Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Application of Biologic Markers to Studies of Environmental Risks in
Children and the Developing Fetus
Robin M. Whyatt and Frederica P. Perera
Columbia University School of Public Health, New York, New York
Abstract
Young children and the developing fetus may be more susceptible to effects
of environmental toxicants than adults due to differential exposure patterns
and developmental immaturities. Biologic markers offer the potential of
quantitative dosimeters of biologic dose and/or indices of biologic effect
associated with fetal/childhood exposures. They can facilitate evaluation
of interindividual variability in response and the magnitude of age-related
susceptibilities. Thus far, biologic markers have not been widely used in
developmental epidemiology of environmental exposures. Research by our group
and others has seen elevations in biologic markers in samples from children
and fetal tissue associated with a spectrum of environmental exposures,
including tobacco smoke (active and passive), ambient pollution, and dietary
contaminants. Studies also suggest that biologic markers can provide powerful
dosimeters for investigating reproductive effects. Validation of biologic
markers offering the greatest promise for developmental epidemiology is
needed. -- Environ Health Perspect 103(Suppl 6):105-110 (1995)
Key words: biologic markers, developmental epidemiology, children,
developing fetus, DNA adducts
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
Supported by grants from the National Institute of Environmental
Health Sciences (PO1-E505249, RO1-ES06722), National Institutes of Health
(CA51196), American Cancer Society (PDT-373A), Department of Energy (DE-FG02-93ER61719),
Colette Chuda Environmental Fund, March of Dimes Birth Defects Foundation,
and Fogarty International Center (NIH).
Address correspondence to Dr. Frederica P. Perera, Columbia
University School of Public Health, 60 Haven Avenue, New York, NY 10032.
Telephone (212) 305-3465. Fax (212) 305-4012.
Introduction
There is evidence that young children and the developing fetus may be
more susceptible than adults to the adverse effects of many environmental
carcinogens and other toxicants. Their increased susceptibility can arise
from differential exposure patterns and/or immaturities in physiological
development. Infants and young children have higher breathing rates, ingest
more drinking water, and consume more calories of food per unit body weight
than do adults (1,2). As a result, they can have significantly
greater intakes per unit body weight of carcinogens and other contaminants
in food, water, and air (1,3). Physiologic immaturities can also
lead to greater absorption, retention, or increased target organ sensitivity,
depending on the toxicant (4,1,5). For certain carcinogens, risk
of cancer has been shown to increase if exposure begins in utero or
infancy rather than in adulthood (6,7). The increased susceptibility
is due presumably to the increased rate of cell proliferation, differing
metabolic capabilities during early development, and the long future life
during which cancers initiated in childhood can develop (8,6,9-11).
While increased susceptibility of the young is of concern, age-related
differences in response to environmental toxicants have not been well characterized.
Epidemiologic studies quantifying effects of environmental exposures during
infancy and childhood are limited (3) and have been hampered by uncertainties
regarding the extent and timing of exposure. Human data are currently available
for only a few toxicants, most notably lead (12-14). Exposures in
carcinogenicity bioassays typically occur after maturation of the test animals
is largely completed (15). In the case of developmental bioassays,
in which exposure begins in utero or during infancy, extrapolation
of results from animals to humans can be compromised by interspecies differences
in developmental patterns and growth rates (3).
The use of biologic markers in molecular epidemiologic studies of fetal
and childhood exposures can circumvent some of these limitations. To date,
biologic markers have not been widely used in developmental epidemiology
of environmental exposures (16,17); however, they offer the potential
to provide quantitative dosimeters of biologic dose and/or indices of biologic
effect associated with fetal and childhood exposures to environmental carcinogens
and other toxicants. Further, they can facilitate quantification of
differences in the magnitude of response in the young relative to that in
adults. The following review provides an overview of biologic markers used
in human studies. Most have involved adult populations with a variety of
environmental exposures. The term environmental is broadly defined
to include lifestyle (cigarette smoke), occupation, and ambient pollution.
Collectively, they demonstrate the sensitivity of a number of biologic markers
to environmental toxicants and support their applicability to developmental
studies. The review concludes with examples from our group and others of
research incorporating biologic markers into studies of environmental exposures
during fetal development and early childhood.
Overview of Biologic Markers*
Molecular epidemiology bridges from basic research in molecular biology
to studies of disease causation in humans by combining laboratory measurements
of internal dose, biologically effective dose, biologic effect, and susceptibility
with epidemiologic methodologies (18-20). Research has shown marked
elevations in biologic markers associated with a spectrum of exposures and
has demonstrated the ability of multiple biologic markers to detect genetic
and molecular damage in humans. Case-control studies in patient populations
also suggest that specific biologic markers may indicate heightened
risk of disease.
Internal dose refers to the measurement of the amount of a toxicant or
its metabolite present in cells, tissues, or body fluids. Examples
of internal dosimeters include DDT and PCBs in serum and adipose tissue
from environmental contamination, plasma, or salivary cotinine from cigarette
smoking, urinary aflatoxin indicative of dietary exposure, and lead
from various exposures. Examples from our group include the findings
of increased urinary 1-hydroxypyrene levels associated with ambient exposures
to polycyclic aromatic hydrocarbons (PAH) in Finnish foundry workers and
dermal exposures in coal-tar- treated psoriasis patients (21,22).
Internal dose markers take into account individual differences in absorption
or bioaccumulation of the compound in question and have the advantage of
being comparatively easy to monitor. However, they do not provide data about
interactions of the compound with critical cellular targets.
Biologically effective dose reflects the amount of toxicant that
has interacted with cellular macromolecules at a target site or with an
established surrogate. Examples include levels of specific carcinogens
bound to genetic material (carcinogen-DNA adducts) or an established surrogate
(carcinogen-protein adducts). This class of markers is more mechanistically
relevant to disease than internal dose, since it takes into account differences
in metabolism (activation vs detoxification) of the chemical in question
as well as the extent of repair of DNA adducts. The biological basis for
measuring DNA adducts derives from extensive experimental data supporting
their role in the initiation and possibly the progression of cancer. Adducts
formed between DNA and PAHs as well as other carcinogens have been correlated
with carcinogenic potency in experimental studies and are therefore considered
to be a relevant indicator of the effective dose and potential risk of carcinogens.
There is evidence that protein adducts can serve as surrogates for DNA adducts.
Numerous studies have shown PAH-DNA and other carcinogen-DNA adducts
in peripheral white blood cells (WBC) of workers to be associated with occupational
exposures, including foundry workers, roofers, coke oven workers, and aluminum
plant workers (23-27). Carcinogen-DNA adduct levels in WBC have also
been associated with ambient air pollution exposures in Poland (28).
Dietary exposures to aflatoxin have been correlated to urinary excretion
of aflatoxin-DNA adducts (aflatoxin-N7-guanine) in
populations studied in China and West Africa (29,30). Some, but not
all, studies have seen increases in carcinogen-DNA adducts in WBC of cigarette
smokers compared to that in nonsmokers (31-35). In lung tissue, a
linear relationship between DNA adduct levels and daily or lifetime cigarette
consumption was seen (36). Adducts formed between 4-aminobiphenyl
and hemoglobin (4-ABP-Hb) are also significantly elevated in smokers
compared to nonsmokers (37,38). In a case-control study of lung cancer
by our group, a significant association was seen between lung cancer
risk and PAH-DNA adduct formation among current smokers after controlling
for the number of cigarettes smoked per day (32). These findings
suggest that adducts are not only an environmentally relevant dosimeter,
but that they may also indicate heightened risk of cancer.
Biologic effect markers reflect irreversible damage resulting from
a toxic interaction, either at the target or an analogous site, which is
known or believed to be pathogenically linked to disease. A wide variety
of biologic markers fall into this category, including gene mutations at
the hprt and glycophorin A (GPA) loci, alterations in oncogenes and
tumor suppressor genes, DNA single-strand breaks, unscheduled DNA synthesis,
sister chromatid exchanges (SCE), chromosomal aberrations (CA), and micronuclei.
None of these markers is chemical- or exposure-specific, and other
factors (lifestyle and environmental) that affect these end points can act
as confounding variables in a molecular epidemiologic study.
Our research has found increases in hprt gene mutations in lymphocytes
associated with occupational exposures to PAHs among Finnish foundry workers.
Consistent with experimental data, the frequency of mutation was significantly
correlated with levels of PAH-DNA adducts (39). In another study
by our group, ambient air pollution in Poland was found to be significantly
related to SCE and CA, including gaps (28). Further, PAH-DNA adducts
were significantly correlated with chromosomal mutation, linking molecular
dose with a genetic effect of air pollution. Research on liver cancer patients
in China and Southern Africa has implicated AFB1 as an etiologic
agent and indicated a possible mechanism by which the carcinogen may be
exerting its effect (40). A total of 26 liver tumors were obtained
from patients living in areas characterized by high exposure to AFB1
and by high prevalence of liver cancer (41,42). Eleven (43%) of the
tumors exhibited a specific mutation (G to T) at codon 249 of the tumor
suppressor gene, p53. This signal mutation is produced by AFB1
when administered to experimental animals.
Susceptibility markers measure individual differences that can modulate
response to exposure. These include individual differences in micronutrient
levels, DNA repair capacity, inherited mutations, and detoxification
mechanisms. Examples include individual variability in "Phase I"
and "Phase II" enzyme activities. The normal role of Phase I enzymes
is to convert lipid-soluble xenobiotics to more water-soluble substances
that can be excreted. However, some of the intermediates in this oxidative
process are highly reactive electrophiles capable of binding to DNA. CYP1A1,
a P450 enzyme with aryl hydrocarbon hydroxylase activity, catalyzes the
oxidation of PAHs such as benzo[a]pyrene. This enzyme system is highly
responsive to exposures to PAHs and other agents, and inducibility has been
associated with higher risk of lung cancer in smokers (43). An MspI
RFLP in the 3´ coding region of the CYP1A1 gene (associated
with a mutation in exon 7 of the gene) has been associated with lung cancer
risk in Japan (44,45). Phase II enzymes conjugate the phase I metabolites
with glucuronide, glutathione, or sulfate, resulting in less reactive, hydrophilic
products for excretion. Glutathione-S-transferases (GST) are a family
of multifunctional proteins that play an important role in the detoxification
of PAHs and other xenobiotics through conjugation with glutathione (46,47).
A polymorphism has been detected in the GSTM1 gene, which has been
shown to be a deletion of the entire gene locus. Published reports indicate
that 30 to 60% of the population may be homozygous deleted for this gene
(48). Smokers with low lymphocyte GSTM1 activity are reported
to be at higher risk for lung cancer (49,50). More recently, in a
cancer case-control study in Japan, a relative risk of 1.87 was seen for
the null genotype and squamous cell carcinoma of the lung (45). A
remarkably high relative risk of 9.1 for squamous cell carcinoma was seen
with the combined CYP1A1 exon 7 mutation and GSTM1 null genotypes.
*Section excerpted from Perera FP and Whyatt RM. Biomarkers
and molecular epidemiology in mutation/cancer research. Mutation Research
313:117-129 (1994), which contains a more detailed discussion, tables, and
references.
Application of Biologic Markers to Developmental Epidemiology
Thus far, biologic markers have not been used widely in studies of developmental
effects associated with environmental exposures. Further, studies incorporating
biologic markers generally have not related them to disease outcomes such
as birth defects or childhood cancers in infants and children. Rather, biologic
markers have primarily been relied on as dosimeters for fetal and childhood
exposure. Research by our group and others has seen elevation in biologic
markers in samples from children and in fetal tissue associated with a spectrum
of environmental exposures including tobacco smoke (active and passive),
dietary contaminants, and ambient pollution.
Since evidence suggests that children may be at heightened risk of cancer
from environmental tobacco smoke (ETS) exposure during early childhood (51),
we initiated a study using a panel of biologic markers to assess ETS exposure
in mothers and their preschool-age children (2-5 years) (52). A number
of markers, including serum cotinine (a metabolite of nicotine) and PAH-albumin
adducts, were evaluated in peripheral blood samples from 87 African-American
and Hispanic mother-child pairs. Children of smoking mothers had significantly
higher levels of both cotinine and PAH-albumin than children of nonsmoking
mothers. Their cotinine was significantly correlated with numbers of
cigarettes smoked daily by the mother. Cotinine was also markedly elevated
in children of nonsmoking mothers who were exposed to ETS from other household
smoking. These results underscore the importance of programs aimed at smoking
prevention among mothers and women of childbearing age.
Monitoring of PAH-DNA and other carcinogen-DNA adducts in placental tissue
of smokers and nonsmokers has also demonstrated increases related to cigarette
smoking (53-56). Hansen et al. (55) found carcinogen-DNA adducts
in both placental tissue and umbilical cord DNA to be associated with smoking.
Adduct levels in the placenta of both smokers and nonsmokers were higher
than corresponding adduct levels in umbilical cord DNA.
Coghlin et al. (57) measured levels of 4-ABP-Hb adducts in paired
maternal blood-fetal cord blood samples from smoking and nonsmoking women.
Adduct levels in both maternal and fetal samples were significantly
associated with cigarette smoke exposure. Fetal adduct levels were consistently
lower than maternal levels.
A recently initiated investigation by our group is using a panel of biologic
markers to assess effects of smoking, diet, and ambient air pollution on
women and the developing fetus. Markers are being assayed in placental tissue
samples and maternal and infant cord blood samples collected from 73 mother-newborn
pairs residing in Kraków, Poland, an industrial city with severe
ambient air pollution, and 90 mother-newborn pairs from a rural town in
Poland with lower pollution levels. Preliminary results show CYP1A1 mRNA
levels in placental tissue and PAH-DNA adduct levels in maternal WBC to
be significantly increased in current smokers compared to nonsmokers
(58). Adduct levels in maternal WBC were also significantly
associated with ETS exposure. Dietary consumption of smoked and fried meats,
cheese, and fish was a significant determinant of placental CYP1A1
mRNA levels, presumably as a result of PAHs formed during cooking. A dose-response
in both placental CYP1A1 mRNA levels and maternal PAH-DNA adduct levels
with ambient pollution was apparent. Unlike the Coghlin et al. findings
of lower adduct levels in fetal compared to maternal samples, in the current
study levels of both serum cotinine and PAH-DNA adducts in infant cord blood
samples were higher than those in the corresponding maternal blood samples.
These findings suggest a reduced ability of the fetus relative to that
of the mother to detoxify cigarette smoke constituents. They also point
to the possibility of increased susceptibility of the developing fetus to
PAH-DNA adduct formation. This is particularly striking, given evidence
from experimental bioassays that transplacental exposure to PAHs is an order
of magnitude or more lower than maternal exposure (59,60).
In a series of studies, Wild et al. (61,62) have investigated
dietary exposure to aflatoxin B1 by measuring AFB1-albumin
adducts in blood samples from residents of Gambia. Umbilical cord blood
and maternal blood were collected from 30 mother-newborn pairs, and blood
was also collected from 323 children (ages 3-8). Adducts were present in
97% of maternal sera, 70% of umbilical cord sera, and over 95% of children's
sera, indicating widespread dietary exposure to aflatoxin in this region
and transplacental transfer of the carcinogen during pregnancy. Cord adduct
levels were highly correlated with, but 10-fold lower than, maternal levels.
Interestingly, children who were positive for the hepatitis B virus (HBV)
surface antigen had significantly higher adduct levels than did children
who had never been infected or who had markers of past infection. These
data suggest that HBV infection can influence aflatoxin metabolism.
Polycyclic aromatic hydrocarbons are present in urban and industrial
air pollution as well as in cigarette smoke and diet. PAH-DNA adduct levels
have been assessed in human fetal tissues and placentas from 15 spontaneous
abortions collected from nonsmoking women (63). Adducts were detected
in 42% of fetal lung specimens, 27% of fetal liver specimens, and 43% of
placentas. In the cases in which adducts were present in both placenta and
fetal tissue, fetal tissue levels were not appreciably lower than the corresponding
placental values. These results demonstrate that tissues of the developing
human fetus are targets for DNA damage from ubiquitous exposures like that
from PAHs.
A study using biologic markers to monitor exposure from an industrial
waste site in Belgium found levels of SCEs (including high frequency cells)
to be significantly higher in blood samples from a small number of
children living near the site than in samples from matched controls (64).
Air contamination by a mixture of genotoxics emitted from the site were
presumed responsible for these cytogenetic effects.
In addition to using biologic markers as dosimeters of fetal and childhood
exposure, several studies have shown associations between specific
biologic markers and reproductive effects. A highly significant association
was found between decreased birth weight and the level of smoking-related
adducts in placental tissue collected from only 30 smoking mothers (53).
By contrast, no association was seen between decreased birth weight and
either intensity of smoking exposure assessed by questionnaire data or biochemical
measures of smoking exposure (cotinine, thiocyanate, and carboxyhemoglobin).
Several other studies have used umbilical cord blood serum cotinine levels
from nonsmoking mothers as an internal dosimeter of fetal ETS exposure.
These studies found a significant inverse correlation between serum
cotinine levels and birth weight (65,66).
Conclusion
This body of research has demonstrated that laboratory methods for detection
of carcinogen-DNA adducts and other biologic markers of effect and susceptibility
are adequately sensitive for studies of environmental exposures in human
populations. Research on exposures during fetal development and childhood
indicates that biologic markers can provide dosimeters of environmental
exposures and tools for evaluating interindividual variability in response
and age-related susceptibilities. However, incorporation of biologic markers
into developmental epidemiology has been limited to only a few markers and
to studies of small sample size. Validation of markers offering the greatest
promise for developmental epidemiology is needed. Criteria for validation
should include low-dose sensitivity and reproducibility of the assay as
well as exposure specificity. Biologic markers can integrate exposure
via multiple routes (inhalation, oral, dermal), multiple sources (ambient
and indoor air, workplace air, cigarette smoke, diet, drinking water), and
across all patterns of exposure (past, current, intermittent, continuous).
This is an advantage, since risks can be assumed to be additive. However,
it is also a disadvantage in that many environmental chemicals are ubiquitous
in the environment and it is difficult to distinguish the effect of
any particular exposure source. Markers vary greatly with respect to source
specificity; for example, 4-aminobiphenyl-hemoglobin (4-ABP-Hb) has
far fewer noncigarette-smoking-related background sources than ethylene
oxide (EtO), PAHs, and N-nitroso compounds. The extent to which the
marker will document specific time periods of exposure will depend
upon the pharmacokinetics of the chemical and the persistence of the marker
in the biologic sample assayed (itself a function of the turnover rate of
the sample and repair processes). The feasibility of the marker should be
determined. That is, how acceptable is it to the public, how cost-effective,
and how stable in stored samples? Finally, because of their ability to provide
information on gene-environment interactions within individuals, the potential
for misuse of biomonitoring data, leading to discrimination related to employment
or insurance, cannot be ignored (20). This review summarizes early
and recent validation research. However, before applying methods in larger
scale developmental epidemiologic studies, it is imperative that guidelines
be developed to protect confidentiality and to guard against misuse
of data.
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