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

human exposure. The most common modifiers used are for interspecies
variability (human to animal) and interindividual variability
(human to human), in which case RfD = NOAEL/100. Other modifiers
can be used to account for specific experimental uncertainties.
When a NOAEL is unavailable, a LOAEL may be used, in which
case another 10-fold uncertainty factor is used. The use of factors of
10 in the denominator for determination of RfD is an application of
the “precautionary principle,” which attempts to limit human exposure
by assuming a worst-case scenario for each unknown variable
(Faustman and Omenn, 2008).
A major concern with animal studies is that they do not detect
effects at low concentrations. Typically, they are designed to obtain
statistical significance with a 10% increase in an outcome. As a
result, there is considerable uncertainty about what occurs below that
level, as demonstrated in Figure 67–1. Toxicologists often assume
that there is a threshold dose (T), below which there is no toxicity.
This condition is true when there are cellular defenses that prevent
toxicity at concentrations below a given level but that can be overwhelmed.
Thresholds usually are observed when the toxic effects of
a chemical are the result of direct cell death. Many carcinogens
and other toxicants with specific molecular targets (e.g., lead) do
not exhibit a threshold. Ideally, mechanistic studies should be done
to predict which dose-response curve is most likely to fit a given
chemical.
Toxicologists perform a variety of mechanistic studies to
understand how a chemical might cause toxicity. Computer modeling
using a compound’s three-dimensional structure to determine
quantitative structure-activity relationships (QSARs) is commonly
performed on both drugs and environmental chemicals. QSAR
approaches can determine which chemicals are likely to exhibit
toxicities or bind to specific molecular targets. Cell-based
approaches in prokaryotes and eukaryotes are used to determine
whether a compound damages DNA or causes cytotoxicity. DNA
damage and the resulting mutagenesis often are determined with the
Ames test. The Ames test uses Salmonella typhimurium strains with
specific mutations in the gene needed to synthesize histidine. These
strains are treated with chemicals in the presence or absence of a
metabolic activating system, usually the supernatant fraction from
homogenized rat liver. If a compound is a mutagen in the Ames test,
it reverts the mutation in the histidine operon and allows the bacteria
to form colonies on plates with limited histidine. Gene chip
microarrays assess gene expression in cells or tissues from animals
treated with a toxicant and provide a very useful tool to identify the
molecular targets and pathways altered by toxicant exposures. The
susceptibility of knockout mice to a toxicant can help to determine
whether the knocked-out genes are involved in the metabolic activation
and detoxification of a given toxicant.
Integrated Risk Assessment and Risk Management
Regulatory bodies at local, state, national, and international levels
all are involved in limiting the adverse effects of chemicals. In the
U.S., several federal agencies are involved, depending on the
source of the exposure. The U.S. Food and Drug Administration
(FDA) regulates the safety of drugs, the food supply, cosmetics,
and now tobacco products. The Occupational Safety and Health
Administration (OSHA) regulates workplace exposures. The U.S.
Environmental Protection Agency (EPA) regulates exposures
from other environmental sources, particularly the air and water.
Regulators use epidemiological and toxicological data to estimate
the risks from an exposure and come up with a level they consider
to be reasonably safe. Regulators can nominate toxicants for a comprehensive
study by the National Toxicology Program if there are
insufficient toxicological data. The final stages of risk assessment
and risk management are not based entirely on science; politics and
economics also help determine which regulations are enacted.
Ultimately, the social, economic, and political benefits predicted to
result from limiting human exposure to a given toxicant are weighed
against the corresponding costs.
Interventions for Environmental
Exposure: Pharmacology and Prevention
There is considerable interest in pharmacological
approaches to prevent disease from environmental
exposures. However, pharmacological interventions for
chronic environmental exposures remain more of a goal
than a reality. There are numerous hurdles for treatment
of exposure to environmental toxicants. Because exposures
occur over long periods of time, treatments must
reverse existing preclinical toxicities or provide protection
for a long time. If a pharmaceutical is to be given
chronically or in the absence of disease, the extent of
side effects and toxicity should be much less than for a
drug being given acutely to treat disease. Currently, the
most effective approaches for preventing diseases associated
with chronic exposures to chemicals are primary
prevention and nutrition. Pharmaceuticals can be useful
for preventive strategies against chronic exposures (e.g.,
nicotine replacement therapy in smoking cessation).
Ongoing research also is examining pharmacological
approaches to prevent cancer in humans exposed to
chemical carcinogens. One class of environmental toxicant
for which there are drugs available to prevent disease
is metals. However, in general, these drugs, known
as metal chelators, are only effective against acute,
high-dose metal exposure and either have no effect, or
actually worsen, toxicity under the low-dose chronic
exposures most commonly encountered from the
environment.
CARCINOGENS AND CHEMOPREVENTION
Carcinogenesis
Many environmental compounds increase the risk of
developing cancer; these chemicals are called carcinogens
(Wogan et al., 2004; Klaunig and Kamendulis,
2008). The International Agency for Research on Cancer
(IARC) classifies compounds into groups based on risk
assessments using human, animal, and mechanism data.
Chemicals in group 1 are known human carcinogens;
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CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS