ECOTOX TOXICODYNAMICS

1. target molecule (3 main types)

2. interaction type at target site (3 main types)

3. type of effect

1. membranes (lipids) -> cell membranes, organelles -> non-specific 

2. peptides & proteins -> enzymes (catalytic function), transporters (ABC, ion channels), regulation (transcription factors), structural proteins -> specific 

3. DNA -> reactive (formation of covalent bonds, biotransformation) 

- lowest intrinsic "minimal" toxicity: change of membrane fluidity/disturbance of channels -> all substances display baseline toxicity, as they have to enter through the membrane 

- reversible

- also called narcosis 

QSAR = quantitative structure activity relationship -> correlation between toxicity of a chemical and it's structure -> you can predict the LC50 (toxicity) of a chemical based on it's KOW (use DOW for ionized substances) 

for polar narcosis: use membrane-water partition coefficient (Kmw) instead of KOW, as KOW cannot predict polar narcosis well. (Distinction between polar & non polar is only made when KOW is used) 

-> measured toxicity values can differ from predicted ones (due to eg different amounts of fat tissue, or rate of biotransformation)

the TR compared predicted & experimental LC50 (predicted/experimental) and indicates wether a chemical exhibits higher than just baseline toxicity 

1. baseline toxicants are expected to have a TR of about 1, and their measured LC50 should lie close to the QSAR line

2. a measured LC50 below the QSAR line indicates a specific/reactive mode of action (measured will be smaller than predicted; ie more toxic) 

TR 1 -> baseline (non-polar narcosis)

TR 5-10 -> baseline (polar narcosis)

TR 10-10^4 -> reactive/specific mode of action 

Benzene -> apolar -> baseline toxicant -> NO 

SDS -> apolar tail, polar head -> like phospholipid -> baseline toxicant -> NO 

Terbutryn: Herbicide -> Fish & Daphnia NO, algae YES

Cyperrmethrin: Insecticide -> Fish & Daphnia YES, algae NO

BPA -> NO for short-term tests, YES for long-term tests (in all 3 species) 

1. ILC50 = internal lethal concentration that causes 50% mortality = LC50 x BCF

2. Estimate: for death due to baseline toxicity (acute lethality), the CBR is generally between 2 and 8 mmol/kg wet weight 

1. the level of the CBR has been shown to be similar for different species -> can extrapolate to other species 

2. the lvel of CBR is independent of exposure scenarios or time -> facilitates comparison between different toxicity tests and exposure scenarios 

3. the CBR helps to link exposure and effect modelling 

1. inhibition of ETC via redox cycling -> chemical that can capture electrons (electron acceptor) can transfer them to oxygen and form radicals -> chemical goes back to normal and can start over again (eg Quinones) 

Example: Paraquat 

2. Competitive binding to electron transport proteins 

Example: Competitive binding of Diuron to QB domain of pheophytin (= first electron carrier in ETC of photosystem II in plants) inhibits photosynthesis 

3. Uncoupling & Disruption of Proton Gradients

- The chemical is negatively charged and gets protonated in intermembrane space -> in matrix it releases proton -> destroys proton gradient built up by ETC 

Eg Dinoseb -> dissociates at pH 7 in the matrix. 

4. Enzyme inhibition -> ATP Synthase 

- chemicals can bind to inhibitory site of ATP Synthase 

Example: Organotin 

1. Enzyme inhibition 

Example: Triclosan -> inhibits enzyme in fatty acid synthesis; Diclofenac: inhibits COX (which converts arachidonic acid to prostaglandins) -> no more pain 

2. Interference with Transmission of Nerve Pulses 

interference with excitatory/inhibitory chemical synapses: sodium & chloride channels, GABA receptors, Acetylcholine receptors,  acetylcholine esterase 

Example: DDT: inhibits proper opening of sodium channles -> no resting potential restored -> overexcitation, tremors 

Organophosphates: bind to acetylcholineesterase -> acetylcholine not degraded/much slower -> overexcitation, tremors. OP have a phospjate group and their biotransformation products are much more potent than their parent compound; eg Parathion 

3. Estrogenic Compounds 

Example: BPA binds to estrogen receptor & estrogen response element -> changes transctiption/translation patterns -> endocrine disruptor 

DNA damage & mutations 

Example: Benzoapyrene: its oxidation product (epoxide) has en electrophilic center which is difficult to reach for biotransformation enzymes -> can covalently bind guanosine -> mutations if not repaired