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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

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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

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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 tissuees- 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

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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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