Exam 2 Flashcards
Endpoint
death, biochemical physiological
Results
LC50, LD50, EC50, ED50, NOAEC, NOAED, LOAEC, LOAED
Selective toxicity ratio
SER
Medial lethal dose or concentraion for species A / meidal lethal dose or concentration for species B
ERA : Factors defined as
Formulation of the chemical Rate of dosing Feeding regimen Temperature Humidity State od health of animals
Standard toxicity testing
Give a measure of toxicity under closely defined sets of operating conditions
Addivity
Combination of two or more chemicals is the sum of the expected individuals response
Antagonism
Exposure to one chemical results in a reduction in the effect of the other chemical
Potentiation
Exposure to one chemical results in the other chemical producing an effect greater than if given alone
Synergism
Exposure to one chemical causes a dramatic increase in the effect of another chemical
Testing earthworms
OECD guideline - standard testing
Vertebrates
Mammals
- Standard testing measuring LD50
- Different dosing method (injection)
Testing with auatic organism
- Direct uptake from water (gills)
- Food
- Sediments
Maintaining a constant concentration of chemicals in water
- Static
- Semi static
- Continous flow
Risk quotient ratio
PEC/PNEC
predicted enviromental concentration / predicted enviromental no effect concentration
Risk ratio above 1 : Potential risk
Risk ration below 1 : Low risk
Alternative methodes
- Using live vertebrates
- Using cellular systems , in vitro systems
- Predictive models
- Fields studies
- Microcosms and mesocosms studies
- Modeling works
Protective biochemical responses
- Induction of monooxygenase enzymes => metabolites
- Induction of MT, metallothionein - binding proteins
- Response that correct damage after it has occured
- Induction of stress protein
- DNA repair
Molecular mechanism of toxicity
3 reasons
- Develop drugs or antidotes
- Lead to the dev of biomarkers
- Helps for extrapolation across taxa
Relationship between the dose and the extend of effecs of chemicals
- At low levet of exposure : May not produce measurable interactions - compounds does not reach the site of action
- At higher level of exposure: Protective mechanism may reduce the amount of chemical that reaches the active site.
Reserve capacity
Intribition of brain acetylcholesterase must exceed 50 %
No minimum safe level
Single molecule interaction can initiate toxic mechanism
Examples of molecular mechanism of toxicity
- Pesticide dimilin, inhibits the synthesis of chitin
- Organophosphorous insecticides, affect the nervous system
- Dinitroorthocresol, mitochondria membrane
Genotoxicity compounds
Cacinogenic compounds that can causes damage on DNA
Production of mutant cells => potentially tumor cells
DNA adduct formation
Covalent binding of the pollutant with DNA
General about genotoxicity
- Good biomarkers of exposure
- Enzymatic metabolism
- Formation of reactive matabolism bind to DNA
- The original compound being relatively stable and not reactive
Neurotoxicity
Nervous system af vertebrates + invertebrates can be affected by chemicals
Natural neurotoxicity
- Botulinium toxic
- Natural insecticides as nicotine and pyrethin
Antroprgenic compounds
- Organochlorine insecticides
- Organophosphorous insecticides
- Carbamates
- Pyrethoid insecticides
GABA receptor
Chlorinated cyclodiene insectice or their metabolites
Is a “calming” neurotransmitter that reduces neuronal excitability
Act as antagonist - reduce flow of Cl
Mitochondria poisons
- Found in all eukaryotes
- Electron transport chain- electrochemical gradient
- Speciel transport of H+ and ATP (production of energy)
Enviromental estrogen
Can mimiric estrogen by binging to the extrogen receptor
Stimulate the transciption activity of estrogen
Known estrogen: Oganochlorine insecticides and tributyl tin
Biomarker:
- induction of vitellogenin
- Enzymatic of aromatase disruptied
Effects at the organ level in animals
- Pollutants compartmetalized in particular organs
- Thyroid gland for radioactive isotopes
- Liver and kidneys for Cd
Effects at the whole organism level
1) Neurophysiological effects
2) Effects on behavior
3) Effects on reproduction
1) Chemicals interacting with the nervous system : Organophosphorus insecticides, organochlorine insecticides, carbamate, pyrethoids
2) Foraging behavior / Failure to avoid predation
3) TBT on molluscs
DDE-induced eggshell thining in raptors and fish
eating birds
Various disruptors of the endocrine system
Energy cost od physiological
Scope for growth = Energy intake - total metabolic losses.
Trade off
Between the loss of production and the mortality
Hepatotoxicity
Liver
General abour the liver
- Largest organ in the body
- Exposed to significant concentrations of chemicals which can results in liver disfunction, cell injury or organ failure
Position in circulatory system
- Encounters: Nutrient, vitamins, metal, drugs, enviromental toxicants, waste of bacteria products
- Main organ metabolizing chemicals
Enterohepatic circulation
Circulation of drugs or other substances from the liver to the bile
- Transport by portal vein
-Absorption from stomach
-Absorption from instestines
Some xenobiotics may be “recycled” many times before they are finally excreted in the feces
Many lipophilic xenobiotics undergo this proces carrying repeated liver damage
Types of liver injury
- Fatty liver (steatosis)
- Cell necrosis
- Cholestasis
- Cirrhosis
- Carcinogenesis
Fatty liver
- Increase in the hepatic lipid content
- Due to diabetes
- Different mechanism that increase the accumulation of lipid in the liver
Cell necrosis
-Cell swelling, leakage, nuclear distergation, influx on inflammatory cells
-Can be massive
-Not always anitical
Example: Tylenol, carbon tetrachlorid, beryllium
Cholestasis
-Decrease volume of bile formed or impaired secretion of specific solutes into biles
-Usually drug-induced
Example: Anabolic steroids, ethanol, paraquat, methylene dianiline
Cirrhosis
- Chronic liver injury
-Accumulation of collagen fibers => formation of fibrotic tissue => Cirrhosis - Alcohol consumption or metal with chronic exposure
Example: Carbon tetrachloride, ethanol with poor diet, reduced vitamine and protein - Not reversible
Carcinogenesis
- Many chemicals are capable of producing tumors in the liver
- Hepatocytes
-Cholangiocarcinorma: Bile duct cell
Example : Carbon tetrachloirde, vinyl chloride, Aflatoxin B1
Toxicant -induced injury
- Ethanol (biotransformation, genetic polymorphism
- Acetaminophen (do not mix with alcohol)
Evaluation of liver injury using blood test
- Acess to functional capability of the liver or capability to extract and metabolize foreign compounds from the blood
- Acess whether there are abnormally high levels in the blood of intracellular hepatic proteins: Endence of liver cell destruction
Stategic location of the liver
Between intestial tract and the rest of the body facilitates its maintenance of metabolic hemostasis in the body
Hepatocytes
Rich supply of phase 1 enzyme that often convert xenobiotics to reactive electrophilic metabolites and of phase 2 enzymes that add a polar group to a molecule and thereby enhence its removal from the body
Balance between phase 1 enzyme and phase 2 enzyme
Determine whether a reactive metabolite will initiate liver cell injury or be safety detoxified
Nephrotoxicity
Kidneys
General about kidneys
Two bean shaped organs
Recieve blood flow from the hearth
Contains 1 to 2 millions nephrons
Morphology and functions for kidneys
- Reciece its blood supply from a single artery that orginates in the aorta
- Circulate into a single vein that connect with the inferior vena cava
3 main anatomical areas
- Renal cortex (90 % blood flow)
- Renal medulla (6-10 % blood flow)
- Renal papilla (1-2% blood flow)
When a bloodborne toxicant is delivered to the kidney a high percentage of the material will be delivered to the cortex
Nephron
Functional unit of the kidney
3 mechanism - Glomerular filtration
- Tubular reabsorption
- Tubular secretion
Kidney injury
- Acute kidney injury
- Abrupt decline in glomerular filtration
- Result in azotemia
- Eleviation in serum creatinine
- Anuric renal failure
- Chronic kidney injury
- Chronic tubolointerstitial fibrosis
- Papillary necrosis
- Adaptation to injury
Susceptibility to the kidney to toxic injury
- Drugs and chemicals in the systemic circulation are delivered to the kidneys in relative high amount
- Process to form urine: concentrate potential toxicants in the tubular fluid, therefore exposing toxicants to tubular cells
- Consequently, a nontoxic concentration of a chemical in the plasma may reach toxic concentrations in the kidney
Specific nephrotoxicants
- Metal (cause renal cellular injury)
- Hg (transfer Hg2+ into the cell of proximal tubular
- Cd
Halogenated hydrocarbons
- Chloroform
- Bromobenzene
Therapeutic agents
- Acetaminophen
- Nonsteroidal anti-inflammatory drugs
- Cis platin
Non-invasive assesment of renal functions
- Blood and serum analysis
- Glomerular filtration rate (creatinine and inulin)
- Indirect markers of glomerular filtration rate (blood urea nitrogen and serum creatinine)
Xenobiotics in kidneys
Will be delivered to the kidney in relatively high amounts
Bioaccumulation
BCF = concentraion of the chemical in the organism / concentration in the ambient enviroment
Bioavailability
Fraction of ingested metal absorbed into the systemic circulation
Bioaccessibility
Fraction of total metal that dissolve in the stomach and is available for absorption during transit through the small intestine
Measure bioaccessibility
- Studying metal speciation in digestive fluid
- In vitro gastric model
- Culturing gut cells
Metalbolism
lipophilic xenobiotics -> (phase 1) -> Metabolite -> (phase 2) -> Conjugate
Increasing in polarity ->
Zero order kinetics
- Concern aspirin and ethanol
- The rate of elimination is constant
- The half-life is not constant
First order kinetics
- Concern most drugs
- The rate of elimination is not constant
- The half-life is constant
Equation for first order kinetic
Ct = C0e^(-kt)
t½ = 0.693/k
