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TOX 2000 Study Guide - Final Guide: Biotransformation, Placenta, Phenobarbital


Department
Toxicology
Course Code
TOX 2000
Professor
Aaron Witham
Study Guide
Final

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Biomedical toxicology final review
Toxicant any substance that causes an adverse biological effect, toxic response
Toxicosis chemically caused disease
Drug- pharmacological effect (use toxic effect for benefit ex. chemotherapy)
Human made chemicals perceived to be more dangerous but have lots of testing, well researched,
many trials compared to natural products perceived to be safe
Endogenous substances normal components in body required or not
Xenobiotics chemicals not normally present in the body (exogenous)
Toxicology principle #1-all substances natural or man-made our poisons (toxicants), the dose
makes the poison
Toxicology principle #2 every toxicant has a threshold dose dose where toxicosis occurs and
below which no adverse effect occurs depends on response measured (acute vs. chronic),
sensitivity of measurement (how low can we detect the level), number of individuals studied
(more individuals greater accuracy)
Toxicology principle #3 –everyone isn’t affected the same way due to biological variability ex.
copper needed in enzymes has optimal range and below which deficiency and death, above
which toxicosis and death with threshold on either level, biological variability depends on
genetics, might have different form of enzyme, may be able to excrete copper more readily
Toxicology principle #4 dose response increase with increased dose (a graded response) as
dose increases a) in individuals: effected increase, symptoms more severe, death; b) in a
population number affected increases
Dose response group exceptions are immunological reactions things system can handle
Hormesis stimulates biological systems at low doses, inhibit them high doses, non-nutritional
substances have beneficial effects at low doses, implications of low dose extrapolation ex.
radiation, alcohol, fluorine
Measures of toxicity: toxicity amount of chemical required to cause adverse effect under
specific conditions, expressed as dosage in mg toxicant/kg body weight (equalizes size
variability)
Toxic endpoints used as predictors a) death (lethal dosage) b) adverse biological effecttoxic
dose “effect” most sensitive effect preferred

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Determine safety: nontoxic endpoints use to determine safe levels a) LOAEL b) NOAEL
safety margin magnitude of the difference between the dose required to produce a maximum
therapeutic effect and that which produces a toxic effect; don’t use just LOAEL, NOAEL
because of statistical uncertainty
Use of the chemical interconnection with nature must protect all living organisms, data to
regulate toxins, better recognition of ethical responsibilities, measures to regulate production, use
and disposal; Chemical use: risk/benefit decision
Chemical production Human exposure risk disposal
Environmental exposure risk <
Benefit determination subjective to change between people and society
Risk probability of toxicosis following exposure to hazardous substance determined by 1.
Potential exposure Regulatory, 2. Inherent toxicity experimental determination
Exposure and toxicosis dose required to cause toxicity may vary within individuals and
between individuals biological variability children vs. adults what determines if toxicosis
occursToxicokinetic parametersconcentration of chemical at body target (site of action)
Pb exposure cognitive defects, low RBC count and anemia, visual toxicity, anticipated human
carcinogen, children are more at risk- absorb more than adults, CNS still developing (few
defense mechanisms), exposure through skin, risks with inner city children poor nutrition not
enough Ca and Fe which compete with Pb for binding, living near major roadways and freeways
(Pb in gas), Pb pipes (older piping)
lupinosis- anagyrine- plant lupine contains anagyrine- lipophilic, stable naturally occurring
chemical teratogen, belongs to quinolizidine alkaloid group, affinity for nicotinic receptors (para-
sympathetic nervous system), acute signs- lethargy, frequent urination, respiratory paralysis,
deformities, thought to be caused by poor tendon muscle and ligament tension from lack of
movement of fetus in womb, stimulation slowed breathing and increased blood flow to GI
because lipophilic passing from animals to humans (milk), anagyrine built up in mothers and
passed on to fetus; Investigation- human mothers were observed to consume goats milk and
cheese lupin goat milk mother fetus
Biological membranes- barriers to movement, compartmentalization (what to keep what to get
rid of); bimolecular layer of phospholipids, primarily phophotidylcholine, and
phosphotidylethanolamine; contains structural and functional proteins, signalling and cell
adhesion molecules

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Principles of lipid/water solubility of chemicals in body, fluid, and tissues- body compartments
have different pH’s, many toxicants are weak acids and bases, chemical movement related to
ionization or lack there of
Membrane barriers- organs ie. skin; tissue ie. epithelium; cells ie. cell membrane; cell
organelles ie. nucleus; extracellular barriers- intercellular junctions, tight junctions, basement
membrane (anchors epithelium)
Barriers control fluid/chemical movement, cells form tissue membranes, kidney has greatest pore
size (filter), then most cells; brain has intercellular junctions (extra filtration), endothelium has
tight junctions that hinder movement (size varies controlled by hormone factors)
Can cross the membranes: lipid soluble chemicals ie. DDT, steroids, PAHs (without energy
requirement), small water soluble molecules through aqueous channels and pores, large water
soluble molecules require special transport mechanisms
Passive diffusion- lipid- transcellular difference, water soluble-pores, para-cellular rate depends
on [ ] gradient (high to low), follow Fick’s law, surface area (larger area more diffusion),
molecular size (smaller diffuse better), transport mechanisms- chemicals use endogenous
substance carriers (Pb2+/Ca2+)- membrane protein carrier, structure specific, saturation and
competition; Types: facilitated diffusion- moved with gradient, no energy required, active
transport- energy dependent low high [ ] (paraquat in lungs), pinocytosis- least significant to
absorption; filtration- energy dependent- water soluble chemical passing through pores and
channels under hydrostatic pressure eg. Pressure of blood flow to a filter, small enough and size
dependent; small molecules bulk flow, where bowel, kidney, capillaries
Membrane damage- most chemicals are irritants that cause local damage to membranes/barriers
via chemically altering membrane composition (hydrolysis, oxidation, reduction; physical
damage or elicit immune response- inflammatory response increases blood flow, alters
membrane) permeability responsible parties: cellular signaling proteins, WBC and immune cell
release compounds that cause physical damage
Membrane compromisedincreased absorption, pH of body compartment (weak acid/base)
effects ionization, lipophilicity/hydrophilicity influencing chemical movement
Xenobiotics- highly lipophilic, organic (more easily absorbed), act as weak acid/base, shift
reactivity/solubility based on pH, stable, non-reactive (survive harsh conditions in gut),
dangerous to human and environment- Equilibrium; partition coefficient measures lipid
solubility increase ionization, increase water solubility, decrease ability to cross membrane
Acidic toxins: Body compartment: increase pH, increase ionization of chemical; decrease pH,
decrease ionization
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