Neurotoxicology and Teratology, Vol. 12, pp. 231-237. © Pergamon Press plc, 1990. Printed in the U.S.A. 0892-0362/90 $3.00 + .00 

Prenatal Alcohol Exposure: 

Comparability of Effects in 

Humans and Animal Models 

CYNTHIA D. DRISCOLL,* ANN P. STREISSGUTHt AND EDWARD P. RILEY:~ 

*Haskell Laboratory for Toxicology and Industrial Medicine 

E.I. du Pont de Nemours & Co., Inc., Newark, DE 19714 

1"Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA 

and (cDepartment of Psychology, San Diego State University, San Diego, CA 

DRISCOLL, C. D., A. P. STREISSGUTH AND E. P. RILEY. Prenatal alcohol exposure: Comparability of effects in humans and 

animal models. NEUROTOXICOL TERATOL 12(3) 231-237, 1990.--Much is known about the potential consequences of prenatal 

alcohol exposure through data developed in animals and man. However, little attempt has been made to compare the human and animal 

literature with respect to qualitative and quantitative similarities and differences. To this end, a comparison was made between the 

effects reported in humans following moderate levels of alcohol exposure and the neurobehavioral effects detected using animal 

models. A good deal of congruence was found with respect to qualitative endpoints. General functional categories, such as deficits in 

learning, inhibition, attention, regulatory behaviors, and motor performance were reported to be affected in both animals and children. 

Quantitatively, although the dose required to produce an effect differs across species, the resultant circulating blood alcohol levels are 

quite similar. In addition, while compelling data are limited, the magnitude of the observed effects are generally dose-related for both 

humans and animals. 

Prenatal alcohol Developmental toxicity Behavioral teratogenesis Developmental neurotoxicity 

EXPOSURE to ethanol during gestation has been associated with 

a variety of negative outcomes including perinatal death, compromised growth, and behavioral deficits (62). The identification of 

the Fetal Alcohol Syndrome (FAS) in 1973 by Jones and coworkers (21) stimulated a great deal of research, while earlier 

work by Lemoine and colleagues (28) had described similar 

characteristics in children of alcoholic mothers. Although diverse 

methodologies have been utilized, the weight of the evidence 

implicates ethanol as a developmental neurotoxicant. The extensive clinical and experimental literature provides a wealth of data 

for assessing the qualitative and quantitative comparability of the 

neurobehavioral effects seen across species following prenatal 

alcohol exposure. 

Three major types of research have contributed to our understanding of alcohol-related developmental toxicity: case, epidemiologic, and animal studies. Case studies and case/comparison 

group studies have provided a detailed clinical profile of FAS. The 

syndrome, recognized primarily in children of women with histories of heavy alcohol consumption, consists of pre- and postnatal 

growth retardation, distinctive facial anomalies, and central nervous system (CNS) abnormalities (21,22). While a diagnosis of 

FAS is specific to prenatal alcohol exposure, the term possible 

Fetal Alcohol Effects (FAE) is used for patients who have some of 

the characteristics, but not enough for a full diagnosis. 

Epidemiologic studies have provided information on the magnitude of neurobehavioral effects in groups of children following 

exposure to alcohol at levels which do not necessarily result in 

clinically significant morphological effects. In addition, other 

confounding factors which can influence development, e.g., 

smoking, nutrition, and other drug use, can be separated from the 

effects of alcohol exposure per se through the use of statistical 

adjustments. 

Animal studies and the development of appropriate animal 

models have provided a wealth of information about the effects of 

gestational alcohol exposure. A variety of neurobehavioral effects 

have been detected in animals following prenatal alcohol exposure 

(12,34). Although a spectrum of study designs have been employed, effects which are qualitatively similar to those described in 

children with a history of gestational alcohol exposure have been 

detected with these animal models (6). 

While many factors impact the precision with which estimates 

of human exposure can be made, the clinical data generally 

support the notion of a dose-response continuum for neurobehavioral effects. The magnitude of the effects are generally greater 

among the more heavily exposed children relative to the children 

of social drinkers. However, while the magnitude may differ, the 

general categories of CNS dysfunction are similar. For example, 

children with a history of prenatal alcohol exposure without a 

diagnosis of mental retardation may still display impaired cognitive performance, hyperactivity, attentional deficits, and motor 

dysfunction (51). 

This paper will highlight data from the Seattle Longitudinal 

Prospective Study on Alcohol and Pregnancy to compare effects in 

humans exposed to moderate doses of alcohol (54,64) to those 

231 
232 DRISCOLL, STREISSGUTH AND RILEY 

detected with animal models. Reference will also be made to 

clinical reports of children with FAS to provide a general basis of 

comparison for estimating dose-response relationships in humans. 

Although a comprehensive review of the prenatal alcohol exposure 

literature is not provided, several recent reviews are recommended 

[e.g., (34,51)]. 

RESEARCH METHODOLOGIES 

Alcohol teratogenesis has been a very popular subject of 

research. The expansive literature provides a rich resource for 

assessing the question of comparability between human and 

animal data. With quantity comes variety, and the literature also 

contains an abundance of methods. Factors such as time, dose, and 

duration of exposure obviously can have a significant impact upon 

the results obtained, regardless of the species tested. Before 

comparing the neurobehavioral data, some points concerning the 

animal models that have been employed in this research (5,41) and 

the assessment of exposure in humans will be discussed briefly. 

The primary method employed for administering alcohol to a 

pregnant animal has been by a liquid diet which serves as the 

animal's sole source of nutrition. Typically, in the rat, a diet 

providing 35% of the animal's daily caloric intake in the form of 

alcohol is administered during pregnancy. This design generally 

includes two control groups. The first is a group that is pairfed to 

the 35% group and receives a similar liquid diet with a carbohydrate substituted for the ethanol derived calories (EDC). This 

procedure equates the total daily caloric intake across groups and 

therefore, serves as a control for liquid diet administration and 

reduced caloric intake which is typical in the 35% EDC group. The 

second control group has continuous access to standard lab chow 

and water. If the alcohol group differs from both control groups, 

and the two control groups do not differ from each other, the effect 

may be attributed to alcohol or some interaction of nutrition and 

alcohol. 

Although with the liquid diet procedure the amount of ethanol 

intake is determined by how much the rat drinks, the average 

absolute alcohol intake typically varies between 10 and 14 

g/kg/day using a 35% EDC diet. Blood alcohol levels (BAL) of 

over 100 mg/dl (equivalent to 0.1% wt./vol.) are achieved during 

a substantial portion of the dark cycle when the rats consume the 

majority of their daily intake. 

Another frequently employed method involves gastric intubation. In this procedure, alcohol is mixed with a vehicle and 

administered directly to the stomach via a tube. Control groups, 

similar to those outlined above, are typically incorporated into the 

design. In rats, the doses administered are generally 4 to 8 

g/kg/day. Unlike the liquid diet method which produces a fairly 

consistent BAL throughout a good portion of each 24-hour period, 

intubation produces higher peak, but more transient, levels of 

alcohol. To increase the portion of the day with measurable BALs, 

the absolute daily dose has occasionally been divided into two 

administrations. Following intubation, peak BALs are often well 

over 200 mg/dl and the rats are obviously intoxicated. 

Since humans consume alcohol voluntarily, there is no experimental control (as there is in the animal studies) over the dose 

administered or the pattern of consumption. One way of dealing 

with this problem is to construct the most elementary summary 

score: the AA (average ounces of absolute alcohol per day), for a 

basic calculation of overall consumption in humans. For example, 

the average AA score of mothers of the Seattle cohort was 0.63 

prior to pregnancy recognition (a little over one drink per day on 

the average) and 0.25 at midpregnancy (half a drink per day on the 

average). However, the AA score alone does not differentiate 

between the woman who drinks 2 drinks every night and the one 

who takes 14 drinks once a week. While the continuous AA scores 

are useful in studying general dose-response questions, pattern 

scores reflecting binge vs. regular patterns of consumption are 

also necessary to understand the full impact of prenatal alcohol 

exposure on offspring development. Ways of dealing with this 

problem include characterizing patterns of consumption such as 

number of drinks per occasion or number of drinking occasions per 

month. 

Although BAL data are generally not available in human 

studies, the BAL concept is useful for comparing exposure levels 

across species. Due to differences in metabolism among species, 

the BAL, rather than the absolute dose of alcohol, provides a more 

meaningful estimate of compound bioavailability. For example, 

although an ethanol dose of 12 g/kg/day for a rat, which would be 

consumed using the liquid diet technique, is considerably greater 

than that reasonably anticipated to be consumed by a woman on a 

body weight basis, the BAL produced is not unrealistic for 

comparisons with human levels. Even the BAL produced by the 

intubation method (over 200 mg/dl) is in line with the BAL 

estimated to be achieved in women who give birth to infants with 

FAS (2). Therefore, BAL may provide a more useful basis for 

cross species comparison than the amount consumed. 

In studying alcohol teratogenesis it is difficult to draw direct 

comparisons between human and animal research for several 

reasons. In humans, actual dose is individually determined, not 

under experimental control, variable across days of the pregnancy, 

and represents many patterns of consumption. Actual exposure is 

further modified by the individual maternal and offspring response 

to ethanol as determined by genetic factors. The numbers used in 

our analyses to reflect "dose" can never reflect the true level of 

exposure to the fetus as it can in animal research. Findings from 

the Seattle Study are generally monotonic--the higher the presumed dose, the greater the effects on offspring (54). For some 

individual outcomes, we can take an arbitrary cutoff on some 

particular alcohol dimension and use this as a crude comparison 

with animal research. For example, there is a significant decrement in IQ between the group exposed at greater than AA 1.5 and 

the rest of the sample (53). This amount, which is not interpreted 

as a biological threshold, would correspond to BALs of around 

100 mg/dl if consumed within about an hour. This BAL would be 

similar to that achieved by a rat on the 35% EDC liquid diet. This 

is a level known to produce many of the neurobehavioral effects to 

be discussed in the qualitative comparison to follow. 

QUALITATIVE COMPARISONS 

The clinical data, in general, support the idea that prenatal 

alcohol exposure is associated with a continuum of effects, with 

heavier exposure being associated with more severe outcomes. 

Many of the animal studies conducted to date have focused on 

identifying and characterizing the potential effects of prenatal 

alcohol exposure. While dose selection has been narrow, concentrating on the upper end of the dose-response curve for neurobehavioral effects (e.g., 35% EDC), the animal data provide 

evidence for a continuum of effects. Similarities are also apparent 

among the clinical and animal data with respect to the types of 

effects detected for various functional categories of neurobehavioral assessment. 

The Seattle prospective longitudinal study has examined the 

effects of prenatal exposure related to levels of alcohol generally 

considered to be associated with social drinking. Less than 1% of 

these mothers reported alcohol-related problems. The children 

have been studied at a number of ages, including birth, 8 and 18 

months, and at 4 and 7 years. Children of social drinkers 

demonstrated (on average) long-lasting neurobehavioral effects, 
PRENATAL ALCOHOL EXPOSURE 233 

TABLE 1 

BEHAVIORAL EFFECTS FOLLOWING PRENATAL ALCOHOL EXPOSURE 

Humans Animals 

Hyperactivity, Reactivity 

Attention Deficits, 

Distractibility 

Lack of Inhibition 

Mental Retardation, 

Learning Difficulties 

Reduced Habituation 

Perseveration 

Feeding Difficulties 

Gait Abnormalities 

Poor Fine and Gross 

Motor Skills 

Developmental Delay 

(Motor, Social, Language) 

Hearing Abnormalities 

Poor State Regulation 

Increased Activity, 

Exploration and Reactivity 

Decreased Attention 

Inhibition Deficits 

Impaired Associative Learning 

Impaired Habituation 

Perseveration 

Feeding Difficulties 

Altered Gait 

Poor Coordination 

Developmental Delay 

Altered Auditory Evoked 

Potentials 

Poor State Regulation 

particularly on attention, memory, and motor development, while 

remaining within the range of normal intelligence. A wide range of 

neurobehavioral effects have also been found using various animal 

models including developmental delays, sensory-motor impairment, and learning dysfunctions. Qualitative examples of the 

continuum of effects associated with prenatal alcohol exposure in 

children and animals are numerous (Table 1). 

Feeding Difficulties 

Infants with FAS are frequently described as being "poor 

feeders" in that they have poor sucking skills and are easily 

distracted or fatigued while suckling (33, 35, 51). This may be one 

indication of an early CNS dysfunction. In the epidemiologic 

studies of children of social drinkers, sucking parameters were 

systematically assessed and were found to be among the most 

sensitive indices of maternal alcohol use. With a pressure transducer attached to a nonnutritive nipple, the more alcohol the 

newborns were exposed to gestationally, the longer they took to 

initiate sucking and the lower their sucking pressure (33). While 

there has been some speculation that these early feeding problems, 

which can be quite severe in children with histories of high levels 

of exposure, contribute to the postnatal growth deficiencies 

frequently seen in these individuals, these are more commonly 

regarded as independent CNS manifestations of alcohol teratogenesis. 

Rat pups exposed to alcohol prenatally also often display preand postnatal growth deficits and feeding difficulties. Up until 

about 9 days of age, alcohol-exposed rats demonstrate longer 

latencies to attach to the nipple of a test dam when compared to 

control pups (13). Young animals with a history of prenatal 

alcohol exposure also show reduced suckling pressure and an 

altered pattern of suckling while attached to the nipple of an 

anesthetized dam (44), although these effects were not apparent in 

15-day-old animals (43). 

State Regulation 

Tremulousness and jitteriness have been reported in neonates 

across a range of prenatal exposures, from those diagnosed with 

FAS to those whose mothers were social drinkers (16, 25, 36, 51). 

Sleep state disturbances have also been reported in children born to 

mothers with histories of heavy alcohol consumption (45,47). 

Infants exposed to more moderate amounts of alcohol in utero 

demonstrated poor habituation as measured on the Brazelton 

Neonatal Behavior Scale, and were characterized by a cluster of 

scores called "Low Arousal," representing frequent state changes 

at the low end of the arousal continuum, primarily alternations 

between awake and drowsy (52). As determined by real-time 

scoring of naturally occurring behaviors, prenatal alcohol exposure in the Seattle studies was also related to increased tremulousness, hand-to-face movements, time with eyes open, decreased 

vigorous bodily activity, and increased bead-tuming to the left 

(25). These are all behaviors that have been previously described 

as characteristic of infants at risk for poor developmental outcome. 

The one infant in this group with a diagnosis of FAS had extreme 

scores on all of these behaviors compared to offspring of social 

drinking mothers. 

Assessment of state regulation has been studied more systematically in the clinical setting than in animal model evaluations. 

There is, however, some indication that state regulation is also 

affected in exposed rats. For example, alcohol-exposed offspring 

thermoregulate poorly until approximately 10 days of age and the 

difference relative to controls is not simply a function of their 

smaller body size (65). Like human infants they also take longer to 

habituate to redundant stimuli. Rat pups typically show an increase 

in respiration when a novel odor is presented. The polypnea 

decreases as the novelty of the odor decreases. Rat pups exposed 

to alcohol in utero also take longer to habituate to a novel odor 

than controls (9). 

Reflex Development and Motor Function 

Prenatal alcohol exposure has also been related to deficiencies 

in reflex development, i.e., weak reflexes, particularly decreases 

in strength of movement, neck tone on the pull-to-sit, glabella 

reflex, knee-jerk reflex, extension of legs when supine, and 

increased frequency of spontaneous startles (50). Clinically significant delayed motor development is frequently observed in 

young children with FAS/FAE (22, 24, 49). Small but statistically 

significant delays in motor development during infancy have also 

been observed in children of social drinking mothers (55). 

On the Wisconsin Fine Motor Steadiness Battery, prenatal 

alcohol, at the level of social drinking, was associated with several 

types of performance decrements including total errors and latency 

to correct errors on groove and maze boards (8). Qualitative scores 

of fine motor functioning derived from examiner ratings were also 

associated with prenatal alcohol exposure. Gross motor function 

deficits, particularly balance, were associated with prenatal 

alcohol exposure, but coordination and distance measures were 

not different from controls (8). Axial ataxia (particularly problems with balance and gait) and kinetic tremor have also been 

noted in children with FAS who were born to alcohol-abusing 

mothers (30). 

Rats exposed to alcohol prenatally also show deficits in reflex 

development and tasks that require balance and motor coordination. Developmental indices which require coordination such as 

the righting reflex (48) and negative geotaxis (27) are delayed. 
234 DRISCOLL, STREISSGUTH AND RILEY 

Preweanling animals exposed to alcohol in utero also had more 

difficulty than controls in staying on a rotating drum, and fell off 

an inclined plane at a less steep angle (3). Walking pattern or gait 

is also affected by prenatal alcohol exposure in rats. Alcoholexposed animals exhibited significantly shorter stride lengths, had 

an increased angle of placement of the hind paws, and had less 

symmetry in their gait relative to controls (19). 

Hyperactivity and Attention Deficits 

Hyperactivity is the most frequently reported behavioral problem in children with FAS (62). While hyperactivity is most 

marked during the preschool years, it is often superseded by 

attentional deficits in the early school years and restlessness and 

agitation in adolescence and adulthood. It seems likely that these 

are all behavioral manifestations of the same pathological processes induced by prenatal alcohol. 

In the Seattle study, alcohol-related attentional deficits were 

noted on the first day of life on the habituation component of the 

Brazelton Scale (51). Attention and reaction time in the 4-year-old 

children were evaluated with a computer-operated vigilance task. 

The child watched a large model of a Victorian house and had to 

respond whenever a cat appeared in a window. Prenatal alcohol 

exposure was associated with more errors of omission (failure to 

press the key when the cat appeared), more errors of commission 

(pressing the key when the cat was not visible), and a smaller ratio 

of correct responses per total number of responses (63). Additionally, prenatal alcohol was related to increased reaction time on this 

vigilance task. The higher the exposure, the longer the reaction 

time and the less accurate the performance on all measures. 

Alcohol-related attentional deficits in four-year-old children born 

to social drinking mothers have also been reported in a separate 

study which employed naturalistic observations in the children's 

homes (26). 

The vigilance findings in 4-year-old children have been replicated with the Seattle cohort at 7 years of age, suggesting that 

these attentional problems are persisting into the school age years 

(57). Errors of commission were most strongly related to prenatal 

alcohol exposure at 7 years. These are impulsive errors in which 

the child presses the response key when the target stimulus is not 

present; this may represent an underlying difficulty with response 

inhibition. 

Deficits in response inhibition have been well studied in animal 

models. When tested in a T-maze without any extrinsic rewards, 

rats typically alternate between the two arms of the maze. This 

tendency to spontaneously alternate develops at the same time as 

cholinergic inhibitory systems are maturing in the rat and therefore 

the tendency to spontaneously alternate is thought to reflect 

inhibitory tendencies. When tested at 21 days of age, alcoholexposed pups showed more perseverative behavior, taking more 

trials than controls prior to their first alternation (40). Testing at 

older ages did not discern alcohol-exposed offspring, suggesting 

that prenatal alcohol exposure delays the development of certain 

inhibitory systems (1). 

Other behavioral dysfunctions reported in animals following 

alcohol exposure during gestation can also be attributed to response inhibition deficits. Perhaps the most common finding 

following prenatal alcohol exposure is an increased level of 

activity or exploration. This has been reported in open-fields (11 ), 

running wheels (31), and in nose-poke and head-dip tests (42). 

The overactivity is thought to be due to an inability to inhibit 

activity and/or exploration or as a deficit in habituation to a novel 

environment. Alcohol-related overactivity, at least as measured in 

the open-field, appears to be both dose and age-related. Weanlings 

and animals tested in old age typically are more active than 

controls, while adolescent or mature subjects are not (1,4). Many 

of the deficits in learning discussed below can also be interpreted 

as inhibition deficits. 

Learning and Intelligence Indices 

Mental retardation is a common manifestation of children with 

a diagnosis of FAS (62) and the more severe the diagnosis, the 

greater the level of retardation (60). Children with FAE may also 

be retarded, but their average intellectual functioning generally 

falls in the borderline range of intelligence (61). Even groups of 

children of alcoholic mothers, selected without respect to the 

physical manifestations of FAS/FAE, have repeatedly been shown 

to have significantly lower IQ scores than matched comparison 

groups without alcoholic mothers (7, 18, 23, 61, 62). 

The Seattle study examined learning and intellectual functioning in children of social drinkers from day 2 through year 7. Two 

simple operant paradigms were used to study learning in neonates, 

an operant head-turning paradigm and an operant sucking paradigm (32). In both paradigms, infants whose mothers were both 

drinking and smoking during pregnancy took longer to extinguish 

a response once it was learned. Such infants continued to perseverate in making the conditioned response even when the response 

was no longer reinforced, thus prolonging the extinction period. 

At 8 months of age, small but statistically significant relationships between prenatal alcohol and mental development on the 

Bayley scales were observed. At 4 years of age, social drinking 

during pregnancy was related to significantly lower IQ scores on 

the WPPSI, although mean scores were well within the normal 

range (53). Low birthweight alone was not a marker for those 

alcohol-exposed children who later demonstrated IQ decrements. 

However, children who had been classified at birth by a dysmorphologist as having FAE, based on the presence of microcephaly, 

certain minor physical anomalies, and growth deficiency (20), 

were at increased risk for lower IQ at age four, compared to 

similarly exposed children without newborn characteristics of 

FAE (53). 

These findings continued to hold up when the Seattle cohort 

was tested at approximately 7 years on the WISC-R. Prenatal 

alcohol exposure was again associated with lower, but still 

normal, IQ, Performance IQ and Verbal IQ (56). Two subtests 

from the WISC-R, Digit Span and Arithmetic, were most highly 

associated with prenatal alcohol, reflecting attention and memory 

deficits (46). On the Wide Range Achievement Test (WRAT-R), 

alcohol-related deficits in arithmetic skills were also observed 

(46). On a neuropsychological battery, prenatal alcohol was 

related to deficits in spatial memory and integration, verbal 

memory and integration, flexible problem solving, and attention 

(58). Behaviorally, alcohol-exposed children were rated as more 

distractible by examiners (58). Classroom teachers also rated them 

as less cooperative and more impulsive. They also had more 

difficulty with grammar, information retention and comprehension 

in their respective classrooms (46). 

These results from the Seattle study are consistent with studies 

on children of alcoholic mothers and children with FAS, which 

have revealed persisting problems with perceptual-motor development, academic achievement (particularly arithmetic), attention, 

and impulsivity during the school-age years (7, 18, 24, 49, 59, 61, 

62). The magnitude of the effects seen in the offspring of social 

drinkers is, however, generally smaller than reported in children 

diagnosed with FAS who have experienced higher levels of 

exposure. 
PRENATAL ALCOHOL EXPOSURE 235 

In young rats, exposure to alcohol in utero is associated with 

poorer associative learning (10,37). Alcohol-exposed pups tested 

as young as 3 days of age showed deficits in associating a specific 

odor with reward (10). Learning deficits in weanling rats were 

among the first effects reported using animal models to study the 

effects of prenatal alcohol exposure. Passive avoidance is a 

relatively easy task for even a young rat to learn and requires the 

animal to remain in one location to avoid shock. Young rats with 

a history of prenatal alcohol exposure took longer than controls to 

learn this task. When older animals were tested, alcohol-exposed 

rats no longer showed a deficit in learning (39). This is probably 

due, in part, to the relatively simple nature of the test which does 

not present a challenge to the typical adult rat, or even those 

known to have substantial brain damage. 

Reversal learning is also disrupted by prenatal alcohol exposure 

(40). Following the acquisition of a simple left-right discrimination, animals had to learn to go to the side opposite that initially 

learned. Animals exposed to alcohol in utero took more trials and 

made more mistakes per trial than did the controls. These effects 

have also been shown to be age-dependent. Alcohol-exposed 

offspring have been reported to show learning deficits on numerous tests including operant learning paradigms, two-way active 

avoidance, and simple discriminations (38). More recently, deficits in spatial learning tasks, such as the Morris maze, have also 

been reported (17). Importantly, these more complex tasks have 

revealed deficits even in alcohol offspring tested as adult. 

Transient Effects: How Important Are They? 

The animal data outlined above cited many examples of 

age-dependent effects. Similar examples exist from the Seattle 

Study where, for example, prenatal alcohol exposure was associated with small decrements in mental and motor development at 8 

months, not at 18 months, but again at 4 and 7 years. Perhaps the 

Bayley scales at 18 months did not provide a sensitive enough test 

of the subtle effects of prenatal alcohol exposure at this age, or 

perhaps the most salient age-appropriate outcomes (such as language) were not measured adequately. These null findings demonstrate the importance of employing sensitive endpoints for 

behavioral teratology studies, the inconclusive nature of a single 

set of negative results, and the necessity for studies to incorporate 

longitudinal assessments of various outcomes. It should also be 

noted that such discrepancies are also more likely to be encountered at the lower end of the dose-response curve, i.e., children 

with FAS usually demonstrate delayed development across all 

ages of assessment (51, 59, 61). Although the effect of alcohol on 

some endpoints may be inconsistent across time, the significance 

of deficits detected at earlier ages should not be underemphasized. 

Careful consideration of the age and abilities of the subject (rat or 

child) at the time of testing is paramount. 

QUANTITATIVE COMPARISONS 

As mentioned previously, the quantitative data for humans and 

animal models are insufficient for clearly characterizing doseresponse relationships. The rat studies are limited because they 

typically have concentrated on the upper end of the dose-response 

curve for studying the behavioral teratogenicity of ethanol and the 

majority of studies have been conducted with only one level of 

alcohol exposure. However, in a few reports, dose-response 

effects of prenatal alcohol were detected after exposure to diets 

containing as little as 11% EDC (29,42). The human literature 

cannot specify exposure levels with the exactness of the animal 

studies. Although the BAL index can only be applied to existing 

data in a general fashion, efforts should be made to incorporate 

quantitative assessment of alcohol exposure in future studies. 

In an attempt to establish dose-response data in a nonhuman 

primate model of prenatal alcohol exposure, macaques were 

exposed to one of 6 doses of ethanol once weekly during gestation 

(14). Absolute alcohol administration per exposure was within the 

range of possible human exposure (0.3-4.1 g/kg/week). In addition, measured BALs were also within the range of human 

exposure, albeit in the 'abuse' zone at the higher levels. Evidence 

of CNS dysfunction was produced at levels which did not result in 

obvious physical anomalies. Although the sample size of this 

study was small, the attempt to correlate BAL with specific 

dysfunctional outcomes is an important step in understanding 

dose-response relationships following prenatal exposure to alcohol. Additional work employing similar designs should be encouraged. Obviously, further consideration needs to be given to the use 

of indices of exposure other than the administered dose, such as 

BAL, in the calculation of acceptable exposure measures. 

CONCLUSIONS 

Researchers have characterized a great number of effects in 

offspring exposed to alcohol prenatally. Although a variety of 

neurobehavioral tools of varying sophistication have been employed, there is little doubt that ethanol could be detected as 

having the potential to produce adverse effects in exposed offspring at or below levels which would also be considered toxic to 

the mother. If little or nothing was known of alcohol's potential to 

affect the developing offspring, simple assessments of body 

weight, activity, development and function could be used to detect 

developmental toxicity. The use of additional tools could provide 

further characterization of effects and elucidation of mechanisms, 

however, they would not be necessary for making the initial 

determination of toxicity vs. no toxicity. Since the developmental 

neurotoxicity battery of tests proposed by the U.S. EPA (see other 

papers from this workshop) includes various parameters of growth 

and development prior to weaning, EtOH would have been 

detected as a developmental neurotoxicant. Other aspects of the 

EPA proposed battery would have further characterized the effects 

of EtOH, but would not have been necessary to implicate EtOH as 

a developmental neurotoxicant. 

Prenatal alcohol exposure has been shown to affect a wide 

variety of neurobehavioral outcomes in humans, with effects of 

greater magnitude associated with higher levels of exposure. There 

is no indication that the effect of prenatal alcohol exposure 

attenuates with increasing age of the child, although some findings 

may be more specific to certain ages. The epidemiologic studies 

have, in general, adjusted statistically for a wide variety of 

potentially confounding factors that must be considered in human 

behavioral teratology studies, such as other prenatal exposures, 

maternal nutrition and socio-demographic variables that might be 

associated with either genetic or postnatal environmental influences on human development. 

The comparison between findings in humans and animals 

exposed to alcohol in utero are fairly congruent. There is a sizable 

body of data indicating deficits in learning, inhibition, attention, 

regulatory behaviors, and motor performance. While the comparisons between human and animal data are primarily qualitative 

in nature, the degree of correspondence is noteworthy. The 

doses reported to have effects in animals are representative of 

the blood alcohol levels achieved in humans and there appears to 

be a reasonable dose-response relationship in both humans and 

animals. 
236 DRISCOLL, STREISSGUTH AND RILEY 

ACKNOWLEDGEMENTS 

This work was supported, in part, by Research Scientist Development 

Award No. AA00077 (E.P.R.) and by the U.S. Department of Health and 

Human Services, Grant Numbers AA01455-14 (A.P.S.) and AA03249 

(E.P.R.) from the National Institute on Alcoholism and Alcohol Abuse. 

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