Drinking Water and Health, Volume 6 (1986) / Chapter Skim
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2. Developmental Effects of Chemical Contaminants
2. Developmental Effects of Chemical Contaminants
Pages 11-34
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From page 11... ...
The frequency and type of structural anomalies are determined by gross inspection of the fetuses and by detailed skeletal and soft tissue analysis. The occurrence of embryo death precludes measurements of growth retardation or identification of malformations, because these two end points are noted only on live fetuses.
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From page 12... ...
The main reason for conducting developmental toxicity studies is to ascertain whether an agent causes specific or unique toxic effects on the conceptus. If these studies are conducted under extreme conditions of maternal toxicity, then identification of exposures uniquely toxic to the conceptus or pregnant animal is not possible.
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From page 13... ...
During that period, there are highly specific periods of vulnerability for different organ systems, thus making the embryo extremely susceptible to the induction of structural birth defects. The periods when the major embryonic organ systems of the rat are most sensitive to teratogenic insult are shown in Figure 2-1.
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From page 14... ...
Insult at these later developmental stages leads to a broad spectrum of effects that can generally be manifested as growth retardation, functional disorders, or transplacental carcinogenesis. The fetus is more resistant to lethal effects than is the embryo, but the incidence of stillbirths is measurable.
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From page 15... ...
If the dose is increased beyond that causing malformations of the entire litter, embryo death can occur, but often in conjunction with maternal toxicity. Fetal malformations are usually accompanied by growth retardation.
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From page 16... ...
As the dosage increases, however, embryo death predominates until the entire litter is resorbed. Growth retardation can precede both outcomes or parallel the malformation curve.
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From page 17... ...
When such a pattern is observed, it is necessary to conduct additional studies with doses within the range causing growth retardation and embryo death. Results obtained at these intermediate doses can indicate whether teratogenicity has been masked by the deaths of the embryos.
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From page 18... ...
In safety studies, the usual sequence of testing begins with dose rangefinding studies in relatively small numbers of pregnant rodents. On days 6 through lS of gestation, animals are exposed to the test agent at doses up to and including those causing limited maternal toxicity or developmental toxicity (e.g., death or severe growth retardation)
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From page 19... ...
For instance, an agent that induces cleft palate in the mouse may elevate the frequency of spontaneous abortion or intrauterine growth retardation in humans. Any manifestation of exposure-related developmental toxicity in animal studies can be indicative of a variety of responses in humans (Kimmel et al., 19841.
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From page 20... ...
Most studies of humans focus on the examination of adverse effects, such as major malformations, stillbirths, low birth weight, and neonatal deaths, at the time of birth or later. Underestimation of adverse pregnancy outcome, and thus true risk and pattern of response, is unavoidable in human studies whenever measurements are made only from the time of birth onward.
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From page 21... ...
Only 20 of these are confirmed or suspected developmental toxicants in humans. Consequently, the major concern in risk assessment today is that far more agents have been shown to be positive in animal studies than have been identified in human studies for
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From page 22... ...
Estimates of risk from exposure to individual chemicals are usually based on animal data alone. An understanding of the potential for underestimating human reproductive risk in epidemiological studies is important in the selection of the safety factor.
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From page 23... ...
Thus, it only took several cases to elevate the incidence of these lesions far above the background. Most developmental toxicants tested in animal and human studies cause more common effects, such as intrauterine growth retardation and increases in the occurrence of minor anomalies and variants rather than major malformations.
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From page 24... ...
incidence of common variants and minor anomalies, are taken into consideration, a more sensitive appraisal of developmental toxicity can be obtained. The influence on power attributable to the end point's historical variability is illustrated in Table 2-4, which shows the number of litters of different strains of rats and mice that would be required to detect 5% and 10% changes in fetal weight or embryo death.
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From page 25... ...
It is generally accepted that developmental toxicity in the form of increased resorptions and decreased fetal body weight can occur at maternally toxic dose levels. The role of maternal toxicity in the induction of congenital malformations is not clear, however.
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From page 26... ...
Compounds in the third category were structurally unrelated to test agents administered at maternally toxic doses that caused increased resorptions and decreased fetal body weight. The characteristic pattern of defects induced by these agents was exencephaly; open eyes; fused, missing, or supernumerary ribs; and fused or scrambled sternebrae.
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From page 27... ...
A low level of concern should be attached to common variations observed in animals, especially if they are the only effects observed and if they only occur in conjunction with maternal toxicity. Greater importance should be given to variations that are dose related or that occur at doses not maternally toxic.
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From page 28... ...
RISK ASSESSMENT Quantitative Assessment of Developmental Toxicity Investigators concerned with the regulatory aspects of risk assessment have focused on the development of a quantitative index for comparing developmental toxicity across species, taking into account concurrent maternal toxicity. Underlying this approach is the perceived need to distinguish between compounds that are uniquely toxic to the embryo and those that induce developmental toxicity at exposure levels that are also toxic to the mother.
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From page 29... ...
Selection of the safety factor could then be based on the severity of the end point. Existing models for quantitative risk assessment do not appear to be adequate for developmental toxicity data.
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From page 30... ...
· Compounds causing developmental toxicity at levels well below those causing maternal toxicity constitute a greater level of risk than compounds causing developmental toxicity only at maternally toxic doses. This greater degree of risk should be reflected by application of a larger safety factor.
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From page 31... ...
Guidelines for Studies of Human Populations Exposed to Mutagenic and Reproductive Hazards. Proceedings of conference held January 26-27,
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From page 32... ...
1982. The relative teratogenic index and teratogenic potency: Proposed components of developmental toxicity risk assessment.
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From page 33... ...
1984. Maternal toxicity A possible factor in fetal malformations in mice.
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From page 34... ...
1973. Environment and Birth Defects.
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