MODULE 3 Flashcards
developmental toxicology
adverse effects of xenobiotics that occur conception to puberty
teratogenesis
adverse effects of xenobiotics that occur between conception and birth
% factors
Known genetic factors 25%:
Known environmental factors 10-15%:
Unknown multifactorial cause 60%:
early development
lower sensitivity to teratogen exposure
organogenesis
Highly sensitive developmental stage, Day 21-56 in humans
fetal period
histogenesis (early organs differentiation) and functional maturation of organs and tissues, significant growth occurs during fetal period and reduced growth is common effect
sexual differentiation
bipotential gonads in early embryonic development
mullerian duct –> female
wolfian duct–> males
neoplasia
new growth
neoplasm
the lesion resulting from the neoplasia
benign
lesions characterized by expansive growth
malignant
lesions demonstrating invasive growth
tumor
lesion characterized by swelling or increase in size
cancer
malignant neoplasm
carincogen
a physical or chemical agent that cause or induce neoplasia
genotoxic
carcinogens that interact with DNA resulting in mutation
covalent binding to DNA
Nongenotoxic
carcinogens that modify gene expression but do not damage DNA
cocarcinogens
increase the effect of carcinogen. Ex. ethanol induces CYP2E1
solid state carcinogens
Group 1 carcinogens
ex. abestos, silica
complete carcinogens
xenobiotic mixtures that consist of chemicals that are involved in all 3 stages of cancer
ex. tobacco smoke, ethanol (synergistic effect together)
ultimate carcinogens
epoxides
groups of carcinogens
Group 1: agent is carcinogenic to humans
Group 2A: agent is probably carcinogenic to humans
Group 2B: agent is possibly carcinogenic to humans
Group 3: agent is not classifiable as to carcinogencity to humans
Group 4: agent is probably not carcinogenic to humans
Step 1: initiation
if cell with altered DNA undergoes mitosis, the mutation is retained and the cell is intiated
Step 2: promotion
intiated tumor cell –> proliferate in presence of promoters
reversible
promotors: toxicants, hormones, calories, ethanol
Step 3: progression
conversion from benign to malignant tumor
irreversible
proto-oncogenes
normally code for proteins associated with cell proliferation, mutation of proto-oncogene results in permanent activation and/or over-expression of gene products
neoplasia occurs
when proto-onogenes are converted to onxogenes
Proto-oncogenes and tumor suppressor genes
implicated in large number of human cancers
P53 tumor suppressor gene: mutated in about half of all humans’ cancers
genotoxic characteristics
Mutagenic
Can be complete carcinogens
Tumorigencity is dose responsive
No theoretical threshold
nongenotoxic characterisitics
Nonmutagenic
Threshold, reversible
Tumorigencity is dose responsive
May function at tumor promotion stage
No direct DNA damage
Species, strain tissue specificity
Why is the liver susceptible to toxicity arising from xenobiotic exposure
1st pass effect
enterohepatic cycling
bioactivation
xenobiotic binding proteins
increased CYP enzymes (qualitative and quantitive)
high blood flow
altered energy homeostasis
active transport
Steatosis
reversible effect
ex. ethanol
necrosis
focal or massive
ex. acetaminophen
chloestasis
yellowish tinge in skin and eyes
ex. ethanol, certain metals, steroids
cirrhosis
extensive fibrosis throughout the liver
ex. chronic ethanol consumption
major functions of kidney
excretion of metabolic wastes
regulation of extracellular fluid volume
electrolyte homeostasis
acid-base balance
blood pressure regulation
metabolizes vitamin D to active form
Nephorotoxicants
Proximal convoluted tubule
sources of lung damage
Oxidative stress
Gases and vapors
Particles and aerosols (size is most important)
acute effects (lung)
can be reversible or irreversible
Airway reactivity: bronchial smooth muscle is target cell type
Pulmonary edema: fluid accumulation in lung, reduces 02/Co2 exchange
chronic effects (lung)
usually irreversible
Fibrosis: lungs get smaller and stiffer
Emphysema: lungs get larger and more stretchy, due to breakdown of lung elastin
Asthma:
Neoplasia: lung cancer (tobacco smoke, metallic ducts and fumes, asbestos, radon gas)
dose-response relationships
Compare drug potencies and efficacies and to determine drug safety
To determine toxicity thresholds of xenobiotics
Graded dose-response relationships
Show responses of individuals and are continuous responses
Y is usually percent response
Provides information about the intensity of response over a dose range
Compare potency and efficacy
Quantal dose-response relationships
Show population responses and are all or none responses
Y is usually percent of individuals responding
Provides information about the number of individuals exhibiting a specified effect over a dose range
Used mainly to determine xenobiotic safety
LD50
LD50: median lethal dose of dose causing death in 50% of population
potency
the further left the more potent
efficacy
the higher up the more efficient
two main principles of animal toxicity tests
are applicable to humans
need to use higher doses to ensure that the response will occur frequently enough to be detected
categories of toxicity tests
Acute lethality: 96 hour LD50
Skin and eye irritations tests:
Subacute toxicity tests: 14 day
Subchronic toxicity tests: Usually 90 days, two species, determine toxicity threshold
Chronic toxicity tests: 6 months to 2 years duration, Mainly used for carcinogenicity testing
mutagenicity test
Ames Test
Somatic cell mutation: major concern is carcinogenesis
Germinal cell mutation: major concern is DNA damage
biomarker
Measurable molecular, cellular, histological, physiological or
behavioural responses that provide evidence of either
exposure to, or effects of, toxicants
biomarker examples
biomarkers of cancer risk (prostate-specific antigen
(PSA), breast cancer susceptibility protein (BRCA)
biomarkers of organ damage (ALT, AST, GGT, etc)
serum cholinesterase activity, CYP enzyme induction,
vitellogenin in male oviparous (yolk-bearing) vertebrates
What makes a good biomarker
Sensitive
Specific to a specific class of toxicants
Easy to measure
Reproducible and reliable
Inexpensive
Non-invasive
Mechanistically-based
Time for response to occur following exposure
Permanence of response
Applicable to field studies; ideally validated in field
bioindicator species
sentinel species
bioindicator species are also “early warning systems” for
human health risk
What makes a good bioindicator species
Size: sufficiently large to allow adequate tissue/blood samples
Longevity: sufficiently long-lived to provide data over prolonged period and be able to accumulate toxicants
Availability: the organism should be abundant
Indigenous species are preferred since they are natural inhabitants of the area of concern
Sensitivity
Residency: ideally should be a year-round resident
Distribution: A broad geographical and ecological distribution is ideal so that comparisons can be made amongst regions
Type of contamination: aquatic vs. terrestrial vs. atmospheric
Safety factor
100 (10x10)
ADI
acceptable daily intake
an estimate of the amount of a chemical that can be ingested daily over a lifetime without appreciable health risk
food additives, pesticides and drugs
TDI
tolerable daily intake
xenobiotics with no reason to be in food
NOAEL
No-Observed-Adverse-Effect-Levels
LOAEL
lowest observed adverse effect level
Risk assessment
hazard identification
dose-response assessment
exposure assessment
risk characterization
Risk
the probability of an adverse outcome
