|
Items in cart [0] |
Questions? Call 888-624-8373 |
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 191
On the identification and
Measurement of
Chemical Time Bombs:
A Behavior Development Perspective
Norman A. Krasnegor
As a society, we in the United States take it as a given that our
children have the right to develop normally. Moreover, our govern-
ment takes a keen scientific and legislative interest in how to protect
our population, both young and old, from the ill effects of chemicals,
environmental pollutants, and contaminants of the food supply. The
tragedies of thalidomide and diethylstilbestrol (DES) sensitized basic
scientists, clinicians, and legislators to the dangers associated with
the administration of drugs prenatally and to the health and well-
being of the developing neonate (Krasnegor, 1986~. Further, evidence
is accumulating that not all the damage suffered by the developing
fetus exposed to toxicants during gestation results in physical or
neurochemical anomalies. Rather, the effects upon the perinate, exposed
to chemicals, may well be manifested in psychological or behavioral
changes such as irritability, impaired learning ability, hyperactivity,
or reduced capacity for information processing (Krasnegor, 1986~. It
is therefore incumbent upon public health officials, clinicians, and
scientists to discover those substances that may be harmful to the
fetus and thereby affect an individual's behavioral development from
birth. This chapter focuses upon an elucidation of new and proposed
approaches for identifying substances (chemicals, drugs, etc.) that
may put the developing human at risk for developmental disability.
191
OCR for page 192
92
NORMAN A. KRASNEGOR
METHODOLOGICAL CONSIDERATIONS
Developmental behavior toxicology is a field of research devoted
to the goals of discovering and elucidating abnormalities in develop-
ment as a consequence of exposure to drugs or other chemicals
(Thompson, 1986~. Researchers in this domain of science are faced
with formidable methodological problems. In the course of their
studies, they are constantly faced with the task of separating devel-
opmental variables from toxicological and other environmental ones.
The developing organism's rapidly shifting behavioral baseline poses
special mensurational difficulties. For example, an organism may
exhibit one set of behaviors early in development. These may subse-
quently disappear from the repertoire only to reappear later in ontogeny.
This state of affairs is commonly observed, particularly in the perinatal
period of development. Without detailed knowledge of this phe-
nomenon, one may erroneously conclude that a toxicant has produced
the change.
Another common problem concerns the issue of developmental
delay. Large individual differences in when behaviors of interest ap-
pear in an organism's repertoire are to be expected. Therefore, precise
knowledge of the expected variability is essential to help differenti-
ate between conclusions of a substance's toxic effects on behavior
and its natural ontogenesis. Experimental paradigms that are appropriate
for assessing the effects of a drug on mature organisms may not
suffice for very young ones. Because the effects of a putative toxicant
may result in damage to the formation of central nervous system
(CNS) structures, which in turn may affect the development of behavioral
processes later in life, researchers may be forced to adopt a longitudinal
design. This tactic, although deemed appropriate for the problem
under study, can significantly increase the cost of research and delay
the publication of data.
Another set of questions involves the choice of baselines that should
be used to assess whether a substance has the potential for being
behaviorally toxic. Should experimental paradigms be employed or
should "naturalistic" behaviors be used? Is it better to study learning
(classical or operant conditioning), conduct open field studies, or in-
vestigate the social and emotional attachment of the neonate to its
care giver? Answers to these queries are contingent to some extent
on the questions being posed and the extant knowledge concerning
the developmental trajectory of the behaviors in question. These
tactical judgments are also based in part upon the availability of ex-
perimental paradigms that can be employed with perinates and the
behavioral mechanisms believed to be affected by the putative toxicant.
OCR for page 193
IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS ]93
A critical issue that confronts researchers in this field of inquiry is
what subject should be employed to assess toxicity. Clearly, studies
which employ prospective designs with substances that are suspected
of having behaviorally toxic activity must employ animal models. A
traditional choice for behavioral toxicity studies has been laboratory
rats. The rationale for their use is based upon the enormous literature
available on aspects of their behavior, physiology, and neurobiology.
However, depending on the question, other organisms may be much
better suited than rats. For example, caffeine use by pregnant women
has been questioned as a potential behaviorally toxic agent. More
specifically, its first metabolite, methylxanthine, has been the subject
of recent studies designed to determine its potential for affecting
behavioral development. The subject chosen for the study was the
female rabbit and her offspring. The decision to use this animal was
based upon the fact that rabbits metabolize caffeine much as does
man (Denenberg, personal communication, 1988; Denenberg et al.,
1986~. Further, the natural behaviors of the offspring and its interaction
with its mother early in development have been well studied in this
animal. Thus, rabbits became the logical choice for studying this
important question concerning exposure of the fetus to methylxanthine
during gestation.
A number of other methodological issues are also unique to the
study of behavioral toxicity in the developing organism. Dosing pa-
rameters, including amount, route, and when during gestation, are
all important considerations in undertaking studies of the developing
organism. The planning for dose-effect relationships, Enough not
unique to the study of young organisms, should be included in any
comprehensive study of behavioral toxicity. Cross-fostering controls
must be employed to obviate the effects that toxic substances may
have on maternal behavior, which therefore affect normal mother-
offspring interactions. Also of importance is the issue of when, after
dosing (the developmental stage), the offspring should be tested.
In summary, the methodological issues associated with the detection
of behaviorally toxic substances are both numerous and complex.
Meticulous attention must be paid to these methodological details
because failure to do so could lead to erroneous conclusions about
the behavioral toxicity of a chemical or drug that may be quite beneficial.
APPROACHES TO DETECTING BEHAVIORALLY
TOXIC SUBSTANCES
Two approaches are generally employed to determine whether a
substance of interest has behavioral toxicity. The first depends upon
- - - r -- -°
OCR for page 194
194
NORMAN A. KRASNEGOR
the availability of epidemiological data that can provide a statistical
basis for evaluating the morbidity and mortality associated with a
substance. Based upon such knowledge, one might design experi-
mental studies, employing animal models, that can assess dose-response
relationships between a substance and putative effects upon behavioral
development. The second approach employs animal models to screen
substances for behavioral toxicity. This tactic is the one most fre-
quently used because regulatory procedures require testing prior to
the release of a drug or chemical for use. Screening is a much more
complex strategy because one is not sure what types of behavioral
effects to expect or when during development they will be manifest.
A typical approach to identifying substances that may impair normal
behavioral development is to employ an animal model (e.g., laboratory
rats). Pregnant females are administered the substance of interest.
Dosing parameters, when dosing occurs, route of administration, how
often, etc., are all variables that are predicated upon the best scientific
information concerning when the substance is believed to undermine
mechanisms that affect behavioral development. Typically, too, the
knowledgeable behavioral toxicologist will cross-foster the offspring
postnatally. He will raise the pups, who were exposed prenatally,
until they attain the developmental stage of interest and then test
them to ascertain whether the substance of interest produces effects
upon behavior.
Two categories of substance are of great interest to those who study
developmental behavioral toxicology. These are drugs given to pregnant
females for preexisting medical conditions or drugs associated with
pregnancy and anesthetics associated with delivery. A short review
of the literature associated with one class of drugs the barbiturates,
given in association with quality medical care to pregnant human
females, is provided below.
Reyes et al. (1986) reported that pregnant rats given high doses of
phenobarbital (10 times the therapeutic dose) had significant increase
in pup mortality and decrease in birth weight of offspring. Voorhees
(1985) and Middaugh (1986) both reported biochemical and behavioral
anomalies in rat and mouse pups, respectively, after prenatal exposure
to low levels of barbiturates. Changes in activity level, learning capacity,
and seizure threshold in rodents were reported after early exposure
to barbiturates (Chapman and Cutler, 1983; Diaz, 1978; Middaugh et
al., 1981; Yanai et al., 1981~.
In addition to these findings, researchers also report changes in
sexual maturation and behavior after prenatal exposure to barbiturates.
The presumed mechanism is alteration in brain loci responsible for
sexual differentiation. For example, Clemens et al. (1979) found that
OCR for page 195
IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS ]95
the adult sexual behavior of male hamsters was altered compared
with controls after prenatal exposure to barbiturates. Females, in the
same study, showed no difference as adults after receiving the same
dosing regimen. Prenatally administered barbiturates are capable of
changing reproductive functions of male and female pups so exposed.
Further, female offspring have lower birth weights at puberty, show
lower fertility, and have delayed onset of puberty (Gupta et al., 1980~.
Testosterone concentrations in plasma and brain of neonatal males
exposed to barbiturates were lowered by prenatally administered
barbiturates (Gupta et al., 1982~. This finding suggests that early
testosterone deficits could be instrumental in altering masculine
development and have a negative impact upon reproductive function
in the adult.
A POTENTIAL TIME BOMB?
Barbiturates, as studied in rodents, have been shown to have the
potential for being time bombs in that the behavioral deficits observed
do not show up until late in development. Physicians have long
prescribed barbiturates to their patients for anxiety, sedation, and
seizure disorders. In the 1960s and 1970s, barbiturates were frequently
prescribed to pregnant women. For example, among the subjects in
the Collaborative Perinatal Project consisting of 50,000 pregnancies,
some 25 percent of the women were prescribed barbiturates at some
time during gestation (Heionen et al., 1977~. Based upon Medicaid
data from Michigan, Rosa (personal communication, 1988) estimates
that approximately 1.5 percent of women receive phenobarbital dur-
ing the first trimester of their pregnancy. Prenatal exposure of the
fetus to barbiturates is not the only time in early development when
this class of drugs is given. Neonates are also prescribed the drug as
a sedative or anticonvulsant. From an epidemiological perspective
then, the number of children exposed, and therefore potentially at
risk, is high.
Although the prescription of barbiturates to pregnant women or
newborns has been considered safe, recent studies employing animal
models suggest that barbiturates may have the potential for neural or
behavioral toxicity (Smith, 1977~. More recent literature reviews also
support this conclusion (Coyle et al., 1980; Fishman and Yanai, 1983;
Ornoy and Yanai, 1980; Reinisch and Sanders, 1982; Yanai, 1984~.
Although there is a rich literature on animal studies concerning
the putative behavioral toxicology of barbiturates, the research find-
ings on humans are meager (van den Berg, personal communication,
1988~. A rigorous analysis of behavioral and biomedical data, by
OCR for page 196
96
NORMAN A. KRASNEGOR
using a case control matching design, is currently underway (Reinisch,
personal communication, 1988). The investigators are employing a
retrospective design, that is, studying a group of young adults (in
their early 20s) whose mothers were prescribed barbiturates during
pregnancy. The subjects comprise a cohort listed in a Danish birth
registry. The study, which is still underway, will be, when completed,
the most rigorously designed and comDrehen.sive one of heron ~v
r ~ ~~ A ~ ~
posed prenatally to barbiturates. The data set includes records from
school, the army, the criminal justice system, and parents. Psychological
and behavioral test scores along with medical records concerning
physical development are being amassed. The researchers will then
be able to pose questions related to the findings from the animal
literature to determine whether behavioral toxicity can be demonstrated
in people who were exposed prenatally to barbiturates.
The example provided by barbiturates is illustrative of the dilemma
posed when the risk/benefit ratio is examined critically. The animal
model data suggest the potential for behavioral toxicity, the behavioral
epidemiology data are not yet complete, and the drug class is seen to
be beneficial to both the mother and her offspring. Until there are
some definitive findings on barbiturates, prescribing practice is unlikely
to change.
NEW METHODS FOR MEASURING
BEHAVIORAL TOXICITY
Although the usual approach to measuring behavioral toxicity is
to dose prenatally and measure changes later in life, an alternative
tactic is to measure behavior as early as possible after exposure. Carried
to its extreme, this approach implies measurement of fetal behavior.
During the early part of this century, there was considerable scien-
tific interest in prenatal behavioral development. The questions of
interest focused upon when during life learning can first be demon-
strated. More specifically, scientists began to query whether learning
could be shown to exist in the fetus. Learning for the purposes of the
present discussion is defined as associative or Pavlovian conditioning.
Workers during the 1930s attempted to classically condition the
human fetus. Ray (1932), for example, paired a neutral stimulus
(vibrotactile stimulus) with an unconditioned stimulus (WCS) that
was known to produce movement in the fetus. The UCS, a loud
noise, if made suddenly in the presence of a fetus is reliably followed
by a startle movement. This latter response can be detected by plac-
ing one's hand on the abdomen of a pregnant woman. The UCS was
OCR for page 197
IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS ]97
paired with the neutral stimulus (CS) for a number of trials deemed
sufficient for the CS alone to elicit the startle response. This study
did not confirm the capacity for classical conditioning in the fetus.
A little over 15 years later, Spelt (1948) employed similar procedures
and claimed success in demonstrating classical conditioning in the
human fetus. He also concluded from the analysis of his data that
the fetus has the capacity for extinction and retention of the classically
conditioned response. It should be pointed out that more recently,
other behavioral scientists have sharply criticized these findings on
methodological grounds (Sameroff and Cavanaugh, 1979), thereby
leaving open the question of whether classical conditioning of the
fetus is possible. Significant progress on this topic had to await
methodological innovations that emerged at the start of the current
decade (Krasnegor et al., 1987~.
The studies of interest employed fetal rats. The breakthrough was
predicated upon methodological innovations that allowed researchers
to directly observe and manipulate the fetus and thereby rigorously
test questions of learning. Blass and Pedersen (1980) and Stickrod
(1981) developed procedures for externalizing the uterus of pregnant
female rats late in gestation and ways to inject substances into the
amniotic fluid of the developing fetus. These new methodologies allowed
the investigators to make their observations, the uterine horns to be
reinserted, and the fetus to complete its development to term. At
that time, fetuses could be delivered vaginally or taken by cesarean
section and be cross-fostered to recently delivered mothers.
At a workshop sponsored by the National Institute of Child Health
and Human Development (NICHD), these and other techniques for
viewing and manipulating the mammalian fetus were summarized
(Kolata, 1984~. Attending that meeting was William Smotherman
who, along with his coworkers, has carried out a number of studies
on fetal behavior and fetal learning. In the first of a series of investigations
on prenatal learning, Stickrod et al. (1982a) demonstrated that late in
development, rat fetuses have the capacity for associative learning.
On day 20 of gestation, the uterine horn of a female rat was externalized
into a warm saline bath. Apple juice (CS) was injected into the amniotic
fluid surrounding the exposed fetuses, and lithium chloride (WCS)
was injected into their peritoneum. A single pairing of an aversive
stimulus (LiCl) with a novel taste or odor (apple juice) causes adult
rats so treated to avoid the taste or odor on subsequent presentations.
The externalized uterus of the dam was reinserted into her perito-
neum; she was sutured; and the fetuses, treated as described above,
were delivered at term. When the pups were 2 weeks old and were
allowed to suckle from an anesthetized dam, they were observed to
OCR for page 198
98
NORMAN A. KRASNEGOR
show preferential nipple attachment in accordance with their prena-
tal experience. Those pups which had been exposed to the associative
conditioning paradigm as fetuses attached less often to nipples that
were painted with apple juice compared to control pups (Smotherman
and Robinson, 1987~. In a follow-up study, Stickrod et al. (1982b)
demonstrated that pups which had been conditioned prenatally showed
greater delays in crossing a runway, where the air contained the odor
of apple juice,.to gain access to their mother. In a variant of the
procedure, these same authors demonstrated that prenatally condi-
tioned pups preferred to stay at the low-concentration end of a box
containing the odor of apple juice. These findings are quite important
because they indicate both that conditioning took place before birth
and that the learned response was retained postnatally.
Smotherman and his coworkers continued their research on sev-
eral fronts. They examined the influence of uterine position, a variable
feature of the prenatal environment, upon conditioned taste aversion
in adult rats (Babine and Smotherman, 1984; Smotherman, 1983~. They
critically evaluated two existing techniques for the preparation of the
female rat for fetal observation and demonstrated that the two procedures,
chemomyelotomy and spinal transection, are not equivalent in their
effects upon spontaneous fetal activity (Smotherman, 1984; Smotherman
et al., 1984~. They also developed a new reversible anesthetic proce-
dure for preparing the dam and observing the fetal rat in utero
(Smotherman et al., 1986~. This method has the advantage of allow-
ing the longitudinal study of behavior of the same subjects before
and after birth. Further, Smotherman and Robinson (1986) made
critical observations on age-related changes in fetal behavior during
the last third of gestation. This work also documents fetal responsiveness
to naturally occurring changes within the uterine environment. Similarly,
it demonstrates the feasibility of observing fetuses after removal from
the uterus and amniotic sac and the quantification of fetal behavior
from day 16 to gestation.
By combining the new observation techniques with the knowledge
gained on the ontogenesis of movement patterns, Smotherman was
able to study the capacity for conditioning to emerge during gestation.
In a series of elegant experiments (Smotherman and Robinson, 1987)
which included rigorous control procedures, the investigator and his
colleagues demonstrated that rat fetuses exposed to a single-trial pairing
of a neutral stimulus (mint) and an interperitoneal injection of LiCl
on day 17 of gestation, are conditioned by day 19 of gestation. This
was shown to be the case because the mint solution alone does not
suppress endogenous movement patterns on day 17 or 19 of gestation,
but when paired with the LiCl injection on day 17, it markedly sup-
OCR for page 199
IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS 799
presses movement by itself in 19-day-old fetuses who had received
the conditioning trial.
The work described above clearly and rigorously documents the
capacity of the fetus for learning during gestation. It also demonstrates
that the organization of fetal behavior patterns has an ontogenetic
trajectory. Both of these conclusions indicate that a new window of
opportunity exists for the behavioral toxicologist. Associative learning
can be established prenatally and followed postnatally. Condition-
ing, in terms of its acquisition and consolidation, can be studied dur-
ing gestation. Thus, substances of interest can be studied for their
effect both at the time of gestation when they have their putative
action upon the developing brain and postnatally during neonatal
development. Indeed, Smotherman and his colleagues (Smotherman
and Robinson, 1987; Smotherman et al., 1986a, 1986b; also, Baron et
al., 1986) have conducted studies of fetal behavior after chronic maternal
exposure to ethanol. These studies are exemplars that point the way
for demonstrating the power of the approach to identify both substances
and mechanisms that may interfere with behavioral development.
ADDITIONAL APPROACHES AND
NEW DIRECTIONS
Two questions with which developmentalists and behavioral toxi-
cologists alike must constantly grapple revolve around the issues of
prediction and validity. The prediction issue is brought out when
studies of development are undertaken with children who are born
at risk (e.g., intrauterine growth retardation, low birth weight). What
researchers interested in such questions would like to know is whether
behavior measured early in life (e.g., the neonatal or infancy phase of
development) is predictive of behavioral development in childhood
(e.g., at school entry). If reliable and valid measures could be estab-
lished, children born at risk who would develop normally, from a
behavioral perspective, could be accurately separated from those who
may evidence behavioral deficits (Bornstein and Krasnegor, 1989~.
Prediction of a different, albeit equally important, type is sought by
behavioral toxicologists. They endeavor to predict whether a substance
of interest has behavioral toxicity and whether early exposure will
lead to behavioral deficits later in development. Further, they employ
animal models which they believe validly relate to the human condition.
Developmentalists and behavioral toxicologists also strive to pose
questions that can elucidate the putative behavioral or neurobehavioral
mechanisms which may subsume the observed deficits.
Is it possible to address these multiple concerns and thereby ad-
OCR for page 200
200
NORMAN A. KRASNEGOR
Vance both fields of inquiry alluded to above? Research in the field
of eyelid conditioning has much to recommend it conceptually and
experimentally as a paradigm for asking questions of relevance to
developmental behavioral toxicologists (Gormezano et al., 1983; Harvey
and Gormezano, 1986; Solomon and Pendlebury, 1988~. There are
three main factors that make the nictitating membrane response (NMR)
an attractive one for addressing developmental questions in general
and behavior toxicology ones in particular.
Multiple Behaviors Can Be Studied
There are at least 10 behavioral factors that can be studied utilizing
the NMR/eye blink model system (Harvey and Gormezano, 1986~.
These are (1) habituation and sensitization, (2) stimulus selection, (3)
mediation associations, (4) motivation, (5) memory traces and short-
or long-term memory, (6) simple and conditional discriminations, (7)
transfer of training, (8) timing, (9) stimulus generalization, and (10)
extinction and conditioned inhibition.
Comparative Developmental Studies Can Be Undertaken
Work on the NMR/eye blink has been carried out by using the
rabbit as a model system. Research on humans has also been under-
taken to study the conditioned eye blink. This has recently involved
developmental studies that compared the acquisition of the classically
conditioned eye blink across the age span ranging from childhood (8
years of age) to the eighth decade of life (Solomon et al., 1989~. Such
work holds out the promise that specific comparative studies of the
model system and the same response system in humans can be
accomplished.
Knowledge Concerning Neurocircuitry and
Neurochemistry of the Response Is Accumulating
Research to date has implicated two different brain circuits in this
model system. These are found respectively in the cerebellum (McCormick
and Thompson, 1984) and the hippocampus (Berger et al., 1986; Moore
and Solomon, 1980~. The data collected by these investigators suggest
that the cerebellum may be the CNS site of simple plasticity for simple
delay conditioning. The hippocampus, on the other hand, has been
implicated in trace conditioning (Solomon and Gottfried, 1981~;
discrimination reversal (Berger and Orr, 1983~; and as a modulator of
simple delay conditioning (Solomon et al., 1983~. Moreover, what is
OCR for page 201
IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS 20]
known concerning the pharmacology of the conditioned response in
rabbits suggests strongly that the cholinergic system is involved in
mediating the response (Moore et al., 1976; Solomon et al., 1983~.
These three factors provide a convincing argument that the condi-
tioning model described may be a powerful tool for developmental
behavior toxicology (see, for example, Yokel, 1983~. Additional research
is needed to obtain developmental data for this model system. This
should be conducted in neonatal humans and young rabbits to fill in
the knowledge gap on the ontogeny of the response. The availability
of such baseline data will provide developmentalists and behavioral
toxicologists with the information needed to evaluate behavioral de-
velopment and the effects of substances over an impressive age span.
It will allow prospective questions to be asked from a developmental
perspective. Most importantly, it will allow researchers to connect
with a model system (the rabbit NMR/eye blink) which can help
differentiate between CNS mechanisms that may be involved in impaired
development. This can in turn provide clues to scientists who work
with babies born at risk, or with those who were exposed to substances
as fetuses, concerning the behavioral and neurobehavioral mechanisms
that may have gone awry.
Some progress toward the goal of collecting data in the neonatal
human baby has already been made. (Although the work described
below is not directly on eye blink conditioning, it is sufficiently related
that inclusion is warranted.) Howard Hoffman and his colleagues
have been studying the development and characteristics of the startle
response for the past two decades. After analyzing this response by
using animal models they discovered that the response could be modified.
In experiments carried out in adult humans, Hoffman found that
when an exteroceptive stimulus precedes one that elicits the glabella
response by 100-200 ms, the resultant eye blink is reduced in ampli-
tude (Hoffman and Ison, 1980~. If the same stimulus is presented
simultaneously with the eliciting stimulus, the eye blink amplitude is
enhanced compared to a control condition in which no stimulus is
presented (Hoffman and Stilt, 1980; Hoffman et al., 1981~.
Hoffman and his coworkers next turned their attention to a com-
parison of adults and newborns to undertake a developmental analysis
of these augmentation-inhibition results. They found that newborns
(16-65 hours old) exhibited reflex augmentation to the simultaneous
pairing of an exteroceptive stimulus and a gentle, calibrated tap between
the eyes (Hoffman et al., 1985~. Although the comparative data are
of interest, the most compelling information relates to the methodol-
ogy. Eye blinks can be reliably measured on the first day of life, and
systematic data on this response can be collected. This strongly suggests
OCR for page 202
202
NORMAN A. KRASNEGOR
that an approach can be worked out to collect eye blink conditioning
data at this time in development and in older infants as well.
In summary, new approaches for measuring simple learning dur-
ing the perinatal period offer an opportunity to assess the potential
for substances to affect behavioral development. Research on these
new windows for observation can provide the field of behavioral
toxicology with additional tools to effectively evaluate, early in an
organism's development, whether and, potentially, how it may become
impaired later in life. Investigations along these lines should be pur-
sued and vigorously encouraged.
ACKNOWLEDGMENT
Thanks are due to Marsha Sotzsky for preparing this manuscript.
REFERENCES
Babine, A. M., and W. P. Smotherman. 1984. Uterine position and conditioned taste
aversion. Behavioral Neuroscience 96:461~66.
Barron S., E. P. Riley, and W. P. Smotherman. 1986. The effect of prenatal alcohol
exposure on umbilical cord length in fetal rats. Alcoholism: Clinical and Experimental
Research 10:493~95.
Berger, T. W., and W. B. Orr. 1983. Hippocampectomy selectively disrupts discrimination
reversal conditioning of the rabbit nictitating membrane response. Behavior Brain
Research 8:49-68.
Berger T. W., S. Berry, and R. Thompson. 1986. Role of the hippocampus in classical
conditioning of aversive and appetitive behaviors. Pp. 203-240 in The Hippocampus,
R. L. Isaacson and K. H. Pribram, eds. New York: Plenum.
Blass E. M., and P. E. Pedersen. 1980. Surgical manipulation of the uterine environ-
ment of rat fetuses. Physiology and Behavior 25:993-995.
Bornstein, M. H., and N. A. Krasnegor. 1989. Stability and Continuity in Mental
Development: Behavioral and Biological Perspectives. Hillsdale, N.J.: Lawrence
Erlbaum Associates.
Chapman, J. B., and M. G. Cutler. 1983. Behavioral effects of phenobarbitone. I.
Effects in the offspring of laboratory mice. Psychopharmacology 29:155-160.
Clemens L. G., T. V. Popham, and P. H. Ruppert. 1979. Neonatal treatment of hamsters
with barbiturate alters adult sexual behavior. Developmental Psychobiology 12:115-
125.
Coyle, I., A. Wagner, and G. Singer. 1980. Behavioral teratogenesis: A critical evalu-
ation. In Advances in the Study of Birth Defects, Neural and Behavioral Teratol-
ogy, T. V. N. Persaud, ed. Baltimore: University Park Press.
Denenberg, V. H., E. B. Thomas, P. Kramer, and J. R. Raye. 1986. Sleep and wake
behavioral state as a developmental assessment procedure. In Advances in Behavioral
Pharmacology: Developmental Behavioral Pharmacology, N. A. Krasnegor, D. B.
Gray, and T. Thompson, eds. Hillsdale, N. J.: Lawrence Erlbaum Associates.
Diaz, J. 1978. Phenobarbital: Effects of long-term administration on behavior and
brain of artifically reared rats. Science 199:90-91.
OCR for page 203
IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS 203
Fishman, R. H. B., and J. Yanai. 1983. Long lasting effects of early barbiturates on
central nervous system and behavior. Neuroscience Biobehavioral Review 7:19-28.
Gormezano, I., E. J. Kehoe, and B. Marshall. 1983. Twenty years of classical condition-
ing research with the rabbit. Pp. 197-275 in Progress in Psychobiology and Physi-
ological Psychology, Vol. 10, J. M. Sprague and A. N. Epstein, eds. New York:
Academic Press.
Gupta C., B. R. Sonawane, and S. F. Yaffe. 1980. Phenobarbital exposure in utero:
Alterations in female reproductive function in rats. Science 208:508-510.
Gupta C., S. F. Yaffe, and B. H. Shapiro. 1982. Prenatal exposure to phenobarbital
permanently decreases testosterone and causes reproduction dysfunction. Science
216:640-642.
Harvey, J. A., and I. Gormezano. 1986. The assessment of drug effects on learning
and stimulus processing by means of classical conditioning. In Developmental
Behavioral Pharmacology, Advances in Behavioral Pharmacology, N. A. Krasnegor,
D. B. Gray and T. Thompson, eds. Hillsdale, N.J.: Lawrence Erlbaum Associates.
Heinonen, N. P., D. Stone, and S. Shapiro. 1977. Birth Defects and Drugs in Preg-
nancy, Chap 24. Littleton, Mass.: John Wright.
Hoffman, H. S., and J. R. Ison. 1980. Reflex modification of startle: I. Some empirical
findings and their implications for how the nervous system processes sensory input.
Psychological Review 87:175-189.
Hoffman, H. S., and C. L. Stitt. 1980. Inhibition of the glabella reflex by monaural and
binaural stimulation. Journal of Experimental Psychology: Human Perception and
Performance 6:769-776.
Hoffman H. S., M. E. Cohen, and C. Stitt. 1981. Acoustic augmentation and inhibition
of the human eyeblink. Journal of Experimental Psychology: Human Perception
and Performance 7:1357-1362.
Hoffman H. S., M. E. Cohen, and L. M. English. 1985. Reflex modification by acoustic
signals in newborn infants and in adults. Journal of Experimental Child Psychology
39:562-579.
Kolata, G. 1984. Learning in the womb. Science 225:302-303.
Krasnegor, N. A. 1986. Introduction: Perspectives and new directions. In Advances
in Behavioral Pharmacology, Vol. 5, Developmental Behavioral Pharmacology, N.
A. Krasnegor, D. B. Gray, and T. Thompson, eds. Hillsdale, N.J.: Lawrence Erlbaum
Associates.
Krasnegor, N. A., E. M. Blass, M. A. Hofer, and W. P. Smotherman, eds. 1987. Perinatal
Development: A Psychobiological Perspective. Orlando, Fla.: Academic Press.
McCormick, D. A., and R. F. Thompson. 1984. Cerebellum: Essential involvement in
the classically conditioned eyelid response. Science 223:296-299.
Middaugh, L. D. 1986. Prenatal matemal barbiturates effects on offspring. In Ad-
vances in Behavioral Pharmacology, Vol. 5, Developmental Behavioral Pharmacology,
N. A. Krasnegor, D. B. Gray, and T. Thompson, eds. Hillsdale, N.J.: Lawrence
Erlbaum Associates.
Middaugh, L. D., L. W. Simpson, and T. N. Thomas. 1981. Prenatal maternal phenobarbital
increases reactivity and retards habituation of mature offspring to environmental
stimuli. Psychopharmacology 74:349-352.
Moore, J. W., and P. R. Solomon, eds. 1980. The role of the hippocampus in learning
and memory. Physiological Psychology (special edition).
Moore J. W., N. A. Goodell, and P. R. Solomon. 1976. Central cholinergic blockade by
scopolamine and habituation, classical conditioning, and latent inhibition of the
rabbit's nictitating membrane response. Physiological Psychology 7:224-232.
Ornoy, A., and J. Yanai. 1980. Central nervous system teratogenicity: Experimental
models for human problems. In Advances in the Study of Birth Defects, Vol. 4,
OCR for page 204
204
NORMAN A. KRASNEGOR
Neural and Behavioral Teratology, T. V. N. Persaud, ed. Baltimore: University
Park Press.
Ray, W. S. 1932. A preliminary study of fetal conditioning. Child Development 3:173-
177.
Reinisch, J. M., and S. A. Sanders. 1982. Early barbiturate exposure: The brain,
sexually dimorphic behavior and learning. Neuroscience Biobehavioral Review 6:311-
319.
Reyes, E., K. Garcia, and J. Wolfe. 1986. Effects of in utero administration of phenobarbital
on gamma-glutamyl-transpeptidase. Alcohol 3:153-155.
Sameroff, A. J., and P. J. Cavanaugh. 1979. Learning in infancy: A developmental
perspective. In Handbook of Infant Development, J. D. Osofsky, ed. New York:
John Wiley & Sons.
Smith, D. W. 1977. Teratogenicity of anticonvulsant medications. American Journal of
Disease of Children 131:1337-1339.
Smotherman, W. P. 1983. Mother-infant interaction and the modulation of pituitary-
adrenal activity in rat pups after early stimulation. Developmental Psychobiology
16:169-176.
Smotherman, W. P.
225:1093.
1984. Letter to the editor: Learning in the womb. Science
Smotherman, W. P. 1985. Glucocorticoids and other hormonal correlates of condi-
tioned taste aversion. In Experimental Assessments and Clinical Applications of
Conditioned Food Aversions, N. S. Braverman and P. Bronstein, eds. Annals of the
New York Academy of Sciences, Vol. 443. New York.
Smotherman, W. P., and S. R. Robinson. 1986. Environmental determinants of behav-
ior in the rat fetus. Animal Behaviour 34:1859-1873.
Smotherman, W. P., and S. R. Robinson. 1987. Psychobiology of fetal experience in
the rat. In Perinatal Development: A Psychobiological Perspective, N. A. Krasnegor,
E. M. Blass, M. A. Hofer and W. P. Smotherman, eds. Orlando, Fla.: Academic
Press.
Smotherman, W. P., L. S. Richards, and S. R. Robinson. 1984. Techniques for observ-
ing fetal behavior in utero: A comparison of chemomyelotomy and spinal transection.
Developmental Psychobiology 17:661-674.
Smotherman, W. P., S. R. Robinson, and B. J. Miller. 1986a. A reversible preparation
for observing behavior of fetal rats in utero: Spinal anesthesia with lidocaine.
Physiology and Behavior 37:57-60.
Smotherman, W. P., W. P. Woodruff, S. R. Robinson, C. Del Real, S. Barron, and E. P.
Riley. 1986b. Spontaneous fetal behavior after maternal exposure to ethanol.
Pharmacology Biochemistry and Behavior 24:165-170.
Solomon, P. R., and K. E. Gottfried. 1981. The septohippocampal cholinergic system
and classical conditioning of the rabbit's nictitating membrane response. Journal of
Comparative and Physiological Psychology 95:322-330.
Solomon, P. R., and W. W. Pendlebury. 1988. A model systems approach to age
related memory disorders. Neurotoxicology 9:443-462.
Solomon, P. R., S. D. Solomon, E. R. Van der Schaff, and H. E. Perry. 1983. Altered
activity in hippocampus is more detrimental to classical conditioning than removing
the structure. Science 220:329-331.
Solomon, P. R., D. Pomerleau, L. Bennett, J. James, and D. L. Morse. 1989. Acquisition
of the classically conditioned eyeblink response in humans over the life span. Psy-
chology & Aging 4~1~:34-41.
Spelt, D. K. 1948. The conditioning of the human fetus in utero. Journal of Experi-
mental Psychology 38:338-344.
Stickrod, G. 1981. In utero injection of rat fetuses. Physiology and Behavior 28:5-7.
OCR for page 205
IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS 205
Stickrod, G., D. P. Kimble, and W. P. Smotherman. 1982a. In utero taste/odor aver-
sion conditioning in the rat. Physiology and Behavior 28:5-7.
Stickrod, G., D. P. Kimble, and W. P. Smotherman. 1982b. Met-5-enkephalin effects on
associations formed in utero. Peptides 3:881-883.
Thompson, T. 1986. Issues in developmental behavioral pharmacology. In Advances
in Behavioral Pharmacology, Vol. 5, Developmental Behavioral Pharmacology, N.
A. Krasnegor, D. B. Gray, and T. Thompson, eds. Hillsdale, N.J.: Lawrence Erlbaum
Associates.
Voorhees, C. V. 1985. Fetal anticonvulsant syndrome in rats: Effects on postnatal
behavior and brain aminoacid content. Neurobehavioral Toxicology and Teratology
7:471-482.
Yanai, J. 1984. An animal model for the effect of barbiturate on the central nervous
system. In Neurobehavioral Teratology: Drugs of Use and Abuse, J. Yanai, ed.
New York: Elsevier.
Yanai, J., A. Bergman, and R. Shafer. 1981. Audiogenic seizures and neuronal deficits
following early exposure to barbiturate. Developmental Neuroscience 4:345-350.
Yokel, R. A. 1983. Repeated systematic aluminum exposure effects on classical condi-
tioning in the rabbit. Neurobehavioral Toxicology and Teratology 5:41-46.
Representative terms from entire chapter:
behavioral development
