Ecotoxicology. Toxicology Uptake and distribution of xenobiotics

Transcription

1 Ecotoxicology Toxicology Uptake and distribution of xenobiotics

2 Functions of the biological membrane Maintain homeostasis Selective uptake and excretion Excitability Ca ++ ph=7.4 [conc. 2] ph = 6.4 [conc. 4]

3 The biological membrane

4 The lipophilic route

5 Phospholipid

6 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

7 The diffusion rate increases with the water-octanol distribution coefficient (Kow) K ow <1 1 >1 >>1 n-octanol Water Kow = [ conc]octanol [ conc] water 1:5 1:1 5:1 21:1

8 n-octanol:water Distribution coefficient ,2',4,4',5,5'-PCB DDT 2,2',4,5,5'-PCB DDE 4,4'-PCB Parathion Naphtalen p-dichlorbenzen Chlorbenzen Toluen 10 2 Benzen Chloroform Benzoic acid Solubility in water (nm)

9 Diffusion rate Kow O and N increase hydrophilic characteristics Alkyl groups increase lipophilic characteristics mnemonic rule: compound lipophilic if C N +O > 4

10 Ionization AH A - + H + BOH B + + OH - ph dependent Water

11 The diffusion follows the concentration gradient given by Fick s law dn dt = P A C P = Permeability constant (mol/cm 2 ) A = Area C = Concentration difference

12 COO - Uptake of Benzoic acid og Aniline Stomach ph 2 COOH COOH Plasma ph 7.4 COO - + H H + NH 3 + NH 2 NH 2 NH H H + 1 COO - Intestine ph 6 Plasma ph 7.4 COOH COOH COO H H + 1 NH 3 + NH 2 NH 2 NH H H + 1

13 The hydrophilic route

14 Channel for divalent cation

15 Pyrethroides effect on excitable membranes

16 Cadmium passes the Ca ++ channel Cd ++ [0,97 Å] Ca ++ [0,99 Å]

17 Endocytosis

18 Endocytosis of iron iron - transferrin complex receptor coated vesikel H + H + lysosome

19 Uptake, distribution and excretion of xenobiotics Alimentary canal Respiratory surfaces Skin Liver Bile Blood and lymph Extra-cellular fluid Organs Fat Kidney Lungs/gills Secretory structures Soft Hard Bladder Alveoli tissue tissue Faeces Urine Air/water Secretions

20 Enterohepatic circulation

21 Ppm Hg (Hg++) Mercury uptake in maggots 10 ppm 1.0 ppm 0.1 ppm Weight (mg) Day no Day no Ppm Hg (MeHg) 60 Weight (mg) Day no Day no

22 Air route Blood / haemolymphe Nose and pharynx Bronchi / Trachea Alimentary channel Bronchioler / Tracheoles

23 The skin Hydrofile Lipofile Wet skin: Increases penetration by a factor 3 Soap and other detergents: Increased penetration of hydrophilic compounds Organic solvents: Irreversible degradation of corneum

24 Xenobiotics are distributed in tissue fluids Extracellular fluid Plasma Intracellular fluid Lipophilic compounds Hydrophilic compounds Plasma: 4% of body weight Extracell. fluid: 13% - Intracell. fluid: 41% -

25 Plasma - protein linkage K 1 K 2 The organism s other compartments K = K 1 K dissociation 2 High K diss Low K diss loosely bound tightly bound Low affinity and high capacity toxicological most important

26 Compartment of distribution Dose Blood sample Apparent compartment of distribution V D V D = Dose(mg) Plasma concentration (mg/l) V D low: high depositing in organs V D high: low depositing in organs

27 Depositing to organs Conc. 1. order Time 0. order Conc. Time

28 Brodie-Gillette s box model Target site Bound Absorption Free Bound Free Bound Free Metabolites Metabolism Depot Excretion

29 Excretory organs Vertebrate kidney Nephridia in earthworm

30 Nephridium of an invertebrate

31

32 Excretion CKonc. 1. order Tid 0. order Conc. Tid

33 % dioxin remaining In body 100 dc dt = k e C 50 T ½ = 30,5 days Time (days) lnc0 lnct ln2 T½ = = = ke ke 0,693 ke