Definition of toxicology
the study of the adverse effects of xenobiotics on biological and ecological systems
Definition of xenobiotics
any substance that is foreign to a biological system
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Definition of toxicology
the study of the adverse effects of xenobiotics on biological and ecological systems
Definition of xenobiotics
any substance that is foreign to a biological system
definition of toxin
substance produced by an organism that can cause harmful effects, like snake venom
definition of toxicant
man-made substance that can cause harmful effects, like DDT
toxic substance can be classified based on why they exist
chemical warfare agents, pesticides, household poisons, drugs, etc.
Toxicokinetics
Toxicodynamics
How the toxicant exerts its effects
How does the BBB keep us safe
Oocyte barrier to toxins
dynamic barrier that changes due to a variety of factors
Placenta as a barrier to toxins
the placenta is NOT a barrier!
anything in the blood can pass to the fetus
Metabolism of toxicants
Hydrolysis
Breaking down complex molecules by the chemical addition of water. Can sometimes make even more toxic metabolite
oxidation
The skin as a barrier
Special barriers to toxins
primary site of metabolism
the liver
Overview of metabolism of toxic compounds
epoxide hydrolase
ADH and ALDH
what performs oxidation
CYTP450s
CYTP450s
18 families of P450 genes, 43 subfamilies with multiple enzymes
conjugation
volume of distribution
Vd = dose/concentration
high serum C means low Vd; it's not in the body's compartments
amount of toxicant variable
So
Vd variability
warfarin Vd variability example
First-order elimination
the rate of elimination is a constant fraction of the dose
Zero order elimination kinetics
the rate of elimination is a constant amount
importance of knowing order of elimination for toxicokinetics
you can know how long the toxicity will last
ex. DDT has a half life of 5 years, so it can stick around for the lifespan of an individual
factors affecting elimination rate
how to identify a target molecule responsible for toxicity:
toxicant must:
reaction types
non-covalent binding
reversible and common
covalent binding
usually irreversible
graded dose response curve
the dose response curve of an individual
quantal dose response curve
the dose response curve of an entire population (average)
dose response curve
how to make probit units
how to use probit units
what's the point of probit units
compare different DRC
probit unit range
1-10, with 5 being 50% response
comparing dose response curves
threshold in toxicology
the concentration above which exposure leads to toxic effects
governments and organizations need to decide safe thresholds
zero threshold
applied to anti-cancer drugs
assuming that there is a linear relationship between the 0 point and the point where we see an effect, no dose is safe
NOAEL
no observed adverse effect level
the highest concentration at which we do not see a statistically significant effect
LOAEL
lowest observed adverse effect (NOAEL)
POD
point of departure
where we start seeing an effect, but it is not significant
can be the NOAEL, LOAEL, or BMD10 depending on the data you have to figure out RfD
MOST IMPORTANT for RfD calculation and based on data
using BMD is preferred
RfD
reference dose in mg/kg/day
= NOAEL/(UF * MF)
an estimate of the maximum acceptable oral dose of a toxic substance
can use NOAEL, BMD, or calculated point of departure
UF
uncertainty factor
MF
modifying factor
ED50
the point at which 50 percent of the test organisms show a negative effect from a toxin.
LD50
the amount of a chemical that kills 50% of the animals in a test population
hormesis
example of hormesis
vitamins
non-monotonic dose response curves
low dose effects
decreasing doses of toxins trigger different responses
toxicant interactions
additive interaction
effects of more than one substance add up (2 + 2 = 4)
synergism
effects of more than one substance work together (2 + 2 = 10)
potentiation
substance that has no toxic effect enhances the toxicity of another substance that is toxic (0 + 2 = 10)
antagonism
occurs when the effects are less than additive; the toxins make each other less toxic (2 + 2 = 3)
ex. Calcium and Selenium
ways toxins can alter biological systems
hazard vs. risk
Hazard = an event that could cause serious harm
Risk = the probability that the hazard could happen
Hazard x exposure = risk
hazard x exposure =
risk
risk = f(??)
risk = f(hazard, exposure)
exposure =
exposure = intensity x frequency x duration
parameters of total exposure
intensity, duration, frequency
exposure pathway
route of a toxin from its source to its end point
5 components of exposure pathway
ingestion and inhalation are examples of which part of the exposure pathway?
exposure route
types of exposure data
best types of exposure data
directly measures data very close to the affected population
quantitative surrogate of exposure
replacement way of measuring levels
ex. estimating quantities of drinking water consumed if measuring exposures to lead in water
which exposure data would be the best approximation of an actual exposure level?
water in your private well showing a reading of 1.3ppm of Copper
issues in measuring exposure
how long to sample?
depends on minimum time needed to obtain sufficient amounts for lab analysis
must consider:
5 major sampling media
particulates and the lungs
0.5-5.0 microns in size can get trapped in the lungs
the smaller, the worse
how to measure air contaminants
through a filter (not good for volatiles) or through an absorbent (to capture gases)
fine particulate matter
2.5µm in size or less is significant indicator of air quality
air quality and industry
strong correlation between air pollution and industry locations
principles of sampling soil
soil sampling grid system
need to collect 20 to 25 samples following a grid system to ensure good distribution
distribution of water samples
more homogenous than soil, but downstream effects are not homogenous
water sampling techniques
per capita consumption rate analysis
Food and Nutrition Surveillance Group
tolerable daily intake (TDI)
estimated quantity of a contaminant that we can be exposed to over a lifetime without posing a significant health risk
Orchratoxin example
Medical vs. forensic tissue testing
medical:
forensics:
sampling tissue examples
done in medical or forensic contexts, experimental studies, environmental studies, workplace sampling, doping testing/urine sampling
toxins to look for in dopings
urine testing limitations
steps for measuring toxins in samples
extraction from samples
separation of samples
involves separating out your chemical of interest
HPLC (high performance liquid chromatography)
popular method for chromatography
reverse phase chromatography
uses a nonpolar card with a polar solvent to separate out something hydrophobic
anion exchange
a form of ion-exchange chromatography in which negatively charged ions (anions) are removed by a positively charged resin
cation exchange
a form of ion-exchange chromatography in which positively charged ions (cations) are removed by a negatively charged resin