Biologic Markers in Reproductive Toxicology (1989) / Chapter Skim
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24. Introduction
24. Introduction
Pages 265-272
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From page 265... ...
Lead, the neurotoxicant with the largest neurotoxicologic data base, is used as a paradigm to examine some of the methodologic issues inevitably encountered in the pursuit of a valid collection of markers. Many discussions of biologic markers and development focus on using markers to ascertain effects of xenobiotic substances on development.
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From page 266... ...
The ability to determine multiple compounds and their breakdown products is critical, because exposures rarely involve pure substances; the blood of people reportedly exposed In Japan and Taiwan to PCB-contaminated rice oil contained products of thermal degradation, such as dibenzofurans (Chen et al., 1981; Kashimoto et al., 1981~. PCB isomers have different half-lives and different biologic effects with respect to enzyme induction (Safe et al., 1985)
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From page 267... ...
Other pharmacokinetic changes during pregnancy include decreased and erratic absorption from the intestine, increased blood volume, increased total body water, decreased protein binding due to a decrease in serum albumin concentration and an increase in endogenous displacing substances, increased glomerular filtration rate, and generally increased renal and hepatic clearance of many xenobiotics. Basing interpretation of body burden of a given lipid-soluble, slowly cleared compound on an isolated blood or serum concentration is extremely difficult.
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From page 268... ...
The toxicity of various halogenated aromatics in different species is correlated with the affinities of various analogues for the receptor and with characteristics of the receptor in specific species and strains. Results of animal studies show that genetically determined receptor differences are correlated with inducibility of specific cytochrome P-450 and with toxic outcomes of exposure to polycyclic aromatic hydrocarbons, including carcinogenesis and teratogenesis (Nebert NEURODE^LOPMENT~ TOMCOL~Y and Jensen, 1979~.
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From page 269... ...
Similarly, vast differences among species in placental derivation and structure make cross-species extrapolation questionable. At-term placenta markers include quantification of halogenated aromatic compounds, determination of histopathologic changes, determination of enzyme induction status, determination of presence and characteristics of aryl hydrocarbon receptor.
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From page 270... ...
Many data are available on kinetic differences, but more work is needed on receptor maturation, response to enzyme inducers, and pharmacodynamic differences, including unique CNS responses of the immature brain; e.g., phenobarbital and antihistamines produce excessive excitation in infants and children and sedation in adults at comparable blood concentrations (MacLeod and Radde, 1985~. Physical examination of newborns exposed to halogenated aromatic compounds should be comprehensive and quantitative (including weight, height, head circumference, and such other measurements as internal and external canthal distances)
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From page 271... ...
Determination of aryl hydrocarbon receptor and P~-450 induction by molecular techniques in available cell types will add to a comprehensive picture of the effects of prenatal exposure on newborn drugmetabolizing capacity. Appropriate psychometric testing of newborns also should be performed for later comparison with results of followup studies.
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From page 272... ...
The simultaneous observation of symptoms, monitoring of persistent specific chemicals, assessment of inducibility of AHH in lymphocytes, and continual monitoring of P~-450 metabolism status will allow determination of the health implications of exposures and induction. Growing understanding of individual differences in inducibility, perhaps related to differences in aryl hydrocarbon receptor characteristics, might make it possible to divide the population with respect to these variables and health outcomes, including long-range susceptibility to cancer.
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