5400 final

What was an example given of the importance of dose-response in the world today?

Air pollution by PM2.5 leading to millions of premature deaths in China (and elsewhere)

Markers/Parameters of pulmonary function: Vital capacity (w/likely direction)

Air volume exhaled by maximum expiration following maximum inspiration; Decrease

How many cell layers thick is the airway epithelium? Respiratory epithelium?

Airway epithelium: 2-3 Respiratory epithelium: 1-2

In the Modern Era, i.e. the 19th century, what have been developed for poisons such as As and Hg?

Analytical methods

What is one sample reaction catalyzed by Cytochrome P450 involving nitrogen hydroxylation (OH)?

Aniline->Phenylhydroxylamine (Add OH)

Receptor antagonism

Antagonist binds to same receptor as agonist, disallowing action; Immediate response

If a tumor is estrogen positive, then you can use an estrogen _____ to fight the cancer.

Antagonist; Such as Tamoxifen

What are used to fight estrogen positive breast and uterine cancers?

Anti-estrogens or SERMs: Selective Estrogen Receptor Modulators; Block proliferation of breast/uterine cancer cells; Bind equally well to E1/E2 (Ex. Tamoxifen)

Supplements (ARE/ARE NOT) regulated.

Are not

What 2 toxicants have recently been found in popular protein supplements?

Arsenic, Lead

What form of Arsenic is most toxic? Which is most prevalent?

Arsenite (As⁺³): Most toxic Arsenate (As⁺²): Most prevalent

In the Middle Ages, poisoning became somewhat of a(n) ______, especially among what people?

Art form; Italians

Markers/Parameters of pulmonary function: Respiratory rate (w/likely direction)

Breaths per minute; Increase

What does the enzyme ADH: Alcohol Dehydrogenase cause in Ethanol, Methanol, and Ethylene Glycol metabolism?

Conversion to aldehyde

Dietary carcinogens have been proven in both ______ and _____ meats.

Cooked; Processed

What was the "Council of Ten" found in Venice, Italy during the Middle Ages?

Council that made contracts to poison political enemies

There are many families of Cytochrome P450s. Some have semi-specificities to certain chemicals. (TRUE/FALSE)

True

There is NO safe exposure level to Asbestos. (TRUE/FALSE)

True

Vinyl Chloride (VC) was one of the first identified human carcinogens. (TRUE/FALSE)

True (B.F. Goodrich plant)

80% of cancer is due to diet and lifestyle. (TRUE/FALSE)

True (Ex. Japanese immigrant men in U.S. incidence of stomach/liver vs. colon/prostate cancer)

Utah is currently a ______ area for PM2.5. What does this mean?

Non-attainment; Not meeting PM2.5 regulations since 2009

In what pulmonary cell type does most cancer start from?

Non-ciliated epithelial or Clara cells

What position on a dose-response curve indicates Potency?

Position along the x-axis

Where do toxic chemicals bind in soil?

Positively charged ions

EVERYTHING can be toxic, just the ______ is different.

Potency; Ex. water, aspirin

Heterocyclic amines: Toxicology

Potent mutagens, animal carcinogens; Possible human carcinogen (2B)

Acrylamide

Potent neurotoxin, reproductive toxin and carcinogen in foods; In baked/fried foods

Vapor pressure

Pressure of a gas in equilibrium with liquid or a solid at a given temperature; Likelihood that a chemical will evaporate at a given temperature

Soil residues of Dicofol decrease ______, but traces remain for more than 1 year.

Rapidly

Acute response

Rapidly developing, with a short and relatively severe course

What is a Margin of Safety?

Ratio of minimal toxic dose (TD₁) to the therapeutic (effective) dose (ED₉₉); TD₁/ED₉₉

Methylisocyanate: Sources

Reagent for manufacture of carbamate insecticides (not end product, used to create other chemicals)

In estrogen target tissues, only estrogens and closely-related molecules interact with ______. Estrogen receptors are ______ in other tissues.

Receptors; Absent

Xenoestrogens bind to estrogen _____ stimulating cell division (______) leading to a higher chance of ______ and therefore _______.

Receptors; Proliferation; Mutation; Cancer

"Amphibole hypothesis"

Recognizes significant differences in toxic potency between the main forms of asbestos; Risk of cancer/other diseases thought to be more closely associated with amphibole asbestos; Remedial efforts therefore focused on amphibole types

What is one way to reduce possible cancers due to the carcinogens found in cooked and processed meats?

Reduce meat intake

PM₂.₅: Environmental effects

Reduced visibility: Absorbs UV light

PM₂.₅: Sources

Refineries, pulp mills, coal/wood burning, volcanism, transportation; dust, asbestos fibers, metals (~ 40% industry, ~15% vehicles)

Enterohepatic Recirculation

Phenomenon in which chemicals emptied via bile into small intestines can be reabsorbed from the intestines into systemic circulation

Acrolein Mechanism of Action/Treatment

Reflex cholinergic stimulation causing bronchoconstriction, leading to increased airway resistance; Treat with bronchodilators (β-2 agonists): epinephrine, salbutamol, salmeterol

Methylisocyanate

Poor "warning properties:" Odor is NOT protective; Human thresholds for odor detection/mucous membrane irritation are greater than TLV

1,1,2-Trichloroethylene (TCE): Environmental chemodynamics

Poor soil binding and highly volatile, therefore it is quickly leached from soil to ground and surface water

What is the net effect of enterohepatic recirculation?

Restores chemical's original Kow, becoming more lipid soluble returning to the bloodstream

Highly lipid ______ drugs/chemicals disappear from the blood quickly (enter cells).

Soluble

Sodium phenobarbital, a weak acid (pKa=7.2), is present in its most lipid _____, non-ionized form in the stomach (pH 2) and the urine (pH 6.5).

Soluble

BPA is found within even canned foods and drinks. (TRUE/FALSE)

True; Found in canned tomatoes within plastic coating (more migrates in more acidic drinks/foods)

What do the regulations of PM2.5 try to prevent?

Try to prevent response of 1 in a million (1x10⁶)

Asbestos Toxicology: Lung cancer

Tumors of airways/alveoli, occurring 20+ years after exposure; Smoking increases risk; Incidence higher to amphibole exposure (miners, shipbuilders) vs. non-amphibole

Concerning emissions, should you idle or turn off your car?

Turn off your car

In a given population, there is a variation of dose responses within the population. What is this occurrence defined as?

Population variability: Exemplified by bell-shaped dose-response curve

Acetylsalicyclic acid (Aspirin) has a Volume of Distribution (Vd) of 0.15 L. What is its distribution in the body?

Vd<3L = Doesn't distribute well

Chlorpromazine (Thorazine) has a Volume of Distribution (Vd) of 21 L. What is its distribution in the body?

Vd>3L = Distributes well

Cyanide (CN): Toxicology

Very toxic; Fast-acting; Characteristic bitter, almond-like odor/taste

How do hydrophobic compounds travel via Passive diffusion across membranes?

Via lipid portions of membrane

Percutaneous route of chemical absorption

Via skin layer several cells thick; Good absorption barrier

Many Aldehydes are formed in urban air, categorized as ______ ______ ______.

Volatile Organic Chemicals (VOCs)

What makes Hg unique?

Volatility (high Vp)+Biotransformation

Markers/Parameters of pulmonary function: Tidal volume (w/likely direction)

Volume of air exchanged per normal breath; Increase

Hazard

The probability that injury will result from a chemical under specific conditions

NED for 50% response = ____.

0

Only ____% CO will produce 50% COHb.

0.1% CO (higher affinity than O₂)

What is the Volume of Distribution (Vd) of water soluble chemicals with a low Kow?

≈3L; Close to blood; Don't distribute well

What is the approximate pH of urine?

≈6.8pH

Asbestos fibers ___ (≥ or ≤) 1µm do NOT penetrate the deep lung.

≥1µm

Asbestos fiber: _____ aspect ratio

≥3:1; Greater than 3X length relative to diameter

PBT

Persistent, Bioaccumulative, and Toxic chemicals

Methemoglobinemia

"Blue baby syndrome;" Oxidants oxidize (take electrons) from Fe⁺² in hemoglobin to form Fe⁺³, which cannot carry oxygen

Pertaining to Cytochrome P450 nomenclature, what are the specific part of "CYP1A2?"

"CYP" = Cytochrome "1" = Family "A2" = Subfamily

Estrone and estradiol are metabolized to what 2 principal products? Which is considered "good" estrogen and which is considered "bad" estrogen?

"Good:" 2-hydroxyestrone (C-2) "Bad:" 16-α-hydroxyestrone (C-16)

Mercury Case study: Danbury Hat Company

"Hatter's Disease; "Hg⁰ toxicity; Mercuric nitrate used in felting process; "Danbury Shakes" neurologic symptoms

What case study is related to Cadmium (Cd) toxicity?

"Itai-Itai" disease in Japan; Cd pollution from mine runoff used for rice; Caused kidney damage leading to Ca2+ loss leading to osteoporosis and skeletal deformity (Less Ca2+ recovered due to inner nephron loop cells being damaged)

What is human's primary exposure to DDT?

"Prime" red meat

What was the drug Thalidomide released in the 1950s used to treat?

"Wonder drug" for morning sickness, sleep aid, sedative, cough, headache

What 2 pulmonary function markers/parameters were measured in Dr. Coulombe's translational PM₂.₅ study?

1) Vital capacity (decreased) 2) Tidal volume (Increased)

NED for 84.1% response = ____.

+1

What are the 3 types of Amphibole Asbestos?

1) Crocidolite 2) Amosite 3) Anthophyllite

Chlorinated Cyclodienes: Chronic toxicity

1) Psychological disorders 2) Intermittent twitching 3) Convulsions 4) Hepatoxic, Carcinogenic

NED for 15.9% response = ____.

-1

How many cell layers thick is the gastrointestinal epithelium?

1

How long does a car need to warm up to cause the least amount of emissions?

1 minute

What 3 sample reactions catalyzed by Cytochrome P450 involving Dealkylation (removal of CH₃ group)?

1) 7-methoxyresorufin -> resorufin 2) Dextromethorphan -> dextrophan 3) Caffeine -> paraxanthine (major product)

What are the biomarkers for Ozone toxicity?

1) 8-OH-dG 2) Malondialdehyde (inflammatory response)

What is the metabolism pathway of Ethanol?

1) ADH: Alcohol dehydrogenase converts Ethanol to Acetaldehyde 2) Acetaldehyde converted by ALDH to Acetic Acid then to Acetyl CoA

What is the metabolism of Ethylene Glycol?

1) ADH: Alcohol dehydrogenase converts Ethylene Glycol to Glycoaldehyde 2) Glycoaldehyde converted by ALDH to Oxalic Acid eventually

What is the metabolism of Methanol?

1) ADH: Alcohol dehydrogenase converts Methanol to Formaldehyde 2) Formaldehyde converted by FMD to Formic Acid

What are the 4 chemical dispositions (ADME)?

1) Absorption 2) Distribution 3) Metabolism 4) Elimination

What are the 2 major Aldehydes? What do both significantly contribute to?

1) Acrolein: More irritating 2) Formaldehyde: Majority Contribute to odor and eye irritation caused by photochemical smog (haziness)

What are some natural, food-borne carcinogens?

1) Acrylamide 2) Heterocyclic amines

What are 3 types of special transport in the body?

1) Active transport 2) Carrier-mediated 3) Endocytosis (Pinocytosis, Phagocytosis)

What are the 4 types of doses or exposures?

1) Acute 2) Subacute 3) Subchronic 4) Chronic

What are the 2 PM2.5 regulations?

1) Acute: 24 hour; 35 µg/m³ 2) Chronic: Annual; 12 µg/m³

What are 3 ways that chemicals can interact?

1) Addition 2) Synergism 3) Antagonism

The formation of Ozone (O₃) is favored by: (6)

1) Air temperature >32 °C 2) Low winds 3) Intense radiation 4) Low precipitation 5) NO2, hydrocarbons (methane, benzene, formaldehyde) 6) Atmospheric inversions

What are the provisions of the Dietary Supplement Health and Education Act (DSHEA) or "Hatch Act?" (4)

1) All dietary supplements assumed to be safe, unless found otherwise by FDA 2) No proof of safety, content, or effectiveness required 3) Burden of proof for safety falls to FDA 4) Allows vague claims of "nutritional support" or "health"

What are the 2 major forms of Asbestos?

1) Amphibole (More potent) 2) Serpentine

Where do the 2 forms of Asbestos distribute in the lungs?

1) Amphibole: Upper lung (Carina-main branch 2) Serpentine: Lower lung

1,1,2-Trichloroethylene (TCE): Toxicology

1) Animal lung/liver carcinogen 2) Probable (2A) carcinogen

What are 3 occupational diseases (all chronic) caused by Asbestos?

1) Asbestosis 2) Lung cancer 3) Diffuse malignant mesothelioma

Bradford Hill's Criteria for Causation (7)

1) Association is strong: Higher relative risks more likely to indicate cause 2) Risk increases or decreases with exposure 3) Consistent findings in several studies 4) Exposure (cause) precedes disease 5) Biologically plausible that exposure could cause disease 6) Association is specific between exposure and single disease 7) Epidemiologic findings fit coherently with information

What are 2 examples of Receptor antagonism?

1) Atropine (antagonist) with organophosphate insecticides (agonist) 2) Naloxone (antagonist) with opioid drugs (agonist)

How can Acrylamide content be reduced in foods?

1) Avoidance: Reduce AA rich foods in diet 2) Selection/breeding for low asparagine varieties 3) Preventing AA formation: Acrylamide-fighting yeast, Lowering pH (citric acid), Thiol food additives

What are 2 factors affecting chemical distribution?

1) Binding to charged circulating molecules 2) Fat storage

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD): Toxicity (following exposure in ppb range)

1) Birth defects 2) Degeneration of liver/thymus 3) Porphyria 4) Immunotoxicity 5) Most potent P-450 inducer known 6) IARC Class 1 carcinogen

What are the 4 body humors of Galen's Disease Theory?

1) Blood 2) Phlegm 3) Black bile 4) Yellow bile

Lindane: Chronic toxicity (in animals)

1) Blood disorders: Leukemia 2) Hepatotoxic, Carcinogenic

What is the general procedure for treating estrogen positive breast cancers?

1) Breast cancer surgically removed 2) Treatment with Tamoxifen (SERM)

Ozone (O₃) Toxicity

1) Bronchitis, fibrosis 2) Cell death, decreased pulmonary function, susceptibility to infection 3) Associated with death from respiratory causes

Styrene: Toxicology

1) CNS effects: Headaches, nausea, memory loss, impaired balance 2) Liver toxicity 3) Class 2B carcinogen

What are the major 2 human diseases caused by Hg poisoning?

1) CNS toxicity 2) Birth defects

Lead (Pb) toxicity (4)

1) CNS toxicity (neurotoxin): Pb follows Ca2+, substituting in NS and bone; Causes learning disabilities 2) Painter's Colic: GI symptoms from oral exposure 3) Anemia from decreased heme synthesis 4) Renal toxicity

What are the primary air pollutants in the U.S.?

1) CO: 48% 2) SO₂: 16% 3) NOx: 16% 4) VOCs (Volatile Organic Compounds): 15% 5) Particulates: 5%

What is the catalytic cycle of P450? (5 steps)

1) CYP in ferric Fe⁺³ oxidized (lost e⁻) resting form binds to chemical 2) CYP reductase causes gain of e⁻ forming ferrous Fe⁺² (able to bind O) 3) 2 Oxygens add to substrate 4) H₂O is released, causing change from Fe⁺² to Fe⁺³ form again 5) Substrate is released with bound Oxygen

What are some examples of Nanoparticles?

1) Carbon nanotubes: Cylindrical carbon tubes used in nanotechnology, electronics, optics, materials science, building materials 2) Fullerene: Ball-shaped clusters of carbon, boron or other materials, used in medicine, electronics, lubricants 3) Metal oxides:Titanium dioxide (food color agent); zinc oxide (SUNSCREEN) 4) Quantum dots:5-50 nm semiconductors used in electronics, LEDs, solar cells, medical imaging, scientific reagents

What is the Internation Agency for Research on Cancer's (IARC) classification scheme for human carcinogens? (w/evidence needed)

1) Carcinogenic to humans: Sufficient evidence 2A) Probably carcinogenic to humans: Limited human/sufficient animal 2B) Possibly carcinogenic to humans: Limited- inadequate human/sufficient animal 3) Not classifiable as to its carcinogenicity: Sufficient animal, but strong evidence against human 4) Probably not carcinogenic to humans: Inadequate human/animal

What are some diseases/effects associated with PM₂.₅?

1) Cardiovascular, cardiopulmonary diseases 2) Early mortality: Stroke, cardiovascular disease, cancer 3) Increased hospital admissions for cardiovascular/respiratory disease 4) Exacerbation of COPD 5) Alzheimer's disease 6) Autism (poss.)

What are some diseases/effects associated with PM2.5? (6)

1) Cardiovascular, cardiopulmonary diseases 2) Early mortality: Stroke, cardiovascular disease, cancer 3) Increased hospital admissions for cardiovascular/respiratory disease 4) Exacerbation of COPD 5) Alzheimer's disease 6) Autism?

What is the contribution of cars and cows that creates the chemistry that promotes such high levels of PM₂.₅ in Cache Valley?

1) Cars: Exhaust contains both NO and VOCs (hydrocarbons) that form atmospheric nitric acid gas (HNO₃) 2) Cows: Excrete nitrogen-containing urea that is converted by natural ureases to ammonia gas (NH₃) 3) HNO₃ and NH₃ combine to form ammonium nitrate (NH₄NO₃), which acts as a sponge to other environmental pollutants

What are the 3 major types of epidemiology studies?

1) Case-control/"retrospective": What was the cause of the observed disease? 2) Cohort/"prospective"/"longitudinal": What disease will be caused by exposure? 3) Cross-sectional/"horizontal": Exposure and outcome of a population at a single time point

What are 3 forms of chemical Antagonism?

1) Chemical antagonism or inactivation 2) Receptor antagonism 3) Dispositional antagonism

What are the 3 factors of the "response" due to a certain dose mentioned?

1) Chemical interacts with molecular receptor to produce a response 2) Response is related to chemical concentration at receptor 3) Chemical concentration at receptor related to dose

What were the results of the Seveso, Italy Dioxin chemical reactor explosion?

1) Chloracne: Major symptom after large TCDD release 2) High serum TCDD 3) Elevated lung, lymphoid, digestive tract cancer 4) Endometriosis (estrogen-R binding) Now prospective study of effects of dioxin

What are some possible "promoters" in the Promotion stage of carcinogenesis?

1) Chronic inflammation 2) Defects in growth control (P53 gene)

Toxic effects of Acrolein

1) Cilatoxic: Decreased mucus clearance (Increased mucus production, but not able to clear) 2) Increased tidal volume/respiratory frequency 3) Vascular/myocardial toxicity

What are the 6 major cell types of the pulmonary epithelium

1) Ciliated cell 2) Mucous or Goblet cell 3) Non-ciliated epithelial or Clara cell 4) Type I or squamous alveolar epithelial cell 5) Type II or granular epithelial cell 6) Alveolar macrophage

4 factors affecting chemical evaporation from soil

1) Concentration of chemical 2) Temperature 3) Soil moisture 4) Soil type

What US federal agencies regulate Asbestos law? (5)

1) Consumer Products Safety Commission (CPSC): Consumer products 2) OSHA: Workplace 3) Agency for Toxic Substances & Disease Registry: Wastes sites, unplanned releases, and other sources 4) National Institute of Standards & Technology (NIST) 5) Mine Safety & Health Administration: In mining activity

What are some occupational exposures to Xenoestrogens?

1) Contraceptives 2) Pesticides

What are 3 groups of Italians known for their poisoning as an "art form" during the Middle Ages?

1) Council of Ten 2) Borgia family 3) Catherine de Medici

What are the 5 probable sources of PM2.5 in Cache Valley?

1) Crustal (soil) elements 2) Light absorbing carbon (LAC): Wood stoves, diesel cars 3) Organic material carbon (OMC): Cars 4) Ammonium sulfate 5) Ammonium nitrate

What are the possible mechanisms for the effects (besides cancer) of prenatal exposure to Polycyclic Aromatic Hydrocarbons (PAHs)?

1) DNA mutations 2) Bind to proteins, lipids (nucleophiles)

What were the results of the Times Beach, MO spraying of crank case oil contaminated with dioxin on roads to control dust?

1) Death to horses, cats, rats (sentinel species) 2) Flood waters spread contamination through town 3) Town evacuated, homes demolished, cleanup completed 1997 4) Immunotoxicity and elevated disease incidence in residents

Symptoms of Beryllium (Be) toxicity (4)

1) Dermatitis 2) Acute pneumonitits 3) "Berylliosis" 4) Probable human lung carcinogen (IARC 2A)

How did Mathieu Orfila (1787-1853), "The Father of Modern Toxicology," establish toxicology as a science? (3)

1) Described toxicant disposition: Absorption, Distribution, and Elimination 2) Compiled chemical/biological information on most known poisons 3) Proposed necessity of chemical analysis to prove cause-and-effect

Dioxin: Mechanism of Action

1) Dioxin binds to cytosolic receptor 2) TCDD-receptor complex travels to structural gene in nucleus 3) Gene repressor is lifted off by TCDD-receptor complex 4) Results in P-450 induction and systemic/multi-organ toxicity

What 2 factors does the Degree of Ionization depend on?

1) Dissociation constant of chemical (pK) 2) pH of environment

What are the 3 toxicological axioms?

1) EXPERIMENTATION to determine action of toxic chemicals 2) Can distinguish between THERAPEUTIC and TOXIC actions of chemicals 3) Therapeutic and toxic action of chemicals usually SPECIFIC

What is included in Cache County's State Implementation Plan (SIP)?

1) Emissions inspection/maintenance program 2) Area emissions reductions: Wood burning stoves, Commercial cooking, Printing/publishing, Painting, Degreasing

What are some examples of supplements that are not risk-free?

1) Enegry drinks 2) Ephedra (↑HR, lethal) 3) Zinc lozenges (olfactory)

The Ames Assay is the most widely-used predictive assay for carcinogens. How is it performed?

1) Engineered Salmonella, requiring histidine, is combined with rat liver, containing CYP 2) Control: Natural revertants 3) Test chemical/possible mutagen: Poured onto plate with trace histidine to allow 1-2 cell divisions; High number of revertants (his- to his+) means potential carcinogen

What are the 3 forms of Estrogen found in the body?

1) Estriol 2) Estradiol 3) Estrone

What is the mechanism of estrogen action?

1) Estrogens or xenoestrogens enter cell, bind to receptor 2) E+Er complex binds to estrogen response elements (EREs) near estrogen-responsive genes 3) mRNA expressed coding for specific proteins that influence cell behavior

What are 3 examples of the Therapeutic Index (TD₅₀/ED₅₀)?

1) Ethanol: 4-10 2) Aspirin: 50 3) Caffeine: 100

What are the target organs for: Ethanol, Caffeine, Silicon, Benzo(z)pyrene?

1) Ethanol: Liver 2) Caffeine: Nervous system 3) Silicon: Kidney 4) Benzo(a)pyrene: Liver

What is the multistage process of carcinogenesis?

1) Exposure 2) Initiation: Initial DNA damage-Genetic change (Activation of oncogenes, deactivation of P53 gene) 3) Promotion: Selective clonal expansion 4) Conversion 5) Progression: Clinical cancer

How does Iron (Fe) utilize free radical mechanisms? (4)

1) Fe induces free radicals 2) Radicals react with unsaturated cis FAs in PM 3) Toxic trans lipids form then lipid peroxides 4) Result in disrupted membrane function, more radical reactions, form MDA which attacks DNA (cancer)

What are the negative effects of Xenoestrogens in human males?

1) Feminization of workers at plastics factory 2) Declining sperm quality/count 3) Increasing testicular cancer 4) Increasing congenital abnormalities

What are 4 factors that make PM2.5 worse in Cache Valley (or not)?

1) Flat-bottomed valley 2) Population leads to cars 3) Few large industrial point sources 4) Agriculturally dominated

What are the negative effects of Xenoestrogens in animals?

1) Genital malformations, poor hatching success, sex ratios skewed toward females 2) Elevated vitellogenin (female-specific protein) in male fish 3) Alligators with altered hormone levels/small reproductive organs from DDT 4) Elevated rates of embryo death, deformities and abnormal nesting behavior in birds 5) Deformed oyster shells

What are the 2 results of Arsenic and Cadmium toxicity in the kidney?

1) Glomerulus becomes porous: Proteins (RBCs, albumin) allowed in urine 2) Damages inner loop cells: Doesn't allow ions to be reclaimed, affecting salt balance

In what 3 ways is inhalation of particles an occupational problem?

1) Grain dusts in agricultural workers 2) Silica and coal dust in miners 3) Metal dusts in foundry and smelting workers

What conditions promote the high PM₂.₅ in Cache Valley?

1) Heavy vehicle use/cold starts -> Incomplete combustion 2) Atmospheric invervsions 3) Deep mountain basin (no fresh air source) 4) High NH⁴⁺ vapor from cows 5) NO₃ from exhaust (VOC + NOx emissions) 6) Formation of NH₄NO₃ 7) Volatile Organic Carbon (VOCs)

3 factors affecting chemical evaporation from water

1) Henry's Law constant (H) 2) High temperature 3) High Kow of chemical

Aquatic Mercury Cycle (starting from Hg⁰) (3)

1) Hg⁰ volatilizes from water into air 2) Hg⁰ deposits into water as Hg⁺² 3) Hg⁺² is either sedimented into soil, reduced to Hg⁰, or biomagnified and methylated by the foodchain to MeHg⁺ 4) MeHg⁺ is either sedimented into soil, demethylated to Hg⁰, or volatilized/deposited again as MeHg⁺ 5) Hg⁺²/MeHg⁺ resuspended from soil to water

What are the 3 forms of Mercury (Hg) in increasing level of lipid solubility?

1) Hg⁺²: Inorganic 2) Hg⁰: Elemental 3) MeHg⁺: Organic

Chemical evaporation from water is promoted by: (4)

1) High Henry's Law constant (high lipid solubility) 2) High vapor pressure 3) High temperature 4) Low water solubility (S), High Kow of chemical

Chemical evaporation from soil is promoted by: (4)

1) High Vp (vapor pressure) 2) High temperature 3) High soil moisture 4) Low organic content

What are 3 factors that make the organic fraction of soil the most active?

1) High cation exchange capability (higher than clay) 2) Abundant hydrophobic domains bind toxicants directly 3) Hydrogen bonding

What 3 factors promote the absorption of chemicals through the skin?

1) High lipid solubility and non-ionization 2) High temperature 3) Abrasion, injury, rash, solvents

What are 3 concerns with PM2.5?

1) Human health 2) Visibility reduction (haze) 3) Deposition of particulate material in sensitive environment

1,3-butadiene (BD): Toxicology

1) IARC Class 1 carcinogen 2) Skin, mucous membrane irritant 3) Narcotic (high concentrations) 4) Lung carcinogen in animals 5) Increased leukemia in exposed workers

Chronic Toxicology: Formaldehyde

1) IARC Class 1 human carcinogen (Animal studies-nasal squamous carcinomas) 2) Chronic irritation of lung, possible contributor to "sick building syndrome" (flu-like effects)

Chlorophenols: Toxicology

1) Immunotoxin 2) Liver/kidney damage 3) Blood/reproductive disorders

What is the general problem (adverse effects) concerning Xenoestrogens?

1) Increased breast, endometrial, testicular cancer 2) Early onset puberty/menses 3) Declining male reproductive capacity - sperm counts 4) Temporal changes in gender ratio 5) Developmental defects males and females

What are the 2 bodily responses to Acrolein?

1) Increased mucus secretion 2) Constriction of airway smooth muscles, mediated by adrenalin

How do Xenoestrogens act?

1) Induce cell division and promote cancer by increasing total lifetime exposure to estrogen (mostly estradiol) 2) Interact with estrogen receptors, which bind to DNA to activate cell division in estrogen-responsive tissues 3) Promote cancer by enhancing production of "bad" estrogen metabolite (16-α-hydroxyestrone)

Ingestion, inhalation, and intervenous routes of exposure in increasing order of potency.

1) Ingestion 2) Inhalation 3) Intravenous

What are 7 routes of chemical exposure?

1) Ingestion 2) Inhalation 3) Intravenous 4) Intraperitoneal 5) Subcutaneous 6) Intramuscular 7) Dermal

Toxicology: PM₂.₅

1) Inhaled/deposited into deep lung 2) Causes pulmonary diseases: Increased respiratory infection, asthma, bronchitis, pneumonia, emphysema 3) Premature deaths

What are the negative effects of the Xenostrogen supplement Genistein (soy isoflavone)?

1) Inhibits angiogenesis: Slows tumor growth 2) Estrogenic: Inhibits osteoporosis, stimulates cell proliferation in estrogen-dependent tumor cells

Methylisocyanate: Acute effects

1) Initial injury in areas of direct contact (eyes/lungs) 2) Severe irritation of eyes, nose, throat, cough, choking sensation, vomiting, diarrhea 3) Corneal ulceration, pulmonary edema, death within minutes

What were the biomarkers that were measured during Dr. Coulombe's translational PM₂.₅ study? (2)

1) Interleukins 2) C-reactive protein (CRP)

Acute Toxicology: Formaldehyde

1) Irritation of mucous membranes, upper respiratory tract, eyes 2) Thickening mucous layer, decreased ventilation, bronchoconstriction 3) Sensitization reactions on skin/lungs from direct contact or inhalation

Chemical concentration reaches a predictable plateau under what 2 conditions?

1) K₁: Zero-order intake constant; Units: amount/time 2) K₂: First-order elimination constant; Fraction of total chemical in body excreted per unit time; Units: proportion of total chemical in body/time

What 3 factors affect the Phase 0: Absorption of Biotransformation?

1) Lipid solubility 2) Molecular size 3) Degree of ionization

What 3 factors does the absorption of hydrophobic chemicals depend on?

1) Lipid solubility (Kow) 2) Molecular size 3) Degree of ionization

DDT: Characteristics

1) Long environmental t0.5 2) Rapidly absorbed, slowly metabolized, enterohepatic cycling

What is the formation of NH₄NO₃ in Cache Valley's atmosphere promoted by?

1) Low temperature 2) High relative humidity (RH)

What is the overall organization of pulmonary anatomy? (5)

1) Lung bi-laterally organized into 5 lobes: 3 right, 2 left 2) Air enters nasal turbinate, then trachea (main conducting airway) 3) At carina, air divides to main bronchi 4) After several generations (7-10), air reaches terminal bronchioles then alveoli 5) O₂-CO₂ exchange occurs at the alveoli, which are heavily vascularized for close association between air and RBCs

How is lipid solubility measured via octanol:water coefficient (Kow)? (3)

1) Measured by adding chemical to mixture of water (polar, hydrophilic) and octanol (non-polar, hydrophobic) in separatory funnel 2) Amount of chemical in each phase is analyzed 3) Relative amount of compound in either phase gives partition coefficient (Kow) of compound

Chlorinated Cyclodienes: Toxicology (4)

1) More acutely toxic than DDT 2) CNS/PNS toxicants 3) Biotransformed to epoxides 4) Possible carcinogens

What are the 3 chemical reactions occurring in a vehicle's catalytic converter?

1) NOx → N+O₂ (Reduction) 2) CO → CO₂ (oxidation) 3) VOCs → CO₂+H₂O (oxidation)

Benzene: Acute toxicity

1) Narcotic effects (sedation) 2) Death 3) Cardiac arrhythmia: Sensitizes cardiac muscle to catecholamine hormones

What are the 5 recommendations concerning supplements?

1) Natural not necessarily safe (Ex. Ephedra, zinc, Interactions with prescription drugs) 2) Supplements no substitute for proper nutrition 3) Supplements unproven against major diseases (Most cause harm) 4) Most don't need supplements (Only under advice from doctor) 5) Save your money

What are the 2 types of Organophosphates? Which came first?

1) Nerve Gases (1st) 2) Insecticides (developed from nerve gases)

What are some chemical agents that lead to a lack of O₂ distributed to tissues (Ex. Hypoxia, Anoxia)?

1) Nerve agents 2) Organophosphates 3) CO 4) CN (birth defects due to lack of fetal O₂)

Many drugs and toxic chemicals exist in either ionized or non-ionized form. How does Degree of Ionization affect absorption of hydrophobic chemicals?

1) Nonionized: More lipid soluble, better diffusion; Higher Kow 2) Ionized: Diffusion hindered by ionic interactions with membranes; Lower Kow

What are the concerns with supplements? (7)

1) Not risk free 2) Some are prescription drugs 3) Can overdose on vitamins/minerals 4) Warning labels not dependable: Possible drug interactions (Ex. Echinaceae) 5) None proven to cure major diseases 6) Quality control: Majority contaminated (or inauthentic) 7) Most people don't need supplements

Final management of risk scheme (4)

1) Observation: Clinic, MDS, scientists 2) Research (long-term): Laboratory, epidemiology, in vitro, animal studies 3) Risk assessment: Probit analysis, risk estimation, political compromise 4) Protective standard (law)

What are the results of zinc toxicity?

1) Olfactory: Anosmia 2) Peripheral nervous system

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD): Toxicology

1) One of the most toxic chemicals known in animals 2) Extremely toxic, highly lipid soluble 3) Soil contaminant: Tightly bound to soils, thus, not a significant ground or surface water problem

What 3 processes can result in Reduction reactions during Phase 1: Metabolism of Biotransformation?

1) P450 2) Oxidoreducatases 3) Intestinal bacteria

What are the 2 types of urban particulate matter?

1) PM₂.₅ (more dangerous) 2) PM₁₀

What is the experimental design used in Dr. Coulombe's laboratory to study Cache Valley's PM₂.₅?

1) PM₂.₅ sampling station 2) PM₂.₅ caught on stainless steel disk 3) PM₂.₅ dislodged by sonification into growth medium 4) Human bronchial epithelial cell assay 5) Cells used in: Gene expression (microarray), disease markers (gene transcripts, DNA, CRP, INF), cytoxicity

What are the 2 general processes by which chemical passage across membranes occurs? Which is the major route?

1) Passive diffusion: Major 2) Active transport

3 factors that influence Biomagnification

1) Persistence: Long environmental half-life 2) Soil type in environment (higher organic material= more binding) 3) Kow of chemical: Bioaccumulation is proportional to lipid solubility (Kow)

Where do Xenoestrogens occur?

1) Personal care products (PCPs) - toothpaste 2) Plastics 3) Red dye 4) Foods, food additives 5) Gasoline 6) Pesticides 7) Water pollutant

What are the 4 phases of chemical Biotransformation in the body?

1) Phase 0: Absorption 2) Phase 1: Oxidation, Reduction, Hydrolysis 3) Phase 2: Conjugation 4) Phase 3: Export

What were the adverse effects in the children of pregnant women who used the drug Thalidomide? (8)

1) Phocomelia: Stunted limbs 2) Maxillofacial malformations 3) Mental retardation 4) Stillborn 5) Absence of lung 6) Ingrown genitalia 7) Malformed GI tract 8) Partial deafness and/or blindness

What is the exact process of enterohepatic recirculation? (4)

1) Polar conjugates (products of phase I/II metabolism) formed in liver are secreted into the intestine via common bile duct and gall bladder. 2) Phase II products hydrolyzed in intestines by endogenous/bacterial enzymes, returning original lipid soluble parent compound 3) Free xenobiotics reabsorbed and transported back to liver via hepatic portal vein. 4) Chemical may undergo several cycles of this resulting in significant increase in "bioavailability," (more chemical in bloodstream) increasing toxicity

What 2 carcinogens are present in cooked meat? (w/examples) Which is more potent?

1) Polycyclic aromatic hydrocarbons (PAH): Ex. Benzo(a)pyrene 2) Heterocyclic amines: Ex. PHIP; More potent (same stuff that is in smoke stacks/exhaust pipes)

What is the result of the catalytic cycle of P450? (4)

1) Product more polar, OH allows H-bonding 2) More water soluble, Lower Kow, Lower Vd 3) Won't enter cells as well 4) More readily excreted

What are the chronic results of Benzene toxicity?

1) Proliferative cell response: Benzene changes P53 tumor-suppressing gene (inhibited) and Ras oncogene 2) Anemic response: Slows down cell division forming large, immature WBCs

What are 3 sample reactions catalyzed by Cytochrome P450 involving aromatic and aliphatic hydroxylation (OH)?

1) Propoxur (Carbamate pesticide) 2) Toluene 3) Oleic acid

Treatment for Thallium (Tl) poisoning?

1) Prussian Blue dye: Acts as ion exchange agent, sequesters thallium, increases excretion 2) Dialysis

Methylisocyanate: Chronic effects

1) Pulmonary function: ↓ vital capacity, ↑ tidal volume, ↓ O2 blood saturation 2) Pulmonary edema, obstruction, fibrosis 3) Pulmonary hypertension 4) Birth defects in children (from reduced O₂)

Cyanide (CN): Symptoms

1) Rapid onset if inhaled (1-2 seconds,1 minute if ingested) 2) Nausea, salivation, convulsions 3) Paralysis, asphyxia, coma, death

What are the 7 markers/parameters of pulmonary function?

1) Respiratory rate 2) Tidal volume 3) Vital capacity 4) Compliance 5) Blood gases: PO₂, PCO₂ 6) Interleukins, Exhaled NO 7) C-reactive protein (CRP)

Toxicology of antiquity mostly originated with what 3 peoples?

1) Romans 2) Greeks 3) Chinese

What are 5 examples of toxicity testing?

1) SAR: Structure Activity Analysis 2) Acute toxicity: Effects within 14 days 3) Subchronic toxicity: 1-3 month duration 4) Chronic toxicity: Lifetime 5) Dermal toxicity using skin cells (Used to use Draize test on rabbits eyes)

What are the 3 main components of soil? List in order of increasing activity.

1) Sand: Not active 2) Clay: Active 3) Organic material: Most active; More binding sites

What are the signs of occupational exposure to Vinyl Chloride (VC)?

1) Scleroderma: Abnormal skin thickening/pigmentation 2) Capillary breakage: Bruises on hands, etc. 3) Liver fibrosis, cirrhosis

What were 2 major incidents of accidental human exposure to Dioxin?

1) Seveso, Italy: Chemical company reactor expolosion; 2) Times Beach, MO: Waste oil containing dioxin sprayed on roads as dust control

Amphibole Asbestos: Characteristics

1) Sharp, rod-like needles, chemically diverse 2) Less important in industry 3) Commonly contaminates talc/vermiculite 4) Penetrates the lung readily 5) Long t₀.₅

Methylisocyanate: Toxicology

1) Short t₀.₅ in body 2) Contact irritant to mucous membranes/respiratory tract 3) Lasting lung damage: Pulmonary congestion, cell death

Cyanide: Treatment (Two-fold therapy)

1) Sodium nitrite: Produces methemoglobinemia (Fe⁺³), causing CN to dissociate from cytochromes 2) Sodium thiosulfate: Provides substrate for rhodanese enzyme, which catalyzes CN conversion to thiocyanate (SCN), which is much less toxic (scavenge CN)

What are the 3 factors that determine soil adsorption?

1) Soil composition (sand, clay, organic) 2) Ionic interactions (cation exchange) 3) Hydrogen bonding

Chemical adsorption to soil is promoted by: (4)

1) Soil type: organic>>>clay 2) Chemical ionization: Cation>>>neutral>>>>>anionic 3) Kow 4) Low H₂O solubility

Toxicology: Sulfur Dioxide (SO₂)

1) Soluble: Mainly affects upper airways 2) Extreme irritant 3) Increased mucous secretion, loss of ciliated cells 3) Bronchial constriction, increased pulmonary resistance 4) Increased susceptibility to respiratory diseases

What are the soil characteristics affecting chemical adsorption? (3)

1) Surface area and charged sites (binding sites) 2) Hydrophobic 3) Hydrogen bonding

Polychlorinated Biphenyls (PCBs): Toxicology

1) Thymic atrophy 2) Wasting 3) Immune system/reproductive toxicity

What are the 3 major factors that make the PM₂.₅ levels so high in Cache Valley?

1) Topography 2) Meteorology 3) Chemistry

The Inflammatory Response

1) Toxic injury 2) Cells release inflammatory messengers (lymphokines): Interleukins, prostaglandins 3A) Small amount of damage: Controlled healing/repair 3B) Persistent injury: Activation/recruitment of inflammatory cells: T, B cells, monocytes, fibroblasts, neutrophils 4A) Neutrophils use free radicals to damage DNA causing cancer (8-OH-dG biomarker) 4B) Sustained upregulation of fibroblasts: Uncontrolled tissue scarring 5) Edema, decreased gas exchange

The Inflammatory Response (5, 3 and 4 two parts)

1) Toxic injury 2) Cells release of inflammatory messengers (interleukins, prostaglandins) 3A) Small amount of damage: Controlled healing/repair 3B) Persistent injury: Activation/recruitment of inflammatory cells 4A) Neutrophils use free radicals to damage DNA causing cancer 4B) Sustained upregulation of fibroblasts: Uncontrolled tissue scarring 5) Edema, decreased gas exchange

What are the 2 routes of Percutaneous chemical absorption? Which is the major route of chemicals?

1) Transepidermal: Major 2) Transfollicular: Diffusion through sweat glands/follicles

What are the primary sources of air pollution?

1) Transportation: 46% 2) Fuel consumption (stationary sources): 20% 3) Industrial processes: 6% 4) Misc.: 6% 5) Solid waste disposal: 2%

What are the 3 enzymes and products involved in Phase 2: Conjugation of Biotransformation?

1) UGTs: Glucuronyl transferase- Glucuronides 2) SULTs: Sulfotransferase- Sulfoconjugates 3) GSTs: Glutathione S-transferase- GSH conjugates

What 3 factors promote chemical absorption in the small intestine (gastrointestinal route)?

1) Ulceration 2) GI irritation 3) Fasting

What are 3 routes that toxicants are eliminated from the body? Which is the most important?

1) Urinary excretion: Most important 2) Fecal excretion 3) Pulmonary tract

What are possible solutions to Cache Valley PM₂.₅?

1) Vehicle emissions testing to reduce NOx, VOC 2) Increase public transportation use (bicycles) 3) Improved emissions technology 4) Better driving habits (Idling, carpooling) 5) Pollution pricing 6) Encourage plug-in, hydrogen cell vehicles 7) Reduce animal agriculture 8) Reduce protein in dairy rations to reduce urea excretion (2% protein reduction, 50% urea reduction 9) Tier III low-sulfur fuels 10) State Implementation Plan (SIP)

Organophosphates: Symptoms of acute exposure (8)

1) Weakness, pale skin 2) Difficulty breathing; ↑ bronchial secretions (mucus) 3) Salivation, sweating 4) Bradycardia (↓HR) 5) Tremors, twitching 6) Miosis (constricted pupils) 7) Cyanosis, apnea 8) Convulsions, death

Organophosphates: Characteristics as a chemical class

1) Well absorbed by ALL routes (except Malathion) 2) Short t₀.₅; Rapidly degrades in environment 3) Little groundwater contamination and bioaccumulation (Advantage over DDT) 4) Requires repeated application

Asbestos: Clinical signs

1) shortness of breath 2) "Asbestos bodies" 3) Positive chest x-ray: Small irregular opacity

What are the normal effects of Acetylcholine (ACh) on the Parasympathetic nervous system (automated functions)?

1) ↑ Exocrine glands 2) ↑ GI tract smooth muscle 3) ↓ HR

What are the normal effects of Acetylcholine (ACh) on the Sympathetic Nervous System ("Fight or Flight")?

1) ↑ HR 2) ↑ Blood vessels 3) ↑ Sweat glands 4) ↓ Smooth muscle: GI tract, lungs

Describe how major indicators of pulmonary function change after exposure to acrolein and ozone?

1) ↑TD 2) ↓VC 3) ↓Surfactin production (↓compliance): Less flexible lungs 4) ↑Mucus secretion 5) Bronchoconstriction

What is the most common contaminant of drinking water in the U.S.?

1,1,2-Trichloroethylene (TCE)

Active transport

Absorption occurs against concentration gradient; Requires energy; Selective

What is the single most important factor in chemical toxicity?

Dose; "The dose makes the poison"

Where is the largest superfund site in the USA? What chemical does it concern?

1.3 million lbs of Polychlorinated Biphenyls (PCBs) dumped into Hudson river by General Electric (GE)

Maximum Contaminant Level (MCL) in drinking water for Arsenic

10 ppb

What is Bisphenol A's (BPA) binding affinity compared to estrogen (E2)?

10,000-fold weaker than E₂

How long is the operating time of vehicles before the emissions devices reach peak efficiency?

10-12 minutes

Concerning routes of exposure, there is a smaller LD50, about ____, for _____ exposure compared to ______ exposure.

10-fold; Intravenous (IV); Oral (PO)

When was the drug Thalidomide released in the UK? When was it licensed?

1957 by Gruuebthal Chemical Co.; 1958

CO has a ____-fold greater affinity for hemoglobin (Hb) than O₂.

200-fold greater affinity

What is the approximate body fluid volume (L) of plasma in a 70kg person?

3 L

There are around _____ chemicals present in the world.

50 million

Bisphenol A (BPA) is found in ___% of urine samples tested by the CDC.

95%

What is the Volume of Distribution (Vd) of lipid soluble chemicals with a high Kow?

>3L; Distributes well out of the blood

For a chemical to cause its effect, it must enter _____. What must occur for this to happen?

A cell; To enter a cell, it must penetrate a biological membrane

On a dose-response curve, what indicates a more potent compound?

A curve increasing farther to the left because less is needed to produce an equivalent response compared to a curve increasing to the right (Effect at lower dose= More potent)

"Decision point" approach to results from Short and Long-term assay: (7)

A) Structure-activity analysis (SAR) of chemical B) in vitro short-term tests (Ex. Ames assay) B) Decision point: tests under A and B C) Limited in vivo bioassays (Ex. Acute studies) C) Decision point: tests under A,B, and C D) Chronic (lifetime) bioassay E) Final evaluation of all tests

At the neuromuscular junction, ______ is released and causes muscle fibers to twitch.

ACh

Where does the antidote for Acetylcholinesterase inhibitors act?

ACh receptor (ACh antagonist)

What enzyme is common to Ethanol, Methanol, and Ethylene Glycol metabolism?

ADH: Alcohol Dehydrogenase

What test has been developed as an early cancer test?

Aberrant Crypt Focus (ACF)

Why is PM2.5 so dangerous?

Able to get into alveoli cells within lungs, whereas larger particulates are not

What is the approximate size of PM2.5 particulates?

About 1/40th of the diameter of hair

Biotransformation

Absorbed chemicals are modified by one of four reactions- Oxidation, Hydrolysis, Reduction, and Conjugation - to increase excretion and limit toxicity

Metabolism of 1,3-butadiene (BD)

Activated by P450 to active, carcinogenic dual epoxide intermediate, which forms 2 carbocations; Disallows DNA division by forming crosslinks

About 300,000 people die in the world from ______ ______ toxicity.

Acute pesticide

The LD50 is only a helpful measure with ______ toxicity.

Acute, not chronic toxicity

DDT Toxicity targets: Acute? Chronic?

Acute: CNS Chronic: Liver (cancer, CNS, hepatotoxicity)

Chlorinated Cyclodienes toxicity targets: Acute? Chronic?

Acute: CNS Chronic: Liver, cancer

What can be done to reduce the carcinogens present in processed meat?

Add reducing agents such as ascorbic acid (vitamin C) during processing process to reduce nitrosamines

Where is DDT stored in the body?

Adipose tissue (All humans have DDT found in body)

What is the hypothesis about Xenoestrogens?

Adverse effects may be caused, in part, by exposure to synthetic chemicals that mimic estrogen in the body; Effects include birth defects and breast cancer

When do carcinogens present in meat that is cooked?

After it is cooked

Atropine (part of dual therapy for organophosphate poisoning)

Alkaloid from plants like Atropa belladonna (deadly nightshade) and Datura stramonium (Jamestown weed); Occupies same muscarinic postsynaptic receptors of PNS as Ach (blocks receptors); Ach antagonist

When do the symptoms of acute organophosphate exposure occur?

Almost immediately (6-7 mins post-exposure)

What is the definitive symptom of Thallium (Tl) poisoning?

Alopecia on back of head

Dispositional antagonism

Alters dispositional fate of toxin (ADME: absorption, distribution, metabolism, or excretion); 1+1=0

Where does PM₂.₅ aggregate in the human pulmonary system?

Alveoli (very small)

Cache Valley PM₂.₅ contains high _____.

Ammonium nitrate (NH₄NO₃)

Between ammonium sulfate and ammonium nitrate, which is more prevalent in the atmosphere around Cache Valley?

Ammonium nitrate; Highest ammonium in the country (trapped in valley)

What is the Volume of Distribution (Vd) based on?

Amount of water in body

What is one sample reaction catalyzed by Cytochrome P450 involving Deamination (removal of NH₂ group)?

Amphetamine -> phenylacetone

Of the 3 diseases caused by Asbestos, which form of Asbestos causes these diseases to a greater degree?

Amphibole (more potent)

Which form of asbestos is more potent? Why?

Amphibole; Contains Fe, which induces free radicals

What is the most potent air pollutant?

Asbestos (not harmful until airborne)

What is an example of a chronic response?

Asbestos related cancer 20-30 years post-exposure

What common compound can reduce the production of cancerous DNA adducts produced from the bioactivation of heterocyclic amines?

Ascorbic acid (reduces)

What is the limiting factor in Acrylamide formation in foods?

Asparagine

Acrylamide formation in foods/Bioactivation

Asparagine (major AA in potatoes/cereals) reacts with glucose during processing of snack foods and breads

Toxicology of anitquity was largely utilized in _______, thus causing the requirement of royal "______."

Assassinations; "Tasters"

Electrophiles created by Cytochrome P450's addition to absorbed chemicals can have what adverse effect?

Attachment to cellular nucleophiles such as DNA, protein adducts creating harmful bioactive intermediates

What were the first synthetic chemicals produced? Via what process?

Azo dyes (carcinogenic); Via Azo reduction

Formation of Heterocyclic amines

Meat, containing creatinine, is heated and forms heterocyclic amines

For Benzo(a)pyrene, what is the ultimate carcinogenic form? Why?

BP-7,8-diol-9,10-epoxide; A diol epoxide that binds to DNA leading to cancer

When do carcinogens present in meat that is processed?

Before it is cooked, by processing or curing process

Estrogen is a double-edged sword. What are its benefits? Harmful effects?

Beneficial: 1) Program breast/uterus for reproduction 2) Control cholesterol production limiting arterial plaque 3) Preserve bone density Harmful: 1) Cell proliferation in breast/uterus 2) Increased cancer risk: breast, uterus

Cell proliferation occurs in estrogen-dependent tissues. What cells proliferate in breast tissue? Uterus?

Breast: Cells lining milk glands-ductal epithelial cells (preparing to produce milk) Uterus: Endometrial cells (preparing for embryo implantation)

Bioactivation of Acrylamide

Bioactivated via CYP to Glycidamide, which binds DNA

Epoxidation IS an example of _______.

Bioactivation (products are more toxic)

Dealklyation and Deamination by Cytochrome P450 is NOT an example of ______.

Bioactivation (products are not more toxic)

Many Organophosphates require ______ before they are effective. What does this include?

Bioactivation; P450s convert from phosphorthioate (P=S) to phoshooxon (P=O) functional group

Biomagnification = ______+_____

Biomagnification = Bioconcentration+Bioaccumulation

What is a prototype Xenoestrogen?

Bisphenol A (BPA)

Symptoms of Arsenic toxicity

Blisters, skin lesions, renal damage (albuminuria) GI problems, proven (IARC 1) human carcinogen (skin, bladder, kidney, lung, liver)

Cyanide: Mechanism

Blocks respiration by binding to heme of cytochrome c oxidase (complex IV) in mitochondrial respiratory chain; Cytochrome c oxidase is the terminal enzyme in electron transport chain, therefore no ATP is produced

Where is the insecticide Lindane stored in the body?

Body fat

The Volume of Distribution (Vd) compares the amount of chemical remaining in the _____ with the amount _______.

Body; Administered

What was the prominent Italian family of "applied toxicologists" during the Middle Ages? Who were some of the more well-known family members

Borgia; Lucretia, Cesare

How are ammonium sulfate and ammonium nitrate similar? Different?

Both are formed in the atmosphere from precursors (Ammonium, sulfate, nitrate); Ammonium sulfate is favored to form from precursors

What is the primary target organ of Cyanide?

Brain

What organ is the most sensitive target of lack of oxygen?

Brain

What was the first antidote specific to metals? How does it work?

British Anti-Lewisite: Antidote to Lewisite; Reduces bioavailability/toxicity by dispostionally forming sulfide bonds with Lewisite arsenic

What is a common symptom of Lead toxicity?

Burton's Line: blue gum line

Why do you multiply by 7 when determining the time required to reach plateau?

By convention, 7 half-lives are required to either eliminate nearly all the chemical or accumulate chemical to Xmax in the body

What was the problem with the usage of the morning sickness drug Thalidomide in the 1950s?

By the early 1960s, more than 10,000 children in 46 countries were born with deformities

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD): Historical sources

By-product of the manufacture of herbicide 2,4,5-T, hexachlorobenzene, and chlorinated benzenes to form dioxin-contaminated "Agent Orange;" Used during Vietnam War to defoliate jungles; Caused birth defects, cancer

A basic chemical will bind more efficiently when ______.

Cationic (Ex. NH₃⁺ vs. NH₂); Because of cation exchange sites of clay and organic material

All else being equal, _____ species bind more tightly than _____ species because of interactions with cation exchange sites.

Cationic species; Neutral

Benzene: Chronic toxicity

Causes appearance of immature, maturation-arrested blood cells or "Shift-to-the-Left;" 1) Blood cell anemia: ↓ blood cells 2) Myelogenous leukemia: ↑ immature (larger) WBCs 3) Aplastic anemia: ↓ in all cell types

What common plants is poison hemlock distantly related to?

Celery, cilantro

What is an example of a chemical that has an acute exposure AND response?

CN

Lindane: Acute toxicity (in animals)

CNS toxicant: More violent convulsions than DDT

Chlorinated Cyclodienes: Acute toxicity

CNS: 1) Dizziness, headache 2) Nausea, vomiting 3) Clonic (thrashing) and tonic (tetani) convulsions 4) Effects eventually subside due to redistribution into fat

DDT: Acute Toxicology

CNS: 1) Tremors, ataxia, seizures 2) Convulsions 3) Respiratory failure

What is the Cytochrome P450 enzyme that converts Codeine to Morphine?

CYP2D6

Is Cache Valley the source of its own PM2.5 or is it coming from elsewhere?

Cache valley IS the source

Concerning Polycyclic Aromatic Hydrocarbons (PAHs) and Benzo(a)pyrene, cooked meats are associated with elevated ______ mortality (and cardiovascular mortality).

Cancer

p53 is mutated in a small proportion of human ______.

Cancers

Toxicity

Capacity of a compound to produce injury

More Americans die from acute poisoning than from ______.

Car crashes

Benzo(a)pyrene

Carcinogen; Result of heating (burning) of carbon compounds; Forms epoxide, then carbocation which causes DNA mutation leading to cancer

All Polycyclic Aromatic Hydrocarbons (PAHs) are ______.

Carcinogenic

What are the potential disease risks of Nanoparticles?

Cardiovascular, cancer

Epoxide hydrolase

Catalyses trans addition of H₂O to epoxides to produce trans diols; Found in microsomal/soluble cellular fractions in liver and other organs;

Toxicology of antiquity involved the ______ and _____ of ______.

Categorization; Characterization; Poisons

Who was "The Bloodiest Queen?"

Catherine de Medici (1519-1589); Wife of Henry II of France; Mother of 3 French kings; Ruler of France

There is an enhanced cancer risk via _______ due to estrogens (Xenoestrogens).

Cell proliferation

Translational study

Cells to people

Chemical antagonism or Inactivation (w/example)

Chemical reaction produces detoxified product; Dimercaprol (antagonist) chelates Arsenic

What does a HIGH Volume of Distribution (Vd) mean?

Chemical will disappear quicker from the blood

Adsorption to soils

Chemicals bind to and are released from soils

What is a diagnostic sign of Carbon Monoxide poisoning?

Cherry-red skin

Dioxin has been used as a potent poison with what indicative early symptom?

Chloracne: Skin disease characterized by outbreaks of acne; Human response to dioxin and PCBs poisoning; Ex. Viktor Yushenko

DDE contains less _____ than DDT.

Chlorine (less toxic)

Estrogens form from what starting product? What class of enzymes perform this action?

Cholesterol; P450s

What is one example of Dispositional antagonism?

Cholestyramine (antagonist) binds to toxic chemicals, preventing absorption

What type of exposures are most relevant to toxicology and risk assessment?

Chronic exposures to small doses of chemicals

Urban PM₂.₅ leads to what type of response? What disease can result from this response?

Chronic inflammation; Cardiovascular disease

What kind of Benzene toxicity is most critical to occupation risk? How?

Chronic; Toxic to blood and blood-forming cells

What is the most common form of Serpentine Asbestos?

Chrysotile: Accounts for more than 90% of world's asbestos

______ has some of the same chemicals as PM2.5.

Cigarette smoke

What is the lipid peroxidation process caused by Ozone?

Cis bonds of cell phospholipid bilayer are converted by free radicals to trans bonds; Trans bonds increase solid nature of membrane; Lipid peroxides lead to malondialdehyde (MDA), leading to cancer

How does Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) form?

Cl+C with high heat = dioxins

Vinyl Chloride (VC): Toxicology

Class 1 human liver/brain carcinogen

Sulfur Dioxide (SO₂): Sources

Coal burning, steel smelters, other sulfur oxides (SOx) from combination of emissions, fog and cool temperatures

1,3-butadiene (BD) properties

Colorless gas; Liquid; High vp

Pulmonary Toxicants: Formaldehyde

Colorless gas; Odor; Irritating to mucous membranes of eyes, nose and throat; Polymerizes readily; Highly water-soluble; Formalin most common form (formaldehyde/methanol)

What is zinc commonly used to treat?

Common cold

1,1,2-Trichloroethylene (TCE): Sources

Common solvent, degreasing metal parts and semiconductors, dry cleaning

What is a Therapeutic Index?

Compares the ratio of the toxic dose (TD₅₀) to the effective (therapeutic) dose (ED₅₀) to 50% of the population; TD₅₀/ED₅₀

Ecological magnification (EM)

Concentration in organism/concentration in water

What is the active principle in Poison hemlock, which killed Socrates? What is its MOA?

Coniine; Acts on peripheral nervous system

What are the symptoms of acute organophosphate exposure consistent with?

Consistent with excess ACh

Asbestos: Sources

Construction materials: pipes, roofing, shingles, concrete Friction materials: brake linings, clutch pads

How does most exposure to Vinyl Chloride (VC) occur?

Consumer exposure from new homes, new cars, food packaging (peanut oil)

Asbestos: Amphibole

Contains Iron (free radical); More potent; Rod-like

How does Methoxychlor differ from DDT structurally?

Contains methoxy groups instead of chlorines (Slightly lower Kow)

What does enterohepatic recirculation contribute to many lipid soluble chemicals?

Contributes to high half-life

What is the rate-limiting factor in Heterocyclic amine formation in foods?

Creatinine in meat

Cyanide (CN): Disposition

Cyanide gas well absorbed by all routes, inhalation most important

Polycyclic Aromatic Hydrocarbons (PAHs) induce what enzyme?

Cytochrome P450

Biotransformation's Phase I Oxidation reaction are catalyzed by ______.

Cytochrome P450 (P450, CYP)

What is the most important Phase 1 enzyme involved in chemical metabolism?

Cytochrome P450 (P450, CYP)

Why is Serpentine Asbestos less potent than Amphibole?

More soluble and cleared from lung faster

Toxicology: Carbon Monoxide (CO)

Efficiently binds to hemoglobin, preventing O₂ binding causing asphyxiation; Reduces O₂ carrying capacity of hemoglobin

Markers/Parameters of pulmonary function: Blood gases: PO₂, PCO₂ (w/likely direction)

Efficiency of gas exchange and index of total alveolar ventilation; Decrease O₂, Increase CO₂

Describe a dose-response curve.

Dose (independent variable) on x-axis, and the effect (dependent variable) on y-axis

Undesirable (toxic, lethal) dose/effect (LD)

Dose at which effects are toxic or lethal

Desirable (Effective) dose/effect (ED)

Dose at which good effects occur

What is the principal metabolite of DDT in the body? How does it compare to DDT?

DDE; Less toxic (yet still toxic); Very Lipophilic

Insecticide: Dicofol (Kelthane)

DDT alternative (trace DDT contamination); Only Acaricide: Kills Acari, spider mites, on fruit, vegetables, tree nuts, ornamentals, hops, cotton

Insecticide: Methoxychlor

DDT replacement; Degrades rapidly in environment; Rapidly metabolized (short t0.5)

What is an important example of reductive dehalogenation?

DDT-> DDE (storage metabolite)

What did the influential botanist Theophrastus (470-286 BC) publish? What did it describe?

De Historia Plantarum; Poisonous plants

Toxicology: Nitrogen Oxides (NO₂, NOx)

Deep lung irritant (less water-soluble) 1) Decreased lung compliance, increased lung resistance 2) Increased susceptibility to pulmonary infections 3) Pulmonary fibrosis (scarring)

Where is the Xenoestrogen Nonylphenol found?

Degradation product of detergents; Migrates from food packaging

Triclosan: Sources

Deodorant, toothpaste, dishsoap, shaving cream, utensils, children's toys (PCBs- personal care products)

What was of note in the records of the poisonings performed by the "Council of Ten" in Venice, Italy? (5)

Detailed records included, 1) name of victim 2) contractor 3) type and dose of poison 4) symptoms 5) results

What is the hepatic Thalidomide metabolite CPS49 being developed into now?

Developmental cancer drug (Inhibits angiogenesis)

What are Normal Equivalent Deviations (NEDs) in Probit Transformation?

Deviation from the mean dose

What is Asbestos' main determinant of aerodynamic behavior?

Diameter

What was the act that was put in place in 1994 that allowed the sale of supplements with no regulation by the FDA?

Dietary Supplement Health and Education Act (DSHEA) or "Hatch Act"

If a Polycyclic Aromatic Hydrocarbon (PAH) contains a Bay Region, they will form _____ ______ more easily that bind well to DNA causing adducts (and cancer).

Diol epoxides

What chemical has the "worst" potency?

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD); PBT chemical

Bioconcentration

Direct uptake of chemical from the medium (ex. water) via skin, gills, or lungs

Partition coefficient (Kow) and Volume of Distribution (Vd) are ______ proportional.

Directly

Toxicology of antiquity mostly had to do with ______ and ______.

Drugs; Poisons

What is the treatment of Organophosphate Poisoning?

Dual antidote therapy: 1) Antropine Sulfate (2-4mg) 2) 2-PAM (1g)

Why is Amphibole Asbestos more potent than Serpentine?

Due to Iron (Fe), which causes a stronger inflammatory response due to free radical nature

Why can PM2.5 increase during the summer months?

Due to wildfires

TRI

EPA's Toxic Release Inventory: Chemical release reports by area

How can a dose-response curve be transformed into a histogram (68-95-99.7)?

Each bar represents the % affected at each dose MINUS those affected at the next lower dose

Aberrant Crypt Focus (ACF)

Early cancer test; Clusters of abnormal tube-like glands (aberrant crypts) in lining of colon and rectum; Precursor to colorectal polyps; One of the earliest changes that may lead to cancer; Putative precursors of colon cancer

Why does the presence of "Bay Regions" in Polycyclic Aromatic Hydrocarbons (PAHs) increase the possibility of cancer?

Easier to bioactivate

Chemical interaction: Antagonism

Effect of A is reduced by antagonist B

What effects have been observed due to prenatal exposure to air pollutants including Polycyclic Aromatic Hydrocarbons (PAHs)?

Effects on the development of brain white matter, cognition, and behavior in later childhood

What are some of the possible responses on a dose-response curve?

Effects quantal (all-or-none) death or continuous (graded), blood pressure, respiration rate, urine output, hormone levels

The bioactivation of benzene to a cancer-causing _____ intermediate via ______ is usually a ______ fraction of the total metabolites formed.

Electrophile; Cytochrome P450; Small

Hg⁰

Elemental Mercury; Volatile (vapor); Absorbed in lung

Nanotoxicology

Emerging field; Nanoparticles absorbed/widely distributed in body following inhalation, dermal, GI absorption; Phagocytized by pulmonary cells, macrophages; Induce cellular mutations, oxygen free radicals, inflammation

How does Cache Valley's Chemistry contribute to its high PM₂.₅ levels?

Emissions: 1) Exhaust (Cars): NO, hydrocarbons 2) Animal excreta (Cows): NH3 from urea

Why is Triclosan of toxicological concern?

Endocrine disruptor (xenoestrogen) in frogs; Can lead to estrogen-sensitive cell divisions; U.S. FDA is re-assessing safety

Insecticides: Chlorinated Cyclodienes (examples)

Endrin, Aldrin, Dieldrin, Chlordane, Toxaphene; All banned except Chlordane for fire ant control in power substations

About 80% of cancers are caused by what type of factors?

Environmental; Genetic factors only account for about 8-10%

Each phase of Biotransformation is catalyzed by ______.

Enzymes

What is an important hydrolytic enzyme for environmental chemicals?

Epoxide hydrolase

Volume of Distribution (Vd)

Estimation of how well a drug distributes through the body from the blood; Ratio of dose present in body to its plasma concentration when distribution in tissues/plasma is at equilibrium; Vd = A/C (A=drug in body, C=Plasma concentration)

What is an antidote therapy for Ethylene Glycol poisoning? Why? What is this an example of?

Ethanol; Because both are metabolized by ADH; Dispositional antagonism

What is the CYP2D6 Polymorphism frequency in those of European dissent? Asian?

European: 7% Asian: 1%

Carbon Monoxide (CO): Sources

Exhaust, coal burning, gasification

LD50's vary depending on routes of _____.

Exposure

Chronic exposure

Exposure > 3 months, often lifetime; Often low dose; Ex. most environmental toxicities

Subchronic exposure

Exposure duration from between 1-3 months

Acute exposure

Exposure for a duration < 24 hr; Often single exposure; Ex. CN, CO, opiodes

What did Paracelsus postulate caused illness, thus challenging Galen's Disease Theory, the "imbalance of the four body humors?"

External agents

Asbestos Toxicology: Diffuse malignant mesothelioma

Extremely rare but fatal tumor of peritoneal lining; Lag time from exposure to disease ≥ 30 years

Who received an award from President John F. Kennedy for blocking the sale of Thalidomide in the U.S.? When?

FDA Inspector Frances Oldham; 1962

Remembering that lipid soluble chemicals can store in fat, how much of a fat person's body weight can be fat? Lean person?

Fat person: 50% of body weight Lean person: 10-20% of body weight

Asbestos: Serpentine

Fibers collect dead macrophages in airway leading to recruitment of inflammatory cells; "Curly;" Lodges in airway bifurcation; Less potent than Amphibole

Insecticides: DDT (chlorinated aromatic)

First "miracle" pesticide; Aedes aegypti principal target; IARC Class 2B carcinogen (possible)

What was a case study involving Lead (Pb)?

Flint, Michigan

What factors decrease chemical absorption in the small intestine (gastrointestinal route)?

Food in stomach

Xenoestrogens (or endocrine disruptors)

Foreign compound with estrogen-like properties

Nitrogen Oxides (NO₂, NOx): Sources

Forms in the atmosphere; Exhaust, silage (Farmer's lung), cigarette smoke

Iron (Fe) is a prime example of toxicants that act through what mechanism?

Free-radical mechanism (Fenton reaction); Induces free-radicals that, like chronic inflammation, ultimately damage lipids, DNA, proteins

How does Cache Valley's Meterology contribute to its high PM₂.₅ levels?

Frequent winter inversions: Stagnant air mass, reactants and pollutants concentrate

What are some examples of natural cyanogenic glycosides in foods (Cyanide-containing)? How do they form cyanide in the body?

Fruit seeds, cassava; Form via saliva enzymes that liberate CN

Cyanide (CN): Sources

Fumigating products, gold/silver extraction, metal polishes, rat/pest poisons, foods

What structure are Polycyclic Aromatic Hydrocarbons (PAHs) based on?

Fused carbon anthracene skeleton (IARC Class 3 carcinogen)

Of the 3 enzymes involved in Phase 2: Conjugation of Biotransformation, which is good? Why?

GST: Glutathione S-transferase; Provides alternative nucleophile for electrophiles

Who's theory did Paracelsus challenge?

Galen's Disease Theory: "Imbalance of the four body humors"

What toxicants are most importantly excreted via the pulmonary tract?

Gases and volatile drugs (Benzene, anesthetics, CCl4, toluene, methanol)

Since Cytochrome P450 has a role in steroidogenesis, you could say that it is important in ______ differences.

Gender

Endocrine receptors trigger ______.

Gene activation

p53 guards the genome against ______ ______.

Genetic damage

What is an example of a Xenoestrogen found in supplement form?

Genistein: Soy isoflavone

What can be done to counteract sodium phenobarbital's, a weak acid (pKa 7.2), absorption in the case of an overdose?

Give a weak base to raise the pH, making the sodium phenobarbital more ionized, thus less lipid soluble (Example of dispostional antagonism)

Carbon Monoxide (CO) has a _____ affinity for hemoglobin than O₂.

Greater

Dioxin-induced Porphyria

Greek "purple pigment" liver disorder; Defective porphyrin metabolism; Results in purple stools, urine, abdominal pain, vomiting, neuropathy, seizures, hallucinations, depression, anxiety, paranoia

What will a [chemical]/time curve look like when enterohepatic recirculation is occuring?

Growing or diminishing peaks and valleys based on if the dose is IV (diminishing) or oral (growing)

Henry's Law

H = Pv/S; Chemical evaporation (H) is proportional to vapor pressure (Vp) and inversly proportional to solubility (S)

What is the limiting factor in ammonium formation?

HNO₃, from cars mostly; Favored at lower temperatures

What equation describes the competition between O₂ and CO for hemoglobin (Hb)?

Haldane equation

Persistence

Half-life of chemicals in the environment

Heterocyclic amines

Heat-induced carcinogens; Cooked foods: Beef, fish, chicken, baked goods

Cytochrome P450 is a ______protein.

Hemoprotein; Iron atom in active site allows oygen to bind

What equation is used to determine a chemical's degree of ionization?

Henderson-Hasselbalch equation

What is the causative agent of the birth defects caused by the drug Thalidomide?

Hepatic Thalidomide metabolite: CPS49

What does the bioactivation of heterocyclic amines commonly lead to?

Heterocyclic amines bind to DNA, resulting in DNA adducts; Cancer

How can Heterocyclic amines cause cancer?

Heterocyclic amines from heated meat consumption are metabolized by P450s causing DNA adducts

Mercury Case Study: Minamata Bay

Hg toxicity due to plant; Fish (dietary staple) contaminated; Infants developed cerebral palsy-like signs, disfiguring birth defects

Mercury Case Study: Iraq

Hg treated seed grain (anti-fungal)

Mercury Case study: Staco Thermometer Company

Hg⁰ in air of worker's homes, clothing, etc.; Headaches, bleeding or sore gums

Adsorption to soil (measured by Kad) is directly proportional to _____ Kow.

High Kow (High lipid solubility- due to lipophilicity of organic material)

What is an example of an acute response? What are the effects?

High dose CN; Immediate loss of consciousness, coma/death in ~ 6 min minutes (KCN poison pills by Nazi leaders)

Aniline, being a weak base (pK=5), will largely be in its non-ionized, lipid soluble form at what pH? Ionized, lipid insoluble form?

High pH; Low pH

Why is stomach and liver cancer so prominent in Japanese men? Colon and prostate cancer in US men?

High salt diet (pickling, curing); High meat diet (protein)

The chemical that initially binds to CYP has a _____ Vd and Kow than after the catalytic cycle is complete.

Higher

Tier III emissions

Higher standard of emissions; Includes less benzene and Sulfur in gasolines

"Three Sigma" or "68-95-99.7 Rule"

Holds that ±1 SD represents 68.3%, ±2 SD is 95.5%, and ±3 SD is 99.7% of the population

Estrogens

Hormones produced in ovaries, adrenal glands, and peripheral tissues; Biosynthesized from Cholesterol

Who were the victims of the poisonings performed by the prominent Italian Borgia family?

Husbands, wives, lovers, political opponents, clergy

Unsaturated carbon chains have less ______ and more _____.

Hydrogens; Double bonds

Are most toxicants and drugs hydrophilic or hydrophobic compounds?

Hydrophobic

Dioxin is highly _____, therefore it has a _____ Kow and a _____ Vd.

Hydrophobic (lipophilic); High Kow (lipid soluble); High Vd (distributes well)

What are the 2 conditions that result from a lack of oxygen due to chemical toxicity such as Cyanide or Methylisocyanate toxicity?

Hypoxia, Anoxia (Decreased to no O₂ to tissues)

What generally occurs during hydrolyses reactions during Phase 1: Metabolism of Biotransformation?

H₂O is added to either ester or ether groups; Hydrolytic reactions

Benzene: Toxicology (acute and chronic)

IARC Class 1 human carcinogen; High Vp, significant occupational exposure via inhalation

Polycyclic Aromatic Hydrocarbons (PAHs): Toxicology

IARC class 1 carcinogen: Lung, liver, skin

What is the [drug] in plasma vs. Time graph of IV exposure? Oral?

IV: Immediate response; High [drug] immediately, then drops quickly Oral: Delayed/reduced response

How should dosing be altered in terms of enterohepatic recirculation?

If enterohepatic circulation is occuring, less drug is needed to reach a therapeutic dose. Can result in a toxic dose as the drug accumulates in the body

How do estrogens indirectly cause DNA mutations leading to cancer?

If one or more cell possesses a DNA mutation, these cells will proliferate in response to estrogen stimulation; Estrogen stimulation increases total number of mutant cells

What is a "Bay Region," and why is it important?

Important structure found in Polycyclic Aromatic Hydrocarbons (PAHs) that determines carcinogenic activity; The presence of "bay regions" increases the possibility of cancer

What does a larger partition coefficient (Kow) mean?

More lipid-like (more lipid soluble)

How are Aldehydes formed?

Incomplete combustion: Car/diesel exhaust, forest fires, wood-burning stoves; Reaction products from photo-oxidation of hydrocarbons

Substituents near the Bay Region of Polycyclic Aromatic Hydrocarbons (PAHs) ______ carcinogenicity.

Increase

Atmospheric Inversion

Increase of temperature with altitude (opposite than normal)

"Bad" diets such as our Western diet can _____ the urinary 2/16 estrogen ratio.

Increase; More bad C-16 estrogen (proliferative)

What is a low urinary 2/16 estrogen ratio associated with?

Increased breast cancer risk (more bad C-16 estrogen-proliferative)

What can prolonged exposure (10 years+) with PM2.5 cause?

Increased mortality (~16%)

Partition coefficient (Kow) ____ with increasing chain length.

Increases (More lipid-like/soluble)

Why is 16-α-hydroxyestrone considered "bad" estrogen?

Increases binding of the estrogen receptor with growth-promoting genes

Markers/Parameters of pulmonary function: Compliance (w/likely direction)

Index of flexibility of lung (Indicates Type II cells); Decrease

What is an example of a natural SERM: Selective Estrogen Receptor Modulator?

Indole-3-Carbinol; Found in broccoli, cauliflower, kale, etc.

What additional drug interaction has been seen in the supplement St. John's Wort that is not listed on the warning label?

Induce CYP in body

Ozone (O₃) Mechanism of Action

Induction of lipid peroxidation (free-radical process), leading to reduction of surfactin production, altered cell membranes (Oxidant that forms free radicals leading to respiratory inflammatory response)

Markers/Parameters of pulmonary function: Interleukins, Exhaled NO (w/likely direction)

Inflammation; Increase

What indicator genes are upregulated in response to PM₂.₅ in Dr. Coulombe's laboratory study Cache Valley's PM₂.₅?

Inflammatory response genes (Interleukins, CRP)

Organophosphates: Toxicology

Inhibits acetylcholinesterase (AChE- degrades acetylcholine); Acetylcholine then accumulates at cholinergic receptors in CNS and PNS

What is the MOA of the hepatic Thalidomide metabolite CPS49 that causes stunted limbs and other birth defects?

Inhibits angiogenesis or synthesis of blood vessels

Benzene: Sources

Inks, rubber, lacquers, paint removers, raw materials for organic chemicals, plastics, gasoline

Hg⁺²

Inorganic mercury; Low absorption in gut; Causes renal toxicity

Dicofol is not effective against ______.

Insects (besides Acari, spider mites)

What does Cytochrome P450 do? What does this process require?

Inserts oxygen molecule into substrate; Requires electrons to reduce Fe⁺³ to Fe⁺²

What are some of the biomarkers that can be used to measure the chronic inflammatory response caused by PM₂.₅ toxicity?

Interleukines, C-Reactive Proteins (CRP)

I.M.

Intramuscular

I.V.

Intravenous

What is an example of supplements not being proven to cure major diseases (and in this case cause more harmful effects)?

Iowa Women's Study: Increased mortality when compared to non-use (except perhaps Ca)

What is important about the Iron (Fe) contained within Cytochrome P450?

Iron (Fe) can give up or take electrons, allowing either oxygen or substrates to bind to it respectively

Organophosphates: Mechanism of Toxicity

Irreversible covalent phosphorylation of the serine active site of the acetylcholinesterase (AChE) enzyme

Toxicology: Acrolein

Irritation of eyes and mucous membranes in sinus and respiratory tract

Benzene's odor (warning property) (IS/IS NOT) protective.

Is not; Odor threshold is 12 ppm, whereas TLV is 0.5 ppm

Where is the highest amount of Cadmium (Cd) found in the body?

Kidney

Urinary route of toxicant excretion

Kidney receives 25% of cardiac output, 20% of which is filtered at the glomerulus

In what British monarch was genetic porphyria a contributing factor to their "madness?"

King George III (1760-1820)

What disease can form due to cassava (cyanide-containing) consumption?

Konzo: Neurologic effects by maternal consumption of cassava; Leg birth defects, mental deficits

What term represents an acute toxic potency? What does it mean?

LD50 (lethal dose): Statistically-derived single dose of a substance that can be expected to cause mortality in 50% of the test animals; Not relevant to chronic exposures/effects of low concentrations

What is Addition chemical interaction based on?

LD50's

There is normally a long ______ time between carcinogen exposure and clinical cancer (Progression).

Lag

What are the respective environmental fates of TRI chemicals?

Land 50%, Air 38%, Water 6%, Underground injection wells 5%

A compound with a _____ Kow diffuses into a cell efficiently.

Large

What are needed to establish greater confidence in toxicity studies?

Large sample sizes

What is considered "Processed" meat? (w/examples)

Meat that has been transformed through salting/curing processes to enhance flavor/preservation; Treated with sodium chloride and sodium nitrites, forming carcinogenic nitrosamines; Ex. Hot dogs, ham, sausage

The ______ the ratio between the Desirable (effective) effect (ED) and the Undesirable (toxic, lethal) effect (LD) the more safety.

Larger

What has the greatest incidence of poisoning than any other metal?

Lead; Oldest metal poison, most widely studied

Chemicals are _____ bioavailable on a full stomach.

Less

What is the result of a CYP2D6 polymorphism in terms of CYP2D6 present in the body?

Less CYP2D6

In a Plasma concentration of chemical vs. Time graph, what is the plasma concentration of the chemical after a meal compared to fasting?

Less chemical in plasma after a meal (Small AUC: Area-under-the-curve, Less bioavailable); More chemical in plasma if fasting (more bioavailable)

Chemicals that are more _____ can pass through the plasma membrane of cells better, thus being more _____.

Lipid soluble; Potent

Biological membranes are primarily ______, therefore what type of compounds are most efficiently absorbed?

Lipid; Non-polar, lipid soluble compounds

How does the body's fat storage affect a chemical's distribution?

Lipophilic (lipid soluble) compounds can store in body fat

What is the units of Volume of Distribution (Vd)?

Liters (L)

Many supplements have been found to be ______ toxicants.

Liver

Where is the highest concentration of the CN-converting Rhodanese enzyme found?

Liver

What is the major site of Cytochrome P450 in the body? How does this affect metabolism?

Liver (membrane bound in SER); Major site of drug metabolism

DDT: Chronic Toxicology

Liver: 1) Synergizes other hepato-toxicants 2) Liver damage/cancer 3) Endocrine disruption

Pulmonary epithelium major cell types: Ciliated cell (Location, Key features, Function)

Location: Airways Key features: Apical cilia Function: Defensive: clearance of foreign matter via mucus

Pulmonary epithelium major cell types: Non-ciliated epithelial or Clara cell (Location, Key features, Function)

Location: Airways Key features: Contains majority of P450 Function: Secretory, metabolic

Pulmonary epithelium major cell types: Mucous or Goblet cell (Location, Key features, Function)

Location: Airways Key features: Secretory; microvilli Function: Secrete mucus

Pulmonary epithelium major cell types: Type II or granular epithelial cell (Location, Key features, Function)

Location: Alveoli Key features: Large; Secretory; Cuboidal with central nucleus Function: Secrete surfactin, a lipid-rich material that keeps the lungs flexible and able to easily inflate; Repair: "Stem cell" of pulmonary epithelium

Pulmonary epithelium major cell types: Alveolar macrophage (Location, Key features, Function)

Location: Alveoli Key features: Mobile, phagocytic Function: Defensive: phagocytic

Pulmonary epithelium major cell types: Type I or squamous alveolar epithelial cell (Location, Key features, Function)

Location: Alveoli Key features: Small, flat, covers 97% of respiratory surface; Most susceptible to toxicants Function: Structure (support) and maintenance of alveoli; Ingestion of foreign matter

Dicofol has a _____ acute toxicity against mammals.

Low

Benzoate (Benzoic acid), being a weak acid (pk=4), will largely be in its non-ionized, lipid soluble form at what pH? Ionized, lipid insoluble form?

Low pH; High pH

Using dose-response curves, what is the response to lower exposure of PM2.5? Higher?

Low: Cardiovascular/cardiopulmonary/ischemic heart diseases High: Lung cancer

Using dose-response curves, what is the response to lower exposure of PM₂.₅? Higher?

Low: Cardiovascular/cardiopulmonary/ischemic heart diseases High: Lung cancer

CYP2D6 polymorphism results in a ______ metabolic rate for opioids.

Lower

Bioavailability

Measure of the extent of drug absorption for a given drug and route

How is lipid solubility measured?

Measured by octanol:water partition coefficient (Kow or Pc)

Porphyrin

Main molecule that holds iron (Fe) in Hemoglobin (Hb); Defective in porphyria (caused by dioxin toxicity)

What is the net effect of Biotransformation?

Make high Kow compounds more water soluble, low Kow, making them more easily excreted via urine/feces

Cooked meat is associated with elevated cancer mortality (and cardiovascular mortality). What is the cancer hazard ratio of men to women? Why is there a difference?

Males: 1.22 Females: 1.20 Females less due to different P450s found in body

Who was "The Father of Modern Toxicology?"

Mathieu Orfila (1787-1853); Spanish-born French toxocologist/chemist; Personal physician to king Louis XVIII

What cancers are most common in men in Japan? Japanese immigrants to US? Sons of Japanese immigrants? Men in US?

Men in Japan: Stomach/liver Japanese immigrants to US: Less stomach/liver; More colon/prostate Sons of Japanese immigrants: Even less stomach/liver; More colon/prostate Men in US: Equal stomach/liver/colon/prostate

Bioactivation

Metabolic activation of compounds into toxic compounds (metabolites)

Formaldehyde is a normal ______ in cells.

Metabolite

Benzene: Metabolism

Metabolized by CYPs to metabolites toxic to bone marrow; Binds to DNA causing bone marrow suppression (anemia); 1) Benzene converted to phenol and hydroquinone by CYPs in liver 2) Hydroquinone converted to phenoxy radical (stimulated by phenol) in bone marrow leading to DNA damage and maturation arrest

Vinyl Chloride (VC): Mechanism of Action

Metabolized to carcinogenic epoxide intermediate

Of the 3, Ethanol, Methanol, and Ethylene Glycol, which are bioactivated via metabolism?

Methanol (Formic Acid), Ethylene Glycol (Oxalic Acid)

How does the amount of biomagnification of Methoxychlor relate to DDT?

Methoxychlor biomagnifies less than DDT

MeHg⁺

Methylated organic mercury; Most potent/lipid soluble form; Crosses membranes (placenta) rapidly; Formed from bacterial alkylation; Common in fish

What chemical was involved in the worst modern industrial disaster?

Methylisocyanate; Union Carbide plant in Bhopal, India; 30-40 tons released during a 2-3 hr period; Killed > 8000; Seriously injured > 200,000

"Asbestos bodies"

Microscopic protein-coated fibers in lungs from lung biopsy; Begins with unsuccessful macrophage that dies and other macrophages accumulate around fiber

Paracelsus (1493-1541) pioneered both ______ and ______ in medicine, including what mineral used to treat what STD?

Minerals; Plants; Mercury for syphilis

What are some high risk occupations to Asbestos diseases?

Miners, shipyard workers, service station workers, demolition workers, associated spouses/families

Estrone

Minor; Only form of estrogen present in post-menopause

The carcinogens present in cooked meat, polycyclic aromatic hydrocarbons (PAH) and heterocyclic amines, are not cancerous to our bodies until what occurs?

Modification by P450 in the liver

Most chemicals that enter the body are _____ via ______, which are often very _______. Many of these metabolites are safe, but some are very ______.

Modified; Enzymes; Promiscuous; Toxic

Zearalenone is a Xenoestrogen found in ______ that has been proven to cause what condition in men (and pigs)?

Molds; Gynecomastia (Enlarged breasts in men)

The (Monomer/Polymer) form of Styrene is the more toxic chemical.

Monomer (Styrene)

The (Monomer/Polymer) form of Vinyl Chloride is the more toxic chemical.

Monomer (produced by incomplete conversion to polymer)

Vinyl Chloride (VC)

Monomer used to manufacture polyvinyl chloride-based plastics (PVC)

What does a LOW Volume of Distribution (Vd) mean?

More of the chemical is found in the blood; Distribution is not as favorable

Codeine is metabolized to a number of metabolites, but analgesia is due to O-demethylation to ______.

Morphine

Gastrointestinal (GI) route of chemical absorption

Most absorption in small intestine (large surface area)

Estradiol

Most biologically active; Present in females and males; Binds to receptor (ER1, ER2); Small proportion active, remainder gets bound by globulin/albumin; Responsible for female development (1°,2° sex characteristics)

Some drugs have a Volume of Distribution (Vd) of greater than 10,000. What does this signify?

Most of drug is in tissue, little in plasma

Distribution

Movement of chemical throughout body; From blood to compartments

In animal studies, how high is the dose relative to the normal dose or exposure experienced by humans? Why?

Much higher; Need to induce response in their short lifetimes

Modern toxicology is ______. What does this mean?

Multi-disciplinary; Utilizes information from many sciences, such as biochemistry, molecular biology, engineering, epidemiology, chemistry, biology, genetics, microbiology, public health, pathology, forensics, nutrition, food science, etc.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD): Sources

Municipal waste incineration, Backyard trash burning, Inadvertent landfill fires, Secondary copper smelting, Medical waste incineration, Forest, brush and straw fires, Cement kilns, Iron ore sintering

Where are the Acetylcholinesterase enzymes found at the neuromuscular junction?

Muscle

Oncogenes are concerning because ______ aren't required for them to initiate cancer.

Mutations

What is NAAQS, and what are the 6 "Criteria Pollutants?"

NAAQS: National Ambient Air Quality Standards 1) Carbon Monoxide (CO) 2) Lead (Pb) 3) Nitrogen Dioxide (NO₂) 4) Ozone (O₃) 5) Particle pollution: PM₂.₅, PM₁₀ 6) Sulfur Dioxide (SO₂)

What does the CYP reductase conversion of ferric Fe⁺³ to ferrous Fe⁺² require to add electrons?

NADPH+H = NADP

What is the value of Probits (Probability+unit)?

NED+5

How does Cache Valley's Topography contribute to its high PM₂.₅ levels?

Narrow, deep, and enclosed mountain valley, leading to no fresh air sources

Polycyclic Aromatic Hydrocarbons (PAHs): Sources

Naturally formed; Creosote, burned carbonaceous materials, exhaust, burnt food, cooked meat (C+∆=PAHs)

Asbestos

Naturally-occurring silicates that crystallize in a fibrous pattern; Not dangerous until mined and processed, then becomes friable; High tensile strength; resists heat and chemicals

What net charge do proteins in the plasma membrane have? How does this charge affect chemicals' ability to cross the membrane?

Negative (-) net charge; Ionized compounds don't pass through well

Acetylcholinesterase inhibitors are utilized in both ______ and ______.

Nerve agents; Organophosphate insecticides

What is the main difference between organophosphate nerve gases and insecticides?

Nerve gases do NOT require metabolism, while insecticides DO require bioactivation by P450s first (P=S to P=O)

What kind of toxicity can result from zinc supplementation?

Neurotoxicity

Mercury is a potent ______.

Neurotoxin

An acidic chemical will bind better to soil when in ______ form.

Neutral (Ex. COOH vs. COO⁻); Because of cation exchange capacity of clay and organic material

What carcinogens are present in processed meat? (w/examples)

Nitrosamines: Ex. DEN (Diethylnitrosamines)

Is the current short-term regulation of PM2.5 adequate?

No

NOAEL

No observable adverse effect level; Point-of-departure used to extrapolate and determine exposure limit standards (RfD, ADI)

Why were the birth defects associated with Thalidomide not known before release?

No reproductive study was done before release

There is no safe ______ or ______ for PM₂.₅.

No safe threshold or exposures

There is no safe ______ or ______ for PM2.5.

No safe threshold or exposures; Short-term exposures not risk-free

Does acute exposure necessarily result in acute response? Does a chronic exposure necessarily result in a chronic response? Give examples.

No; 1) Acute exposure may result in acute or chronic effects: Acute exposure to asbestos may lead to cancer (chronic) 2) Chronic exposure may result in chronic or acute effects: Chronic lead exposure may lead to subacute or acute symptoms

Does bioactivation occur in the metabolism of Ethanol to Acetyl CoA?

No; Acetyl CoA is not very toxic

What does Benzene's "shift-to-the-left" effect mean?

Normally stems cells with bone marrow differentiate into large, immature WBCs, which differentiate into smaller, circulating WBCs. Benzene causes maturation arrest of stem cells, therefore more large, immature WBCs are seen in the blood

Chronic Benzene toxicity can produce oncogenes such as the one that turns off P53, the tumor-suppressing gene. What is the result of this?

Normally stops excessive cell division (especially of cell's with abnormal DNA), but when turned off cells continue to divide along with DNA errors

Insecticide: Lindane (misnamed benzenehexachloride or "BHC")

Not well absorbed through skin; Carcinogen

Cytochrome P450 in Phase 1: Metabolism creates either ______ or _____.

Nucleophiles; Electrophiles

Is the Xenoestrogen Bisphenol A (BPA) safe?

Numerous studies show adverse reproductive and physiological effects in rodents at doses lower than ADI

What book did Paracelsus publish making him possibly the first industrial hygienist? What did it document?

On the Miners' Sickness and Other Miner's Diseases; Documented silicosis and other occupational hazards of mining

Ras is a "______", while p53 is a "______" gene.

Oncogene; Tumor suppressor gene

COBRA

Online tool to determine cost-benefit of environmental regulation

Atropine, part of dual therapy for organophosphate poisoning, is extremely toxic. What symptoms can it cause?

Opposite symptoms to Oranophosphates (Acetylcholinesterase inhibitors) 1) ↑HR (pink cheeks) 2) Dilated pupils 3) Dry mouth

P.O.

Oral

Environmental ______, such as nitrates, nitrites, and nitroaromatics, can lead to a condition called ______ or Blue Baby. This condition occurs when these chemicals are reduced via oxidation taking electrons from hemoglobin (Hb) to form methemoglobin, which prevents ______ from binding.

Oxidants; Methemoglobinemia; Oxygen

The first step of the two-fold treatment of cyanide toxicity is Sodium nitrite, which is a ______. How does this cause CN to dissociate from cytochrome c oxidases?

Oxidizing agent; Oxidize heme so that CN will not bind (nor O₂)

Toxic chemicals often interfer with ______ distribution throughout the body.

Oxygen

What does the "P450" portion of Cytochrome P450 mean?

P = pigment; 450 = Max absorption wavelength in spectrum when bound to CO

What enzyme is Benzo(a)pyrene commonly first converted by? What does this conversion create?

P450; Epoxides, which are chemically unstable electrophiles that freely react with electron-rich nucleophiles, such as DNA, causing cancer

What can cancer Promotion be prevented by?

P53 genes

Inhalation route of chemical absorption

Rapid; Principal route of gases, vapors, aerosols

What are the restricted uses of the insecticide Lindane?

Pet collars, dog shampoos, non-food animals, home ornamentals, wood treatment, lice control in people

Soil: Organic fraction

Soil components from breakdown of biota, plant and animal matter

What is the route of metabolism of Polycyclic Aromatic Hydrocarbons (PAHs), especially Benzo(a)pyrene?

PAHs are activated by a multi-step process to the ultimate carcinogen: 1) Benzo(a)pyrene is converted by P450s to an epoxide (some neutralized by GSTs) 2) Epoxide hydrolase converts the epoxide to a diol epoxide, the ultimate carcinogen, which further binds to DNA

Polychlorinated Biphenyls (PCBs): Toxicologic Properties

PBT chemical: Persistent: Resistent to biodegradation, proportional to % Cl Bioaccumulates in environment: Highly lipophilic Toxic

Chlorophenols

PBT chemical; Banned by EPA for general use

Where are Cytochrome P450's found? What is their general function?

PM; Add an oxygen (promiscuous enzymes)

Is PM₂.₅ or PM₁₀ more potent?

PM₂.₅

Who developed the concept of "dose?"

Paracelsus

Who was instrumental in the development of toxicology as a science during the "Age of Enlightenment?"

Paracelsus (1493-1541)

Some compounds are well-absorbed in the small intestine regardless of pH/pK (affected lipid solubility). What is one example of this? How is it accomplished?

Paraquat: 2 positive charges; Transported via transport proteins

Organophosphates: Insecticides Examples

Parathion, Malathion, Diazinon

Respiratory disposition pattern depends on ______.

Particle size; Smaller particles travel farther into lungs to alveoli, while larger particles travel less far

What is PM₂.₅?

Particles (suspended in ambient air) < 2.5 μm aerodynamic diameter

Nanoparticles

Particles with diameter <100µm

What is PM2.5?

Particulate Matter less than 2.5µm (micrometers) in diameter

CYP2D6 ______ subjects do not have active CPY2D6 isoform to make ______, therefore no analgesia is accomplished from ______.

Polymorphism; Morphine; Codeine

Ozone (O₃): Sources and Formation

Photolysis of NO2 (from auto emissions) in the atmosphere using sunlight (UV light) (Formed in atmosphere)

What is a biomarker for Organophosphate exposure?

Plasma cholinesterase

Vinyl Chloride: Sources

Plastics, water pipe, food wrap, records, aerosol propellants

Water is highly ______, therefore it has a _____ Kow.

Polar (hydrophilic); Low Kow (non-lipid soluble)

1,3-butadiene (BD): Uses

Polymer component in synthetic rubber (starting material)

Absorption

Process by which toxicants cross body membranes and enter bloodstream

Estriol

Produced exclusively during pregnancy in fetus

What are DNA adducts?

Products of DNA repairs that are excreted into the urine

Chronic response

Progresses slowly; May be mistaken for other diseases, since cause-and-effect often difficult to determine

"Bad" estrogen: 16-α-hydroxyestrone (C-16)

Proliferative: 1) Potent proliferative effects through receptor affinity 2) Binds to histones altering DNA packaging 3) Binds to DNA directly, causing mutations

Xenoestrogens act as "tumor ______," causing, among other things, cell division in estrogen-sensitive tissues. Xenoestrogens and other tumor promoters are carcinogenic, but active in the "______" stage in carcinogenesis.

Promoters; Promotion

Biological membranes are composed of a ______ bilayer. The lipid portion is primarily ______, which have _____, _____ head groups oriented outward, and _____ ______ chains oriented inward. The globular structures represent integral membrane _____, which may be transport, receptor or other types of proteins.

Protein-lipid; Phospholipids; Ionic, polar; Lipid chains; Proteins

Asbestos Toxicology: Asbestosis

Pulmonary interstitial fibrosis: Excessive deposition of collagen in lung, progressive lung stiffening, impaired gas exchange (reduces ability to diffuse oxygen; ↑O₂, ↓PO₂,↓TV)

The negative estrogenic effects of Genistein demonstrate what interesting chemical property?

Pure chemical (soy isoflavone) behaves differently than natural food product (soy)

Organophosphates: Nerve Gases

Pyrophosphates; Developed in 1940s in Germany; NO metabolism required; Extremely acutely toxic

What are dose-response curves important in creating?

Regulatory policies

What generally occurs in the process of De-sulfuration by Cytochrome P450?

Removal of Sulfur atom

Subacute exposure

Repeated exposure < 1 month (between 1 day and 1 month)

Organophosphates: Insecticides

Require bioactivation by P450s

Endocytosis (Pinocytosis, Phagocytosis)

Requires energy; Peptides, antigen/antibody complexes

Why do Cache Valley cars in particular create such high PM₂.₅ levels?

Residents make many short distance trips, not allowing emission devices to be optimized while driving

Why have some insects become immune to DDT?

Resistance due to different enzymes (P450s, Phase II)

Why are chlorinated aromatics resistent to biodegradation?

Resistance is proportional to % Cl

What is happens to a compound after it has be oxidized by Cytochrome P450 in Phase I: Metabolism of Biotransformation?

Results in a stable detoxified metabolite, but sometimes a more toxic metabolite; Product may either be excreted or further metabolized by Phase 2: Conjugation

Inversion

Reversal of the normal decrease of air temperature with altitude; Increase in temperature with altitude trapping colder air

Who first discovered the carcinogenic nitrosamines found in processed meats?

Richard Scanlon (Oregon State)

Risk = ______x______

Risk = Hazard x exposure

PM₂.₅: Epidemiology

Risk factor for cardiopulmonary mortality/lung cancer

Unlike healthy breast cells, cancer cells don't always have estrogen receptors (ERs). ER+ cells are responsive to ______. ER- cells are not governed by estrogen, therefore ______ do not inhibit ______.

SERMs; Proliferation

What factors does the Volume of Distribution (Vd) depend on?

Same as absorption (Lipid solubility, molecular size, degree of ionization)

Organophosphates: Nerve Gases Examples

Sarin, VX, Tabun

What alkaloid related to Atropine is used for motion sickness?

Scopolamine

In soil adsorption, the soil is the ______, the chemical is the _____, and water is the ______.

Soil: Adsorbent (adsorbing) Chemical: Adsorbate (adsorbed) Water: Solvent

Concerning dose-response and the "68-95-99.7 Rule," most respond close to the mean dose, and nearly all responses occur within ±3 SD of the mean. Those responding to lower doses are ______ and those responding to higher doses are ______.

Sensitive; Resistant

Formaldehyde (COH₂): Sources

Shampoo; Cosmetics, deodorants, leather, wood and paper, resins, plastic/textile processes, funeral homes, pathology/biology laboratories, particle board, carpet, upholstery materials, insulation, disinfectants, dyes, exhaust, tobacco smoke, gas, oil, coal, wood incineration, photochemical smog

Why was Catherine de Medici nicknamed "The Bloodiest Queen?"

She was an early toxicologist that experimented on the underclass, homeless, and sick; Poisoned political enemies for hire; Documented signs and symptoms

The LD50 is a measure of ______-term response.

Short

What were the pulmonary results of Dr. Coulombe's translational PM₂.₅ study?

Significant decrease in pulmonary function (Reduced pulmonary function, Increased lung/systemic inflammation)

What can SMALL reductions in PM2.5 lead to?

Significant public health improvement

What can SMALL reductions in PM₂.₅ lead to?

Significant public health improvement

How do the symptoms of Methoxychlor relate to DDT?

Similar acute symptoms to DDT

Superfund site

Site where hazardous waste has been spilled; That company is responsible for cleaning the site (EPA law)

What are the normal effects of Acetylcholine (ACh) on the Central or Somatic Nervous System (Brain, Spinal cord)?

Skeletal muscle control

What does the histology of Aberrant Crypt Focus (ACF) show leading to early detection of cancer?

Slight enlargement, irregularity, and elongation of ducts

How does molecular size affect absorption of hydrophobic chemicals?

Small particles are absorbed more readily than larger particles

The LD50 becomes ______ as a chemical becomes more potent.

Smaller

The ______ the particle (PM₂.₅) the further down into the lungs it can get.

Smaller

What is an example of chemical Synergism?

Smoking (or environmental pollutants)+asbestos = 40x more risk to lung cancer than non-smokers

Who was the most celebrated poisoning victim? What were they poisoned by?

Socrates (470-399 BC); Poison hemlock (died next day)

How can the acidosis caused by the bioactivation of Methanol to Formic Acid be treated?

Sodium bicarbonate: Weak base to counteract acidosis

What is the "largest threat" to consumer safety by supplements according to the FDA?

Some supplements contain or are prescription drugs

______-enriched dietary supplements may increase cancer risk by stimulating cell ______ in estrogen-dependent tissues.

Soy Isoflavone; Proliferation

How is pulmonary function tested/measured?

Spirometry

Mercury (Hg) has a high affinity for what groups?

Sulfhydryl groups ("mercaptan")

The production of Polycyclic Aromatic Hydrocarbons (PAHs) increases with increased ______.

Temperature

Vapor pressure is directly proportional to ______.

Temperature

Styrene: Sources, Uses

Starting material for numerous consumer products; Polystyrene: Loose-fill packaging, disposable dinnerware, appliances, picnic coolers

What are some factors that determine the Uncertainty Factor (UF)? (3)

Starts at 100; 1) Interspecies extrapolation: animal-to-human (x10) 2) Intraspecies extrapolation: human-to-human 3) Experimental inadequacies: Less-than-lifetime exposure in animal studies, Variations/absence of NOAEL

What does the dose-response curve for PM₂.₅ look like?

Starts at the origin = No safe dose

Phase 1 Cytochrome P450 enzymes have a normal function in what bodily process?

Steroidogenesis

Opioids are ______ depressants. What is one undesirable effect (LD)?

Stop breathing

Acrylamide: Toxicology

Strong affinity to tissue sulfhydryl groups (SH); Multi-site animal carcinogen; Probable (2A) human carcinogen

Toxicology: Ozone (O₃)

Strong oxidizing agent (free radical damage) and deep lung irritant affecting terminal bronchioles and alveoli

Soil: Clay

Structures of silica/alumina; Hydrophilic surface/water-holding capacity; Ion (cation) exchange capacity

Styrene is metabolized to ______. How is this toxic?

Styrene oxide; Epoxide is unstable and forms carbonium ion (C⁺) that binds to DNA forming cancer

S.C.

Subcutaneous

What is the form of Iron (Fe) present in Cytochrome P450 that combines with the Substrate? Oxygen?

Substrate: Fe⁺³: Ferric Oxygen: Fe⁺²: Ferrous

What are some properties of Thallium (Tl) that have made it a popular poison for murders?

Tasteless, odorless, works slowly

What other treatment is needed along with the two-fold therapy treatment for cyanide toxicity?

Supportive O₂

Subacute response

Symptoms usually not as severe or rapid as an acute response

Where are Acetylcholinesterases found in the body? Why?

Synaptic junctions; Ach is released into synaptic cleft to post-synapse or muscle to propagate signal; Acetylcholinesterases degrade Ach thereby controlling signal

Xenoestrogen: Bisphenol A (BPA)

Synthetic estrogen (abandoned after DES); Increases durability/clarity of polycarbonate plastics; Migration from plastics (widespread exposure/residues in people)

Markers/Parameters of pulmonary function: C-reactive protein (CRP) (w/likely direction)

Systemic and cardiopulmonary stress; Increase

What naturally occurring neurotoxin is present in Fugu?

Tetrodotoxin

What drug was released in the UK from German company in the 50's to treat morning sickness, amongst other things, in pregnant women, only to cause severe birth defects?

Thalidomide

The Cytochrome P450 conversion of caffeine to paraxanthine eliminates what?

The activity of caffeine

Chemical interaction: Addition

The combined effect of 2 chemicals is usually predictable, based on their known potency; 1+1=2

Threshold Limit Value - ceiling (TLV-C)

The concentration that should not be exceeded during any of the working exposure

Threshold Limit Value - short-term exposure limit (TLV-STEL)

The concentration to which workers can be exposed continuously for a short period of time without suffering from irritation, chronic or irreversible tissue damage, or narcosis

What notable utensil did Catherine de Medici, "The Bloodiest Queen," introduce to the people of France?

The fork

In the 1930s-1940s, ______ started funding research studies. Why?

The government; Saw that a healthier population would benefit everyone

Safety

The practical certainty that injury will not result from use of a substance

Potency

The relative toxicity of a compound

Paracelsus focused on the importance of the ______. What is this?

Toxicon: Toxicity is a result of a chemical entity

Threshold Limit Value - Time weighted average (TLV-TWA)

The time-weighted average concentration for a normal 8hr word day and a 40hr workweek, to which nearly all workers may be repeatedly exposed without adverse effect

Who was a student of Aristotle and the most influential botanist of antiquity?

Theophrastus (470-286 BC)

What is the reality of the Adverse Event Reporting to the FDA concerning harmful effects of supplements?

There are many more adverse events than reported (Ex. Iceberg)

Why are epoxides dangerous?

They are electrophilic and can therefore attack DNA causing cancer

What is the biomarker for Vinyl Chloride (VC)?

Thiodiglycolic acid; Has S due to GST

How do hydrophilic compounds travel via Passive diffusion across membranes?

Through aqueous channels in membrane

What are utilized in Phase 3: Export of Biotransformation?

Transport proteins

A large enough sample size is necessary to have good confidence in toxicologic research. (TRUE/FALSE)

True

An increase in tidal volume, usually means that the body is trying to maintain enough O₂. (TRUE/FALSE)

True

Benzene has both acute and chronic toxicities. (TRUE/FALSE)

True

Cache Valley has some of the highest urban PM₂.₅ measured in USA. (TRUE/FALSE)

True

Cache Valley has the highest air pollution in the United States. (TRUE/FALSE)

True

Cancer in early life is due mostly to "bad luck," while as we age, cancers are more due to diet and lifestyle. (TRUE/FALSE)

True

Carbon Monoxide (CO) has both acute and chronic toxicities. (TRUE/FALSE)

True

Logan HAS had the worst air quality concerning PM2.5 in the nation. (TRUE/FALSE)

True

Once a chemical enters the blood, it is free to act normally. (TRUE/FALSE)

True

Organophosphate nerve gases are much more potent than insecticides. (TRUE/FALSE)

True

PM₂.₅ is smaller in diameter than a human hair. (TRUE/FALSE)

True

PM₂.₅ upregulates several oncogenes. (TRUE/FALSE)

True

Polychlorinated Biphenyls (PCBs)

Typical PBT chemcial; Tradename Aroclor

There are many charged proteins and other molecules in the blood (Ex. albumin, immunoglobulins, transport proteins) to which chemicals bind. How does chemical binding to charged circulating molecules affect the chemical's distribution?

Unbound chemical: Crosses membranes Bound chemical: Diffusion hindered

What is the current status of Bisphenol A (BPA)?

Under review; Already banned in many states and countries

In Probit Transformation, what can the response be transformed into?

Units of deviation from the mean, called Normal Equivalent Deviations (NEDs), then, to avoid negative numbers, to probability units called Probits

"Good" estrogen: 2-hydroxyestrone (C-2)

Unlike estradiol, which increases cell proliferation, C-2 has protective anti-estrogenic effects through receptor antagonism

Pulmonary Toxicants: Acrolein

Unsaturated aldehyde; More irritating than formaldehyde; Major contributor to irritating quality of cigarette smoke/smog; Combustion product of fuels/cellulose materials

What location of the respiratory system does formaldehyde and Acrolein affect? Why?

Upper respiratory tract; Water-soluble

Bioaccumulation

Uptake of chemical from diet

Ozone (O₃) is a major _____ and _____ pollutant.

Urban; Industrial

What is the biomarker for Styrene?

Urinary mandelic acid

Benzene: Biomarker

Urinary phenol

What is a Probit Transformation?

Used to adjust for extremely high doses in animal studies to apply to humans; Convert all responses from a 68-95-99.7 histogram; Used to create ambient standards Ex. PM2.5 (35 µg/m³), Hg (10 ppb)

What geographical aspect can enhance inversion?

Valleys

Benzoic acid is a weak _____, with a pk of _____.

Weak acid; pk=4

Henderson-Hasselbalch equation for Weak Acids (w/example)

Weak acids: pKa-pH = log [nonioinized]/[ionized]; Ex. R-COOH

Aniline is a weak _____, with a pk of _____.

Weak base; pK=5

Henderson-Hasselbalch equation for Weak Bases (w/example)

Weak bases: pKb-pH = log [ionized]/[nonionized]; Ex. R-NH₂

In what pH gradient do chemicals diffuse the most in the small intestine?

When chemical in most lipid soluble form: 1) Weak Acids diffuse best at lower pH (stomach pH 2) 2) Weak Bases diffuse best at higher pH (intestines pH 6)

Warning properties

When odor of chemical is protective; When you smell the chemical, leave the area

Chemical interaction: Synergism

When the combined effect of 2 compounds is GREATER than the predicted sum of their effects; Less common; 1+1=10

When do chemicals become toxic to the body?

When they enter body's cells

Triclosan

Wide spectrum antibacterial, antifungal agent; Low acute/chronic toxicity; Moderate environmental accumulation; Forms dioxin when exposed to sunlight; Structurally similar to thryoid hormone

Estrogen and estrogen-like molecules circulate and interact with target tissues. What are these estrogen target tissues for women? Men?

Women: Breast, uterus, bone, brain, heart, liver Men: Testes, breast

Chlorophenols: Sources, Uses

Wood preservatives (railroad ties, telephone poles, fence posts), pesticides (evaporates from treated wood)

Residues of Polychlorinated Biphenyls (PCBs) are found ______.

Worldwide: Atmosphere, oceans, ponds, lakes, sediments, fish, animals, human adipose/blood, breast milk

Xmax equation

Xmax = K₁/K₂

Does bioactivation occur in the metabolism of Methanol to Formic Acid?

Yes; Formic Acid is more toxic and causes acidosis

Does bioactivation occur in the metabolism of Ethylene Glycol to Oxalic Acid?

Yes; Oxalic Acid is more toxic; Causes crystal formation in kidneys leading to renal failure

Polychlorinated Biphenyls (PCBs): Sources

cooling/insulating fluids for transformers/capacitors, hydraulics, plasticizers, waxes, carbonless paper

Chemical half-life (t₀.₅) equation or time to reach plateau (Xmax) or eliminate nearly all chemical from body

t₀.₅ = 0.693/k₂ ×7

Where does most occupational exposure to Benzene occur?

~2x10⁶ workers in petroleum refining, coke and coal, tire manufacture, truck transport