Module 3 Flashcards
What is meant by the term developmental toxicology?
adverse effects of xenobiotics that occur between conception and puberty
What are the three causes of developmental toxicology and their relative percentages for causing issues?
Genetic factors-25%
Environmental factors- 10-15%
Unknown multifactoral causes-60%
What are the first two principles of Wilson’s general principles of toxicology?
Susceptibility to teratogenesis depends on the genotype and the manner in which it interacts with its adverse environmental factors and depends on the developmental stage at which the time the exposure occurred
What is the first developmental stage and the subsequent effects of xenobiotics at this stage
Early developmental-fertilization to implantation
usually lower sensitivity at this stage, gastrulation occurs during this so malformations of eyes, brain and face are most common
What is the second developmental stage and the effects on xenobiotics on the fetus at this stage
Organogenesis (1st trimester)-VERY sensitive due to the divison, remodelling, differentiation occurring in this stage. Effects vary as key developmental events coincide with particular events
How is thalidomide an example of how organogenesis is most sensitive to teratogens?
The difference between amelia and phocomelia depended on which day the pregnant women were given the drugs
What is the third developmental stage and what are the effects on xenobiotics to the fetus in this stage?
Fetal period-this involves and histogenesis and functional maturation of tissues and organs so the effects are more on the function of the organs and less on the development of them. This would mean the CNS, immune system, and reproductive systems are most effected. Reduced birth weight/growth is most common effect of teratogens during this phase
What is principle three of Wilson’s general principles of teratogenicity?
Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events
What are examples of teratogenic mechanisms?
Gene mutations and chromosomal abnormalities, altered mitosis or apoptosis, altered nucleic acid integrity, reduced precursors or substrates for metabolism, reduced energy sources, osmotic imbalances, altered cell membranes and enzyme inhibition
What are the four most common pathogenetic response to teratogens?
altered apoptosis (increased or decreased), altered cell-cell interaction, reduced biosynthesis of endogenous compounds and inhibition of morphogenesis
What are the three sources of teratogenesis
direct effects, placenta and mother
Why is the placenta a source of teratogensis?
Is the site of gas exchange, nutrition and waste removal, produces hormones, bioactivate and detoxify xeno, target of xeno
How is the mother a potential source of teratogenicity?
disease, malnutrition, genetics, stress or ethanol/drug consumption
What is principle 4?
The access of adverse influences to developing tissues depends on the nature of the influence
How do agents gain access to developing tissues in embryo?
Same rules as ADME-highly lipophilic molecules can cross into placenta, maternal CO increases and plasma proteins decrease, biotransformation enzymes are less in placenta and fetal blood has slightly lower pH
What is principle 5?
The four manifestations of deviant development are death, malformation, growth retardation and functional deficit
At which stages of development do each manifestations occur most frequently?
death-embryonic
malformation-organogenesis
growth and functional deficit-2nd and 3rd trimester
What is principle 6?
Manifestations of deviant development increase in frequency and degree as dosage increases, from the no effect to totally lethal effect
What is the explanation on principle 6?
teratogenicity is considered a threshold phenomenon and depends on timing and dose of exposure
What is DES
Diethylstilbestrol-gave to women to prevent miscarriage, gave clear cell adenocarcinoma to daughters and granddaughters
What is FASD?
Developmental and structural disorder due to exposure to ethanol during pregnancy, 2-5% of children have FASD
How can tobacco smoke impact pregnancy?
abortion, sudden infant death syndrome, brain/behaviour disorders and lower birth weight
How do drugs of abuse impact offspring?
CNS and behaviour issues
What are common classes of drugs that can cause teratogenicity today?
retnoids and AEDs both cause structurtal and functional deficits
What are the classes of drugs that cause issues to areas of reproduction and sexuality
endocrine disrupting hormones
What are examples of xenoestroges
bisphenol A, pthalates, organochlorides and alkylphenols
What are some common symptoms of issues caused by EDCs
undescended testicles and uretha opening at wrong location, decreased semen quantity and quality, increase in cancers like breast, ovarian, uterine, prostate and testicular
What are the two largest factors contributing to cancer?
Diet and tobacco
What are the three main mechanisms of cancer?
failure of DNA repair, failure of apoptosis. and failure to terminate cell proliferation
What are the three stages of carcinogenesis?
Initiation, Promotion and Proliferation
What is initiation?
When altered DNA undergoes mitosis and mutation is retained
What are two large causes of neoplasia?
proto-oncogenes converted into oncogene or tumor suppressor genes being turned off
What are proto-oncogenes?
code for proteins associated with cell proliferation
What occurs in the promotion stage?
When initial tumor cell is proliferate in presence of promoter
What are examples of promoters?
toxicants, hormones, calories and ethanol
What occurs in the progression stage?
Not much known, conversion of benign to malignant tumor
What are the 6 types of carcinogens?
Genotoxic, epigenetic, cocarcinogens, solid state, complete and metals
What are genotoxic carcinogens?
Xenobiotics that are procarcinogens that are bioactivated to yield ultimate carcinogen
What mechanisms are involved in genotoxic carcinogens?
activation of proto-oncogenes and inactivated tumor surpressor genes
What is a common example of a genotoxic carcinogen?
Benzo-a-pyrene that gets activated into an epoxide that bind to DNA (is a polycyclic hydrocarbon)
What are nongenotoxic carcinogens?
Promoters of mitosis and or inhibitors of apoptosis-do not damage DNA but can methylate it
What are cocarcinogens and provide an example?
Increase the effect the effect of a carcinogen, mostly through effects on ADME, e.x. alcohol on CYP2E1
What is a solid state carcinogen and provide examples?
Cause fibrosis, oxidative stress and irritation in alveoli, asbestos and silica
What are complete carcinogens and provide examples
Xeno that have chemicals that are involved in all three stages of cancer e.x. tobacco smoke and ethanol
What are some examples of metals that are carcinogenic and what are the possible mechanisms for them?
Arsenic, cadmium, chromium, nickel and beryllium, ROS and oxidative stress
What are the toxicokinetic factors affecting organ selective toxicity?
organ selective uptake, distribution, and accumulation of xenobiotics and organ selective metabolism and bioactivation
What are the toxicodynamic factors affecting organ selective toxicity?
Tissue specific expression of receptors, binding of xeno to macromolecules, expression of tfs, adaptive responses, deficiencies in pathways of detoxification and repair
What are the four major anatomical parts of the liver that contribute to the increased risk of toxicity?
Portal vein
Hepatic artery
Kupffer cell
Bile canaliculi
How does the portal vein increase risk of toxicity
Anything passed through GI tract brought here to be detoxified-increased enzymes
How does the hepatic artery increase risk of toxicity
Highly perfused area
How do the Kupffer cells increase risk of toxicity?
Resident macrophages that produce ROS and in bursts can cause toxic effects
How do the bile canaliculi increase the risk of toxicity
xenobiotics can accumulate in here up to 5000x due to biliary excretion and active transport pumps
What are the 5 toxic responses of the liver
Steatosis
Necrosis
Cholestasis
Cirrhosis
Carcinogenesis
What is steatosis, its causes and clinical markers?
Fatty liver, reversible, acute or chronic exposures, alcohol and marker is serum triglycerides
What is necrosis, its causes and clinical markers?
either death of entire liver or parts, irreversible, involves decreased ATP or Ca2+ regulation, clinical markers ALT, AST and GGT
What is cholestasis, its causes and clinical markers?
decreased bile formation and biliary secretion, caused by ethanol, certain metals, steroids and certain drugs, ALP, GGT and bilirubin in plasms
What is cirrhosis, its causes and clinical markers?
extensive fibrosis throughout the liver, ethanol, steatsosis and necrosis can lead to fibrosis, marked by ALT, AST and GGT in plasms
What is the common form of cancer called and what can contribute to causing it and marker in blood?
Hepatocellular carcinoma, improperly stored grains can accumulate fungi and can cause this, alphafetoprotein can cause this
What part of the kidney is most susceptible to toxicity and why?
Proximal tubule- greatest CYP, most mito (metabolism), transport of xeno occur here
What are examples of nephrotoxicants?
heavy metals, halogenated hydrocarbons, antibiotics and analgesics
What does the presence of proteins in urine suggest?
Small proteins: loss of PCT reabsorption
Larger proteins: loss of glomerular function
What enzymes and carb can be used to test for decreased kidney function?
glucose and GGT
What compounds when found in blood indicate loss of kidney function?
Urea, nitrogen and creatinine
What are sources of lung damage
oxidative stress (ozone, smoke)
gases and vapours (chlorine, ammonia)
particles and aerosols
Why is size so important when talking about toxicity of lungs?
anything less than 2.5 um is considered toxic because it can go into bronchioles and alveoli
What are the acute effects of lung toxicity?
airway reactivity and pulmonary edema
What part of the respiratory system is targeted in airway reactivity and what triggers this?
muscle contraction in bronchial smooth muscle, pollution and asthma cause this
What part of the resp system does edema target and what causes it
fluid accumulation in the lungs which reduces O2 exchange, Cl2 and Nh3 gases
What are the four chronic effects of resp. toxicity?
Fibrosis, emphysema, asthma and neoplasia
What is fibrosis and why is it bad?
Increased ECM proteins in alveoli, lungs get smaller and stiffer
What is emphysema and why is it bad?
breakdown of elastin in alveoli, lungs get bigger and more stretchy, can’t exchange gases
What is neoplasia and what are some major causes?
lung cancer, tobacco smoke, metallic dusts and fume, radon gas and asbestos
What are the two types of dose-response relationships?
graded and quantal
What is a graded dose-response relationship?
show responses of individuals and are continuous responses, provides information of about the intensity of a response over a dose range
What is a quantal dose-response relationship?
shows a population response and are “all or none” response. Shows number of individuals showing a specific effect over a dose ramge
What does the bell shaped curve represent in the quantal response?
frequency of a response in a population
What does the s curve represent in a quantal response?
cumulative response in a population
What does a linear graph represent in a quantal response?
Shows LD50 or other numbers
What is potency and where on a graph would potency be placed if it were more toxic?
concentration or dose causing a certain percent of maximal response, further left is worse
What is efficacy and where would it be on a graph if it were more toxic?
Efficacy is what % maximal effect it can achieve therefore the higher it goes, the more toxic
What is the Therapeutic Index
TD50/ED50
What is the margin of Safety
TD1/ED99
What is the Hormesis curve?
There will always be individuals showing adverse effects at different concentrations of xenobiotics so there is a u shaped curve showing the average concentration at which a xenobiotic produces its desired effect with no toxicity
What is the acute lethality test?
96hr LD50, shows how chemicals react in body
What is the subacute toxicity test?
14 day repeated dose
What is the subchronic toxicity test?
90 day test for two species, 10% of lifespan, determine the No Observed Adverse Effect Level
What is the chronic toxicity test?
6 months to 2 year duration, mostly for cancer causing test, problem is that control group mice get cancer anyways
