PMO 549 (Toxicology)


**Review for exam. These are my personal notes from today's review. They are very disjointed and piecemeal. Feel free to cleanup and make them better if you wish—Quantumdoc

Quiz 1 Review

No immunotox on quiz. Quiz will be through Biotransformation.
20 questions, 30 minutes. Standard multiple choice, T/F, or fill-in-the-blank multiple choice. Select from something on page. Questions similar to what you may see on board.


Know types of toxicologists
Know what a CAS number is, and why we care.

Physical properties vs. chemical properties.
Mixtures Slide
Atoms Slide (protons, neutrons, electrons),
i.e. which one has .0005 amu and negative charge.
Noble gases - what is a cation/anion.
Nothing about which group does this…
No nomenclature questions!!
Covalent Ionic Bonding, Ionic, recognize covalent compounds.
Dipole-dipole interactions.
van der Waals - H bond is the strongest of the van der Waals.
No oxidation number calculations.
Difference between oxidation and reductions. (Oxidation loss of electron. Reduction gain of electron) Oxidation numbers. Definitions of oxidation and reduction: Any reaction that decreases the hydrogen content or increases the oxygen, nitrogen, or halogen is oxidation. And vice-versa for reduction.

Reduced gluthathione slide. Understand this slide.
Acid - donates protons. Wants an electron pair (Lewis) Electrophile.
Bases - takes hydrogen. Wants to give an electron pair (Lewis)
No pH calculations.
No ka type or H/H questions.
Know italicized statements about H/H equation slide.
Know direct naming of hydrocarbons (first intro slide). (e.g."Which of the following four choices is an ether?" on a recognition basis) Ether, Alcohol, Ketone Carboxy acids.

Conceptual recommend reviewing all slides, whole talk is fairly high yield.
Definitions important. Potential and elements of exposure Acute, subacute, subchronic, and chornic. Incdent duration and frequency.
Exposure definitions. Intensity, frequency, duration
Definition of alkaloid - natural amine produced by a plant.
Toxicological paradigm - match with the part of paradigm. Example from Biotransfformation.

  • Exposure, internal dose, biologically effective dose=toxicokinetics (what we do to xenobiotic)
  • Early biological effect, altered structure/function, disease=toxicodynamics (what xenobiotics do to us)

Hazard is a function of the biologically effective dose.
Dose Definition

Key point calling xenobiotic. What is a hazard - has to do with bioeffective dose. Gave example of sucrose that you would have to be hurt by the dump truck dumping a load of it on you before it would do damage.

DO NOT know relative toxicity ranking.
Know ultimate toxicant.
CCl4 attacks lipids. Ah receptor, dioxin.
Know what an adduct is.
Know stochastic and deterministic and hormesis (Bad - U shaped. Good - dome shaped)
Hazard/risk/safety definitions No safety trick questions.
Nothing on chloroform other than chloroform in water supply.
Categories of toxicity
Chemical interactions (additive, synergistic, antagonistic, etc.)!!
Causes of variabilitiy in a toxicity test xenobiotics (important slide).

Factors moving through membranes. pKa, Partition coefficient.
Types of aerosols, Ventilation vs. perfusion dependent. Nothing on particle size.
Disposition (distribution, elimination)
First order elimination vs. zero order.
No pharmocologic-like models.
Half-life constant 0.7
Excretion pathways
Sequestration is not the same as elimination.
Elimination/Excretion - why you have bile. What is reabsorbed. Lung is passive diffusion.
Bile excreted in feces but have enterohepatic circulation which can perpetuate toxicant.

What's particulate and what's photons
Non-ionizing vs. ionizing.
Different types of particles and what they do. (Alpha, Beta, Gamma, Neutron)
Rad measurment unit. Rem has a quality factor.
Regulatory stuff. 10CFR and NRC. FDA regulates hospitals. DOT deals with transport, EPA environment, DoD military.
360 mrem annual average background radiation. Radon biggest environmental source.
10 CFR annual dose limits (5 REM whole body, pregnancy 500mrem, public 100mrem)
Radiation does not cause a sensation unless lethal dose.
Know whole body effects and radiation doses associated with syndromes. Survival estimation.
No treatment questions. Nothing on polonium. No cell cycle questions.
Radiation has both stochastic and deterministic effects.
No sister chromatid exchange questions
No radiogenic cancers.
Time, distance, shielding.
Terminology Stochastic (cancer caused by radiation) and Deterministic (Cataracts caused by radiation)
Two example questions at end of ppt.

Define biotransformation. Why you have biotransformation.
Liver is chief organ of biotransformation.
Aflatoxin binds to DNA and causes liver tumors and is mopped up by glutathione. cP450 metablolizes it and makes it worse.
Phase I - Hydrolysis, Reduction, Oxidation (HRO)
Phase II - More water soluble or masks groups
Flavoprotien and cP450 in same place in endoplasmic reticulum.
Microsome=smooth ER
Catalytic cycle n p450 oxidation and reduction of iron. If uncoupled get bad things.
No questions on type of reactions for p450. Know that it does lots of stuff.
Question like True or False, CP450 only does oxidations, answer False, it does lots of stuff.
p450 has a bunch of isozymes.
Vary alleles (bottom of slide page) in bold letters
Suicide inactivation
Flavin monooxygenase overlaps with p450, detoxifies, and can inactivate p450. forget pathway.
Recognition of carboxylesterase reaction products
Coccaine and alcohol (Methyl ester) = badness
Benzopyrene metabolized by p450 and epoxide hydrolase to an epoxide. Antagonistic role of p450 and epoxide hydrolases.
Reductions happen in low oxygen tension.
Glutathione deals with disulfide bonds.
Forget sulfoxide
Quinone - know semiquinone radical and cause oxidative stress and opposed by superoxide dismutase. and can kick off oxides. Adriamycin. Low superoxide dismutase in heart muscle.
MAO and MPTP. Ends up MPP+. Looks like paraquat.
ADH and ALDH. Different types of alcohols. Enzymes can make different products, good or bad. Formic acid and glycolate (acidosis)
Tylenol - p450 hurts you and hurts liver. Glutathione mops up. Prostaglandin H Synthase hurts kidney (more concentrated there). Phase II can metabolize tylenol before phase I.
Phase II key point slide. Which things make more water soluble and which don't.
Glutathione creates mercapturic acid in urine.
NO Cofactors.
N-acetyltransferase - slow acetylators. NAT2
Ah receptor. Dioxin is the most important stimulator. Increases p450.
No species differences.

Mid-Term Review

Principles of Tox II (Dose Response Relationships)
Population dose response (quantal) "all or none" response for animal testing as opposed to an individual response. Know dose-response curve and cumulative dose-response curve. Range of responses per given dose in a population of animals. These doses are combined to make the cumulative dose-response curve. Log transform to make them look more linear. No specific reason for it, just makes it look like a straight line.

Probit units - Log transformed and create, standard normal distribution. Add 5 so that you have no negative numbers and plot standard normal distribution in Probit units. Will not ask to calculate Probit units. Recognize that there is a frequency response curve and distinguish from cumulative and log transformed.

Abbreviations for LD50, ED50, etc. Know this. Sentinel dose is like a sentinel event. Dose for something like a nasty smell. Plot a dose-response curve for it and create a SD50. Used for protection purposes. Curve is in the book. SD100/TD01 most protective.

Know approximation of dose from animals to humans.
Do not know acute toxicity rankings.
Potency vs. Efficacy. Potency always has to do with dose on X-axis. Most potent drug is always one where you see response at lower dose (see graphs). Response (efficacy) greater response for a given dose (at the maximum end of dose-response, where you end up on the Y-axis).

Sentinel Dose. One substance with several curves. Amount of overlap between curves determines margin of safety. Described through a ratio, calculated in relation to SD. Larger the value, the better. Curves further apart. Be able to calculate.

Animal testing. Lots of fodder for questions. Draize test. IARC and NTP.

Definitions important. Innate vs. adaptive immunity. Effector cell slide (don't memorize). No cytokine questions.

Know what complement is and what it can do (opsonize and make MAC and neutralize virus).
No specific questions on toll-like receptors. Know that there are pathogen-assocated molecular patterns.
Adaptive immunity. Things have to captured and processed by APC. Understand dfference between Class I and Class II.

TH can activate other kinds of effector cells like NK, etc. No cytokines.

Know what is an antigen slide.
Know types of cells involved and their relationships.
Overview of humoral and cellular responses. Know these slides.

No antibody structure or function questions. No Ig classes.

Know what antibodies do.

Anaphylaxis and amines in hypersensitivity reactions.
Gell and Coombs classification. Know antibodies in each type.
Type I reaction - Don't know specific examples. Familiarize yourself with depiction of what happens. Must do a prick or intradermal skin test. In vitro test is less specific, don't crosslink and degranulate mast cells like skin test.

Type II - Cytotoxic. Blood transfusion reaction. Coombs testing associated with type II.
Type III - No categories of immune complex reaction.
Type IV - patch testing.

Anergy panel - looking for someone who is anergic.
In vitro tests
Lymphocyte stimulation - know that lymphocytes are stimulated.
Mixed lymphocyte - stimulate under someone else's lymphocytes.
Immunotoxicity in animals- Humoral and cell mediated immunity. Tier I aned Tier II. First tier is simple stuff like tests of T and B lymphocyte response to mitogens and MLR, Tier II progresses toward more additional tests like immune challenge.

Know immunotoxcity outcomes.
Beryllium important and lymphocyte proliferation test.
Dont' know immunotoxicants slide. No autoimmune reactions slide. No multiple chemical sensitivity.

Non-ionizing radiation
Know definitions.
Thermal injury is key slide. Skin damage from lasers. No thermal damage and summary of basic biological effects. Class IIIb and IV have occupational exams. Class I the weakest. IV is the highest. No grades of retinal lesions. No examination protocol.No RF and MW. No critical organs. No RF sources. No EMI from pacemakers. There is no cutpoint for occupational exam and dosimetry for RF.

Know what a cytotoxin is. Know tetanus slide.
No Nicotinic Ach questions other than botulinum toxin, cobra (elapid) venom, and pit viper. Won't have to label. Know what a cytolysin is. Some toxins affect signal transduction. Try to pick up general concepts from remainder of lecture. Know that toxins associated with dinoflagellates. Know Scombroid poisoning. Plants make cardiac glycosides. Make alkaloids. Foxglove, hemlock. Ricin is peptide toxin from beans. Know contact dermatitis from plants. Abdominal rigidity from black widow. Hymenoptera - 1% type I hypersensitivity. Know how fungus can harm human. Know what a mycotoxin is. Aflatoxin, hepatitis and liver cancer. Ergot alkaloids-abortafacient. Stachybotrys and pulmonary hemorrhage. KNOW THE MOLD STUFF!!!!!!!!!!!!! before the other stuff.

Nothing on DNA structure other than definitions.
Know somatic mutation theory of cancer slide.

Mutagenicity and Carcinogenicity slide.
Clases of mutagens and free radicals.
Nothing on addition and subtraction.
Genes, alleles, definitions
No endonuclealse and DNA glycosolase questions.
Gene mutations and genetic damage slide (Macrolesion and microlesion)
Base pair slide. Point mutation where there is and is not a framshift. No translocation, transversion questions.
Mutagenicity tests in lower organisms.
General idea of the Ames test. For mutagenicity. It's a reverse mutation.
Know difference between somatic and sex cell.
No cell cycle questions.
Macrolesion - Chromosome Aberration slide is important.
No chromosome vs. chromatid questions.
In vivo mutagenicity tests in mammals important. These slides forward to end of lecture.
Somatic vs. germ-line mutation slide is key.
Sperm morphology slide.

Quiz 2 Review

Quiz through Derm/Ocular (not cardiovascular)


Question on function slide. Two reasons major target: First pass metabolism (why liver is major target). However, no matter where you take in toxicant, liver still primary site of biotransformation.

Next slide that matters – functional acinus slide. Know the three zones. Zone 1 with most O2. No names, only know zone numbers.

What is the point slide. Zone1 better access to O2 and higher levels of glutathione. Zone 3 has more P450 (sets you up for zone 3 tox exposure).

Cell types slide – recognize endothelium and sinusoids in liver. Kupfer cells are resident macrophages. Ito cells – synthesize collagen and have major role in cirrhosis.

Types of Hepatocellular degernations – know difference between necrosis and apoptosis. Different patterns of necrosis. If dose gets high enough, individual patterns overcome.

Putative hepatocyte slide – know the definitions. Hypersensitivity uncommon in liver but associated with halothane and Voltaren (NSAID). Type II hypersensitivity.

Know what steatosis is (fatty liver).

Cholestasis slide – know methylene dianiline association.

Aflatoxin slide (print out on Blackboard). Hepatitis B and aflatoxin exposure are synergistic for causing hepatocellular carcinoma. Cytochrome P450 biotransforms aflatoxin to ultimate carcinogen. Binds to DNA in liver and causes tumors or is detoxified by glutathione. Know using oltipraz (chemoprevention) that induces production of GSH to ramp up phase II process. In urine, mercapturic acid-aflatoxin adducts eliminated.

Cirrhosis slide – When collagen laid down, you have walls that separate hepatocytes. No nourishment, more death, more collagen. Viscious cycle.

Tumor slide – Two major types: hepatocellular carcinoma or angiosarcoma (endothelial cells). Know bold face type.

CYP2E1 – Know this isozyme. Involved in metabolism of the EtOH, CCl4 and acetaminophen. ADH and ALDH saturable. Once switch to zero order kinetics, now metabolized in microsomes by CYP2E1 and creates acetaldehyde. Acetaldehyde itself is toxic and creates adducts. Get a big build up in acute poisonings. On a chronic basis, CYP2E1 is induced and acetaldehyde builds up (but may not have effects). Tylenol and CCl4 are bigger risks for chronic drinkers.

CCl4 and alcohol slide – When CCl4 metabolized by CYP2E1 makes a radical and get lipid peroxidation. If a chronic drinker, get synergistic effect.

Injury and enzyme induction – In a typical person, acetaminophen mopped up through sulfation and glucoronidation. In a drinker, more metabolism through CYP2E1 and get bad metabolite (adducts with hepatic proteins inducing necrosis). Glutathione can mop it up. But don’t have a lot of it in zone 3 so, it’s not mopped up.

N-acetylcysteine – makes more glutathione. Rate limiting step (cysteine) in GSH synthesis.

Last three slides – CCl4, methyline dianiline, trichloroethylene, vinyl chloride from first slide. Nothing on last two slides.


Renal susceptibility slide – kidney gets a lot of blood. Processes that concentrate urine, concentrate substances in urine. Can precipitate and cause obstruction. Kidney sensitized to vasoactive substances.

Renal functions slide – review it.

Consequences slide – need erythropoietin and need a functional kidney. Renin-agiotensin axix.

Vitamin D – kidney gives most active form of vitamin D. Source of renal osteodystrophy and “ouch ouch” disease.

Glomerular filtration – If bound to plasma proteins, not filtered. Only unbound filtered. If some process makes glomerulus more permeable, get more protein in urine.

Proximal tubule – Absorbs lots of stuff and secretes things. Big target for xenobiotics.

Additional tidbits slide – As you take out nephrons, others have to make up for it. Nothing on heat shock proteins. Know metallothionin. Induced by the presence of heavy metals and binds them.

Bladder slide – Important slide. Bladder has more Prostaglandin H Synthase than C-P450. Takes aromatic amines and activates them. Carcinogens can be acetylated by N-acetyltransferase (Phase II). Slow acetylators can get bladder cancer.

Phase I Oxidation slide – Kidney and bladder have higher concentration of peroxidases.

Cadmium slide – Kidney is the most sensitive organ and you can ingest it, smoke, or inhale via occupational exposure. B2 microglobulin is LMW proteitn. More of it peed out if you get tubular damage. Can be measured / detected in urine.

Methallothionen slide – Kidney major repository for cadmium. Metallothionen doesn’t help with cadmium. Can absorb free cadmium or Metallo-cadmium complexes. Lysosomes break down and cause damage.

Itai-Itai byo (Ouch Ouch disease) – Link this to contaminated water and mining. People eat rice laced with cadmium. Incidence declined when contamination abated.

Use of cadmium – skim this over for uses.

Cadmium medical monitoring – Only know that B2 microglobulin measured in urine due to OSHA standard.

Other metals of primary concern slide – Inorganic mercury and lead hits proximal tubule. Saturnine gout from lead (causes uric acid build-up).

Halogenated hydrocarbons slide – CCl4 and chloroform hit proximal tubule. Chloroform becomes metabolized to phosgene.

Obstructive uropathies – Xenobiotics concentrated in kidney. Know methoxyflurane. It becomes fluoride and oxalate. Oxalate causes obstruction.

Aminoglycosides slide – Pulled into proximal tubule lysosomes. Inhibit enzymes in lysosome that degrade phospholipids and pop and causes necrosis.

Dietary Supplements slide – Don’t have to prove safety unless supplement is new. No postmarket reported or surveillance. Only way FDA enforces unless adulterated or false/misleading claims made.

Balkan Endemic Nephropathy – Familiarize with BEN’s features. A lot of things thought to casue it. Thought to be three things (aristocholic acid, ochratoxin A, and pliocent lignite). Best culuprit is aristocholic acid. Found in herbal remedy and BEN. DNA adducts in both “Chinese herbs” and BEN.

Neurotoxicology (do review questions)

Blood brain barrier – Integrity of barrier can be damaged. Lipophilic greater than hydrophilic. Not as well developed in children.

Peripheral neuropathies – Know symptoms. Know lead, diabetes, carbon disulfide, n-hexane.
Developmental case example – more lead absorbed in GI tract of children than adults.

Injury to neuron slide – solvents lipophilic and destructive to cell membranes, particularly neurons. Know trichlorethylene (solvent).

Orgonochlorine slide – DDT resistant to degradation. Lindane.

Injury to the neuron slide – sensitive to anoxia. CO, CN, and HS can starve neuron of oxygen that it needs.

Disruption of action potential – some solvents mess up neurofilaments. Know n hexane.

Tetrodotoxin – blocks fast sodium channel. Binds to pores.

Review of synapse – Ach enzymatically degraded. Others use different mechanisms. Uptake and diffusion are other mechanisms. No specific neurotransmitter questions.

Organophosphates – Pesticides. Recognize names (sarin, parathion, malathion). Rapidly degraded in environment. Very lipophilic and readily absorbed. Dermal exposure important. Potentiate Ach through inactivating Ach esterase. Know atropine and 2PAM.

Botulinum – keeps vesicles from docking and fusing. Irreversible. No release of Ach.

Carbon disulfide exposure limits slide. OSHA creates PELs (Permissable Exposure Levels). ACGIH does TLV (exposure limit) and BEI (blood and urine tests drawing conclusion about internal dose.). NIOSH does REL. OSHA is a regulatory agency, so PELs are like laws. Others are guidelines. Do not know PPM levels.

Parkinsonian symptoms – Know MPTP and Manganese cause.

Inhalational Toxicology

Anatomy slides - Alveoli and respiratory bronchioles are gas exchange regions.

Respiratory tract slide – Rodents obligatory nose breathers. Can absorb in nose. CN I directly to brain for some solvents like xylene.

Clearing mechanisms – know mucociliary escalator and alveolar macrophages.

IH certfications – ACGIH gives TLV. Industrial hygienist training requirements. CIH designation. They don’t have a license from state.

Aerosol types – Know them. Don’t know particular particle sizes. Fiber count and shape is more important than mass.

Bioaerosols – know this slide.

Isolation rooms – Need for less than 5 micrometers. Lodges in alveoli.

Precaution and isolation slides – know them. Know droplet vs. airborne. Droplet environment – surgical mask. Isolation – N95 needed.

Particles graph – not every particle same size, Have to come up with average size called count median diameter. Not always same shape, so have to account for aerodynamics (AED), also known as Mass Median Aerodynamic Diameter (MMAD).

Air velocity slide – Gets lower as you go down the respiratory tract. Less directional change in alveoli.

Particle deposition mechanisms – know this and watch video.

Particle deposition and AED – If bigger than 10 microns (nasopharynx). Less than 5 (alveoli). Less than 0.3 Brownian motion.

Odors – review basic concepts.

Acute Responses – airway reactivity, pulmonary edema, hyperplasia.

Classification of acute inhalational toxicants – know respiratory toxicants that effect lungs and systemic ones that give inhalational fevers. Irritant gas – target is respiratory system.

Simple asphyxiants – Hydrogen lighter than air. Natural gas heavier than air.

Acute toxic inhalation – High water soluble (formaldehyde and ammonia). Can be life threatening. Intermediate chlorine. Low is phosgene (delayed pulmonary edema). If dose high enough, generalizations go away.

Inhalation fevers – high yield slide. Flu-like symptoms. Normal CXR, PFT, and ABGs. Rapid resolution after removal from exposure. Metals can cause metal fume fever. Teflon can cause polymer fume fever. Bioaerosols can cause organic dust toxic syndrome.

Chronic responses of lung – Fibrosis and emphysema. Alpha-1 antitrypsin protects lungs from proteolytic enzymes.

Chart – Asthma can be hypersensitivity mediated or polyimmunologic. IgE mediated is high molecular weight. Polyimmunologic uses haptens. Others are non-immunologic. Pharmacologic works via either direct histamine release (cotton, hemp, etc.) or potentiating Ach (organophosphate and carbamate insecticides). RADS due to inhalation of corrosive irritants (may or may not get better). Reflex bronchoconstriction (cold air, exercise, etc.)

RADS – Be familiar with chest physicians criteria. Healthy and then get asthma-like symptoms right away (single exposure incident). Can be totally reversed, but doesn’t have to be.

Byssinosis slide – Just cotton and byssinosis and Monday morning asthma.

Hypersensitivity pneumonitis – Combination of immune-complex mediated (Type III) and cell mediated (Type IV) but NOT an asthma. Can be high or low molecular weight thing.

Hard metal disease- tungsten and cobalt.

Bronchiolitis obliterans – popcorn workers. Diacetyl.

Pneumoconioses – Stanosis (benign caused by Tin)

Asbestosis – classical dose response relationship. 10-20 year latency. Less than for cancer.

Silicosis – acute is always fatal. Chronic (progressive massive fibrosis)

Coal Workers – Coal macule. Caplan’s syndrome ( Coal Workers Pneumoconiosis and Rheumatoid Arthritis ).

Tobacco slide – important

Asbestos – mesothelioma. Pathognomonic for asb exposure.

Sinonasal cancer – hexavalent chrome and wood dust

Lung cancer – asbestos, radon, hexavalent chrome.


Defense roles of skin.

Barrier function – stratum corneum information

Systemic delivery slide

Dermatitis – majority of contact dermatitis is irritant rather than hypersensitivity.

Contact dermatitis is mostly irritant-based rather than allergic. For irritant, either work through primary irritant pathway involving direct damage to tissue (strong acids or very reactive xenobiotics) or non-direct (majority of them) whereby secondary inflammatory effects mediate damage via the innate immune system. Neither primary, nor indirect are allergic.

Common causes of irritant – water most common cause (works via secondary, indirect pathway).

Clinical appearance of Allergic Contact Dermatitis (ACD) – vesiculation, erythema, scaling, and finally lichenification.

Allergic contact dermatitis – type IV. Two exposures needed.

Photosensitivity – Damage we would all get from UV light or ionizing radiation. Everyone susceptible.

Phototoxicity – Something on your skin is modified by UV light to ultimate toxicant.

Photoallergy – actual allergic reaction. Prohapten becomes haptenized in presence of UV light.

Hyperpigmentation – coal tar.

Ulcers – chrome holes in nose.

Fibers – can cause dermatitis.

Nothing on formaldehyde

Ocular toxicology

Alkalai worse than acids. Acids denature proteins unfold and coagulate/conglomerate and makes barrier that can plug outflow of aqueous and can lead to increased intraocular pressure (IOP) otherwise known as glaucoma.
Chromic acid for acid. Sodium hydroxide for base.

Corneal endothelim vulnerable because gets supply from diffusion. Can destroy blood supply to eye.

UV radiation – No nanometer questions. Know welders flash. UV exposure associated with cataract formation.

Eye can be exposed systemically or topically. Know the systemic toxicant methanol.

Final Exam Review

No Formaldehyde, fuels, derm, or ocular.

Cardiovascular Tox

Entire first page – eliminate

Second page – myocardial ischemia and reperfusion associated with oxidative stress.

Mitochondrial dysfunction slide – electron transport chain is target of cyanide (CN).

CN blocks different parts of electron transport chain.

Hb slides – Hb has one heme group and 4 polypeptide chains (globins). Chains associate themselves into two dimers and the way dimers interact effects whether Hb has affinity for O2 or not. Taught and relaxed structures. When you have taught structure, you have H bonds which are active keeping it taught and unloads O2. CO2 associated with taught. Relaxed – O2 breaks up H bonds and increases affinity for O2. CO keeps bonds broken (has more affinity for heme groups). Takes a whole heme unit out of commission. Not affected by normal things that make O2 unload.

Don’t know mechanisms of hemoglobin binding slide details. No left and right shift questions.

Methemoglobinema – Iron oxidized to ferric iron. Won’t bind O2. Autoxidation occurs and we get small amount of methemoglobin. Nitro amino compounds and arsine. Two pathways to eliminate methemoglobin (ferric back to ferrous).

No toxicity levels for methemoblgin.

Cytb5 reductase is main path to eliminate Methemoglobin. Minor path is NADPH methemoglobin reductase. Methylene blue speeds up reaction of NADPH reductase. Uses up NADPH. Regenerated by G6PD. Hemolysis will occur if give methylene blue to G6PD deficient patients. Leads to glutathione deficiency. Cell succumbs to oxidative stress.

Nothing on Heinz bodies, ethanol.

Carbon disulfide – accelerated atherosclerosis. Used to make rayon.

CO – nothing on minor mechanisms.

Angina and CO – cigarette smokers at 5% carboxyhemoglobin.

Methylene chloride – metabolized to CO. Toxicity indistinguishable from CO.

Nitrates – munitions workers. Monday Morning Angina. Become tolerant to effects of nitrates and need them. When withdrawn over weekend, get symptoms. Relieved by return to work or through nitrate medications.

Dysthrythmias – chlorofluorocarbons and huffing solvents (know toluene).

CN antidote – Give a nitrite first. Sequesters CN. Nitrites stimulate formation of methemoglobin which sops up CN. Bound CN to methemoglobin, then dissociates. Increase rhodenase activity through sodium thiosulfate to get to inactive product.

Cobalt and beer – cardiomyopathy.

Lead – Works at heme pathway. ALA-d and ferrochelotase. Get ZPP build up from inhibited ferrochetelase.

Aplastic anemia – Benzene and chloramphenicol. Ionizing radiation.

AML – Benzene.


Primary determinants slide important. Longer carbon atoms get, the more CNS depression and toxic (more lipophilic). Less saturated, more lipophilic.

Phys properties – lipophilicity increases with increasing chain length. Some solvents are amphipathic best for derm. DMSO prototype.

Toxicokinetics – Pulmonary absorption primary route of exposure. Skin is important enough there is a skin designation by ACGIH.

Distribution – Tend to be lipophilic and go to lipid rich tissues. Many solvents cross placenta and go into breast milk.

Effects – CNS depression and skin irritation.

CNS Depression- Increased by top three concepts on slide. Halogenated most depressing.

Irritation – some things irritate due to pH extremes. Double bonds more irritating than alkanes. Increased carbon chains increase irritation. Amines have the high pH. Acids low pH. Both are primary irritants.

Paraffin slide – Low amounts of C means it is a gas. Sweet spot for toxcicity are middle sized (vapor form) – gas or skin irritant. Over 10 C, liquid.

More Alkanes slide – Glue sniffers neuropathy (diketone neuropathy). Methyl ethyl ketone potentiates toxcicity, but does not cause by itself.. N-hexane and methyl-n-butyl ketone causes it by creating ultimate toxicant 2, 5 hexanediione.

Alkenes – used to make polymers. Ex: polypropylene.

1.3 butadiene – IARC 2A, Associated with leukemia and lymphosarcoma.

Benzene – in cigarretes. Causes aplastic anemia and AML.

Toluene – huffing. Causes arrythmias and CNS depressant. Does not cause cancer.

Alcohols – If there is a functional group, alters tox picture. Lengthened C chain can reduce toxicity of functional group. Methanol – formic acid. Degreaser’s flush.

Glycols – ethylene glycol. Oxalic acid.

Aldehydes – formaldehyde is a sensitizer.

Ketones – methyl-n-butyl ketone (neuropathy). Methyl-ethyl potentiates.

Chlorinated hydrocarbons – dry cleaning. Perchloroethylene. Does it cause spontaneous abortions?

Methylene chloride – CO metabolite.

Amines – highly toxic (high pH). Very bad. Sensitizers. Asthma. Benzidine=bladder cancer.

1,2 DBCP – sterility in male workers.

Carbon disulfide – atherosclerosis and rayon workers.


Metal cations interact with negatively charged groups.

Absorption – sensitization with nickel. Primary irritant hexavalent chromium.

Biotransformation – Oxidation reduction. Most metals bound to proteins.

Chelators – can chelate essential metals and concentrate toxicants in kidneys. No specific chelator questions.

Acute toxicity – metals bind sulfhydryl groups when binding proteins. Or they go somewhere and displace essential metal in body.

Arsenic – Arsine gas relates to arsenic. Methemoglobin former.

Chronic arsenic exposure – hyperpigmentation, hyperkeratosis, skin cancer. Hepatic angiosarcoma and lung cancer.

Cadmium – Kidney primary repository for Cadmium. IARC1 for lung cancer.

Chromium - Trivalent out in nature. Hexavalent created through industrial process. Hexavalent gives toxicity. Irritation and chrome holes. Hypersensitivty type outcomes. Lung and sinonasal cancers (IARC Group I).

Lead – Mostly inhalational in business world. In general population, ingestion. Kids have more GI absorption than adults. Long term storage in bone. When bone broken down, potentiall mobilizing lead.

Lead nervous system – motor neuropathy. Wrist and foot drop.

Lead and other organ systems – anemia, proximal tubule damage, colic, hypertension, Saturnine gout.

Lead and reproduction – Nothing but considered reproductive toxicant for low dose.

Kids – Want less than 10 ug/dl. Review slide.

Tetraethyl lead – hallucinations.

Mercury – Terminate with extreme prejudice. Hot button issue with dental amalgams, fish, thimerisol.

Risk Assessment

Definition of risk.

Steps of risk assessment –review.

Hazard Assessment, dose response, exposure, risk slides – Review slides.

Qualitative – You don’t go through all machinations. Show that humans don’t come into contact with toxicant and of no risk.

Ecological risk assessment – review.

Exposure measurement – Review slide. More accurate. Limited to present situation.

Exposure modeling – Review slide.

Dose response – NOAEL, LOAEL, SHD

No specific uncertainty factors – know that they are multiplied and know what they are. Basic concepts on uncertainty factors.

NOAEL – ignores shape of dose-response curve. Focuses on low doses.

Benchmark dose – models. Takes the whole response into account and brings shape into it.

Important point slide. Know.

Non-threshold – De minimis concept.

Risk assessment problem slide onward to example calculations – no way to measure the very low dose effects in animals. Measure as low as you can in animals and extrapolate from there. The largest differences are in the unobservable range. Most models are quite similar in the observable range.

Evaluation of mixtures – three broad approaches.

TEF/RPF – Relative potencies. RPF differs depending on end points. TEF common mode of action.

No calculations other than COL Mallon’s.

Hazard quotient/index – deal with threshold things and mixtures.

Criticisms and burden of proof – review for chip shot question.

Observable and uncontrollable stuff – What is feared by people (unobserved/uncontrollable are feared).


Products of combustion and in herbicides. Stable and lipophilic. Burning municipal wastes.

Definitions – Know congener definition.

Structures – Review briefly.

Human exposure is through food (biomagnifications through food chain).

Vietnam – Agent Orange. Dioxin contaminant in agent orange.

Chloracne – Yushenko question. Vietnam vets.

Seveso, Italy and Times Beach – Faggedaboutit.

Terminate page 5 except for Ah receptor site activity. Most common response is chloracne and changes sex ratio. Group I carcinogen. Thyroid cancer.

No genotoxic questions.

PCBs – Yusho (rice oil disease). Rice oil contaminated. Chloracne and hyperpigmentation. Least amount of support for cancer association (suspected).

PAH – From incomplete combustion of organic matter.Bay region is key. Predicts where PAH bind to DNA to create adducts. Linked to cancers, but historically linked to cancer (IARC IIa). Percival Pott – scrotal cancer. Require metabolic activation.

Ah receptor – Everything in lecture acts at this receptor.

Be able to calculate toxic equivalency factor.

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