Human Biomonitoring for Environmental Chemicals

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3
Framework to Characterize Biomarkers
and Uses of Biomonitoring

RATIONALE FOR A FRAMEWORK TO

CHARACTERIZE BIOMARKERS
The pace at which developments of biomarkers occur tends to exceed the
biomonitoring community's ability to cope with its obligations to en sure proper
transmission of information on the meaning of the measurements. There are
increasing anecdotal stories in the mass media about the concerns of people whose
blood has been found to contain more than 100 chemicals. But the fact is that the
numbers of studies, subjects, and substances determined in human biomonitoring
are increasing (e.g., National Health and Nutrition Examination Survey), as is the
awareness of the general public of those chemicals in our bodies (e.g., Sexton et al.
2004). Consequently, there is a need for clarification of what biomarkers can and
cannot be used for. Despite proper warnings to the effect that "the measurement of
an environmental chemical in a person's blood or urine does not by itself mean the
chemical causes disease" (CDC 2005), people who have almost unlimited access to
good and bad information about chemicals no longer appear satisfied with such
general words of caution. Not only is the general population entitled to know the
advantages and limitations of biomonitoring, but those with public-health responsibilities
also need to be adequately informed. The correct interpretation of biomarker
measurements is therefore of utmost importance.

In many cases, data on biomarkers are obtained with the sole purpose of
collecting information about their background concentrations in the

71

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72 HUMAN BIOMONITORING FOR ENVIRONMENTAL CHEMICALS

general population, not to assess health risks associated with the measure-
ments. As will be discussed in later chapters, such studies are laudable in
that they contribute to our knowledge about human exposure to environ-
mental chemicals. But the limitations of that type of information are not
necessarily recognized by all who need to know and understand them. The
committee considered that clarification of the properties of the various
biomarkers of exposure would be useful in helping to understand and
clarify what can be said about a given measurement. A systematic frame-
work to characterize the properties of biomarkers would help to inform
scientists and the general population about biomarkers and their meaning
when they are used in biomonitoring studies. It would also allow assess-
ment of potential research gaps that need to be addressed to meet the
requirements of specific uses of biomarkers. Detailed information about the
interpretation of biomonitoring data is provided in Chapter 5. The present
chapter focuses on the properties that characterize biomarkers of exposure
in general. These properties are based on a weight-of-evidence approach
that takes into account the specific context of a biomonitoring study under
consideration.

TYPES OF BIOMARKERS
Chapter 1 describes the relationship between exposure to a toxic chemi-
cal and its clinically relevant health effects as a series of steps along a
continuum. There often is no clear-cut distinction between some of the
steps, and Figure 1-1 can help position three types of biomarkers: biomark-
ers of exposure, of effect, and of susceptibility.
As the name implies, biomarkers of exposure allow assessment of expo-
sure to a chemical on the basis of its measurement in a biologic matrix (N RC
1991). Typical examples are the measurement of dioxins in blood or blood
lipids, mercury in hair, benzene in exhaled breath, and cadmium in urine. In
itself, quantification of such a biomarker in a biologic matrix proves only
that the chemical is in the organism. If the substance is not otherwise known
to be endogenous, it can be concluded that there has been a transfer from the
external environment to the individual organism. Any further interpretation
of the concentration of a biomarker of exposure requires additional informa-
tion about some of the relationships in the continuum. If the biomarker of
exposure indicates that a chemical reached a critical target in the organism
for example, if it formed a DNA adductthere is a greater likelihood of a
potential link with a biological perturbation. As discussed in Chapter 1, this
report focuses on biomarkers of exposure.
Biomarkers of effect are used to assess changes that have occurred in
the biochemical or physiologic makeup of an individual. The further to the
right in the continuum the biomarker is, the greater the clinical or health

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FRAMEWORK TO CHARACTERIZE BIOMARKERS AND USES 73

relevance of its measurement. An abnormal value of a biomarker of effect

near the center of the continuum may not signal detrimental effects on the
health of an individual or group if, for example, the perturbation is revers-
ible and steps are taken to ensure that the exposure that caused it ceases.
However, the abnormal value can serve as a trigger for a remedial action.
Examples of bi omarkers of effect are plasma cholinesterase activity, urinary
02-microglobulin, and packed red-cell volume (hematocrit).
The passage from one step to the next along the continuum will often
depend on a person's characteristics. A biomarker that allows the assess-
ment of a person's susceptibility to alter the progression along the contin-
uum is called a biomarker of susceptibility. Examples are enzymatic geno-
types and phenotypes, such as those seen with glutathione-S-transferase
M, a phase II conjugation enzyme that often contributes to the
detoxification of some electrophilic compounds (Perbellini et al. 2002).

KEY USES OF BIOMONITORING DATA

Biomonitoring has been a key tool in some landmark public-health

actions. The incentive to reduce collective exposure to lead and thereby to
protect the public in general and children, who are more sensitive to its
deleterious neurotoxic effects, would probably have been less if we had not
known how much lead was reaching our bodies and how much lead in our
bodies was problematic. Just as important, the prospective followup and
monitoring of blood lead clearly illustrated that our exposure-reduction
strategies were successful in lowering it (Pirkle et al. 1995). The lead case is
developed further in Chapter 5. The determination of aflatoxin-derived
DNA adducts was also a key step in increasing our understanding of the
carcinogenic effect of this naturally occurring toxin. It allowed us to
derive a quantitative risk assessment of its hepatocarcinogenicity, which
guided exposure reduction (Sharma and Farmer 2004). More recently, the
measurement of biomarkers of exposure to methyl parathion was
instrumental in understanding local epidemics of poisoning with this
insecticide and in establishing remediation strategies (Rubin et al. 2002).
The once unthinkable efforts to reduce exposure to second-hand smoke were
proved successful through the Centers for Disease Control and
Prevention (CDC) National Reports on Human Exposure to Environmental
Chemicals. I ndeed, from 1988 to 2002, a 68% reduction in urinary
concentrations of cotinine (a specific biomarker of exposure to nicotine)
was demonstrated in children 4-11 years old (Sinks 2005). Without specific
measurements, the actual dose resulting from second-hand smoke
would have been only inferred from expensive external measurements of
airborne nicotine from cigarette smoke. The indirect assessment might also
have been considered merely conjectural and unproved. But the
unambiguous demonstration that it was

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74 HUMAN BIOMONITORING FOR ENVIRONMENTAL CHEMICALS

an important pathway of exposure to chemicals contained in tobacco smoke

and that control policies reduced exposure was a key step in the success of
the public-health strategy related to smoking (active and passive). Some
argue strongly that public-health professionals and clinicians would benefit
from access to a large pool of well-characterized biomarkers to guide both
prevention of adverse health effects and health promotion (Jackson 2005).
Biomonitoring can also serve as a valuable tool in various public-health
activities aimed at avoiding the deleterious effects associated with exposure
to toxic substances. From a risk-assessment and risk-management perspec-
tive, the determination of markers of internal exposure may serve a number
of purposes that can be situated along a continuum of risk-assessment and
-management activities (e.g., Burke et al. 1992). Four broad categories are
represented here because they pertain to activities that use biomonitoring:
scoping, status and trends, exposure and health research, and risk assess-
ment. Examples of types of activities included in each category are listed in
Box 3-1. Scoping is a basic risk-management activity that may provide the
first indication of a potential problem. The qualitative information gath -
ered through scoping assists in addressing fundamental questions such as, is
a chemical present in the biomonitoring sample (Burke et al. 1992)? Ex-
amples of scoping include screening, exploratory and source investigations,

BOX 3-1

Continuum of Risk-Assessment and -Management Activities

Related to Exposure Biomonitoring

Scoping
Scree ning
Exploratory investigations
Source investigations
Societal-hazard identification
Status and Trends
Exposure surveillance
Population research
Pathway research
Decision validation and health surveillance
Exposure and Health Research
Epidemiologic research (ecologic and analytic)
Toxicologic research
Pharmacokinetic and pharmacodynamic research
Community and occupational investigations
Risk Assessment
Population risk characterization
Clinical applications

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FRAMEWORK TO CHARACTERIZE BIOMARKERS AND USES 75

and societal hazard identification. Status and trends provide an assessment

of the concentration of chemical in the population (for example, blood or
urine) and whether the concentration of the chemical may be varying over
time, across geographic regions, or within populations. Information on
status and trends can assist with population surveillance and research. The
biomonitoring data may be utilized to assess potential sources of exposure
when combined with pathways research. Biomonitoring data can be used to
support exposure and health research. Population-based biomonitoring data
used in epidemiologic studies can identify highly exposed subpopulations
and health endpoints of concern. This in turn can be applied to community
and occupational studies. The data can also identify information needs for
toxicologic, pharmacokinetic, and pharmacodynamic research. Biomoni-
toring data can be applied in clinical evaluations (that is, childhood lead) to
assess individual risks or exposure.
All those activities have specific purposes and may be conducted alone
(for example, for priority-setting among public-health actions) or as parts
of a multitier strategy. Links between risk-assessment and -management
activities (why biomonitoring is conducted) and the properties of the bio-
markers (what characteristics our biomonitoring tools need to have for us
to be able to conduct these activities) will be presented below.

PROPERTIES OF AND GROUPING FRAMEWORK FOR

BIOMARKERS OF EXPOSURE

A simplified version of the relationships described in the continuum

presented in Figure 1-1 shows the links between external dose,' internal
dose, and biologic effects as a triangle (Figure 3-1). The diagram illustrates
the "operational" relationships between these elements, not the biologic
relationships. Indeed, a systemic toxicant has to penetrate the organism
before exerting its action. The direct link between external dose and bio -
logic effect has no toxicologic meaning itself, but, as will be discussed
below, more published information is available on the relationship between
the external dose of toxicants and their biologic effects than between the
internal doseas assessed by a biomarker measurementand biologic ef-
fects. The interpretation of biomonitoring data, and thus possible key uses,
will depend on the body of knowledge about these links from animal or
human studies.

lExternal dose, as used in the report, refers to the amount of chemical that is inhaled, is
ingested, or comes in dermal contact and is available for systemic absorption. External dose
is typically expressed in units of milligrams of chemical per kilogram of body weight per day
(mg/kg/day).

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