
Free
Metabolism
Metabolites
Bound
Free
Free
Depot
Excretion
Excretory organs
Vertebrate kidney
Nephridia in earthworm
Nephridium of an invertebrate
Excretion
CKonc.
1. order
Tid
Conc.
0. order
Tid
% dioxin remaining
In body
dC
= -ke  C
dt
100
T½ = 30,5 days
50
30
0
10
20
30
Time (days)
40
50
lnC0 - lnCt ln2 0,693
=
=
T½ =
ke
ke
ke