Biologic Markers in Reproductive Toxicology (1989) / Chapter Skim
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1. Report of the Oversight Committee
1. Report of the Oversight Committee
Pages 15-36
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From page 15... ...
This increase appears to be linked to several factors, including changes in the incidence of sexually transmitted diseases, but other factors, such as xenobiotic exposures, have not been well studied, and may contribute to reproductive impairment. The adverse effects on human reproduction of high doses of polychlorinated biphenyls, dibromochloropropane, and alcohol are well established, but the consequences of lower doses of these and other materials have not been well studied.
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From page 16... ...
Many diseases are now defined, not by overt signs and symptoms, but by the detection of biologic markers at the subcellular or molecular level. For example, liver and kidney diseases are often diagnosed by measuring enzymes in blood or proteins in urine; lead poisoning can be diagnosed on the basis of blood lead concentrations and such biologic changes as increases in heme biosynthesis components in red cells and urine; and many inborn errors of metabolism, such as phenylketonuria, are diagnosed on the basis of cell biochemistry, rather than expressed dysfunction.
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From page 17... ...
Few such biologic markers have been demonstrated to identify early stages of health impairment or toxicologically relevant internal doses. The detection of increased alpha-fetoprotein in a pregnant woman's serum and in amniotic fluid has been used to identify fetuses at risk of neural tube defects.
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From page 18... ...
BIOLOGIC MARS TABLE 1-1 Examples of Charactenstics of Exogenous Agents, Organic or Targets That Influence Choice of Biologic Marker Agent-specific characteristics Physicochemim1 properties Interactions Routes of exposure Exposure Exposure concentration Pattern of exposure Metabolism Activation Detonation Organism-specific characteristics Species Age Sex Physiologic state Pharmaco~netic characteristics Genetic factors Lifestyle factors Organ- or tissue-specific characteristics Location Blood flow Membrane permeability Transport Receptors Function Homeostasis Structure Physiologic state The committee has found it useful to define three general categories of biologic markers: those of exposure to chemical or physical agents, those of effects of exposure, and those of susceptibility to the effects of exposure. A biologic marker of exposure is an exogenous substance or its metabolite~s)
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From page 19... ...
Because such receptor sites are often not known, or are not accessible for sampling, it is frequently necessary to use a surrogate site for which the dose has been correlated with the biologically effective dose or the identifiable biologic effect at the target. There is a continuing need for the development of more accurate markers of internal dose that reflect the biologically effective dose.
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From page 20... ...
Diet alters intestinal motility and gastric emptying time, as well as the transport of specific substances, for example, diets low in iron appear to facilitate intestinal uptake of lead (Silbergeldetal., 1988~. The presence of active mechanisms of transport into an organ or tissue and the density of receptor sites can all influence internal dose and biologically effective dose.
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From page 21... ...
If exposure to a toxicant and internal dose is great enough, disease will develop, because the biologically effective dose will be sufficient to affect some function irreversibly or for a substantial period. Disease that occurs soon after exposure might be directly linked to the toxicant.
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From page 22... ...
. An intrinsic characteristic or pre-existing disease state that increases the internal dose or the biologically effective dose or that amplifies the effect at the target tissue can be a biologic marker of increased susceptibility (NIEHS, 1985; Omenn, 1986~.
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From page 23... ...
. A1though each of these tests has inherent limitations of specificity and sensitivity and varying predictive value as a biologic marker of male reproductive function (e.g., sperm density fluctuates daily, and sperm motility is difficult to measure)
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From page 24... ...
For example, a prenatal exposure that results in altered structure or function in the child or adult might be BIOLOGIC MARKERS difficult to identify on the basis of markers associated with the altered structure or function. Animal Models In validating biologic markers, animal models are useful for understanding mechanistic bases of the expression of markers and relationships among exposure, early effects, and disease.
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From page 25... ...
Sensitivity of Measurements Other general quality-assurance issues are related to sensitivity and specificity. Estimations of sensitivity must include considerations of the so-called background rate of events or concentrations likely to be found in persons without particular exposures, as well as considerations of the magnitude of external exposure or internal dose likely to be received by the population being sampled.
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From page 26... ...
USE OF BIOLOGIC MARKERS IN RISK ASSESSMENT Cellular and molecular markers can be powerful new tools for the assessment of risks associated with exposure to environmental toxicants. Markers that indicate the receipt of an internal, biologically effective dose or the induction of a disease process can be useful in hazard identification—i.e., as the qualitative step by which an environmental agent is causally associated with an adverse effect.
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From page 27... ...
Another major role of biologic markers pertinent to risk assessment is in clarification of the extent and distribution of exposure and effect in human populations, as well as of the variability and susceptibility among individuals in a population (Fowle, 1984; Perera et al., 1986~. EXTRAPOLATION FROM ANIMALS TO HUMANS The validity of a specific biologic marker for the identification of an adverse health effect depends on the reliability of studies that provide the background data, particularly on mechanisms.
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From page 28... ...
IMPLEMENTATION OF BIOLOGIC MARKERS IN POPULATION STUDIES The identification of biologic markers that indicate exposure, effect, or susceptibility is a complicated process involving studies in animals, refinements in laboratory assays, and studies in special human populations. Moreover, even when a marker has been validated in such studies, its use in larger populations is not straightforward.
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From page 29... ...
USE OF BIOLOGIC MARKERS IN REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY With the above general description of the concepts and definitions of biologic markers as background, the remainder of this report will focus on the use of biologic markers in reproductive and neurodevelopmental toxicology. Hypothetical examples of the utility of biologic markers follow.
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From page 30... ...
Biologic markers of internal dose might include maternal and fetal blood concentrations, amounts excreted by the mother in urine and feces, and concentrations in maternal or fetal tissues, including placenta. It might be possible to monitor for some metals in the target tissue with noninvasive techniques such as neutron activation or magnetic resonance imaging.
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From page 31... ...
Biologic Effects · Testicular Swelling · Decreased Testosterone · Decreased Libido · Altered Serum LH · Sperm Concentration · Changes in Sperm Quality and Function · Reduced Fertility I ncreased Heritable Mutations Health Monitoring ( Feces) Media for biologic monitoring FIGURE 1-2 Hypothetical male reproductive toxicant used in an industrial process and emitted into air.
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From page 32... ...
it\ 1 1 Ingestion Trac irato | ~ 3 ' 1 1 be, ( Blood / l l Kidney (,,l~ l Liver BIOLOGIC MARKERS Biologic Effects · Decreased Serum E2 · Increased Serum FSH · Menstrual Irregularity · Decreased Ovulatory Rate · Decreased Fecundity Health Monitoring Organs | O Media for biologic monitoring FIGURE 1-3 Hypothetical female reproductive toxicant with exposure through ingestion, skin, and inhalation. Top, potential environmental monitoring media and markers.
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From page 33... ...
. __ I ~ Blood Kidney ( Urine Biologic Effects Placental Function · Fetal Growth · Fetal Malformation · Fetal Death Health Monitoring Ingestion 1 ~ ~ I Liver I Organs Gl-Tract O Media for biologic monitoring FIGURE 1~ Hypothetical pregnancy to~ncant found in air, water, and some foods.
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From page 34... ...
a/ 3 0 Media tor biologic monitoring Internal Dose Indicators · Blood Level · Urine Level · Fecal Level · Enzyme Concentration Blood Urine · Hormone Levels Biologic Monitoring Biologic Effects · Cell Proliferation · Cell-Cell Interaction · Impaired Organ Growth · Impaired Organ Function Health Monitoring FIGURE 1-5 Hypothetical developmental tomcant found as a contaminant In food. Top, potential environmental monitoring media and markers.
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From page 35... ...
imperfect tests outweigh the difficulties that arise from low predictive values when the tests are used in individuals or communities with low a priori probability of exposure or disease. Careful consideration must be given to how a test for a biologic marker of exposure will perform in the field.
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