Exam 2

Question 1

diseases characterized by uncontrolled proliferation of cells leading to autonomous growth of tissue (neoplasm), can be caused by infectious agents, radiation, and chemicals

Answer 1

cancer

Question 2

a physical or chemical agent that causes or induces neoplasia, can be genotoxic or nongenotoxic (epigenetic)

Answer 2

carcinogen

Question 3

the ability of an agent to induce heritable changes in genes that exercise homeostatic control in somatic cells

Answer 3

genotoxicity

Question 4

interact physically with DNA to damage its structure, mutagenic (able to produce mutations), no theoretical threshold (theoretically just 1 molecule can interact with DNA and cause cancer), examples include PAHs, NNK, aromatic amines, alkylating agents, arsenic, chromium VI, may be direct or indirect acting (require metabolic activation)

Answer 4

genotoxic carcinogens

Question 5

affect DNA function without modifying or damaging its structure, nonmutagenic, threshold reversible, no direct DNA damage, examples include asbestos, dioxin, ethanol, DES, phenobarbital, PCBs, dieldrin

Answer 5

nongenotoxic carcinogens

Question 6

caused by parent chemicals (like heavy metals or their metabolites - PAHs or aflatoxins), requires 1 or more rounds of cell division for fixation of cell damage, typically results in the formation of a carcinogen-DNA adduct, cellular machinery can still repair the structural alteration (DNA repair mechanisms), altered cells can also be destroyed by apoptosis

Answer 6

tumor initiation

Question 7

results from the clonal expansion of initiated cells, effect is reversible although continuous exposure to the promoter maintains the initiated cell population, tumor promoters do not interact with DNA and are not mutagenic and may not even be carcinogenic, examples of tumor promoters includes TCDD (dioxin) and phenobarbital

Answer 7

tumor promotion

Question 8

proliferation of initiated cells to the malignant cell population of the neoplasm, further genetic changes occur (activation of proto-oncogenes, inactivation of tumor suppressor genes)

Answer 8

tumor progression

Question 9

a carcinogen which affects tumor cells in all stages of development (UVR, asbestos, cigarette smoke)

Answer 9

complete carcinogen

Question 10

formed by high temperature combustion of fossil fuels especially under low oxygen conditions (soot, coal tar, gasoline exhaust, tobacco smoke, smoked and barbecued foods)

Answer 10

polyaromatic hydrocarbons (PAHs)

Question 11

benzo[a]pyrene is a ________ that requires bioactivation via CYP450 to reactive intermediates, these in turn are metabolized via epoxide hydrolase and CYP3A4 to the ultimate carcinogen diol epoxide which combines with DNA

Answer 11

procarcinogen

Question 12

phase II conjugative enzymes such as UGT, GST, and SULT play an important role in this, resulting metabolites are not carcinogenic

Answer 12

detoxification

Question 13

this is the most carcinogenic compound in tobacco smoke, bioactivated by CYP450 in the lungs, another related potent carcinogen in NNN, both of these form DNA adducts and act as a tumor initiator

Answer 13

NNK

Question 14

the study of chemicals that prevent, inhibit, or slow down the process of cancer, drugs include aspirin and tamoxifen, antioxidants like vitamins C and E and phase II inducers like isothiocyanates, vitamins like retinoids and vitamin D analogs, treating early stages of malignant process will halt or delay the progression of neoplasia

Answer 14

chemoprevention

Question 15

• drug taken as directed (therapeutic dose) leading to adverse effects, idiosyncratic reactions (very rare or unexpected reactions), drug interactions
• drug taken in overdose (acute toxicity)
• habitual abuse (chronic toxicity (exposed over long period of time)

Answer 15

different types of drug toxicities

Question 16

• 15-20 tabs of this cause fatal liver damage, toxicity may be masked by other drugs taken at the same time resulting in a missed diagnosis and delayed treatment
• acute toxicity (children greater than 200 mg/kg, adults greater than 6-7 g)
• chronic toxicity (children and adults greater than 150 mg/kg/day for more than 2 days, decreased CYP450 metabolism of this in children less than 10-12 years which is a good thing)
• overdose causes altered metabolism of the drug, conjugative pathways are saturated, bioactivating oxidative pathway predominates
• NAPQI reacts with protein
• alcohol or barbiturates makes pt more susceptible to toxic effects of this drug through enzyme induction of CYP450
• fasting and malnutrition and this leads to liver toxicity because not enough liver enzymes to metabolize the drug

Answer 16

acetaminophen toxicity

Question 17

this is the antidote for acetaminophen overdose, it is a glutathione analog given within 8-10 hours of the overdose, increases the metabolism of NAPQI by GST into mercapturic acid

Answer 17

n-acetylcysteine

Question 18

• acute ingestion (mild intoxication 150-200 mg/kg, severe intoxication 300-500 mg/kg)
• chronic ingestion (especially in elderly, intoxication 100 mg/kg/day for more than 2 days, increased risk of mortality with respect to acute toxicity)
• 1 tsp of oil of wintergreen contains 5 g of methyl salicylate which is equivalent to 7.5 g of this, fatal to children
• consuming multiple products that contain this
• four main metabolites, conjugative pathways are saturable so the drug metabolites accumulate leading to toxicity
• half life increases even with small number of tablets leading to an increase in Cp, accumulation in tissues, and increase in Vd

Answer 18

aspirin

Question 19

• uncoupling of ATP production in mitochondria leads to decreased ATP production/increased O2 use/increased CO2 production
• this leads to hyperventilation, increased blood pH, respiratory alkalosis
• this increases bicarbonate (base) elimination, in children or severe adult overdose this drastically decreases blood pH and it becomes acidic, metabolic acidosis
• this decreases urinary pH, increased protonation to unionized species leading to reabsorption, decreased excretion of the drug increasing the concentration of the drug
• this is a positive feedback loop that will continue in toxicity

Answer 19

aspirin toxicity and acidosis

Question 20

dose, genetics, HLA type, sex, duration of therapy

Answer 20

factors which predispose towards drug toxicity

Question 21

individuals may be classified according to how fast they metabolize a drug (poor, intermediate, extensive, ultra), higher incidence of side effects/toxicity in _____ metabolizers, therapeutic failure in ______ metabolizers, this is often due to genetic variation in enzyme(s) metabolizing the drug

Answer 21

poor, ultra

Question 22

slow acetylators of this drug are at an increased risk of systemic lupus erythematosus (SLE, type of immunological toxicity)

Answer 22

hydralazine

Question 23

large number of genes related to immune function, type DR4 occurs in 27% of the population

Answer 23

human leukocyte antigen (HLA)

Question 24

multiple drug prescribing, several mechanisms of this:
- interference in the metabolism of one drug by another (induction, inhibition)
- interference in the disposition (kinetics) of one drug by another
- alteration of the pharmacological response to one drug by another
toxicity of drug may be increased or decreased, efficacy of drug may be increased or decreased

Answer 24

toxicity due to drug interactions

Question 25

- drug induced hemolytic anemia due to G6PD deficiency, idiosyncratic reaction, deficient G6PD enzymes in red blood cells, drug causes RBCs to lyse, rare in most ethnic groups but more common in some

Answer 25

drug toxicity due to altered responsiveness

Question 26

- acute exposure usually accidental - inhalation of solvents can cause asphyxiation, unconsciousness, death - chronic exposure most common in industry - inhalation of metal fumes, gases, solvents initially leads to irritation and allergy, long-term effects include respiratory diseases and cancer

Answer 26

toxic effects of industrial chemicals

Question 27

two organ systems most commonly affected by industrial chemicals, easy routes of exposure

Answer 27

skin and respiratory system

Question 28

most prevalent occupational disease

Answer 28

dermatitis

Question 29

this directly damages cells if in contact with the skin in sufficient concentration and for sufficient time, solvents degrease skin, alkalis will denature skin proteins

Answer 29

irritant

Question 30

a substance that can induce an overreaction of the body's immune system, nickel causes contact dermatitis in metal workers, toluene diisocyanate causes asthma

Answer 30

sensitizer

Question 31

a greater than expected number of cancer cases that occurs within a group of people within a defined geographical area over a specific period of time

Answer 31

cancer cluster

Question 32

heavy metal, industrial use in alloys, batteries, plating, pigments, solar cells, food is the major source for general population, inhalation is the major route of exposure in occupational setting, half life 7-30 years (accumulates and is hard to get rid of), toxic effects (renal, reproductive, inhalatory, skeletal, carcinogen), combines with metallothionein protein (MT) in liver - transported in blood, complex accumulates in kidney (target organ), toxic to tubular cells and glomeruli, renal function markedly impaired, Itai-itai disease (Japanese women eating rice contaminated with this - severe bone pain and respiratory distress)

Answer 32

cadmium

Question 33

used in rubber and dye industry, aniline, 2-naphthylamine (bladder and colon cancer), 4-aminobiphenyl in cigarette smoke and charbroiled meats (lung, breast cancer), slow acetylators exposed to more of the compound

Answer 33

aromatic amines

Question 34

chemically inert but still toxic, exposure via inhalation (shipbuilding, demolition, home remodeling, heavy exposure for prolonged period, fibers will cause fibrosis, macrophages unable to phagocytose fibers, macrophage cell membrane is damaged, immunological mechanism, lung cancer or bronchial carcinoma

Answer 34

asbestos

Question 35

only associates with asbestos exposure, develops in non-occupationally exposed people, long latent period (toxicity takes a long time to develop), often fatal, non genotoxic mechanism

Answer 35

mesothelioma

Question 36

limits levels of toxic substances in the workplace, setting exposure levels based on human epidemiological data and animal toxicity studies, OSHA, ACGIH, NIOSH

Answer 36

legislation controls exposure to chemicals

Question 37

maximum level of exposure, calculated on the basis of exposure over a normal working day from a knowledge of the toxicity of the compound in experimental animals, a margin of safety is always included

Answer 37

threshold limit, TLV

Question 38

intentionally added to foods, wide range of chemical types, beneficial (for example preservatives to reduce the chance of bacterial and fungal contamination affecting food, colors to improve the attractiveness of food), tested in animals with large doses for a short period of time, humans have small doses over a lifetime so testing is not always predictive

Answer 38

food additives

Question 39

widely used orange dye, beverages, foods, pharmaceuticals, intolerance manifests as urticaria/hives, cross-reactivity with other colors, salicylates, hyperkinesia in children (controversial, not sure if this actually causes hyperkinesia), sensitivity to this involves this immune system, this is reduced by gut flora to potentially immunogenic and carcinogenic metabolites, banned in some European countries, US FDA requires the presence of this be declared

Answer 39

tartrazine (yellow #5)

Question 40

can be at least as toxic as artificial colors, beta carotene, curcumin, annatto (shown to cause urticaria/hives)

Answer 40

natural food colors

Question 41

artificial sweetener used since the 19th century, low acute toxicity, not metabolized, several studies of toxicity were inconclusive, Canadian study found that this produced bladder tumors in rats, suspended used in April 1977 under the Delaney Clause of the Food, Drug, and Cosmetic Act, public outcry because this was the only artificial sweetener available for diabetics and obese people, Nov 1977 label required, epidemiological studies found no incidence of bladder tumors in humans (species difference in toxicokinetics), 1991 ban repealed, 1996 label removed

Answer 41

saccharin

Question 42

bacterial toxins (botulinum), fungal toxins (aflatoxin), toxic degradation products from cooking, accidental additions to food (Epping incident)

Answer 42

food contaminants

Question 43

mycotoxins produced by the mold Aspergillus flavus, grows typically on grain and peanuts in hot humid climates, B1 type causes liver cancer in humans and livestock, 1 ppb in the diet causes liver tumors, occurs in Iowa, found in "natural" peanut butter (didn't have enough preservatives to keep it safe), bioactivated to the reactive epoxide, guanine adduct excreted in urine is used as a biomarker of exposure, formation of DNA adduct in DNA from livers of mice that consumed contaminated food with this, AFB1-N7-GUA is the DNA adduct, dose correlates with number of liver tumors

Answer 43

aflatoxins

Question 44

1930 - reports of people suffering from cramps and sore calf muscles followed by paralysis or foot drop, 50,000 people permanently paralyzed, drinking adulterated versions of Jamaica Ginger (Ginger Jake, alcoholic pharmaceutical preparation)k, paralysis known as Jake Leg, contaminated with TCP (used as a plasticizer, solvent, used as adulterant for Jamaica Ginger, neurotoxin (structure similar to organophosphate herbicides, inhibits acetylcholinesterase leading to a buildup of acetylcholine in synapses

Answer 44

Ginger Jake affair

Question 45

symptoms of pulmonary infiltrate on chest X-ray, headache, asthenia (general weakness), scalp itchiness, slight fever, initially diagnosed as atypical pneumonia, 20,000 people ended up being affected and over 300 dead in first 10 months, rapeseed oil denatured with 2% aniline for industrial use, refined and sold as olive oil but some people showed symptoms that did not take the contaminated oil, rapeseed oil is also not toxic to rats, organophosphate pesticides, US military experiment?

Answer 45

toxic oil syndrome

Question 46

occurred in US in 1989, high WBC (like an infection but not an infection), severe muscle pain, consumption of tainted L-tryptophan (L-Trp), L-Trp banned from sale in the US in 1991, PAA was a contaminant of the L-Trp batches, symptoms of this resembled those seen for the Spanish toxic oil syndrome, causal toxic agent is now thought to be PAP derived from aniline, quinoneimine metabolites bind to proteins

Answer 46

eosinophilia-myalgia syndrome (EMS)

Question 47

designed to target a particular biological, metabolic, or other feature of the species (biological - warfarin, metabolic - malathion, paraquat), features rarely unique to target species, toxic to humans (acute poisonings or chronic exposure, non-target organisms like birds and honeybees), most humans have detectable levels of these

Answer 47

pesticides

Question 48

- 1945 - control of malarial mosquitoes, extremely successful, highly potent against the insect nervous system (neurotoxic effect), relatively non-toxic to humans (pretty selective), probably targets motor nerve fibers and motor cortex - this chemical and its metabolites are chemically stable, highly water insoluble, and soluble in body fat so metabolism and excretion are very slow (chemical and metabolites will accumulate) - levels of this chemical increase at each higher trophic level of the food chain (biomagnification), decreases egg shell thickness, toxic to rats, fear of hormonal disruption in humans - banned in 1972 but still ubiquitous in animals and in environment, once attached to soil this chemical and byproducts can persist for as long as 15 years - in humans and other animals most of this chemical is found in body fat with a half life of about 6 years, a reduction in fat results in increased levels in the blood, accumulates in the breast milk leading to higher exposure in infants

Answer 48

DDT

Question 49

insecticides based on nicotine, imidacloprid most widely used insecticide in the world, high levels bind to and overstimulate insect nicotinic ACh receptor causing paralysis and death, honey bee colony collapse disorder (navigation and immunotoxicity), unlike imidacloprid the desnitro metabolite binds to the mammalian nicotinic receptor, toxic to insect-eating birds, restricted use in Europe

Answer 49

neonicotinoids (neonics)

Question 50

high mammalian toxicity, several mass human poisonings, organophosphorus insecticide

Answer 50

parathion

Question 51

organophosphorus insecticide, more selective than parathion

Answer 51

malathion

Question 52

these compounds bind to acetylcholinesterase enzyme preventing the attachment of acetylcholine, inhibition leads to build up of acetylcholine resulting in excessive stimulation of the nerve, selective toxicity is only efficient at low exposure levels, at high levels humans suffer from excessive cholinergic stimulation (headaches, nightmares, salivation, diarrhea, bronchoconstriction, death due to neuromuscular paralysis and central depression

Answer 52

organophosphorus insecticides