Toxicology Test 4

Front 1

What are various environmental and lifestyle factors causing human cancers?

Back 1

-tobacco products (smoking, chewing tobacco, snuff)
-diet (natural ingredients,, contaminated food, preservatives, caloric restriction, how we cook it)
-occurpation (dye industry, creosote, and asbestos)
-reproductive and sexual behavior (viral infection of cervix, aids associated tumors)
-geophysical (UV radiation, natural radiation, natural metals, asbestos)
-medicines (anticancer drugs)
-alcohol (increase drug absorption and metabolism)

Front 2

What is the pathway of multi-step carcinogenesis?

Back 2

-normal epithelium--> hyperplasia--> metaplasia--> dysplasia-->carinoma in situ (CIS)--> invasive cancer

Front 3

What is the carcinogenic process?

Back 3

-initiation (generation of cells with DNA mutation)
-promotion (expansion of mutated cell population)
-progression (continued mutation and expansion)

Front 4

What is the intiation step of carcinogenesis?

Back 4

-A rapid and essentially irreversible alteration of cell genome by carcinogenic intiators
-most initiators are either electrophile or metabolically electrophile and able to bind to DNA to induce permanent DNA sequence change
-they are mutagens

Front 5

What is the promotion step of carcinogenesis?

Back 5

-expansion of initiated cell population by altering singal transduction, immune function etc
-considereed reversible, non-genetic
-promoters themselves may not be carcinogenic and usually are not electrophiles, but they are able to increase the number of tumors or decrease the latency period.

Front 6

What is the progression step of carcinogenesis?

Back 6

-continued mutation and expansion leading to an increased capability to survive, grow, and metastasize

Front 7

What is the metabolism pathway of polycyclic aromatic hydrocarbons (PAHs)?

Back 7

-benzo[a]pyrene (procarcinogen) gets metabolized by CYP1A1 with NADPH and oxygen
-then with water, then with same cofactors and enzymes as step 1
-to make benzo[a]pyrenediolepoxide (BPDE) (ultimate carcinogen)

Front 8

What is the mechanism of DNA adduct formation?

Back 8

-benzo[a]pyrenediolepoxide binds covalently with deoxyribose irrevesibly

Front 9

What is the mechanism of aflatoxin and liver carcinogenesis?

Back 9

-aflatoxin B1 gets metabolized by cytochrome p-450 to aflatoxin B1-8,9-oxide
-goes through epoxide hydrase or glutathione S-transferase for detoxification
-or covalently binds to DNA if no detox available

Front 10

What is the mechanism of heterocyclic amines and colon carcinogenesis?

Back 10

-PhIP with exocyclic amine gets metabolized by CYP1A2 to N-OH-PhIP
-it then binds covalently to deoxyguanosine irreversibly

Front 11

What are UV-induced DNA adduct formation?

Back 11

-forms pyrimidine dimers (major photoproduct) and pyrimidine pyrimidinone photoproduct

Front 12

What are specific promotors in cancer generation?

Back 12

-12-O-tetradeecanoylphorbol-13-acetate (TPA) or phorbol-12-myristate-13-acetate (PMA)
- isolated from croton plants, potent promotor in tumorigenesis and strong protein kinase C activator
-bile acids for human colon cancers
-estrogen for human breast cancers
-chronic inflammation for majority human cancers

Front 13

What are oncogenes?

Back 13

-function as growth factors, receptors, signal transducers, transcription factors, and cell cycle components
-similar to protooncogenes, but lack of regulation

Front 14

What are tumor suppressor genes?

Back 14

-function as cell proliferation inhibitors
-involved as cell proliferation inhibitors
-involved in cell cycle checking apoptosis pathways

Front 15

What is the association between inflammation and cancer?

Back 15

-many inflammatory condituons predispose to cancer and arise at chronic sites
-functional polymorphisms of cytokine genes are associateed with cancer susceptibility and severity
-distinct populations of inflammatory cells are detected in many cancers
-chemokines are detected in many cancers, they are associated with inflammatory infiltrate and cell motility
-deletion of cytokines and chemokines can protect against carcinogens

Front 16

What is the mechanism of inflammation as a tumor promotor?

Back 16

-various types of inflammatory stimuli occur
-causes recruitment of inflammator cells, endothelial cells and stimulation of TNF-alpha transmitter
-binds to TNF receptor
-caused proliferation of tumor cells, more einflammation, or apoptosis based on chemical transmission
-stimulated prostraglandin H2 pathway for loss of contact inhibition, achorage-independent proliferation, loss of E-cadherin, and increased proliferation with formation of prostaglandin E2

Front 17

What is the length of multi-step carcinogenesis with colon cancer?

Back 17

-takes 5-20 years to bcome an adenoma
-then 5-15 years to bcome cancer

Front 18

What is the length of multi-step carcinogenesis with head and neck cancer?

Back 18

-with tobacco use and 4-10 years to become dysplastic oral leukemia
-then 6-8 years to become cancer

Front 19

What is the length of multi-step carcinogenesis with cervical cancer?

Back 19

-with CIN 1 and 9-13 years to become CIN-3/CIS
-then 10-20 years to bcome cancer

Front 20

What is the length of multi-step carcinogenesis with lung cancer?

Back 20

-with smokers, 20-40 pack years to become cancer

Front 21

What is the length of multi-step carcinogenesis with breast cancer?

Back 21

-with atypical hyperplasia, becomes ductal carcinoma in situ
-then 6-10 years to become cancer

Front 22

What is the length of multi-step carcinogenesis with prostate cancer?

Back 22

-takes 20 years to become prostatic intraepithelial neoplasia
-after at least 10 years, becomes latent cancer
-then 3-15 years later, cancer

Front 23

What is the pathway of carcinogen activity to cancer growth?

Back 23

-exposure leads to metabolism (which also can get excreted
-causes genotoxic mechanisms (DNA adducts, and chromosome breakage, fusion, deletion, mis-agregation, and non-disjunction) which can cause genomic damage
-or non-gentoxic mechanisms (inflammation, immunosuppression, reactive oxygen species, receptor activation, and epigenetic silencing) which leads to altereed signal transduction
-both lead to hypermutability, genomic instability, loss of proliferation control, and resistance to apoptosis
-which lead to cancer

Front 24

What are the possible causes of prostate inflammation?

Back 24

-infectious agents (viruses and bacteria)
-hormonal changes (estradiol-->estrogen)
-physical trauma (corpora amylacea)
-urine reflux (uric acid build up)
-dietary habits (charred meat and PhIP)

Front 25

What is prostate neoplasia progression?

Back 25

-normal-->proliferative inflammatoiry atrophy (PIA)--> low-grade PIN--> high-grade PIN--> invasive carcinoma

Front 26

What is mutagenesis?

Back 26

-the generation of genetic mutation

Front 27

What is a mutation?

Back 27

– Hereditary changes in the DNA molecules due to
either spontaneous DNA replication errors or
mutagen-induced chemical alterations.

Front 28

What are mutagens?

Back 28

– Chemical and physical agents (either endogenous or
exogeneous) that increase the frequency of
mutations.

Front 29

What are consequences of mutations?

Back 29

– No major changes in phenotype
– Could be harmful to the individual organisms, leading
to fertility disorders, embryonic and prenatal death,
malformations, hereditary diseases and cancers.
– Offering advantages in survival

Front 30

What are types of DNA damage?

Back 30

• Base alterations
– Point mutation by chemical modification
(alkylation, deamination, oxidation)
– insertion/deletion
– cross-linking (intrastrand, interstrand)
• Strand breaks
– single strand vs. double strand
• Chromosomal rearrangements (translocation)

Front 31

What is point mutation?

Back 31

• Depurination
• Depyrimidination
• Deamination
-Oxidation
-alkylation
-DNA adducts

Front 32

What is depurination?

Back 32

-loss of
purine bases

Front 33

What is depyrimidination?

Back 33

-loss
of pyrimidine bases

Front 34

What i deanimation? What does it lead to?

Back 34

-loss of amine groups
-Leading to transition mutation: one pyrimidine replaced by another,
e.g.C to T

Front 35

What does oxidation lead to?

Back 35

-Leading to transversion mutation: one pyrimidine replaced by a purine
(or the opposite), e.g. G:C to G:A

Front 36

What is alkylation?

Back 36

-attaching alkyl groups covalently to
the DNA base

Front 37

What is DNA intrastrand cross-linking?

Back 37

-cross-linking of 2 adjacent pyrimidine or purine bases
-caused by UV rays

Front 38

What is DNA intertran cross-linking?

Back 38

-cross-linkign of a pyrimidine and purine that are diagonal to each other
-caused by nitrogen musturd

Front 39

What is DNA repair?

Back 39

• Widespread in nature
– similar in prokaryotes and eukaryotes
• Critical to survival of cells/organisms
– mutations (spontaneous and induced)
– errors in DNA replication
• Direct vs. excision repair

Front 40

What is DNA repair by DNA photolyase?

Back 40

-separates intrastrand cross-linking with a blue light

Front 41

What is DNA repair by DNA methyltransferase?

Back 41

-MGMT dealkylates DNA

Front 42

What is DNA repair by nucleotide excision repair?

Back 42

-DNA danamge rcognized by several proteins
-TFIIH complex binds to damaged DNA section
-DNA helix is unwounds by helicase
-endonuclease cuts segment of DNA
-DNA polymerase fills in gap
-DNA ligase seals strand

Front 43

What is DNA repair by base excision repair?

Back 43

-DNA glycolyase removes damaged base
-AP endonuclease breaks strand and removes
deoxyribose phosphate group
-DNA polymerase replaces missign nucleotide
-DNA ligase seals

Front 44

What is DNA repair by mismatch repair?

Back 44

-complex of proteins binds to mismatch pair
-Exonuclease activity removes 100-1000 nucleotides
from strand with mismatched base
-DNA polymerase fills in gap using other strand as a
template
-DNA ligase seals it

Front 45

What is teratogenesis?

Back 45

– Production of developmental malformations. Greek terato
means a monster.
– Teratology: the study of malformations.

Front 46

How are genetic factors a general principle of teratology?

Back 46

– Susceptibility to teratogens depends on the genotype
of the organisms
– Due to differences in the distribution, metabolism,
transplacental passage of teratogens, tolerance to
teratogens… in different organisms.
– E.g. humans, monkeys and certain strains of rabbit and
rat are very sensitive to Thalidomide whereas most
other mammals are quite resistant

Front 47

How are critical periods a general principle of teratology?

Back 47

-The type of malformation is determined by the developmental
stage of the fetus at the time of exposure

Front 48

How are intiating mechanisms a general principle of teratology?

Back 48

– Different initiating mechanisms often lead to similar
abnormalities

Front 49

What are various intiatial changes for defect pathway of teratology?

Back 49

-Gene mutation
-Chromosomal abnormality
-Mitotic interference
-Lack of nutrients
-Lack of key proteins
-Enzyme inhibition
-Membrane abnormality
-Osmolar imbalance
-Inhibition of
angiogenesis

Front 50

What are examplees of pathogenesis?

Back 50

Excessive cell death
Reduced cell death
Reduced biosynthesis
Impeded cell migration
Mechanic tissue disruption

Front 51

What are consequences of deformed developement as a general princicplee of teratology?

Back 51

– Death
• Damages during the implantation period, rarely occurs.
• Often requires high doses.
• Embryotoxic agents are not teratogens.
– Malformation
• Damages during the organogenesis period.
– Growth retardation
• Damages during the fetal period.
– Functional disorder
• Damages during the fetal period

Front 52

How is access to the embryo and fetus a general principle of teratogenesis?

Back 52

– Only some physical forces (e.g. radiation, ultrasound) can
penetrate directly through the maternal tissue.
– Chemicals and their metabolites have to go through embryo fluid
or placental blood barrier.
– Generally, most unbound lipophilic compound with MW less than
600 can pass through placental blood barrier through passive
diffusion.

Front 53

How is the dose-response relationship a general principle of teratology?

Back 53

-higher doses lead to more damage

Front 54

What is human teratogenesis?

Back 54

• About 3-7% of human babies are born with malformations serious
enough to require treatment.
• In most cases, the causes for these malformations are not known.

Front 55

What is thalidomide and how does it affect teratogenesis?

Back 55

6
• Synthesized in Germany in 1953 as an antibiotics
• No antibiotic or any other obvious effects found
• 1955: free distribution to doctors as sedative
without any experimental evidence
• 1956: A first thalidomide-induced birth defect
Thalidomide
• 1957: Thalidomide was sold in Germany and more than 40 other countries as
the first choice for pregnant women with morning sickness.
• 1960: Thalidomide was submitted for FDA approval six times, which were all
rejected by FDA’s newest reviewer Frances Kelsey who was in the agency for
only one month.
• 1959-1961: More and more birth defects were reported worldwide.
• Nov 1961: German authority removed thalidomide from the market.
• 2006: FDA approval of thalidomide for multiple myeloma.
Thalidomide
• One of the most potent human teratogens known
• One tablet taken at any time from the third to the
seventh week of pregnancy is effective in producing a
teratogenic effect.
• Thalidomide administration beyond embryonic period
does not cause malformations.
• The most pronounced defect is the shortening or
missing of limbs.
• Very species specific
– Humans: as low as 0.5-1.0 mg/kg during the embryonic period
– Most mouse or rat strains: more than 4000 mg/kg
• Teratogenic mechanism is still controversial.
– Intercalating into DNA G-C rich region
– Antiangiogenesis

Front 56

How does alcohol cause teratogenesis?

Back 56

-– Fetal alcohol syndrome (FAS): (1) prenatal or postnatal growth
retardation; (2) characteristic facial anomalies (microcephaly,
small eye opening, thinned upper lip); (3) CNS dysfunction (mental
retardation, developmental delays).
– Teratogenic mechanism is still not clear. Hypoxia has been
suggested to be involved in it.

Front 57

What are the untis of atomic energy?

Back 57

Units:
Joule = kg m2/s2 (SI unit)
Electron Volt = kinetic energy gained by an electron accelerated through
1Volt. 1 eV = 1.6 x 10-19 J

Front 58

What are energy calculations of atomic energy?

Back 58

E = hν
h = Plank’s constant
ν = photon frequency
h = 6.626x10-34 J s = 4.135 x 10-15 eV s

Front 59

What is rest energy of a mass?

Back 59

E = mc2

Front 60

What is binding energy?

Back 60

-The energy required to remove an electron from the atom
-increases with proximity
to the nucleus.
-It also
increases with increasing number of protons (Z) in the nucleus.

Front 61

What is radiation?

Back 61

energy transmitted by electromagnetive wave or particles
through medium

Front 62

What is electromagnetic radiation?

Back 62

-includes the normal spectum of light
-microwaves
-x-rays
-gamma rays
-etc.

Front 63

What is non-electromagnetic radiation or particle radiation?

Back 63

Alpha radiation: helium nuclei (2 protons and 2 neutrons), short traveling
path due to heavy weight and charges.
• Beta radiation: electrons or positrons, longer path than Alpha, often
followed by Gamma ray.
• Neutron radiation: neutrons, longer than Beta, often inducing Gamma ray.

Front 64

What is ultraviolet radiation as non-ionizing radiation? sources? Classification? adverse effects? biological targets?

Back 64

– natural (sunlight), artificial (tanning beds, etc.)
– UV-A (320-400 nm), UV-B (290-320 nm), UV-C (100-
290 nm)
-– Eyes (cataract)
– Skin (sunburn, premature aging, cancer)
-T-T photodimers → DNA mutations →cancer
– inflammation → sunburn

Front 65

What are micrwaves as non-ionizing radiation? sources? adverse effects? biological targets?

Back 65

– Natural, artificial (microwave ovens, radar guns,
TV/radio broadcasts, etc.)
– Thermal effects (major)
– Non-thermal (not significant)– -thermal injury due to tissue heating
– unknown for non-thermal injury

Front 66

What are electomagnetic fields as non-ionizing radiation? sources? adverse effects? biological targets?

Back 66

– natural (Earth), artificial (cell phones, power
lines, electrical appliances, etc.)
– reproductive effects (teratogenesis?,
spontaneous abortions?, etc.)
– other (cancer?)
– ion fluxes
– ↓ melatonin synthesis
– immunosuppression
– ↓ RNA/protein synthesis
– altered metabolism

Front 67

How are x-ray or gamma rays ionized electromagentic radiation? sources? discovery?

Back 67

– Natural (80%): cosmic rays, isotopes…
– artificial (20%): medical uses, occupational or
accidental exposures.
– 1895 German physicist Roentgen WK discovered X-ray

Front 68

What is the interaction of x-ray with matter?

Back 68

Probability is low and decreases significantly with increasing energy

Front 69

What is Reileigh scattering as interaction of x-rays with matter?

Back 69

-scattered photon has same wavelength as incomign photon

Front 70

What is compton scattering as an intereaction of x-rays with matter?

Back 70

-scattered photon has a higher wavelength than the incoming photon

Front 71

What is the photoelectric effect as an interaction of x-rays with matter?

Back 71

-A photon of energy hν is absorbed and an electron of kinetic energy
EKE = hν - Eb is ejected.
-As the energy of the electron decreases below the binding energy of a shell, then the contribution to the overall cross section drops to zero from that
shell.

Front 72

What is pair production as an intereaction of x-rays with matter?

Back 72

-incident photon produces a negatron an a positron (matter and anti-matter) as matter is scattered

Front 73

What are basic cellular mechanisms of radiation damage?

Back 73

-radiation forms free radicals for indirect damage or damages DNA directly (fast)
-which is then either repaired or causes a mutation which leads to a biological response (slow)

Front 74

What are basic DNA mechanisms of radiation damage?

Back 74

-base deletion
-base substituition
-hydrogen bond disruption
-single strand or double strand break

Front 75

What are short term effects of radiation?

Back 75

• Generally associated with acute exposure
• Clinical symptoms seen within hours to weeks
• Cell cycle determines tissue sensitivity
– Proportional to the number of cells in growth phase
– Most sensitive: skin, GI tract, bone marrow
– Least sensitive: muscle, CNS
• Acute radiation effects
– Hematopoietic syndrome due to the destruction of
bone marrow stem cells
– Gastrointestinal syndrome due to the destruction
of epithelial cells in the GI tract
– CNS syndrome due to the destruction of neurons

Front 76

What are the 3 kinds of acute radiation death?

Back 76

1) cerebrovascular syndrome – 24-48 hrs, 100Gy
- neurologic and cardiovascular breakdown
2) gastrointestinal syndrome – days later, 5-12 Gy
- diarrhea and destruction of gastrointestinal mucosa
3) bone marrow death (hematopoietic syndrome)
– weeks later, 2.5 – 5 Gy
- destruction of blood forming organs

Front 77

What are deterministic long term effects of radiation?

Back 77

– above a threshold dose the effect increases linearly
with dose.
- results from direct cell death effects
(eg. radiation induced cataracts)

Front 78

What are probabilistic long-term effects of radiation?

Back 78

– change in cell occurs, but does not induce death
- severity of condition is not increased with dose, but
probability of occurrence increases.
- assumption of no threshold dose
(eg. Cancer, genetic mutation).