ECOTOX TOXICOKINETICS PART 1 & 2

1. Phase: the exposure to the contaminant at a constant concentration -> uptake & elimination 

-> wait until concentration in tissues is at SS -> calculate BCF = ctissue/cwater = ku,w/ke (BMF = ctissue/cdiet = ku,d/ke)

BUT: reaching SS can take a long time, can be more efficient to determine BCF based on uptake & elimination rates 

2. Phase: depuration, contaminant is removed -> only elimination happens 

= a measure of the increase of a chemical in organisms across trophic levels: czooplankton/cphytoplankton

BMF <1: chemical is effectively metabolized/eliminated by the organism

BMF >1: chemical accumulates from the diet in zooplankton

- researchers have found elevated PCB levels within crabs 

- PCBs = endocrine disruptors 

-> BCF = Corg/Cw = ku,w/ke at SS -> Corg (SS) = Cw * ku,w/ke (if you increase Cw by 2, Corg increases by 2 but BCF stays the same, as ratio) 

- we have an allometric relationship for the bioaccumulation in fish; uptake rate depends on size for chemicals with logKOW >3

- t1/2 = ln(0.5)/-ke -> elimination is also heavily size/weight-dependent 

chemical: solubility, molecular size, partitioning behavior, degree of chlorination/halogenation (examples) 

biological: organism composition (protein, lipids); feeding routes (water, sediments), diet, physiology, growth rate, feeding behavior (feeding rate), assimilation efficiency, temperature, size of organism

= what a cell/organism can do to a chemical 

1. fundamental unit for providing all toxicokinetic processes 

2. cell wall + membrane as important barriers for toxins 

3. cell membrane & surface proteins/channels are key for uptake & elimination of chemicals/toxins 

4. cellular compartments are important: depending on their composition (protein like nucleus, lipid like membrane), depends where chemical will end up 

1. passive transport (incl. facilitated transport) 

2. active transport 

3. endo,- & exocytosis 

4. biotransformation 

function as: 

1. active "internal barriers" -> blood/tissue, liver, kidney -> multidrug resistance 

2. active "environment-tissue barriers" -> external surfaces like gills/lungs, intestine -> multixenobiotic resistance

1. oxidation (loss of electrons), 2. reduction (=gain of electrons),3.  hydrolysis (addition of water) 

Enzyme: Cytochrome P450

goal: increase the chemical in polarity and size -> make it more hydrophilic 

1. glucuronide conjugation (via UGT)

2. sulfate conjugation (via SULT)

3. glutathione conjugation (via GST) 

1. via constant expression: generally kept at low level

2. inducible expression: upregulation of the enzyme upon need/when conditions/cellular environment change 

Receptor-mediated activation via AHR 

1. chemical enters cell & binds receptor 

2. receptor-complex undergoes conformational change

3. transport to nucleus 

4. binding to DNA responsive element

5. DNA transcription is activated

6. Phase I&II enzymes or ABC transporters expression/activation induced

1. biotransformation products can be eliminated or also pose an environment risk: one parent molecule can give rise to many transformation products, which are usually less, but sometimes more toxic 

2. biotransformation products are generally more stable and more mobile (which makes them more prone to leach into groundwater) 

1. the active moiety remains intact during biotransformation 

2. if the uptake is enhanced due to pH-dependence of increased hydrophobicity (Kow)

3. if the transformation results in a product with a different & more potent mode of action 

1. allyl alcohol in adult zebrafish is more toxic as in embryos as they are better at biotransformation & produce more acrolein, which is toxic 

2. cocaine is turned into a liver toxicant when present with phenoarbitrol as phenoarbitrol induces CYP which biotransforms cocaine to a liver toxicant 

3. the (already biotransformed) epoxide of aflatoxin is sterically difficult to reach for biotransformation enzymes and thus a spontaneous reaction with DNA (covalent binding) and adduct formation can happen faster