-: Welcome to module three.
Chapter six in your textbook provides
a really good introduction to toxicology,
but in this presentation we'll take a closer look
at dose response relationships
that don't follow the traditional pattern,
and hopefully reinforce some of the key takeaways
for this module.
I strongly recommend that you watch the two short videos
about dose response before continuing with this presentation
because this lecture will build upon
the concepts presented in those videos.
So let's start out with a reminder
of a few key definitions in toxicology.
First, it's always good to remember
that toxins are substances of natural origin,
while toxicants are synthetic substances.
Next, a key definition in toxicology is the threshold.
The threshold is the level above which effects will occur
and below which no effects will occur for a given substance.
The reference dose, often written as RfD,
is the EPA's estimate
of the daily lifetime dose of a substance
that is unlikely to cause harm in humans.
In other words,
it represents the maximum acceptable daily dose,
typically through an oral route of a toxic substance.
Let's keep going with a few more definitions.
The NOAEL is the no observed adverse effect level.
So it's the highest dose
at which there was not an observed toxic or adverse effect.
This is the experimental equivalent of threshold,
which we covered on the last slide.
LOAEL is the lowest observed adverse effect level.
In other words, it's the lowest dose
at which there was an observed toxic or adverse effect.
MTD is the maximum tolerated dose.
And then finally,
a monotonic dose response relationship
is one where as the dose increases, so does the response.
In other words, this is what is thought of
as the typical dose response pattern.
Not all substances follow
the traditional dose response pattern.
Nonmonotonic dose responses go against
predictable or typical dose response patterns.
With nonmonotonic dose responses,
the dose response curve changes direction
within the range of doses examined
and can create unusual shapes,
such as inverted U-shape, U-shapes, or multiphasic curves,
as shown in this figure.
This figure provides examples illustrating
slightly more complicated nonmonotonic dose response curves
at different portions of the dose response curve
relative to the no observed adverse effect level,
or the NOAEL, and the reference dose.
In part A, circles indicate doses typically examined
in conventional toxicity tests,
which are used to calculate the reference dose.
This figure shows the expected relationship
between human exposure levels
and the reference dose, as well as the NOAEL.
So here you've got your reference dose.
Here's the NOAEL,
and then here's your LOAEL,
the lowest observed adverse effect level.
And then up here your maximum tolerated dose
and then this is an overtly lethal dose at the top.
No adverse effects are expected at human exposure levels,
the reference dose or the NOAEL,
if the NOAEL represents
a true threshold for adverse effects.
So these three would all have no response,
if that holds true.
In part B of the figure,
nonmonotonicity is observed above the NOAEL.
So here's the NOAEL, and we see a reaction above that
at high levels of exposure.
So the study that's mentioned down here,
noted a couple different examples of this type of curve,
including one study in male mice that were exposed
to a chemical called Dichlorodiphenyltrichloroethane or DDT,
during their development.
In part C,
the nonmonotonicity occurs between the reference dose here
and the NOAEL.
One example cited in the literature
showed that 1.5 milligrams
per kilogram per day of Permethrin
altered dopamine transport in mice,
whereas higher and lower doses were ineffective.
So that's where you see this increase in response,
that you don't see at both lower and higher doses.
So the effects were observed above the reference dose
and below the NOAEL.
In part D, nonmonotonicity occurs
at exposures below the reference dose.
So here's the reference dose
and you're seeing an increased effect at lower doses.
Doses at or below the reference dose
are rarely directly tested in conventional toxicity studies.
Studies utilizing standard test guidelines
typically aim to identify the NOAEL
and then examine only three or four doses
that are usually higher than that.
So if nonmonotonic dose response curves
are observed below the reference dose, as in case D,
it would indicate that the reference dose
and by extrapolation, the NOAEL, are scientifically flawed
and insufficiently protective of public health.
More than 30 such examples have been observed
in human epidemiology studies and fall into this category.
They provide evidence that human exposure levels,
which are likely below the reference dose,
can result in adverse health outcomes
and PCBs are a good example that fall into this category.
The important items
that I want you to take away from this lecture
are that the dose response relationship
is a fundamental tool in toxicology
that's used to determine how much of a substance it takes
to cause harm in humans,
as well as how much of a substance
humans can be exposed to without causing harm.
Not all substances have predictable
or typical dose response patterns,
which show that as the dose increases so does the effect.
You don't need to remember any of these facts
about nonmonotonic dose response curves
that I covered in the last slide.
Just be aware that some of these exist
and that you can't always expect a specific agent
to have a typical dose response pattern.