pub health 179 environmental toxicology

midterm 1

how to determine risk in toxicology

1. identify hazard

2. exposure

exposure “formula”

exposure = how long (duration) x how much (dose) = severity of harmful effects (response)

• hazard = agent that is harmful

• exposure = duration and dosage

dose-response relationship (fixed exposure time) → CO exposure example

• as conc goes up → increasing effect

  • headache, dizziness, weakness

  • at max conc → max effect → confusion, unconsciousness, death

dose-response relationship (population-based)

as dose increases, % of population responding (as in showing some sort of effect) increases

LD50

dose given at once and causes the death of 50% of test population

how can you reduce risk for yourself even if you are all exposed to same toxic agent

limit exposure

is everything toxic

yea it depends on dose

dose response assessment

describes how the lkelihood and severity of adverse health effects (responses) are related to the amount and condition of exposure to an agent (dose) → typically as dose increases the toxic responses increases

no observed adverse effect level (NOAEL)

the highest observed exposure level (dose) at which there is no biologically or statistically significant increase in frequency or severity of any adverse effects (response) of the tested protocol

the reference dose (RfD)

is an oral or dermal dose derived from the NOAEL or LOAEL by application of generally order-of-magnitude uncertainty factors (UFs)

• UFs take into account variability and uncertainty reflected in possible diff between animals and humans bc we are still diff

• RfD = NOAEL/100

• RfD = LOAEL/1000

common env toxicants in US

• Mercury

• Formaldehyde

• Lead

• Asbestos – carcinogen

• Air pollution - VOCs (volatile organic compounds),

PAHs (polycyclic aromatic hydrocarbons), PM (particulate matter), dioxins

• Per- and polyfluoroalkyl substances (PFAS, PFOA)

• Pesticides - glyphosate

• PCBs – carcinogens, developmental toxicity

chemically stable

(long half-life, non-biodegradable) – e.g. DDT, dioxins, plastics, PFAS

elements that can accumulate

metals (Pb, Hg, As, Cd)

bioaccumulation

the buildup of a toxic substance within a single organism over time because it absorbs the substance faster than it can eliminate it

• eg. mercury gradually accumulating in a fish's tissues

***INDIVIDUAL ORGANISM

biomagnification

the increase in concentration of a toxic substance as you move up the food chain

• eg. small fish contain mercury → larger fish eat many small fish → larger fish accumulate higher mercury concentrations → top predators have the highest concentrations

***ACROSS THE SPECIES

important criteria of toxicity

• specific toxic effects

• selectivity to the target (e.g. receptor binding, targeting particular

mechanism)

• route of exposure (e.g. oral)

• distribution to the body and/or target organ

• detoxification

• easiness to be excreted from the body

ADME

• Absorption

• Distribution

• Metabolism

• Excretion

absorption

route of exposure (from)

- Skin (dermal)

- GI tract (oral)

- Respiratory tract (inhalation)

- Injection (blood)

- Wound (blood)

- Placenta (fetus, during pregnancy)

- Mucus

***final destination is BLOOD

4 major routes of exposure

1. inhalation, instillation, aspiration

2. derrmal

3. intravenous, intraperitoneal

4. food, water, oral

rank the 4 major routes of exposure based on rate of absoprtion (how quickly a toxicant reaches the blood)

1. Injection – Directly enters tissues or bloodstream; can bypass protective barriers

2. Inhalation – Rapid absorption through the lungs into the bloodstream

3. Ingestion/Oral – Absorbed through the digestive tract; may undergo first-pass metabolism

4. Dermal absorption – Enters through the skin, which acts as a protective barrier

***goal is to get to the blood FAST

the quicker the toxin gets in the blood

the more toxic the response

once the toxicant enters the blood circulation

it will be distributed throughout the body

is the distribution of toxins reversible

yes

what type of molecules can cross the cell membrane via simple diffusion

• small nonpolar molecules

• steroid hormones

• small uncharged polar molecules (kinda but more difficult)

what type of molecules CANNOT cross the cell membrane via simple diffusion

• large polar molecules

• charged molecules

factors affecting distribution

• Perfusion-limited tissue distribution

  • Rate of blood flow to organs determines distribution

  • Highly perfused tissues = more vulnerable (liver, kidney, lung, brain)

  • Poorly perfused tissues = less vulnerable (skin, fat, bone)

• Tissue affinity (transport)

  • Fat tissues — lipophilic toxicants

  • Bones — Pb

  • Liver — aflatoxin

normal blood capillaries

• Small gaps in capillary wall (not tightly sealed)

• Allow penetration of small hydrophilic molecules in blood (100A or smaller)

• Lipophilic molecules can permeate capillary wall

brain capillaries

• Sealed by tight junction (no gaps) = BBB

• Hydrophilic molecules not permeable

• Lipophilic molecules can permeate through BBB by transcytosis (passive transport)

• Efflux transporters are located on the blood side to move xenobiotics back to the blood

why is it hard for drugs to reach the brain

drugs must cross blood-brain barrier (BBB) and blood-cerebrospinal fluid

distribution

crossing the plasma membrane of target cells

external membrane barriers

skin, GI tract, lungs

covalent bond/molecular bond

chemical bonding between two atoms by sharing 2 electrons (1 electron from each atom to form 1 covalent bond between atoms)

are atoms forming covalent bonds stable

no because on their own the outer ring of electrons rae not failed

if there is no net charge on molecule what is that

polar

why are charged molecules (ions) and polar molecules water soluble

water molecules can surround and segregated them from each other (this is hydration shell)

are polar molecules water soluble

yes because partial negative and partial positive charges can interact with water molecules via dipole-dipole or H-bonding

are nonpolar/lipophilic/hydrophobic molecules (covalent bonding) water soluble

no because they lack partial charges necessary to form bonds with water

electronegativity

atom’s ability to attract electrons toward itself in a chemical bond

what happens if the substrate is lipophilic

it readily crosses the plasma membrane via simple diffusion and enters the cell (because the membrane is made of LIPIDS)

how can toxicants enter the cell through other ways

1. simple diffusion

2. passive/facilitated diffusion

3. active transport

4. endocytosis (pinocytosis and phagocytosis)

even if a channel or transporter is meant for transport of specific molecule how can toxicant enter

if it has similar chemical structure or physical property with the intended ligand

what organ is primarily responsible for detoxification

organ metabolizes toxicants

inorganic compounds

chemical substances lacking C-H bonds

organic compounds

chemical substances with CH bonds

toxic substance and drugs are generally

lipophilic chemicals, making them readily absorbed from the GI tract, lung, skin, and other routes and distributed through the body (can pass through the cell membrane, bad because once it reaches cell it kills it and that is what produced negative physiological effects)

goal of metabolism

converting these lipophilic toxins into smth more water-soluble/hydrophilic chemicals, so they can be readily excreted from the body via urine or bile

phase I metabolsim

adds small polar groups -OH, -SH, -NH2, -COOH, epoxide

• cytochrome p-450/CYP is a key enzyme

***in this class lowk focus on -OH and epoxide addition

• -OH is added to Cs (Cs adjacent to EN atoms are favored because these atoms have lone pairs that can donate e- density)

• epoxide added to C=C

phase II metabolsim

adds a large polar or charged molecule to substantially increase water-solubility of the metabolites

• transferases are responsible for this reaction (conjugation reaction)

phase I metabolism: hydrolysis

adding H2O and break the covalent bond of the substrate

• eg. esterases, hydrolases, CYPs

why are carbons a good target (specifically the carbonyl carbon)

the carbon is electron deficient because the oxygen is EN and is pulling the e- density

• water has a lone pair that can attack the e- deficient atom (nucleophilic attack)

phase I metabolism: dehydrogenation

removing hydrogens from a molecule, final product will become more water soluble and therefore less toxic because it can be excreted

eg. ethanol (toxic thing in alcohol) → acetaldehyde → acetate

phase I metabolism by cytochrome P-450 (CYP)

• target C and add -OH group

• target C=C and add oxygen (O) atom (epoxide formation)

• replace sulfur (S) with oxygen (O)

dehalogenation by CYP

removing halogen atoms because presence of halogens may significantly increase chemical stability (hard to be broken down) in the environment and in the body (very slow process tho)

• PFAS is known as the “forever chemical” because of how halogenated it is

in phase I metabolism why it so important to add these small polar groups

-OH, -NH2, -SH are added to make molecules more water soluble and reactive

• O, N, and S are electron rich, have lone pairs of electrons

• they can donate electron density to electron deficient atoms

electron deficient atoms (like certain carbon atoms) have fewer carbon atoms because EN atoms pull all the electron density away → these carbons can attract electrons from electron-rich atoms

***this makes it more reactive → we are prepping for phase II

does every toxin need to undergo phase I and phase II metabolism

no

what does oxidation do

(phase I) create electron-deficient carbons (epoxides or carbonyl groups)

what does hydrolysis/reduction do

(phase II) can expose or create electron-rich groups such as -OH, -SH, -NH2

what does phase II metabolism do

adding a large polar molecule or charged molecule to the substrate to make it very hydrophilic

examples of phase II metabolism

• electron-deficient carbons can be attacked by electron-rich glutathione (contains -SH) forming a conjugate (R-SG)

• electron-rich groups (-OH, -SH, -NH2) can participate in reactions such as sulfonation (R-SO3H), acetylation (R-Ac), and glucuronidation (R-Gl)

enzymes responsible for phase II metabolism

transferases

• glucuronidation → UDP-glucuronosyltransferases

• sulfonation → sulfotransferases

• glutathione (GSH) conjugation → glutathione transferases

most major type of phase II metabolsim

glucuronidation → >40%

characteristics of glucuronic acid

large, highly polar molecule with lots of -OH

characteristics of sulfate SO3 group

highly polar and (-) charged so that increases water solubility

characteristics of glutathione

large molecule with electron-rich -SH group → sulfur attaches to reactive sites on toxins

metabolism of aflatoxin

1. hydroxylation (Phase I): Aflatoxin B1 → Aflatoxin M1 or Q1 → eliminated through urine (sometimes after Phase II conjugation)

2. epoxidation (Phase I): Aflatoxin B1 → Aflatoxin 8,9-epoxide (highly reactive and toxic)

From here, the epoxide can undergo several reactions:

• glutathione conjugation (Phase II): qttaches GSH → forms aflatoxin-SG → eventually eliminated in urine

• DNA binding: epoxide binds to DNA → forms DNA adducts → can cause mutations and liver cancer

• hydrolysis: epoxide → dihydrodiol → dialdehyde → can bind to proteins (albumin) and enter the blood

3. glucuronidation (Phase II): certain aflatoxin metabolites → glucuronide conjugates → eliminated through urine

excretion

all mechanisms of elimination of toxicants from the body

• by kidney, lung, GI tract, and others (secretion — sweat, tears)

• through milk (risk of secondary exposure of toxicants)

what is clearance (CL) defined by

CL = CL (GI tract) + CL (kidney) + CL (other)

urinary excretion

glomerular filtration and tubular excretion by passive diffusion and active tubular secretion

• lipophilic toxicants are re-absorbed back to the blood efficiently

• polar, water-soluble toxicants are excreted with urine (AVG pH 6-6.5)

• weak bases are easily excreted with urine

fecal excretion

• non-absorbed ingested toxicants

• biliary excretion → absorbed toxicant is transported from the blood to hepatocytes where it is metabolized by phase I and II reactions and excreted into the bile duct

• bile duct → intestine → poop

pesticide usage in CA

CA alone uses 10-20% of all pesticides used in the US

are pesticides toxic to humans, mammals, plants, trees, veggies

ideally no, we should choose ones that highly selective to kill or remove pests

do pesticides persist in the environment

some stay active for a long time but some are easily degraded

pyrethroid

class of natural/active compounds found in Chrysanthemum cinerariae

pyrethrin

natural alkaloid, stronly act on insects (not on mammals) very short-lived in the environment (half-life) → ~2 days in soil and ~14 days in water

allethrin

synthetic pyrethroid compound (half-life) → ~60 days in soil

mechanism of action of synthetic pyrethroid pesticides

blocking inactivation of voltage-gated Na+ channel (prolonged opening and depolarization) in excitable cells

• Normally: Na⁺ channels open → Na⁺ enters the neuron → depolarization occurs → channels inactivate, stopping Na⁺ entry

• With pyrethroids: Na⁺ channels stay open longer because their normal inactivation/closing is disrupted

• Result: Prolonged Na⁺ entry → prolonged depolarization → abnormal or repeated nerve signaling

• Toxic effect: Overstimulation of nerves and muscles, potentially causing tremors, paralysis, or seizures

examples of excitable cells in the body

• neurons

• muscles (skeletal, cardiac, smooth)

***these cells generate action potential

membrane potential

• all cells have high conc of K+ and low conc of Na+ INSIDE

• all cells have resting membrane potential (-60 to -70 mV)

• resting membrane potential generated by efflux of K+

• excitable cells can depolarize (add more +) membrane potential

• membrane depolarization (action potential) is triggered and generated by influx of Na+

so why pyrethroids toxic to insectds

prolonging the open state of Na+ channels, leading to prolonged depolarization, disrupting nerve signaling

3 states of voltage-gated Na+ channels, how does this generate and propagate an action potential one way through the axon

• Closed/Resting State: Na⁺ channels are closed. More Na⁺ is outside and more K⁺ is inside the cell, maintaining a resting potential of −60 to −70 mV

• Open State (Depolarization): Once threshold is reached, Na⁺ channels open → Na⁺ rushes in → inside becomes more positive, generating an action potential

• Inactivated State: Na⁺ channels inactivate, stopping Na⁺ entry and preventing immediate reopening. This helps ensure one-way propagation of the action potential

• Repolarization: K⁺ exits the cell → inside becomes more negative → Na⁺ channels eventually return to the closed/resting state, ready for another action potential

cause of death by pyrethroids

• muscle paralysis

• respiratory failure

• cardiac arrest/arrhythmia

• due to disruption of action potential in axons

metabolism of pyrethroids

1. Phase I – Oxidation (CYP450):

• Adds –OH groups to carbons on the aromatic rings (hydroxylation).

• Makes deltamethrin more polar

2. Phase I – Hydrolysis (Esterase):

• Breaks the ester bond, splitting deltamethrin into two smaller molecules

• Produces carboxylic acids, including 3-phenoxybenzoic acid

• Can occur before or after hydroxylation

3. Phase II – Conjugation:

• Adds sulfate or glucuronic acid groups to the metabolites

• Increases water solubility, making them easier to excrete

why mammals much less susceptible to pyrethroids

• lipid solubility favors entry through insect cuticles

• diff in detoxification (mammals can metabolize pyrethroids quickly)

• negative temp coefficient (more effective below 25 degree celsius) → we are warm-blooded while insects are cold-blooded

• diff voltage-gated Na+ channel (binding affinity of pyrethroids in much less in mammalian voltage-gated Na+ channels)

potential problem of long-term use of pyrethroids to control mosquitoes in the environment

long-term exposure → builds resistance to pesticides

• 1% survive, reproduces, now resistance gene becomes more frequent in the population

• super mosquitoes → we see these pyrethroid-resistant mosquitos spreading in some regions

synthetic pesticides and toxicity

• organochlorine insecticides:

  • DDT

• organophosphate insecticides:

  • parathion, malathion

• neonicotinoid pesticides:

  • imidacloprid

• glyphosate (herbicide)

DDT

• first synthesized in 1873

• its pesticide effect was first reported in 1939

• commercially available during WWII in the US

• cheap mass production allowed massive use of DDT

• use: insecticide on flies and mosquitoes)

effects of DDT

• carcinogen → not yet proven (IARC group 2B)

• neurotoxicity → targets voltage-gated Na+ channels

• endocrine disruption → environmental hormone

***in 1972 → US EPA banned the use of DDT (still used in India and many countries in Africa to control malaria)

neurotoxicity of DDT

• DDT blocks inactivation of voltage-gated Na+ channels

• voltage-gated Na+ channel in insects is more sensitive to DDT than that in humans

• LD50 (insects) = 14 mg/kg

• LD50 (rat, oral) = ~800 mg/kg

• LD50 (rat, dermal) = ~3,000 mg/kg

• so pests are killed due to acute neurotoxicity

• humans are not killed by doses used for pest controls

is DDT safe

perhaps but its environmental persistency and chronic toxicity are of great public health concerns

chronic adverse health effects of DDT

• carcinogenicity → DDT exposure has been shown to increase risk of breast and liver cancer BUT scientific evidence linking DDT and cancer remains mixed → IARC classifies DDT as Group 2B

• endocrine disruptor → DDT can mimic the effects of estrogen in the body,, bind to estrogen receptor, and disrupt hormone balance, and normal development

DDT environmental persistency

• DDT is still found in the US soil and sediment due to its stability in the environmeny

• half-life (soil) → ~15 years

• half-life (aquatic sediments) → 2-15+ years

metabolism of DDT

1. DDT: Highly fat-soluble (lipophilic), allowing it to accumulate in fatty tissues → half-life ≈ 3–6 years

2. DDT → DDE (Dehydrohalogenation):

• Removes HCl and forms a C=C double bond

• DDE remains fat-soluble and persists even longer (half-life ≈ 6–12 years)

• Difficult for the body to eliminate

3. DDT → DDD (Reductive dechlorination):

• Removes a chlorine atom and replaces it with hydrogen

• DDD can undergo further metabolism

4. DDD → DDA (Oxidation):

• Forms a carboxylic acid group (–COOH)

• DDA is more water-soluble, making it easier to excrete through urine

additional toxic effect of DDT in wildlife

can cause eggshell thinning by disrupting calcium and prostaglandin metabolism of the eggshell gland in birds → reduce bird populations

what are positive effects of DDT

cheap insecticide that is readily available in poor countrues → the use of DDT effectively controls the mosquito population in countries with malaria, Zika virus, etc

superfund

the common name given to the law called the Comprehensive Environmental Response, Compensation and Liability Act of 1980, or CERCLA

superfund sites

emergecy and hazardous waste sites needing long-term cleanup, which are identified by the Congress

DDT contaminated superfund site in SoCal → Montrose Chemical corp in Torrance

largest technical-grade DDT production in the US in 1947-1983 → wastewater was discharged into sewers and entered into the Pacific Ocean → contaminants: DDT and other chemicals

DDT contaminated superfund site in SoCal → Palos Verdes Shelf (PVS)

because Montrose Chemical Corp discharged wastewater (containing DDT and other chemicals) into sewers, PVS was highly contaminated with these chemicals

environmental impact of DDT waste in SoCal

• at least 27,000 (and possibly as many as 500,000) drums containing DDT and industrial waste were dumped in LA coast

• chemical waste dumping might have started in 1930s and continued through 1970s (legally with state approval)

• it is estimated as much as 700 tons of chemical waste was dumped → it was sealed in bottle though so we are good????

• montrose chemical corporation of california → the largest manufacturer of DDT in US from 1947-1982)

• mysterious increase of cancer among CA sea lions in the coastal areas due to DDT exposure

organophosphates (OPs)

• mech of action → acetylcholine esterase (AChE) inhibitor

• relatively non-toxic to humans

• OPs cause more serious illness than any other class of pesticides → sulfur groups converted to oxygen via phase I metabolism → so phase I metabolism in this case actually does more harm than good (wait hyacinth asks prof or ta abt this)