Exam 1 -Tox

Mechanistic :

regulatory:

descriptive:

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

1. inactivates lipid soluble drugs

2. increases polarity

3. bioactivation (LDOPA)

4. 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

1. inhalation (nasal mucosa and lungs)

2. oral (liver metabolizes in smooth ER enriched with CYP) (GI has efflux pumps and wide substrate specificity)

Steps of Phase I oxidation

1. oxidized CYP Fe3+ combines with drug

2. NADPH donates e- and reduces Fe to Fe2+

3. 2nd e- transferred to redue e-

4. reactive O2 transferred to drug

5. 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

1. increases water solubility

2. 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