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Mechanistic :
regulatory:
descriptive:
mechanistic: molecular basis
regulatory: communicates hazards
descriptive: industry and testing
Use info from mechanistic, regulatory and descriptive to form
Human Health Risk Assessment
3 types of toxicology and examples
Forensic: Yushchenkow dioxin poisoning- developed chloracne
Pharmaceutical: accutane
Environmental: Bhopal methyl isocyanate (MIC) release
What is the problem with indoor pollution?
focuses on emission rather than exposure
3 types of indoor air pollutants
VOC, respirable particles, carbon monoxide
Chloroform
does what to the body?
produced by what reaction?
depresses CNS, liver damage, carcinogen
produced by Haloform reaction
Tetrachloroethylene
does what to the body?
comes from where?
CNS depressant
dry cleaning solvent, degreaser, contaminates soil
Formaldehyde
does what to the body?
comes from where?
probable carcinogen
from incomplete carbon combusion, used in construction materials so INDOOR AIR POLLUTANT
4 classes of pesticides
polychlorinated hydrocarbons,
organophosphates
carbamates
pyethroids
Alternative to pesticides
borates
dichloromethane / methylene chloride
does what to the body?
comes from where?
metabolized in body to CO, may be carcinogenic, mutagen
paint stripper
1,4 Dichlorobenzene
does what to the body?
comes from where?
may be carcinogen
moth repellant and toilet deodorizer
Radon 222
what does it present as?
does what to the body?
comes from where?
colorless, odorless
2nd leading cause of lung cancer, elevated in 1/5 homes
What is the most commonly encountered poison that is responsible for more deaths than any other poison?
carbon monoxide
At low percentages, CO causes ____
At high percentages, CO causes ______
causes headaches
causes death in minutes, neuro effects
Sources of CO exposure
incomplete combustion of carbon
improper ventilation
exhaust
paint stripper
what has the most CO emissions but what has the most exposure?
transportation has the most CO emissions and
central heating has the most exposure
what location has the most % of CO cases?
single families
common sources of in home CO
GAS water heater, furnace, boiler, kitchen
vehicle in garage
What does CO do to the body?
binds to hemoglobin with 250 higher affinity than O2
negates O2 cooperativity binding and reduces O2 available to tissues
What to do in CO poisoning?
1) remove from exposure
2) admin 100% oxygen (reduces ½ life to 1 hr)
3) use hyperbaric oxygen chamber (reduces ½ life to 30 min)
How to protect outselve from accidental CO poisoning
CO detector
furnace serviced
read early CO signs
Warning signs of chronic CO exposure
flu symp with no congestion
multiple cases
pets sick
no remedy
Slobodan Praljak
general convicted of war crimes, ingested CN in court
What is one of the most lethal poisons?
CN
What has a bitter almond smell?
CN
Cassava root/manioc is high in
cyanogenic glycosides
how is CN used in industry
photographic chemicals, metallurgy, electroplating, metal synth, organic synthesis
how is CN used in medicine
sodium nitroprusside in hypertension
vitamin B12 has CN ligand
what chem is used in illigal fishing?
CN added to water
what is produced by burning of plastics, silk nylon?
HCN
What chemical compound is in Zyklon B?
CN
Why is CN toxic?
interferes with aerobic respiration /ATP synth
binds to heme center of cytochrome c oxidase in ETC
e- cant pass through
O2 cant bind
e- cant make proton gradient
Steps in CN poison management
1) amyl nitrate pearls under nose to convert hemoglobin to MET hemoglobin so it competes for CN and frees up cyt c ox A3
2) start sodium nitrite IV
3) admin sodium thiosulfate to convert MetHbCN to thiocyanate that is excreted in urine (B12 can also bind)
what gas is reddish brown?
nitrogen dioxide
what gas has a pungent odor?
ozone
what is the main source of ozone?
photochemical air pollution
what gas is a powerful oxidizing agent?
ozone
Ozone reacts with lungs to form _____ that have what effect on body?
atheronals that help with build up of atherosclerotic plaques
why can ozone travel deep in lungs
low water solubility, small
Oxygen and NO2 form cycle where ____ enters and ____ leaves
hydrocarbons enter and aldehydes leave
Peroxyacyl nitrates (PANs)
does what to the body?
comes from where?
respiratory and eye irritant
produced by peroxyradicals and VOCs, secondary pollutants
Where is the stratospheric ozone?
20km altitude, upper layer of atmosphere
What UV is blocked and which reaches ground?
UVb blocked by ozone, UV a reaches ground
Where is the ozone hole and when?
south pole/Antarctica in 2003. Depletes in october (summer)
why is antarctica a perfect place for O3 destruction
has polar stratospheric clouds made up of frozen crystals that provide the surface for the reaction. Chlorine is a catalyst and is recovered
Acid air pollutants
sulfur oxides and nitrogen oxides
secondary air pollutants
sulfuric acid, nitric acid, ozone
Acid rain is
precipitation of secondary air pollutants, sulfur dioxide and nitrogen oxide reacting with water
Why does northern US have high acid rain damage?
low buffer capacity soil
Flue Gas desulfurization reaction
CaCO3 (limestone) + SO2 —> CaSO3 (calcium sulfite) + CO2
Where does airborne particulate matter come from?
man made- industry
natural- desert
mix- forest fires
PM2.5 is from
combustion particles, organics
PM 10 particles are from
dust, pollen, mold
Why are PM particles considered Group 1 carcinogens?
inhaled and get deep into lungs, go into blood streams, cause DNA mutations and other probs
the smallest PM particles go to alveoli and enter the blood stream through
diffusion
When is the first and second time we saw really bad air quality?
Beijing-755 ug/m³
Harbin- 1000 ug/m³
Where are most polluted cities?
southeast asia
What is the purpose of alveoli space?
ensures erythrocytes get loaded with O2 via diffusion
what is the primary defense for inhaled particles?
cilia. tracheal and bronchiolar cilia “beat” at certain frequency to move sputum out of lungs to mouth
exposure to lung irritants over time can lead to
increased mucus production and decrease in diameter of bronchial tube
difference between
asthma
COPD
fibrosis
asthma is inflamed bronchial tube
COPD is when you lose alveoli function
fibrosis is scarring from COPD
how does VOC/PM lead to chronic lung diseases?
Phagocytosis by macrophages of particles release ROS which leads to oxidative stress and inflammation
Asbestos categories and characteristics
Serpentines/Chrysotiles: more common, pliable, lytic at high conc
Amphiboles- more dangerous, rod like, generate ROS
3 ways amphiboles generate ROS
1) frustrate macrophages
2) Si and Fe facilitate ROS
3) activates redox dependent cell signaling
the disease caused by asbestos depends on
the cell type it affects
What are xenobiotics
foreign compounds not produced or normally found in the body, absorbed from environment
4 effects of metabolism of lipophilic xenobiotics
inactivates lipid soluble drugs
increases polarity
bioactivation (LDOPA)
parent drug more toxic (benzene)
Describe Phase I and II biotransformation
Phase I: oxidation, reduction, hydrolysis
Phase II: adds polar conjugate group (can skip or preceed phase I)
Sites of biotranformation
every tissue but primarily liver and GI
2 routes affected by first pass
inhalation (nasal mucosa and lungs)
oral (liver metabolizes in smooth ER enriched with CYP) (GI has efflux pumps and wide substrate specificity)
Steps of Phase I oxidation
oxidized CYP Fe3+ combines with drug
NADPH donates e- and reduces Fe to Fe2+
2nd e- transferred to redue e-
reactive O2 transferred to drug
CYP 450 recycled
Oxidation demethylation example
codeine to morphine
aliphatic alcohol oxidation example
ethanol to acetaldehyde via cyp2E1 and ADH
what CYP metabolizes 50% of drugs
CYP 3A4
if you have a prodrug and a CYP metabolized drug, what would you do to the dose ?
decrease
Which Phase is faster?
Phase II
Where do phase I and phase II occur?
Phase I: microsomes, membrane
Phase II: cytosol (except glucouronidation occurs in ER mem)
Two things that conjugation does
increases water solubility
increases size of drug
4 types of conjugation: Sulfation
enzyme:
cofactor:
fun fact!
4 types of conjugation: Sulfation
enzyme: sulfotransferases (SULTS)
cofactor: PAPS
creates reactive metabolites associated w cancers
4 types of conjugation: Glucuronidation
enzyme:
cofactor:
fun facts!
4 types of conjugation: Glucuronidation
enzyme: NAT
cofactor: Acetyl coenzyme A
MOST COMMON PHASE II
ISONIZAID
4 types of conjugation: Methylation
enzyme:
cofactor:
4 types of conjugation: Methylation
enzyme: MT
cofactor: SAM
4 types of conjugation: Glutathione
enzyme:
cofactor:
4 types of conjugation: Glutathione
enzyme: GST
cofactor: glutathione tripeptide
example of unwanted reactive intermediates in metabolism?
acetaminophen
if glucuronidation and sulfation pathways saturated, CYP used to metabolize and creates reactive intermediates
4 mechanisms that control enzyme activity
enz inhibition, activation, synthesis, structure change
8 factors affecting drug metabolism: Drug drug int
cyp inducers increase drug action
ex: inc metabolism of warfarin with st johns wort
cyp inhibitors: comp and noncomp= toxic
8 factors affecting drug metabolism: Diet and nutrition
(things that increase cyp, inc met, and inc dose)
burnt food and veg
alcohol
low carb high protein
8 factors affecting drug metabolism: Diet and nutrition
(things that decrease cyp, dec met, and dec dose)
high carb
grapefruit juice
8 factors affecting drug metabolism: age
increase age, decrease dose
8 factors affecting drug metabolism: disease
basically all diseases dec metabolism so dec dose
8 factors affecting drug metabolism: gender
testosterone inc CYPs
pregnancy dec CYPS, some metabolized in fetus
8 factors affecting drug metabolism: hormones
hypo lengthens half life, decreases metabolism, dec dose
hyper is opp
8 factors affecting drug metabolism: GI flora
some enzymes can deconjugate and decrease metabolism
8 factors affecting drug metabolism: genetics
genetic polymorphisms can alter CYP gene
Note 
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