Midterm Exam Flashcards
Definition of environmental toxicology
Study of adverse chemical effects on living organisms, communities, populations, and ecosystems.
Definition of toxicology
Study of adverse chemical effects on living organisms
Who was the father of modern toxicology, and why was he important
Paracelsus. Said that the dose determines the poison. Anything can be toxic; what matters is the dose.
How did the field of toxicology start?
Evolution of human culture. Hunters/gatherers, needed to know what could be eaten.
What event completely changed toxicology?
The industrial revolution and the advent of organic chemistry. Thousands of new chemicals were synthesized. Today, about 100,000 chemicals have been synthesized.
For what percent of chemicals do we have basic toxicity data?
~5%
when did modern toxicology begin?
after 1930
Who is the mother of modern environmental toxicology?
Rachel Carson. Wrote the book Silent Spring which described the dangers of pesticides (DDT) and biomagnification in the food chain, which was wiping out bird populations.
What is descriptive toxicology?
Defines the window of adverse effects. Major tool is the toxicity test.
what is mechanistic toxicology?
studies how chemicals get into organisms and produce adverse effects.
what is the LD50?
lethal dose where 50% of the population is estimated to die.
what is the window of toxicity?
the range where we see adverse effects.
how do you perform a toxicity test?
array of beakers with daphnia. give different doses, wait a given amount of time, and count how many die. can also count reproductive output, tumors, etc.
what is the ED50?
effective dose where 50% are affected. we aren’t always measuring lethality as our endpoint.
difference between LC50 and LD50
dose: concentration that past biological membrane
concentration: amount in environment
what does a dose response curve show?
plot of concentration vs mortality.
what is potency?
toxicity at low concentrations. more potent= more toxic at low concentrations
what is efficacy?
how fully the chemical can affect the population.
what are the three areas of toxicology?
descriptive, mechanistic, regulatory
what are some ways that toxic agents are classified?
target organs, uses, sources, effects, physical state, chemical stability,
what is an allergic reaction?
when an antibody finds antigens that have crossed the biological membrane.
what is an idiosyncratic reaction?
an abnormal reaction usually due to variation in individuals. some individuals are hyper-sensitive.
local vs systemic.
local: effects right where it occurs.
systemic: toxin crosses the biological membrane, distributes through the body, and that’s where the effects are observed.
what is an additive reaction?
no interaction between the chemicals
synergystic
if effects are > additive
antagonistic
if effects are < additive
functional antagonism
function of one compound influences the function of another compound
chemical antagonism
A and B undergo a chemical reaction, which changes the effects
dispositional antagonism
absorption/distributional phase is affected. ex compounds to induce vomiting
receptor antagonism
something comes in and blocks biological receptor.
routes of exposure, from most effective to least effective
intravenous, inhalation, oral, intramuscular, intraparateneal cavity, dermal
acute
high conc, short-term, mortality is typically the end point
chronic
lower conc, longer time, look further than mortality for the endpoint, for example, disease, tumors.
acclimation
change in tolerance caused by change in physiology of the individual.
adaptation
change in tolerance at the population level, caused by natural selection
frequency
increased frequency usually means increased toxicity, although this isn’t always true because of tolerance acclimation
types of transport
diffusion, filtration, active transport, secondary active transport, facilitated diffusion
major ABC transporters/proteins
MRP and MDR transporters move xenobiotics/toxicants
first pass effect
everything from the digestive tract is first brought to the liver, where it is filtered. toxicants are pumped into the bile, which is pumped back into the duodenum for excretion.
factors to consider in lung absorption
number of alveoli, membrane thickness. microcillia protect us from particles. if particles enter the alveoli, then they cause an immune response.
methods of excretion
urinary, fecal (non-absorbed digesta, biliary excretion)
kidney structure (3 nephron regions)
- filter. Bowman’s capsule, which contains the glomerulus
- tube. loop of hence. fine-tuning
- duct. collecting duct. water re-absorption
function of the liver
to remove toxicants. takes on all of the vasculature from the digestive tract. set up as a big filter/sieve. portal triad in conjunction with the liver central vein
volume distribution
plasma water: water held in blood
interstitial water: water held in tissues
intracellular water: water held in cells
factors facilitating distribution
porosity of the endothelium
specialized transport
accumulation in organelles
reversible intracellular binding
factors opposing distribution
binding to plasma proteins (#1 is albumen)
specialized barriers ex. blood-brain barrier, blood cerebral spinal fluid barrier, blood-placental barrier
distribution to storage sites (liver, kidney, bone, fat)
association with intracellular proteins can make it hard to get inside a cell
export from cells
what is the purpose of metabolism?
to make fat-soluble compounds more water-soluble so that they can be excreted. this is critical because otherwise the compounds would just accumulate in fat.
phase 1 metabolism
enzyme adds a functional group to compound, which results in small increases in water solubility
phase 2 metabolism
adds and endogenous substrate to the molecule. results in a large increase in hydrophilicity by producing a water-soluble substrate that s easily excreted.
bioactivation
when metabolism causes a compound to change into a more toxic form
2 main organs active in metabolism
liver, kidneys
cellular location of phase 1 metabolism
ER
cellular location of phase II metabolism
cytosol
microsomes
a product that biochemists make from ER
phase I reactions
hydrolysis, reduction, oxidation
phase I functional groups
hydroxyl, amine, thiol, carboxylic acid
examples of oxidation
oxygen addition (sulfoxidation, N-oxidation)
hydrogen removal
epoxidation
examples of reduction
oxygen removal hydrogen addition (unsaturated bonds to saturated) donor molecules (FAD, NADPH)
examples of hydrolysis
splitting of amide and ester bonds
what is the most important phase I enzyme?
cytochromes p450. this handles the bulk of the traffic
basic reaction of cytochrome p450
RH +O2 + NADPH + H+ -> R(OH) + H2O + NADP+
Where is the highest concentration of Cytochrome p450?
liver, although it is present in virtually all tissues
characteristics of cytochrome p450
great catalytic versatility and large number of metabolized substrates.
heme-containing proteins. heme iron complex acts as the catalytic center by donating and accepting electrons
end result is that a hydroxyl group is added to the toxicant to make it more water soluble
some examples of cytochrome p450 catalysis
epoxidation, hydroxylation, dehydrogenation, ester cleavage, desulfuration
constitutive p450s
constantly being made. only expressed in a few tissues and their activity is relatively constant
inducible p450s
synthesis is triggered by xenobiotics. enzymatic activity is triggered in response to a substrate until no longer needed, then it returns to baseline levels. responsible for drug/xenobiotic metabolism
nuclear receptors
relay message to nucleus to start transcribing cytochrome p450. regulatory molecules allow the transcription to be induced.
2 main organs active in metabolism
liver, kidneys
cellular location of phase 1 metabolism
ER
cellular location of phase II metabolism
cytosol
microsomes
a product that biochemists make from ER
phase I reactions
hydrolysis, reduction, oxidation
phase I functional groups
hydroxyl, amine, thiol, carboxylic acid
examples of oxidation
oxygen addition (sulfoxidation, N-oxidation)
hydrogen removal
epoxidation
examples of reduction
oxygen removal hydrogen addition (unsaturated bonds to saturated) donor molecules (FAD, NADPH)
examples of hydrolysis
splitting of amide and ester bonds
what is the most important phase I enzyme?
cytochromes p450. this handles the bulk of the traffic
basic reaction of cytochrome p450
RH +O2 + NADPH + H+ -> R(OH) + H2O + NADP+
Where is the highest concentration of Cytochrome p450?
liver, although it is present in virtually all tissues
characteristics of cytochrome p450
great catalytic versatility and large number of metabolized substrates.
heme-containing proteins. heme iron complex acts as the catalytic center by donating and accepting electrons
end result is that a hydroxyl group is added to the toxicant to make it more water soluble
some examples of cytochrome p450 catalysis
epoxidation, hydroxylation, dehydrogenation, ester cleavage, desulfuration
constitutive p450s
constantly being made. only expressed in a few tissues and their activity is relatively constant
inducible p450s
synthesis is triggered by xenobiotics. enzymatic activity is triggered in response to a substrate until no longer needed, then it returns to baseline levels. responsible for drug/xenobiotic metabolism
nuclear receptors
relay message to nucleus to start transcribing cytochrome p450. regulatory molecules allow the transcription to be induced.
phase II metabolism
conjugation reactions. add an organic molecule to a xenobiotic to make it more soluble, recognizable, and easily excreted.
two types of conjugation reactions
type I: xenobiotic + reactive conjugating ligand->conjugated product
type II: reactive xenobiotic + conjugating ligand -> conjugated product
examples of type I conjugation rxn
methylation(has CH3 attached to S), sulfating (has sulfate group attached), glucuronidation (has ring attached), acetylation(has O=CCH3 attached)
examples of type II conjugation rxn
amino acid conjugation (has H2N attached), glutathione conjugation (has SH attached)
cofactors required for type I
reactive/activated cofactor
ex. UDP, PAPS, acetyl CoA, SAM
cofactors required for type II
reactive xenobiotic
ex. glutathione, amino acids (glycine, glutamine, taurine)
what is the most important and widespread form of conjugation?
glycoside formation
glucoronidation and glucosidation
glucoronidation is a major pathway in vertebrates excepts for what animal?
cats!
what is a major pathway in plants and invertebrates?
glucosidation
what affects glucoronide excretion?
the molecular weight determines if it will be excreted through the urine or through the bile. MW cutoff is somewhat species dependent
what are some genetic and developmental deficiencies?
deficiency in glucoronidation causes predisposition for jaundice, increased risk of toxicity fro drugs. gilbert’s disease, criglar-Najjar syndrome
sulfate conjugation (sulfation)
biotransforms xenobiotics as well as endogenous compounds
excretion of thyroid and steroid hormones
activity is low in pigs, high in cats.
higher in males than females
methylation
common but minor pathway
makes substrate less water soluble and masks available functional groups for conjugation
occurs in the cytosol, uses metals
guinea pigs have unusually high capacity to methylate
acetylation
major route for xenobiotics containing an aromatic or hydrazine group
cytosolic
wide species variability
there are fast and slow acetylators
amino acid conjugation
amino acids = glycine, glutamine, arginine, and taurine in mammals and primates, ornithine in reptiles and birds
activity herbivores> omnivores>carnivores
what is the most important phase II enzyme system?
glutathione.
binds extremely reactive intermediates, plays an extremely protective role in the cell.
