DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
An example of an unusual exposure biomarker is X-ray fluorescent
measurement of bone lead levels, which estimates lifetime exposure
to lead. Biomarkers of toxicity are used to measure toxic effects at
a subclinical level and include measurement of liver enzymes in the
serum, changes in the quantity or contents of urine, and performance
on specialized exams for neurological or cognitive function.
Biomarkers of susceptibility are used to predict which individuals
are likely to develop toxicity in response to a given chemical.
Examples include single nucleotide polymorphisms in genes for
metabolizing enzymes involved in the activation or detoxification of
a toxicant. Some biomarkers simultaneously provide information on
exposure, toxicity, and susceptibility. For example, the measurement
in the urine of N7-guanine adducts from aflatoxin B 1
provides evidence
of both exposure and a toxic effect (in this case, DNA damage).
These types of biomarkers are particularly valuable because
they can support a proposed mechanism of toxicity.
Several types of epidemiological studies are used to assess
risks, each with its own set of strengths and weaknesses. Ecological
studies correlate frequencies of exposures and health outcomes
between different geographical regions. These studies are inexpensive
and can detect rare outcomes but are prone to confounding variables,
including population migration. Cross-sectional studies
examine the prevalence of exposures and outcomes at a single point
in time. Such studies are an inexpensive way to determine an association
but do not provide a temporal relationship and are not effective
for establishing causality. They also can be subject to bias, as a
perceived health outcome might cause someone to eliminate his
exposure. Case-control studies start with a group of individuals
affected by a disease, which then is matched to another group of
unaffected individuals for known confounding variables.
Questionnaires often are used to evaluate past exposures. This
method also is relatively inexpensive and is good for examining rare
outcomes because the endpoint is known. However, case-control
studies rely on assessments of past exposures that often are unreliable
and can be subject to bias. Prospective cohort studies measure
exposures in a large group of people and follow that group for a long
time to measure health outcomes. These studies are not as susceptible
to confounding variables and bias and are good at establishing
causality. However, they are extremely expensive, particularly when
measuring very rare outcomes, because a large study population is
required to observe sufficient disease to obtain statistical significance.
One of the key types of human studies used in drug development
is the randomized clinical trial (discussed in Chapter 1). These
studies cannot be used to directly measure the effects of environmental
toxicants (for obvious ethical reasons) but can be used to
examine the effectiveness of an interventional strategy for reducing
both exposure and disease.
Toxicological Approaches to Risk Assessment
Toxicologists use model systems, including experimental animals, to
examine the toxicity of chemicals and predict their effect on humans
(Faustman and Omenn, 2008). The significance of these model systems
to human health is not always established. Toxicologists also
test chemicals at the high end of the dose-response curve in order to
see enough occurrences of an outcome to obtain statistical significance.
As a result, there often is uncertainty about the effects of very
low doses of chemicals. To determine the applicability of model
studies, toxicologists study the mechanisms involved in the toxic
effects of chemicals, with the goal of predicting whether that mechanism
would occur in humans.
To predict the toxic effects of environmental chemicals, toxicologists
perform subchronic (3 months of treatment for rodents) and
chronic studies (2 years for rodents) in at least two different animal
models. Subchronic experiments provide a model for occupational
exposures, while chronic experiments are used to predict effects from
lifetime exposures to chemicals in food or the environment. Doses
for these studies are based on shorter preliminary studies, with the
goal of having one concentration that does not have a significant
effect, one concentration that results in statistically significant toxicity
at the low end of the dose-response curve, and one or more concentrations
that will have moderate-to-high levels of toxicity. A
theoretical dose-response curve for an animal study is shown in
Figure 67–1. An animal study provides two numbers that estimate
the risk from a chemical. The no observed adverse effect level
(NOAEL) is the highest dose used that does not result in a statistically
significant increase in negative health outcomes. The lowest observed
adverse effect level (LOAEL) is the lowest dose that results in a significant
increase in toxicity. The NOAEL is divided by 10 for each
source of uncertainty to determine a reference dose (RfD), which is
commonly used as a starting point for determining regulations on
human exposures to chemicals. The modifiers used to determine the
RfD are based on the uncertainties between the experimental and
% Toxic Response
30
25
20
15
10
5
T
*
NOAEL
0
0 2 4 6 8
Dose (μg/kg BW)
Figure 67–1. LOAEL and NOAEL. The theoretical dose-response
curve from an animal study demonstrates the no observed
adverse effect level (NOAEL) and the lowest observed adverse
effect level (LOAEL). Below the NOAEL level, there is considerable
uncertainty as to the shape of the response curve. It could
continue linearly to reach a threshold dose (T) where there would
be no harmful effects from the toxicant, or it could have a number
of different possible inflection points. Each of these curves
would have very different impacts on human populations.
*Statistically significant.
*
LOAEL
*