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OCR for page 247
Biologic Markers of Exposure During Pregnancy:
Pharmacokinetic Assessments
This chapter discusses pharmacokinetic
considerations that are unique to pregnan-
cy as well as standard considerations.
These have important implications for the
interpretation of concentrations of chem-
icals and their metabolites either from
the maternal tissues or fluids or from the
fetal tissues or fluids.
Issues related to pharmacokinetics
have become central to toxicity risk as-
sessments (Kuemmerle and Brendel, 1984;
Fabro and Scialli, 1986~. The new field
of toxicokinetics and evaluation of bio-
logic markers of exposure focuses on the
presence and consequences of xenobiotic
chemicals over specific intervals. Stud-
ies are being undertaken to assess the
absorption, distribution, and excretion
of a substance, as well as its metabolism
to other substances and their distribu-
tion, metabolism, and elimination. With
the rapid development of highly sophisti-
cated and sensitive analytic techniques,
exposures can be evaluated to determine
an organism's risk of toxic effects.
Metabolite profiles and measurements of
tissue content, chemical half - life in
various tissues and blood, and total excre-
tion can be used to determine therapeutic
efficacy or to indicate toxic response.
At issue are what measurements should be
made, what media or tissues should be used,
247
and what techniques can best determine
the expression or potential expression
of toxic action.
Many general pharmacokinetic consid-
erations are relevant, including:
· Are the techniques for analyzing a
chemical compound sufficiently sensitive
to detect it at low, nontoxic concentra-
tions?
· Do the techniques fulfill all aspects
of quality-control standardization?
· Does the substance reach the organ
or target site in a concentration suffi-
cient to produce the effect noted?
· Does the effect stop when the organ
concentration of the substance decreases
to a particular point?
· What intervals are necessary for re-
peated administration of the substance
to elicit or maintain the effect noted?
· What conditions in the organism will
modify the effect noted, in light of an
evaluation of the compound's structure-
activity relationship?
In many instances, only small tissue
samples can be obtained because of the
inaccessibility of the conceptus, al-
though new noninvasive procedures such
as ultrasonography and magnetic resonance
imaging are becoming available. The only
OCR for page 248
248
tissues or fluids readily available from
the conceptus are the placenta at delivery
or after therapeutic interruption of preg-
nancy, placental tissue obtained by chori-
onic biopsy, amniotic fluid, on rare oc-
casions fetal blood samples, and fetal
tissue taken by biopsy before delivery
(Table 22- 1).
The following critical pharmacokinetic
factors are peculiar to pregnancy:
· Dramatic and continuing physiologic
and biochemical changes in mother and con-
ceptus that can persist throughout gesta-
tion.
· Two separate and distinct genomes
existing in the same organism (the mother).
· Two separate and distinct blood sup-
plies with a unique interface at the troph-
oblast.
· Rapid and selective growth of specific
cell types in the conceptus at particular
stages of gestation.
· Direct and indirect interactions
among mother, embryo or fetus, and placen-
ta (Miller and Kellogg, 1985~.
TABLE 221 Tissues and Fluids Available Dunng
Pregnancy for Laboratory Assessments
Fetal tissue analysis at delivery
Placenta
Cord blood
Fetal blood
Amniotic fluid
gas
Hair
Adipose tissue
Unne
Feces
Maternal tissue and fluid analysis throughout
gestation
Blood
Urine
Feces
Adipose tissue
Air
Hair
Mild
En do m et riu m
First-trimester fetal tissues and Buids
Chonon~c villi (less than 10 weeks)
Amniotic fluid and cells
TOXICI7YDURING PREGNANCY
ASSESSMENTS FOR
PHARMACOKINETIC ANALYSES
Initial considerations for pharmaco-
kinetic analysis include the analytic
technique involved, its sensitivity, and
standardization of quality-assurance
protocols associated with it. Quality
assurance must be rigorous and described
thoroughly in publications, particularly
in cases where blood or tissue sample sizes
are limited, as in samples from a concep-
tus. Problems in comparing results from
different laboratories, for example,
difficulties encountered in trace-metal
analyses of human tissues (Friberg, 1983),
can be alleviated by adopting universal
standards for any analysis, regardless
of technique. Necessary in quality assur-
ance are control samples from established
sources, preanalytic control of collec-
tion containers and patient information,
statistical evaluation of all samples for
maximal allowable deviations, and exter-
nal monitoring and review programs (state,
national, and international). Because
the technique used for a chemical compound
often is specific, this chapter does not
review individual techniques, but sug-
gests reviews for further consideration
(Friberg, 1983; Kaul et al., 1983; Kay and
Mattison, 1986; Miller et al., 1988~.
Classic pharmacokinetic studies de-
pend on single acute exposures to deter-
mine half-life of a chemical for a specific
tissue or fluid compartment. More accurate
pharmacokinetic analyses require repeated
sampling of the same tissue or fluid com-
partment and constructing a curve from
these data that relate tissue or fluid
concentration of a chemical or its metabol-
ites with time since exposure. Examination
of the concentration-time curve makes it
possible to establish the amount of chemi-
cal in the organ or fluid. Such analyses
can be applied to the whole body by measur-
ing the urinary, pulmonary, or fecal excre-
tion of the compound.
In humans, blood concentrations of a
chemical often are used to describe the
characteristics of distribution; but the
physicochemical characteristics of the
chemical might be the primary factors de-
termining absorption in and distribution
OCR for page 249
PHARMACOKINETIC ASSESSMENTS
to body compartments. Those characteris-
tics include molecular weight, lipid solu-
bility, ionization capability, protein-
binding capability, and metabolism
(Longo, 1972; Miller et al., 1976; Kuemmer-
le and Brendel, 1984; Mattison, 1986~;
and changed hormonal balance in pregnant
women can affect all of them. Tissue and
fluid compartments other than the ones
available for testing can become Deep
compartments, in which the chemical ap-
pears to be irreversibly trapped; the pla-
cental interface might limit chemical
transit to the conceptus. If the chemical
is largely bound to plasma albumin, less
of it will be found in fetal blood than in
maternal blood, because less albumin is
found in fetal circulation. However, the
amount of free chemical-the critical fac-
tor-can be identical, and simply measuring
one or two compartments might not accurate-
ly reflect a third compartment.
Metabolism of xenobiotics might differ
substantially between pregnant and non-
pregnant women. Biotransformation can
reflect lower blood concentrations of a
substance, as well as shorter half-lives.
Such changes can be important to maintain
therapeutically effective concentrations
of a substance, e.g., phenytoin. Changes
in half-life might reflect not only metab-
olism to inactive water-soluble metabo-
lites, but also increased renal clearance
of these metabolites. During pregnancy,
renal plasma flow increases by 30%, while
the glomerular filtration rate increases
by 50% (Davison and Hytten,1975~.
Besides the physiologic changes in he-
patic and renal function, body fat content
usually increases, and mammary glands
enlarge during pregnancy. Highly lipid-
soluble compounds can be stored in those
maternal depots. Compared with an adult,
the fetus has little body fat; a lipid-
soluble chemical is distributed to what-
ever lipid is available. Lipid-soluble
chemicals-usually concentrate in the fetal
CNS because it composes much of the lipid
in the conceptus, and a large percentage
of the umbilical blood flow goes directly
to the brain (Stave, 1978~.
Accurate assessment of distribution
and biotransformation of a chemical in
the conceptus is hampered by inaccessibil-
249
ity. During the 1960s and early 1970s,
clinical data became available from thera-
peutic interruptions of pregnancies dur-
ing which drugs had been administered and
products of conception obtained and
analyzed for the parent chemical and its
metabolites (Miller et al., 1976~. Chose
investigations identified chemical dis-
tribution in single pregnancies at single
points. Information also is needed from
continuous sampling from individual pa-
tients over time. At term, continuous
sampling can be achieved with fetal scalp
blood sampling (Miller et al., 1976), in
which multiple samples are obtained during
the course of delivery.
Until recently, only direct fetal bi-
opsy of tissues provided information on
pharmacokinetic response; however, MRI
has demonstrated movement of paramag-
netic ions, such as manganese and gadolin-
ium glutamic-pyruvic transaminase, be-
tween mother and fetus in primates (Kay
and Mattison, 1986; Miller et al., 1987a,b,
1988; Mattison et al., 1988; Panigel et
al., 1988~. The potential to label chemi-
cals with carboni3 and determine their
distribution is an example of noninvasive
techniques that might resolve some prob-
lems; for example, identifying compart-
ments that can be measured to give an ac-
curate distribution index. Of the com-
pounds evaluated most frequently, heavy
metals and anticonvulsants have provided
the most information on exposure.
Observations made during human pregnan-
cy usually reflect chronic exposure
throughout pregnancy, and tissue, mater-
nal blood, and fluid concentrations re-
flect exposure, rather than response.
The placenta has been used as an exposure
index for many heavy metals, because they
are concentrated in it (Miller and Shaikh,
1983~. Maternal occupational exposure
and lead content in human placentas at term
have been measured, as have environmental
exposure from bath and drinking water (Mil-
ler et al., 1987a). Other studies have cor-
related an increase in cadmium in the pla-
centa with maternal cigarette-smoking
(Miller et al., 1987a). The amounts and
types of mercury compounds also have been
confirmed in the placenta (Miller, 1983~.
CVS might provide an early screen for en-
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250
vironmental exposures to heavy metals
(Fabro and Scialli, 1986~.
Early placental tissue and amniotic
fluid cells might be useful to assess the
presence of chemicals and their interac-
tions with fetal tissues. Shum et al.
( 1979) demonstrated that birth defects
due to benzoapyrene in the mouse were
caused not only by the genetic makeup of
the mother, but also depended on the fetal
genome and the ability of the conceDtus
TOXICI7~YDURING PREGNANCY
and is the substrate for AHH, the presence
of benzoapyrene and its metabolites could
be related to the effects of smoking on
fetal development; but no dose-response
relationship has been established for the
effects of smoking and for benzoapyrene
as a teratogen and perinatal carcinogen.
AHH induction in the human placenta is
related to the number of cigarettes smoked
per day and the enzyme activity reaches
its maximum at 20-25 cigarettes/day (Gur-
to metabolize benzoapyrene to putative too et al., 1983~. Demonstration of a dose-
reactive intermediates. That indicates response relationship is difficult, be-
that the conceptus might partially regu- cause of individual variation in genetic
late the consequences of therapeutic or composition and enzyme inducibility
environmental exposures. (Juchau, 1980; Gurtoo et al., 1983; Man-
Phenytoin, an anticonvulsant, is also
metabolized to putative reactive inter-
mediates via mixed-function monoxygen-
ases, whose expression can be controlled
genetically (Martz et al., 1977~. The
incidence of fetal phenytoin syndrome
might be low because the genetic makeup
of many conceptuses contains the alleles
of the less active monoxygenases. A case-
reported woman who had two consecutive
pregnancies during which she maintained
phenytoin therapy, but bore only one child
with phenytoin syndrome indicated that
identical exposures can affect fetuses
differently (Won" et al., 1 985a). Those
kinds of observations are not conclusive,
but suggest that the fetus might respond
uniquely to selected agents. If a specific
embryonic cell population could be sampled
and susceptibility of the conceptus to
phenytoin determined, then therapy or
environmental exposure could be modified.
The trophoblast might be a tissue for such
evaluations. Measurement of monoxygen-
ases or other xenobiotic metabolizing
enzymes could indicate the sensitivity
of the conceptus.
The placenta selectively metabolizes
xenobiotics and polycyclic aromatic hy-
drocarbons. Placentas of cigarette-smok-
ers produce 8-10 times as much arylhydro-
carbon hydroxylase (AHH) as placentas of
nonsmokers (Welch et al., 1969), although
not all placentas of smokers produce it.
Cytochrome P~-450 also has been identified
in the human placenta (Song et al., 1985;
Jaiswal et al., 1 985a). Because benzoa-
pyrene is a constituent of cigarette smoke
chester et al., 1984~.
The placenta might act as a filter to
prevent passage of reactive substances
into the conceptus. Fetal tissue—es-
pecially endothelium from the umbilical
vein-did not produce AHH from pregnant
women who smoked, but endothelial AHH ac-
tivity was induced in primary cell cul-
tures. The placenta might protect the
fetus from exposure to low-concentration
environmental pollutants (Manchester
and Jacoby, 1984; Manchester et al.,
1984~. Amniotic fluid cells also could
be used for these studies, but these cells
usually are not available until the end
of the first trimester.
Interactions with selected cellular
constituents other than enzyme induction
and inhibition can be assessed. Randerath
and associates (Randerath et al., 1981,
1985; Lu et al., 1986) have suggested that
examination of DNA adducts provides infor-
mation about the nature of environmental
chemical interaction with the genome.
Selected reproductive tissues-especially
the human placenta-have been used to de-
termine whether exposure to cigarette
smoke during pregnancy alters the DNA-
adduct pattern (Everson et al., 1986,
1 987~.
CURRENT AND PROMISING
MARKERS
Many markers of exposure to xenobiotics
are specific to one chemical and its reac-
tivity and distribution. For example,
the pharmacokinetics of methylmercury
OCR for page 251
PHARMACOKINETIC ASSESSMENTS
can be monitored with blood or hair con-
centrations (Clarkson, 1987~; but, if
2,3,7,8 -tetrachlorodibenzo-p-dioxin
is of concern, these concentrations are
not as useful as milk or adipose tissue
concentrations. Thus, the monitoring
site is as important as the sensitivity
of the analytic procedure.
Human hair reveals mercury exposure
for many months, and a dose-response rela-
tionship can be established on the basis
of hair and blood concentrations relative
to toxic outcome (Clarkson, 1987~. With
the exception of methylmercury, no human
dose-response relationships are available
for prenatal exposures to xenobiotic com-
pounds. The only similar examples are
based on at-term placental tissue analyses
for cadmium or lead and correlation of the
results with environmental exposure,
smoking, and pottery paint (Miller et al.,
1988~. Tissue analyses at delivery provide
little useful information other than docu-
mentation of exposure. Monitoring mater-
nal blood concentrations of drugs, such
as phenytoin, has assisted in maintaining
adequate control of seizures, but has shown
no correlation with teratogenicity
(Kuemmerle and Brendel, 1984~.
Studies have demonstrated that blood
from cigarette-smokers, cancer-chemo-
therapy patients, or patients on anticon-
vulsant therapy produces malformed em-
bryos when added to a culture medium of
embryos (Chatot et al., 1980; Klein et al.,
1980, 1982; Carey et al., 1984~. Such
techniques have been proposed as a screen
to identify populations at risk (Klein
et al., 1982~. However, epidemiologic
investigations have not been undertaken
rigorously.
Drosophila and bacteria have been used
in bioassays to screen amniotic fluid
(Bournias-Vardiabasis, 1985; Everson,
251
1987~. These screening procedures could
identify carcinogenic or teratogenic
properties of amniotic fluid. Other pro-
grams have used cultured human cells to
screen potential teratogens (Braun et al.,
1979, 1982; Yoneda and Pratt, 1981; Pratt
et al., 1982~; however, human fluids
have not been used. These procedures ap-
pear appropriate for human screening.
Recent studies measuring of DNA-adduct
patterns in human placenta and animal tis-
sue indicate that pattern of DNA adducts
can be a basis for separating chemicals.
Thus, the compounds or their reactive
metabolites that directly alter cellular
constituents might be identifiable
(Everson et al., 1987~. As noted earlier,
some DNA adducts in the human placenta are
correlated with cigarette-smoking
(Everson et al., 1986~. If very early tis-
sue samples could be obtained from the
conceptus and adducts could be measured,
risk to the conceptus could be determined.
CVS might prove useful in this regard.
Other promising techniques for investi-
gating biologic markers of exposure are
MRI and spectroscopy. Use of those tech-
niques in pregnant women is substantially
restricted; however, as knowledge con-
cerning the safety of MRI in humans becomes
more available, more extensive studies
will be undertaken. MRI and spectroscopy
are used primarily to examine the fetal
structure for malformations and to detect
placenta previa. However, the opportunity
to follow the distribution of compounds
selectively labeled with carboni3 or para-
magnetic ions is appealing. Studies in
nonhuman primates have demonstrated the
feasibility of this, as have studies in
the perfused human placenta. Nonetheless,
direct, noninvasive spectroscopy within
specific embryonic and fetal tissues is
in the future.
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Representative terms from entire chapter:
human placenta
