Tox Test 3

anatomy of respiratory tox

nasal cavity, pharynx, epiglottis, larynx, bronchi, lungs, bronchioles, alveoli, pulmonary arteries and veins, mucous gland and mucosal lining

arteries

deoxygenated blood, away from heart, towards lungs

veins

oxygenated blood, toward heart, away from lungs

parietal pleura

outer membrane of the lungs

visceral pleura

membrane inside lungs

pleural cavity

in between lung membranes, filled with fluids that lubricates and holds the membranes together

inspiration and expiration

use of diaphragm and external intercostals (muscles that move ribs)

lung capacity diagram

residual volume

when you blow out as much as possible and there’s still stuff left

expiratory reserve volume

beyond what you’d normally do, “push”

tidal volume

normal breathing

change in respiratory volumes

indicates issues occurring

receptors in body’s arteries and brain

monitor pH, high CO2 levels lead to inc. \[ \] of carbonic acid lowering pH, low CO2 levels = inc. pH, the trigger to inhale/exhale comes from pH of blood

clara cells

metabolism in lung, P450 activity, type 1 epithelial, type 2 cuboidal, produce a surfactant that decreases surface tension in alveoli which allows sacs to inflate during breathing

water effect on lungs

high surface tension so prevents lungs from undergoing gas exchange

toxicant effects on respiratory system

lungs can be a target organ for inhaled, lungs/respiratory systems can be affected indirectly

respiratory defense mechanisms

cilia (mucociliary escalator), macrophages (deal with pathogens we breathe in), mucous (assists escalator), mitosis

what happens if mucous is too thick?

escalator shuts down, causes cystic fibrosis, infections, allergic rxns, asthma, bronchitis

exposure levels for measuring tox

occupational exposure measured in ppm if vapor at standard conditions, exposure limits are usually in mg/m^3

TLV

threshold limit value, average max \[ \] in which workers can be exposed without undo risk

TLV-TWA

time weighted average, max allowable average over an 8 hour work day

TLV-STEL

short term exposure limit, max allowable for 15 min, STEL > TWA

TLV-C

ceiling, never to be exceeded

gases

water solubility is key to where in the resp. tract they are absorbed, high solubility makes it easier to pass through mucous (upper tract) and hydrophilic, low solubility more likely to get into lower tract (hydrophobic)

fibers

may be intercepted in the upper airway, long the fiber the more potential to be caught in upper airway

large fibers

>5 micrometer, can directly impact upper airway

medium fibers

1-5 micrometers, may settle as sediment in trachea, bronchi, bronchioles, etc., can reduce air exchange

small fibers

nanoparticles

aerosols

dusts, fumes, smoke, mists, fogs

dust

via mechanical grinding,

fumes

generated via vapor condensation

smoke

generated via combustion

mists

spraying of liquid

fogs

condensation of vapors

responses to respiratory toxicants

irritation, involvement of immune system, free-radical damage

irritation

large number endpts, injury of epithelial cells lining resp. tract, extreme cases increase blood permeability which leads to edema, epithelial cells vasodilate because of the histamine release during an injury so the WBCs can pass through arteries leading to inflammation and fluid accumulation, bronchoconstriction, immortalized corneal cells

bronchoconstriction

impact on muscles surrounding bronchioles, indirect effect which leads to other problems like less oxygen uptake

immortalized corneal cells

cancerous, Draize test- adding 10mls to rabbit eye to see if something is toxic

involvement in immune system

allergic responses, inflammation, release of histamine and/or prostaglandins

free-radical damage

common, reactive oxygen (O2- superoxide anion) which is result of normal oxidative phosphorylation; hydroxyl radical =OH

formaldehyde

respiratory irritant

nitrogen oxide and ozone (O3)

promote accumulation of fluid in the alveoli, cell death can occur with 1 ppm exposure, ozone exposure = smog, ozone protects from UV in atmosphere but it isn’t good at our level

macrophages

line the soft palate/sinuses, chronic exposure to macrophages can induce fibrosis- inflammation that results in the over recruitment of fibroblast which lead to overproduction of collagen hence reducing elasticity

silicosis

silica crystals, issue with mining, grinding, stoneworks

asbestosis

asbestos is a fibrous silicate, symptoms can be delayed for years, can be precursor to a rare form of cancer: mesothelioma

inhalation study apparatus

nose only, chamber

static inhalation study

fixed air volume, toxicant introduced, inexpensive but problematic due to limited oxygen content, hence short term only

dynamic inhalation study

constant circulation of toxicant in inhalation chamber, most flexible and useful to determine toxic thresholds, respiration rates must be measured along with toxicant \[ \] in the air to understand the amount material dosed to lungs

resting potential

\-70 mV, neg. charge ions outnumber pos. charge ions inside cell, more neg. inside, more neg. outside, potassium flows through potassium ion channels to create the neg. resting potential

excitatory action potential

depolarization, membrane potential moves toward pos., resting potential increases from -70mV and may even be pos.

inhibitory action potential

hyperpolarization, membrane potential moves more neg., resting potential decreases from -70mV to something like -90mV

threshold potential

50mV, summation exceed → action potential

action potential

triggered when threshold is exceeded, all or nothing response, doesn’t decay along axon

peaks near 40mV (top of chart)

myelinated axons → action potential moves faster, saltatory conduction

sodium-gated channels

Na+ flows into axon, leads to rapid pos. membrane potential to inc. the pos. charge, depolarization

potassium-gated channels

K+ flows out of axon, hyperpolarization

refractory period

keeps conductance moving in one direction

action potential chart

depolarization

Na+ rush into axon due to open voltage gates

hyperpolarization

K+ leaks out of the axon through potassium ion channels and voltage-gated channels

sodium-potassium ATPase

can be inhibited by toxicants, helps maintain resting potential and recovery, 3 Na out, 2 K in

chloride ions

Cl-, more on outside of axon at resting stage

what would happen if Cl- ions got into the axon?

hyperpolarization, the nerve cell will be less likely to hit the threshold potential and won’t be able to fire, resting potential gets more neg.

tetrodotoxin

found in frogs/fish, pufferfish/fugu, blocks the generation of an action potential by binding to the outside and inside of a neuron and the sodium channels

saxitoxin and brevetoxin

produced by dinoflagellates, fish toxins, some shellfish can accumulate sufficient quantities to make humans sick/die, blocks voltage-gated sodium channels

batrachotoxin

produced by South American poison arrow frogs, inc. the permeability of the resting neural membrane to sodium by preventing the closing of voltage-gated sodium channels, can act from either outside or inside membrane due to high logKow, nerve continues to fire and eventually runs out of ATP

action potential for BTX

\

action potential for TTX and STX

prevents action potential from being created, bind and block sodium channel

action potential for scorpion, sea anemone, pyrethroids, etc.

similar to BTX but elongated, pyrethroids inhibit Na/K ATPase reducing ability to recover to a resting state, keep sodium channel open

no action potential

nothing happens, can’t reach hyperpolarization, paralysis

pyrethrum

natural insecticide made from dried flowerheads of chrysanthemums, binds to sodium channels and keeps them open, very safe for mammals due to metabolic breakdown of toxicant, easily broken down by UV radiation and biodegradation, short half life

DDT and synthetic pyrethroids

block/inhibit voltage-gated sodium channels, sodium can’t deprotonate membrane so it won’t hit the threshold or fire

pyrethroids

fenvalerate, deltamethrin, permethrin, high logKow, persistent

DDT

log Kow 5-7, very persistent, no ester

fenvalerate and deltamethrin

log Kow 6.2, ester aided degradation leads to lower persistence

high logKow is an advantage for

pesticides, stays in soil longer

why are pyrethroids more toxic for insects than mammals?

increasing refractory phase, insect neurons are more sensitive, rate of detoxification/hydrolysis of ester in liver, acid and alcohol products less toxic, mammals digest esters faster

pre-synaptic membrane

axon

post-synaptic membrane

dendrite

excitatory neuroreceptors

binding opens sodium channels, making membrane more pos., action potential is based on summation of many excitatory binding events, can be released at same neuron as inhib.

inhibitory neuroreceptors

binding opens potassium and chloride channels, results in more neg. membrane, dec. probability of having action potential, potassium leaves, chloride enters

post-synapse effect

relationship of proportion of inhibitory vs. excitatory

neutrotransmitters

acetylcholine, biogenic amines, amino acids, neuropeptides, nitric oxide, carbon monoxide

autonomic nervous system

controls involuntary muscle movement, organ systems, SNS and PSNS

sympathetic nervous system

fight or fligtachycardia, dilation of bronchioles, dilation of pupils, constriction of peripheral blood vessels, decreased digestive activity

parasympathetic nervous system

rest or digest, brachycardia, constriction of bronchioles and pupils, increased digestive activity, peristalsis, increased secretions

both SNS and PSNS

connected via CNS

release of acetylcholine in dendrite

calcium dependent, ACh is constantly released but is increased when there is a rapid influx of calcium due to an action potential

where is acetylcholine stored?

synthesized in neuron and stored in vesicles in cytoplasm

post-synaps

muscarinic receptor

response to muscarine, found where the neurons of the PNS connect to smooth muscle and glands, atropine blocks muscarinic receptors

muscarine

alkaloid derived from certain poisonous mushrooms

AChE is blocked by

organophosphates, carbamates

botulinum toxin blocks

ACh release

organophosphates

malathion, no pest strip, methyl parathion, dichlorvos

carbamates

sevin, apnox, temik, carbaryl, pirimicarb, aldicarb

toxicity effects of AChE inhibitors

overstimulation of PSNS

treatment for AChE inhibitors

atropine blocks muscarinic receptors, 2-PAM accelerates the reversal of AChE inhibition