sies and, more recently, neuroimaging studies (Riley et al., 1995; Sowell et al., 1996; Swayze et al., 1997) give an indication of central nervous system effects in humans. However, animal models—with experimental manipulation of alcohol exposure and direct examination of brain tissue—continue to provide crucial information. In the mouse, for example, exposure to alcohol on days 7 and 8 of gestation results in not only the typical facial deformities of fetal alcohol syndrome but also brain anomalies, such as small overall size and deficiencies in cerebral hemispheres, striatum, olfactory bulbs, limbic structures, the corpus callosum, and lateral ventricles. Exposure later in gestation generally does not produce such gross structural malformations but nonetheless kills nerve cells and interferes with synaptogenesis, formation of myelin, and other biochemical processes, including reduction of NMDA receptor binding in the hippocampus.

Research with humans also shows that the timing of prenatal alcohol exposure has differential effects (Connor and Streissguth, 1996; Institute of Medicine, 1996; Jacobson et al., 1993, 1998; Sampson et al., 1994; Streissguth et al., 1996a, 1996b). The unusual facial features of fetal alcohol syndrome in the human infant (e.g., low-set ears, short philtrum, cleft palate, cleft lip) appear to be due to heavy exposure early on, in the first trimester, when the structures that come together to form the face are developing. Fetal exposure to alcohol during the second and especially the third trimester of pregnancy appears to be a time of particular vulnerability for the impaired neurobehavioral development, although some data suggest that these effects extend throughout pregnancy. Dividing cells appear to be particularly sensitive to the toxic effects of alcohol, and hence a period during which extensive neurogenesis occurs would be a time of acute sensitivity to the effects of alcohol. The cognitive effects associated with exposure to alcohol later in pregnancy, for example, may be associated with the high level of neuronal cell division in pertinent parts of the brain that occurs during the third trimester.

The severity of exposure is another important factor in understanding ill effects, perhaps as important as the timing. For prenatal alcohol use, greater exposures are associated with worse effects. In addition, episodic binge drinking appears to be more harmful to the developing brain than equivalent levels of alcohol consumed steadily. Experimental animal studies indicate that ingestion of a given dose of alcohol over a short period of time generates a greater peak blood alcohol concentration than the same dose ingested over several days (Bonthius and West, 1990). Thus, the developing fetus is actually exposed to a higher level of alcohol in binge drinking and has been found in animal research to experience greater neuronal (Bonthius and West, 1990) and behavioral (Goodlett et al., 1987) impairment. In humans, binge drinking is more of a problem than is usually recognized, because moderate drinkers, who consume 1-2 drinks



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