Human Reproduction Update 1997, Vol. 3, No. 6 pp.
575–592  European Society for Human Reproduction and Embryology
Perspectives on the use of the baboon in
embryology and teratology research
A.G.Hendrickx1 and P.E.Peterson
California Regional Primate Research Center, University of California, Davis, CA 95616–8542, USA
TABLE OF CONTENTS
Introduction
Embryology
Teratology
Acknowledgements
References
This paper summarizes the developmental stages of the
baboon during the period of organ formation and
provides comparative information for other primates,
including the human. Special attention is directed to the
early development of the nervous system, eye, ear and
nose/palate. The similarity in development of these
structures with humans indicates that the baboon is a
suitable model for studies of normal and abnormal
neurological development. Spontaneous prenatal loss
rates in the baboon (2.4–11.2%) are slightly lower than
those reported in rhesus and cynomologus monkeys. The
baboon, in addition to the cynomologus monkey and
macaque, has been used as a model in teratology
research to assess the potential risk of thalidomide, sex
steroids, Bendectin and rubella virus, as well as to study
the pathogenesis of malformations associated with the
corticosteroid triamcinolone acetonide. The rate of
spontaneous malformations (<1%) in baboons, similar
to that reported for other commonly used primates,
supports their continued use as a teratological model. In
this regard, a sample protocol is provided for the safety
evaluation of biotechnology products using nonhuman
primates, which are the most appropriate model for
those compounds which are bioactive in species closely
related to humans.
Key words: baboon/embryology/neurological
development/organ formation/teratology
1To whom correspondence should be addressed. Tel: (530) 752 0420; Fax: (530) 752 8201
Introduction
Studies of embryonic development in the baboon (Papio
575 sp.) were first reviewed by Hill (1932). Subsequent studies
575 were carried out by Gilbert and Heuser (1954), Schuster
583 (1965), and Boyden (1967) in P. ursinus, P. doguera, P.
591 cynocephalus and P. anubis respectively. Zuckerman
591 (1963) provided an excellent history of nonhuman pri-
mates in biomedical history for the first half of the 20th
century. His account credits Galen of Pergamen, who based
descriptions of human anatomy on baboons and other pri-
mates.
The importance of basic studies in development have not
diminished with time; in fact there has been a resurgence in
embryology research with the steady influx of new mol-
ecular technologies that have enabled us to probe develop-
mental events at the subcellular level. Studies in primates
are advocated on the basis of their phylogenetic relatedness
to humans, as reflected in anatomical, reproductive, gen-
etic/molecular, immunological and embryological/terato-
logical similarities (Hendrickx et al., 1983; Hendrickx and
Binkerd, 1990). Their use in applied studies has also in-
creased from the past, when they were used primarily as an
additional test species to the more commonly used rodents
(Wilson, 1973). For the majority of biotechnology prod-
ucts intended for human use, nonhuman primates are the
only species used for safety assessment because these
products are bioactive only in species closely related to
humans (Trown et al., 1986; Henck et al., 1996).
Embryology
Division of the developmental process into a series of
stages has been a useful method for studying embryology.
The developmental staging of the human embryos in the
Carnegie Collection, introduced by Streeter (1942, 1945,
1948, 1951) and Heuser and Corner (1957), was greatly
expanded upon by O’Rahilly (1972, 1979) and O’Rahilly
and Gardner (1971) and revised by O’Rahilly and Müller
576 A.G.Hendrickx and P.E.Peterson
Figure 1. External views of baboon embryos of developmental stage 8 (A), 9 (B), 10 (C), 11 (D) and 12 (E). The bar in each figure represents
0.14 mm (A), 0.21 mm (B), 0.35 mm (C), 0.43 mm (D) and 0.66 mm (E).
(1987). Developmental staging of embryos undergoing or-
ganogenesis incorporates four major criteria, i.e. external
and internal morphological features, greatest or crown–
rump length and fertilization age (conception), to establish
each critical period of development. These criteria, estab-
lished for human embryos and adapted for baboon embry-
os (Hendrickx, 1971a), are summarized in Table I.
Description of stages 8–23 (period of
organogenesis)
The development of external form as well as the histologi-
cal ontogeny of several organ systems, including the brain
and spinal cord, eye, ear, nose and palate is described in this
section for each sequential stage.
Stage 8 (Figure 1A)
The primary features of embryos at this stage are the pres-
ence of a neural groove, primitive node and primitive
groove. The primitive node, situated near the middle of the
embryonic disc, marks the cranial end of the primitive
streak which extends caudally. The notochordal process
extends to the cranial end of the disc. All of these midline
structures are visible in the dorsal external view of the
embryo, which resembles a pear-shaped disc.
 Baboon embryology and teratology 577

Table 1. Developmental stages in baboon embryos

Carnegie Age Size Somites Features

stage (days) (mm)
8 19–21 0.6–0.9 Primitive streak and pit; notochordal and neurenteric canals
9 23 ± 1 1.0–2.0 1–3 Formation of neural folds; somites appear
10 25 ± 1 2.0–3.5 4–12 Neural folds begin to fuse; 2 pharyngeal arches; otic disc
11 27 ± 1 2.0–4.5 13–20 Rostral neuropore closes; optic vesicle
12 28 ± 1 3.0–4.5 21–29 Caudal neuropore closes; 3–4 pharyngeal arches; upper limb buds
13 29 ± 1 4.5–6.0 30+ Four limb buds; lens disc; otic vesicle; three primary brain
vesicles; endolymphatic duct
14 30 ± 1 6–7 Lens pit and optic cup; nasal pit
15 31 ± 1 6–8 Lens vesicle; antitragus beginning; hand plate; future cerebral
vesicles distinct
16 33 ± 1 7–9 Nasal pits face ventrally; retinal pigment visible externally;
17 35 ± 1 10–13 Head relatively large; trunk straighter; nasofrontal groove;
auricular hillocks distinct; finger rays
18 37 ± 1 14–17 Body more cuboidal; elbow region and toe rays appearing; eyelid
folds begin; tip of nose distinct; ossification may begin
19 39 ± 1 16–17 Trunk elongating and straightening
20 41 ± 1 17–18 Upper limbs longer and bent at elbows
21 43 ± 1 18–21 Fingers longer; hands and feet approach each other
22 45 ± 1 21–23 Eyelids and external ear more developed
23 47 ± 1 25–28 Head more rounded; limbs longer and more developed

Stage 9 (Figure 1B) Stage 11 (Figure 1D)

During stage 9, the neural folds and groove are distinct,
producing obvious head and caudal folds externally. The
primitive streak occupies one-third to one-fourth the length
of the embryo. Somites appear as condensations of the
paraxial mesoderm lateral to the neural folds near the
cephalic end of the notochord. Each somite is set off by an
intersomitic groove, a slightly depressed area between
each somite. A slight dorsal flexure develops in the somite
region.
At stage 11, the neural tube and folds extend the entire
length of the embryo and the cranial (anterior) neuropore is
closing or closed, while the caudal neuropore is still appar-
ent. The cervical flexure is detectable and both the optic
vesicle and the slightly invaginated otic pits are distinct.
The first two pharyngeal arches are well defined and the
S-shaped loop of the developing heart is visible. A dorsal
flexion of the body also occurs as the embryo becomes
elevated above the yolk sac, while the broad communica-
tion between the vitelline sac, foregut and hindgut persists.

Stage 10 (Figure 1C) Stage 12 (Figure 1E)

Stage 10 embryos are characterized by a more cylindrical,
elongated shape which results from the initiation of fusion
of the neural folds to form the neural tube. Fusion of the
neural folds occurs first between the 4th and 8th somites,
which flank the folds in the medial region of the longitudi-
nal axis. The optic primordia appear as bulges in the cran-
ial-most region of the neural folds and the otic placodes are
recognized as slight plate-like depressions of the surface
ectoderm on each side of the developing hindbrain. The 1st
(mandibular) and 2nd (hyoid) pharyngeal arches appear
and the heart forms a distinct bulge which is visible ventral-
ly. The cranial (cephalic) flexure is prominent and the tri-
geminal and otic prominences appear as two dorsolateral
thickenings caudal to the flexure.
The C-shaped curvature of embryos at stage 12 distin-
guishes them from embryos of the previous stage. The
three primary subdivisions of the brain, prosencephalon
(forebrain), mesencephalon (midbrain) and rhombence-
phalon (hindbrain), are recognizable and the thin roof the
rhombencephalon is faintly visible. The optic vesicles ap-
pear as opaque circles with transparent centres and the otic
pit is in the process of closing. There are three distinct
pharyngeal arches separated by three pharyngeal grooves.
A slight depression, the cervical sinus, appears in the cau-
dal portion of the arch region. The heart bulge is very
prominent and the primordium of the forelimb bud be-
comes apparent at the level of somites 8–13. The caudal
neuropore is either in the process of closing or closed.
578 A.G.Hendrickx and P.E.Peterson
Stage 13
As the cervical flexure develops, there is a flattening in the
upper cervical region. The sacral flexure and curvature of
the trunk are also more extensive. The anterior subdivision
of the forebrain, the telencephalon, expands slightly, and
the roof of the rhombencephalon becomes thinner. The 1st
pharyngeal arch is subdividing into maxillary and man-
dibular processes and the cervical sinus has deepened, but
four pharyngeal arches and grooves remain visible. The
otocyst is completely closed and is separating from the
overlying ectoderm. The tip of the forelimb bud is begin-
ning to curve ventrally and the primordium of the hindlimb
bud appears.
Stage 14
The shape of the embryo is angular owing to well-defined
cervical and sacral flexures. The rostral area of the embryo
is in close contact with the heart bulge and the developing
cerebral hemispheres and mesencephalon can be identi-
fied. The maxillary process is beginning to swell and both
lens and olfactory placodes are visible. The endolymphatic
diverticulum becomes apparent as a conical projection dor-
sal to the otocyst which appears as a clear vesicle aligned
with the 2nd pharyngeal arch. The deep cervical sinus con-
ceals the 3rd and 4th pharyngeal arches. The trigeminal
ganglion is a large dense area dorsal to the 1st arch and the
smaller facioacoustic primordium is less defined at the
cranial aspect of the otocyst. The forelimb buds, located
opposite somites 7–13, are slightly elongated and curve
ventromedially. The hindlimb buds are visible as small
swellings at the level of somites 27–30.
Stage 15 (Figure 2A)
The body of the embryo is becoming more C-shaped as the
cervical flexure becomes more prominent as it attains near-
ly a 90° angle. Pigmentation of the retina and the nasal pits
are first detectable externally. The cerebral hemispheres
have expanded prominently and the roof of the posterior
portion of the hindbrain (myelencephalon) flattens. The
vagus and spinal accessory nerves can now be clearly dis-
tinguished. Both the forelimb and hindlimb buds elongate,
and slight differentiation of the forelimb bud into a distal
hand segment and a proximal arm–shoulder segment takes
place.
Stage 16
The trunk of the stage 16 embryo is slightly curved and
dominated by an acute cervical flexure angle. The retinal
pigmentation is more distinct and the nasal pits face ven-
trally as the lateral nasal processes develop. Both mandibu-
lar and maxillary processes are prominent, and the auditory
hillocks are recognizable on the second (hyoid) pharyngeal
arch. The cervical sinus has closed, concealing the 3rd and
4th pharyngeal arches. The distal segment of the arm bud is
beginning to form a crescentic flange, the primordium of
the digital plate.
Stage 17 (Figure 2B)
Although the trunk of the stage 17 embryo is straighter than
that of the previous stage, the cervical flexure is still acute.
The nasal pits open towards the front and the enlarged
maxillary arch extends ventromedially. The auricular hill-
ocks consist of six elevations, three on the surface of the
mandibular arch and three on the hyoid arch. In the hand,
the finger rays are becoming visible and the rim of the plate
shows signs of crenation. The leg bud consists of a rounded
foot plate and leg/thigh regions.
Stage 18
The trunk region continues to straighten and the head is
beginning to move upward, decreasing the cervical angle.
The upper and lower eyelids are making their appearance
and the nose is set off from the forehead by the frontonasal
angle. The prominent auricular hillocks are merging to
form the auricle. Distinct finger rays are present in the hand
plates with interdigital notches (crenations) on their rims.
Toe rays appear in the foot plate but there is no sign of
crenation. The forelimbs have moved upward and partially
cover the face, and the axes of both the arms and the legs
are almost perpendicular to the dorsal line of the body.
Arms and legs are rotated in a medial direction so that the
palmar surfaces face mediocaudally, while the plantar sur-
faces face medially and slightly cranially.
Stage 19 (Figure 2C)
The cervical angle becomes less acute as the head starts to
elevate. The upper jaw protrudes beyond the plane of the
forehead and the coalescing auricular hillocks are less dis-
tinct. Epithelial plugs appear in the external nares that are
well formed and open laterally. Constrictions at the elbow
and wrist divide the forelimb into arm, forearm and hand,
and there is some bending at the elbow. The palmar sur-
faces of the hand point caudomedially and the interdigital
notches are distinct. Digital rays are prominent in the foot
plate.
Stage 20
The trunk lengthens and straightens with continued lifting
of the head. Blending of the premaxilla and maxilla pro-
duces a smoother facial contour at stage 20 than at previous
stages. The auricular hillocks have joined into one mass
which surrounds the external auditory meatus. Eyelids

Figure 2. External views of baboon embryos of developmental stage 15 (A), 17 (B), 19 (C) and 21 (D). The bar in each figure represents 1.1 mm
(A), 1.6 mm (B), 2.1 mm (C) and 2.7 mm (D).
cover approximately one-fifth of the developing eyes. The
fore- and hindlimbs lengthen, with the bends at the wrist
and elbow becoming more pronounced. The hands are
more medial in position, located just lateral to the nose and
ventral to the heart, with the palms directed more caudally.
The interdigital notches of the foot are present.
Stage 21 (Figure 2D)
The cervical angle is >90° and the forehead and neck are
more defined. The upper and lower jaws elongate at the
same rate, but the upper jaw remains further extended. The
eyelids cover approximately one-fourth of the developing
eyes. With decrease of the interdigital tissue, the fingers
Baboon embryology and teratology 579
become longer and closer together. The toes become more
evident as the interdigital notches of the foot deepen.
Stage 22
Jaw protrusion is evident at this stage, with the lower jaw
growing more rapidly than the upper jaw. The eyes are
rotated to the front of the face and the thickening eyelids
cover approximately one-third of the eyes. The tragus and
antitragus are apparent in a more definitive auricle. With
additional lengthening of the limbs, the fingers on one side
overlap those on the other side, and the feet move closer
together. Touch pads appear as slightly raised areas on the
terminal phalanges of the fingers.
580 A.G.Hendrickx and P.E.Peterson
Stage 23
The neck is extended and the head is elevated from the
chest. More definite contours appear in the face as the
lower jaw protrudes almost as far as the upper jaw and the
auricle is assuming its definitive shape. The forehead is
prominent, and the eyelids cover most or all of the eyes.
The arms have lengthened considerably, and the hands
overlap in front of the face with the palms pointed mostly
caudally. The plantar surfaces of the feet face each other,
with the tail between, and the distal phalanges of the toes
are separated.
Nervous system (stages 8–16)
In the cephalic region at stage 8, the neural plate is the first
visible sign of the developing nervous system. The rostro-
caudal axis is well defined, with the prochordal plate evi-
dent in cranial regions. The notochordal plate and process,
which are fused with the endoderm, extend from the pro-
chordal plate to the primitive streak. The latter structure
occupies approximately one-half of the embryonic length
and terminates at the cloacal membrane.
During stage 9, the neural folds flank the longitudinal
axis of the embryonic disc. Early in stage 10 the neural tube
is formed, converting the disk-like embryonic shield into
an elongated cylindrical shape. Closure first takes place
between somites 4 and 8 and progresses cranially and cau-
dally at nearly the same rate. The cranial neuropore closes
in stage 11, and the caudal neuropore closes in stage 12.
The primary brain vesicles, i.e. prosencephalon, mesence-
phalon and rhombencephalon, appear in stage 10. Neural
crest cells contributing to the trigeminal and facioacoustic
ganglia are also emigrating from the preotic rhombence-
phalon at this stage. In the subsequent stage (11) the glosso-
pharyngeal–vagal crest emigrates from the post-otic
rhombencephalon. Rhombomeres are becoming distin-
guishable at stage 11, and thinning of the roof of the rhom-
bencephalon begins during stage 12. The telencephalic
area appears as a dorsal outgrowth of the prosencephalon
during stage 13; the boundary of the telencephalon and
diencephalon are not yet distinguishable. The rhombence-
phalon is characterized by its very thin roof and seven
prominent rhombomeres in its floor. The primordia of the
ganglia of cranial nerves (trigeminal [V], facial [VII] vesti-
bulocochlear [VIII], glossopharyngeal [IX] and vagal [X])
also begin to form within their respective neural crests
during stage 13.
At stage 14 the telencephalon expands rapidly, presaging
the distinct formation of the cerebral vesicles in the subse-
quent stage. Primordia of the epithalamus, dorsal thalamus,
ventral thalamus and hypothalamus appear as thickenings
demarcated by dorsal and ventral sulci in the lateral walls
of the diencephalon. The mesencephalon also shows a
rapid increase in size and is subdivided into alar and basal
plates by the sulcus limitans. A slight marginal zone ap-
pears in the tectum, which is beginning to differentiate. The
area of the basis pedunculi of the tegmentum begins to
enlarge and has marked neuroblastic proliferation medial
to it. The pontine flexure is prominent in the rhombence-
phalon and the pons area enlarges as the pyramidal tract
area forms. Each of the cranial neural crest in the rhom-
bencephalon has transformed into distinct cranial nerves
which develop both motor and sensory neurons.
During stages 15 and 16, the cerebral hemispheres be-
come distinct vesicles. The olfactory fila make contact with
the olfactory bulb area in the ventrolateral surface of the
vesicles. The medial striatal ridge (medial ventricular
ridge) appears as a thickening in the basal part of the te-
lencephalic wall. A primordial epiphysis can be recognized
in the roof of the telencephalon. The mesencephalon com-
prises two thin-walled neuromeres with wide lumina.
Rootlets of nerves VII, IX and X are distinct. Decussating
fibres of the trochlear nerve (IV) are present dorsally at the
junction between the caudal neuromere and the metence-
phalon. Both the basal and alar plates of the metencephalon
have widened and constitute the rhombic lips which define
the area of the cerebellum. The primordial gyrus dentatus
and cornu Ammonis of the hippocampal formation also
appear in stages 15 and 16. A rapid cellular proliferation
also appears in the mammillary body during this time.
Eye (optic vesicle, stages 10–23)
The optic primordia appear in the cranial-most region of
the neural folds during stage 10, and by stage 11 the optic
vesicles are formed as evaginations of the lateral walls of
the forebrain. The vesicle is very close to, but separated
from, the surface epithelium by a thin layer of mesen-
chyme. During stage 12 the optic vesicle and cavity, which
communicate widely with the ventricle of the forebrain, are
enlarged. The placodes of the lens appear as thickenings of
the surface ectodermal epithelium during stage 13. By
stage 14 the optic cup is invaginated and comprises a
double-layered structure with a thick inner layer (future
neural retina) and thin outer layer (future retinal pigment
epithelium). The optic stalk, which separates the optic cup
from the brain wall, is apparent by stage 15, and the first
indication of pigmentation is evidenced as small brown
granules in the outer layer of the optic cup near the rim.
During this stage, the lens pit is in the process of closing, or
is closed, and remains in contact with the surface epithe-
lium. The restored surface epithelium constitutes the anter-

ior epithelium of the future cornea. During stage 16 the lens
vesicle, containing early lens fibres, is separated from the
surface epithelium by a thick mesenchymal sheath.
The lens body contains longer, more distinct fibres and
the lens cavity decreases in size and becomes crescentic
during stages 17 and 18. The developing eyelids first ap-
pear at stage 19 and the inner neural and outer pigmented
layers of the optic cup become more distinct. The cornea
continues to differentiate such that by stage 20 these
mesodermal cells become organized into a discrete layer
which is continuous peripherally with the scleral condensa-
tion. Three corneal layers can be identified in stage 21
embryos, as well as the anterior chamber between the cor-
nea and the thin pupillary membrane. In stage 22 embryos
the sclera is a discrete layer subjacent to the pigmented
retina. The optic canal gradually disappears as it transforms
into a very prominent optic nerve by stage 23. At this stage,
the eyelids almost completely cover the eye and begin to
fuse at the periphery of the eye.
Ear (otic vesicle, stages 10–23)
The otic placodes appear as indistinct ectodermal thicken-
ings early in stage 10 adjacent to the future rhombencepha-
lon. The placodes thicken and begin to invaginate to form
the otic pit early in stage 11 and are cup-shaped late in stage
12. During stage 13 the otic vesicles (otocysts) close and
detach from the superficial epithelium and remain con-
nected via an ectodermal stalk. A rudimentary endolym-
phatic appendage also forms as a conical outgrowth from
the dorsomedial surface of each otocyst, and the mesen-
chyme around the otocyst begins to condense to form the
otic capsule at this time. The otic vesicle enlarges and its
walls show differential thickening during stage 14. In addi-
tion, the elongating endolymphatic diverticulum becomes
set off from the future utricular portion of the otic vesicle
by the developing utriculo-endolymphatic fold. The coch-
lear and vestibular pouches are distinct and the cochlear
and vestibular ganglia as well as the vestibulocochlear
nerve form at stage 15. The differential thinning of the
walls of the otocyst presage the appearance of the semi-
circular canals, while the endolymphatic diverticulum con-
tinues to elongate during stage 16. The primordia of both
the superior and caudal semicircular ducts appear in stage
17 and 1–3 semicircular ducts are differentiated by stage
18. The slender, ventral portion of the otic vesicle differ-
entiates into the cochlear duct, which is L-shaped, just prior
to stage 19. The duct subsequently changes rapidly by
extensive lengthening and progressive spiralling such that
it approaches 2.5 turns by stage 23.
Baboon embryology and teratology 581
Nose/palate (stages 12–23)
The olfactory or nasal placodes are first evident in stage 12,
and appear as ectodermal thickenings on the ventrolateral
surfaces of the head by stage 13. The placodes become
thickened and begin to invaginate to form nasal pits during
stage 14. The nasal pits are widely separated on the frontal
surface of the head and are bordered by the medial and
lateral nasal processes during stage 15. In stage 16 embry-
os, the maxillary process has developed cranially and con-
tributes to the ventrolateral margin of the nasal pit. The
epithelium separating the mesenchyme of the maxillary
and medial nasal processes forms the nasal fin which is
continuous, cranially with the epithelium lining the nasal
pit, and caudally with the epithelium lining the roof of the
developing oral cavity. The nasal fins expand during stage
17 and then degenerate as the primary palate is formed
during the subsequent stage. Olfactory nerve fibres also
appear along the craniomedial aspect of the primary nasal
cavity and pass toward the telencephalon during stage 17.
By stage 18, the primary palate has formed as a continu-
ous bridge of mesenchyme extending laterally from the
midline area that is caudal to the developing nasal septum
to the maxillary process mesenchyme. The bucconasal
membrane at the caudal edge of the primary palate separ-
ates the blind end of the primary nasal cavity from the
bucconasal cavity. The primordium of the nasal septum
cartilage appears as a condensation of mesenchymal cells
in the area between the primary nasal cavities. The bucco-
nasal membrane ruptures at stage 19, allowing the nasal sac
to communicate with the oral cavity through the primitive
choana. The lateral palatine processes are blunted and pro-
ject medially, maintaining a close association with the lat-
eral surface of the tongue. The anlage of the nasal capsule
appears as a mesenchymal condensation lateral to the de-
veloping conchae and maxillary osteoblasts can be identi-
fied rostral to the primitive choana. Although the palatine
processes lengthen, little change occurs in their orientation
during stages 20 and 21. The area of maxillary osteoblasts
increases in size and differentiation of chondroblasts is
apparent in the nasal septum area in stage 20 embryos. By
stage 21, cartilage formation is readily apparent in the nasal
septum and premaxillary and maxillary bone formation
can be distinguished. The middle portion of the lateral
palatine processes undergoes considerable medial rotation,
which gives the appearance of lifting the tongue by stage
22. In the subsequent stage (23), the rostral two-thirds of
these processes has moved to a horizontal position above
the tongue, and the epithelia that separate them from each
other and from the nasal septum have fused and are degen-
erating. The lower jaw is depressed and the tongue appears
582 A.G.Hendrickx and P.E.Peterson
Figure 3. Relationship between developmental stage (8–23) and the
ranges for age (A) and length (B) for the baboon embryos summa-
rized in Table I.
to be contracted, which may facilitate the removal of the
tongue from its earlier position between the processes. At
the ossification centre of the palatine bone, the processes
are in a state of transformation from a vertical to a horizon-
tal position. Soft palate formation in the midline is not yet
complete.
Comparative features
Baboon embryos vary by approximately 2–3 days in age
for each developmental stage during organogenesis (stages
8–23; Figure 3A). In contrast, greatest or crown–rump
length (mm) is much more variable between the stages
(Figure 3B); variation is greatest in stages 11, 17, 18, 21
and 23. Differences in length at stage 11 can be explained,
in part, by the degree of the cephalic flexure.
Figure 4. Comparative developmental stage relationships between
baboon, cynomolgus monkey, rhesus monkey and human embryos
using mean values for age (A) and length (B).
Embryonic development has been studied extensively in
the rhesus and the cynomolgus monkeys (Macaca mulatta
and M. fascicularis), as well as in the baboon. Develop-
mental stages 10–23 are virtually identical with regard to
time and external characteristics in these macaque species
and baboons (Figure 4A) (Hendrickx, 1971a; Hendrickx
and Sawyer, 1975; Hendrickx and Cukierski, 1987; Grib-
nau and Geijsberts, 1981, 1985). On the other hand, during
stages 8–12, human embryos are slightly younger than
nonhuman primate embryos. By stage 14, this situation is
reversed and human embryos are several days older than
nonhuman primate embryos (Figure 4A). This divergence
continues throughout the remainder of organogenesis:
stage 23 human embryos are approximately 6–8 days older
than their nonhuman counterparts. The length of both
human and nonhuman primate embryos studied was simi-
lar, except for the increased length in human embryos
noted for stages 21–23 (Figure 4B).
 Baboon embryology and teratology 583

Table II. Comparative neurological development in the baboon, cynomolgus monkey, rhesus monkey and
human (stages 8–16)

Developmental event Embryonic stage

Baboona Cynomolgus Rhesus Humand
monkeyb monkeyc
Otic disc formation 10 10 10 9
Optic sulcus formation 11 10 10 10 10
Rostral neuropore closure 11 11 11 11
Caudal neuropore closure 12 12 12 12
Trigeminal primordium 12 11 12 12
Facioacoustic primordium 13 12 13 13
Glossopharyngeal/vagal primordium 13 13 13 13
Three primary brain vesicles 13 13 13 13
Endolymphatic duct formation 13 14 13 14
Motor root, trigeminal 14 14 14 15
Nasal pit formation 14 14 14 15
Lens pore closure 14 15 15 14
Retinal pigmentation 15 15 15 15
Cerebral hemispheres distinct 15 15 15 15
Internal sulcus (hippocampus) >16 >16 >16 15

References: aHendrickx (1971); bMakori et al. (1996); cHendrickx and Sawyer (1975); dO’Rahilly and Müller
(1987, 1994).

The development of the brain and its derivatives in the
baboon (Hendrickx, 1971a) from stages 8 through 16
closely corresponds to that described for humans (Gasser,
1975; O’Rahilly and Müller, 1994), the rhesus monkey
(Hendrickx and Sawyer, 1975; Gribnau and Geijsberts,
1981) and the cynomolgus monkey (Makori et al., 1996).
These similarities mainly relate to the chronological order
of differentiation of specific structures of the developing
brain, although their appearance may differ slightly in
terms of the stage of the embryos in which they appear
(Table II). The overall similarity to humans in the char-
acteristics of early brain development indicates that the
baboon, in addition to the macaques, would serve as a
suitable animal model for further studies of normal and
abnormal neurological development. These observations
also emphasize the importance of using embryonic stage
rather than embryonic age in any comparative studies in-
volving the central nervous system (CNS) and other em-
bryonic organ systems in these species.
Spontaneous incidence of prenatal loss
Prenatal loss represents failure of the maternal–fetal–pla-
cental unit to maintain a normal relationship due to a var-
iety of endogenous or environmental factors. The
incidences of abortion [gestational day (GD) <140] and
stillbirth (GD ≥140) reported for one baboon colony over
an 8 year period were 3.9% (14/357) and 11.2% (40/357)
respectively (Hendrickx, 1966). The frequency of loss dur-
ing the period of organogenesis (~GD 20–50) in the ba-
boon was relatively low, i.e. 2.4% (3/122) in another
colony (Hendrickx and Binkerd, 1980). Slightly higher
rates have been reported more recently for rhesus and cy-
nomolgus monkeys (Hendrie et al., 1996). Embryonic
death rates during organogenesis were 5.1% (68/1332) and
9.2% (42/455) for the rhesus and cynomolgus monkey
respectively. The incidences of total prenatal loss through-
out gestation for each species were 17% (226/1332) for the
rhesus monkey and 17.8% (81/455) for the cynomolgus
monkey.
Teratology
A primary objective of experimental teratology is to deter-
mine potential adverse effects of chemicals and other envi-
ronmental agents on development prior to widespread
human exposure. Since ethical considerations prohibit the
testing of compounds for teratogenicity in the human po-
pulation, we must make extrapolations of potential human
risk from data obtained in experimental species. The use of
nonhuman primates in this capacity has been advocated on
the basis of their phylogenetic relatedness to humans, as
reflected in anatomical, reproductive and embryological
584 A.G.Hendrickx and P.E.Peterson

similarities. Testing agents in nonhuman primates has in-

volved recognition of the teratological principles outlined
by Wilson (1973), which include sensitive periods, dose–
response relationships, maternal toxicity, as well as the
various manifestations of deviant development (death,
malformation, growth retardation and functional deficit).
Appropriate protocols have been developed and utilized in
safety evaluation of new chemicals, drugs and biotechno-
logy products. In addition to risk assessment, nonhuman
primates have been used as models for basic studies of
congenital malformations. These models have contributed
valuable information regarding the morphological charac-
terization as well as the pathogenesis of a number of human
malformation syndromes. The contribution that the ba-
boon has made to both of these areas of experimental tera-
tology is summarized below.

Thalidomide

The potential value of nonhuman primates as models for

human responses in early development and safety asses-
sment of drugs and chemicals in pregnancy was not real-
ized until the thalidomide disaster of the late 1950s and
early 1960s. This drug, commonly prescribed for morning
sickness associated with early pregnancy, was subsequent-
ly associated with a syndrome of malformations involving
the limbs (amelia, phocomelia), external ears, heart and
kidney in exposed infants (Lenz, 1961; McBride, 1961).
Initial studies clearly demonstrated the similarity in re-
sponse to thalidomide in human, macaque and baboon em-
bryos in three main areas: the sensitive period, the pattern
of malformations and the lowest effective dose required to
induce a developmentally toxic response.
In a relatively large series of experiments involving
single and multiple dose treatments from 4 to 24 mg/kg/
day, a sensitive period between days 25–29 of gestation
was defined for the baboon (Hendrickx et al., 1966; Hen-
drickx, 1971b). Macaque species have also demonstrated a
similar sensitive period to thalidomide. A cranio-caudal
gradient of development was also evident, in that treatment
on day 25 most commonly affected the upper limbs, treat-
ment on day 27 affected the lower limbs, and treatment on
day 29 only affected the tail. Limb reduction defects, in-
cluding amelia and phocomelia, were the most common
observation in macaques as well as in baboons (Figure 5).
However, isolated cases of polydactylism, which is a
multiplication defect, were also observed.
Sex hormones
Sex steroidal hormones have been used singly and in com-
bination for a variety of clinical purposes world-wide as
Figure 5. Baboon fetus (gestational day 100) exposed to thalidomide in
utero exhibiting phocomelia (forelimbs) and polydactyly (arrow).
oral contraceptives, oral pregnancy tests, treatment for ha-
bitual or threatened abortion and antineoplastic therapy.
Common hormonal agents used for purposes of pregnancy
detection consisted of a combination of either the natural or
synthetic oestrogens and progesterone. Although preg-
nancy tests involving steroidal hormones are not currently
used, similar combinations, especially the synthetic forms,
are still used for purposes of contraception. Concern about
possible harmful effects of sex hormones has existed since
their introduction and reports of their adverse effects on the
genitalia of the developing fetus first appeared in the 1950s
(Wilkins et al., 1958; Wilkins, 1960). Subsequently, a large
body of literature has been accumulated and extensively
reviewed (Schardein, 1980; Wilson and Brent, 1981; Wise-
man and Dodds-Smith, 1984; Katz et al., 1985) The main
objectives of these reviews were threefold: (i) to determine
whether the observed defects were genital (i.e. target tis-
sue) or nongenital malformations; (ii) to identify the hor-
mones by their chemical nature (steroidal or nonsteroidal,
 Baboon embryology and teratology 585

synthetic versus natural) or by biological activity (oestro-

genic, progestational, androgenic) and (iii) to correlate out-
come with agents used singly or in combination. These
studies showed that alterations in development of the exter-
nal genitalia resulted only from administration in utero of
hormones which were heterologous to the female genetic
sex. Clitoral hypertrophy, labial fusion and increased ano-
genital distances were observed following exposure to
such hormones with androgenic properties.
Comparative studies were done in the baboon and rhesus
and cynomolgus monkeys to determine the potential em-
bryotoxicity of the combination of norethisterone acetate
(NEA) and ethinyl oestradiol (EE). The pregnant females
of all three species received daily oral doses that ranged
from 1 to 1000 times the human dose equivalent (HDE)
from day 20 to day 50 of gestation (NEA and EE: human
dose 0.2 mg + 0.0004 mg/kg). This regimen, encompassing
the period of organogenesis, was chosen to evaluate terato-
genicity associated with clinical use of the drug, i.e. one
tablet taken orally on consecutive days during early sus-
pected pregnancy.
Embryo lethality was the primary outcome of treatment
in all three species. While there was no clear-cut dose de-
pendency, it appeared that the critical dosage level for em-
bryotoxicity was 100× HDE. The time during which the
pregnancy losses occurred was also similar for all three
species. Maternal toxicity was only seen in the cynomolgus
monkey at the highest doses. In addition to embryo lethal-
ity, various forms of masculinization, including clitoral
enlargement, increased anogenital distance and reduced
vaginal opening, represented pertubations of the hormone–
target organ relationship. The masculinization effects were
seen only at extremely high doses, i.e. 300× and 1000× the
HDE, clearly suggesting a wide margin of safety for these
drugs.
Medroxyprogesterone acetate (MPA; Depo-Provera), a
long-acting injectable synthetic progestin used as a contra- Figure 6. Male baboon infant exposed prenatally to medroxypro-
ceptive by 1.2–2.5 million woman world-wide, was also gesterone acetate exhibiting micropenis (arrow) and underdevel-
studied in baboons to determine its embryotoxic effects oped scrotum (B) compared to control (A).
(Tarara, 1984; Prahalada et al., 1985a,b). A single dose of
MPA was administered i.m. on day 27 of gestation at three
different doses. The dosage corresponded to 1 (2.5 mg/kg), in any of the fetuses examined. Embryo lethality was not
10 (25 mg/kg) and 40 (100 mg/kg) times the HDE. MPA increased at the two lower doses; however, one-half of the
was not teratogenic or embryolethal at 1× HDE. The terato- pregnancies at 40× HDE aborted prior to day 100 of gesta-
genicity was confined to the higher doses and was limited tion.
to malformations of the external genitalia of both male and The maternal serum MPA concentrations, which were
female fetuses at 10× and 40× HDE and adrenal hypoplasia high during the critical period of adrenal and genital devel-
at 40× HDE (Figure 6). These abnormalities in MPA-ex- opment, partially explained the severity of malformations
posed fetal baboons were categorized as ‘target organ’ ef- in fetuses exposed to the two highest doses. However, the
fects of an administered sex hormone. Non-target organ paradoxical effects observed in male and female baboon
abnormalities (i.e. heart or limb defects) were not present fetuses were poorly understood. Various possible mechan-
586 A.G.Hendrickx and P.E.Peterson
isms that can lead to masculinization of females and/or
feminization of males have been discussed in detail else-
where (Prahalada et al., 1985a,b). Female pseudohermaph-
roditism is known to occur following maternal ingestion of
androgens or synthetic progestational agents during exter-
nal genital differentiation (Grumbach et al., 1959, 1960).
The decrease in adrenal weight observed at the high dose in
baboons was attributed to the glucocorticoid activity of
MPA. Nonhuman primate fetuses have a well-developed
fetal adrenal zone which responds to the stimulating effects
of adrenocorticotrophic hormone (ACTH), as in human
fetuses.
Collectively, these studies in baboons and macaques
showed that the primary manifestation of embryotoxicity
following exposure to combined sex steroids as well as a
synthetic progestin during early pregnancy was embryonic
or fetal death in the absence of nongenital teratogenicity.
These results support epidemiological and laboratory data
which indicate that there is no clear association between
sex steroid exposure in utero and nongenital teratogenicity.
Triamcinolone acetonide
Corticosteroids have been extensively used as teratogenic
agents for many years to study cleft palate and related
craniofacial defects (Rowland and Hendrickx, 1983). The
human data concerning teratogenicity of corticosteroids
are equivocal and they are generally considered to lack
teratogenicity. Triamcinolone acetonide (TAC) is the only
corticosteroid that has been studied during the embryonic
period in nonhuman primates (Hendrickx et al., 1980).
This study consisted of a comparison of craniofacial and
brain defects in the baboon, rhesus monkey and the bonnet
monkey after exposure to various doses of TAC (5–20
mg/kg) administered on single or multiple days between
GD 23 and 31. The TAC sensitive period (GD 23–31) for
brain and craniofacial defects encompasses neural tube
closure, formation of the primary divisions of the brain
(forebrain, midbrain and hindbrain) and early formation of
pharyngeal arches, which are major contributors to the face
and head. The pattern of malformations was essentially the
same in all these species and was similar following single-
and multiple-day treatments, with the principal difference
being an increased severity of the defects following mul-
tiple-day treatments. The CNS and cranium were the most
commonly malformed areas in all three species. Intrauter-
ine growth retardation, as well as increased prenatal mor-
tality, were also observed in these studies (Hendrickx et al.,
1980).
Cranium bifidum, associated with encephalocele, me-
ningocele and, less frequently, hydrocephalus, was a com-
monly observed skeletal defect in the multiple-dose
treatment groups (Figure 7). Cranium bifidum occultum, in
association with aplasia cutis congenita or in the absence of
any exterior gross lesions, was more frequently observed in
cases treated for a single day. The calvarial bones were
characterized by an underossification of the frontal, parie-
tal and occipital bones, with a thin membranous tissue
(dense fibrous connective tissue) covering the unossified
areas. The underossification was most apparent at the mid-
line and involved the metopic, sagittal, coronal and lamb-
doid sutures. Abnormalities of the cranial base were also
observed, mainly affecting the occipital, frontal and sphe-
noid bones.
A variety of facial abnormalities, described collectively
as craniofacial dysmorphia, were seen in all three species.
These were frequently accompanied by cleft or arched pal-
ate, with arched palate being much more frequent (Figure
7). In addition to the encephaloceles and hydrocephalus
discussed earlier, a number of cerebellar and midbrain de-
fects were described. Minor malformations of the skeleton
and viscera were also observed, including scoliosis and
kinked tail. The effects of TAC (3–28 mg/kg) administered
for 1–4 consecutive days during later periods of develop-
ment (i.e. GD 37–48, during the time of palate closure)
included resorption, abortion and growth retardation, as
well as defects of the craniofacial region, chest (funnel
chest; Figure 7), lower limbs and thymus (Hendrickx et al.,
1975). A larger portion of the rhesus and bonnet monkeys
had craniofacial defects than did the baboon fetuses, prob-
ably because the doses used in the baboon were somewhat
lower than those administered to the macaques.
From these studies it was concluded that the baboon and
rhesus and bonnet monkeys responded to the teratogenic
and developmental toxic effects of TAC in a similar
manner, each displaying the major features of the mal-
formation syndrome. The ability to induce meningoence-
phalocele consistently in the nonhuman primate, which is a
suitable model for human neural development, may also
aid in clarifying the pathogenesis of this defect and other
CNS lesions (Hendrickx and Tarara, 1990).
Bendectin
Bendectin (doxylamine succinate and pyridoxine hydroch-
loride) was a widely prescribed drug for the treatment of
nausea and vomiting in pregnancy before 1983, when the
manufacturers voluntarily ceased production; the drug re-
mains on the market in Canada. It was the only antiemetic
drug specifically approved for use during pregnancy by the
Food and Drug Administration. Because of the increasing
notoriety over the possibility of adverse effects from the

Figure 7. Various features of the triamcinolone acetonide (TAC)
syndrome in baboon fetuses are indicated (arrow) in each figure: en-
cephalocele (top), arched palate (middle) and funnel chest (bottom).
use of Bendectin during human pregnancy, studies were
carried out in baboons and rhesus and cynomolgus
monkeys to ascertain the developmental toxicity of this
antinauseant during early pregnancy, the most likely time
for pregnant women to experience nausea and to be pre-
scribed the drug (Brent, 1983; Cordero and Oakley, 1983;
Kalter and Warkany, 1983; Hendrickx et al., 1985a,b).
Baboon embryology and teratology 587
Previous studies in rodents and rabbits reported no increase
in embryotoxicity following exposure in utero to Bendec-
tin (Scott, 1984).
Pulverized Bendectin tablets, each containing 10 mg of
doxylamine succinate and 10 mg of pyridoxine hydrochlo-
ride, were administered orally to all three species. Deca-
pryn, containing 10 mg of doxylamine succinate, was also
used in baboons as a substitute for Bendectin in order to
reduce the total amount of the drug orally administered to
these somewhat intractable animals. Bendectin was admi-
nistered daily from days 22 to 50 of pregnancy in all three
species. Dosages of 10×, 20× and 40× HDE (0.667 mg/kg/
day based on a 60 kg woman taking four tablets/day) were
used in the rhesus and cynomolgus monkeys and 1× and
10× HDE in the baboon. Decapryn was given at 10× HDE
(also 0.667 mg/kg/day). Fetal examinations were per-
formed during mid-gestation (GD 100) and at term (GD
165–175).
Bendectin exposure during organogenesis resulted in an
isolated defect of the heart, interventricular septal defect
(VSD), which involved an abnormal communication of the
left and right ventricle following fetal examinations at GD
100 (Hendrickx et al., 1985a). No interventricular septal
defects, or any other defects, were found following exam-
inations at term (Hendrickx et al., 1985b). These data
clearly suggested that Bendectin caused a delay in forma-
tion of the muscular interventricular septum that was spon-
taneously corrected with further development, resulting in
a normal heart rate at birth. No significant differences in
VSD were observed for the different doses in any of the
three species. The majority of the cases of VSD involved
the muscular portion of the interventricular septum: ap-
proximately one-half of the fetuses had defects in the
smooth portion of the septum and one-half had defects in
the trabecular portion (Figure 8; Hendrickx et al., 1985a).
One fetus, a baboon, had multiple defects involving the
face, hands and genitalia, in addition to heart defects. This
malformed case was considered unrelated to treatment be-
cause similar defects were not observed in macaques at
higher doses (i.e. lack of a dose response) and because of
the isolated nature of the non-cardiac defects (see the sec-
tion Spontaneous Malformation). The incidence of abor-
tion (prenatal death) was within background rates for each
species (Hendrie et al., 1996; Hendrickx and Binkerd,
1980).
The natural history of VSD in humans is well docum-
ented and shows that large defects require surgical correc-
tion, while many VSD will reduce in size with age and
small defects will close spontaneously with no further
treatment. The rate of closure is ~30% within the first year
of life and as high as 50% within 10 years. The specific
588 A.G.Hendrickx and P.E.Peterson
Figure 8. Defects (arrows) in the muscular portion of the interven-
tricular septum observed in a gestational day 100 baboon fetus fol-
lowing exposure in utero to Bendectin.
nature of VSD in Bendectin-treated baboons and macaques
makes it an excellent candidate for the study of pathogene-
sis of VSD formation and the mechanism of spontaneous
closure of the defect.
The results of human epidemiological studies on the
association of Bendectin with cardiac malformations have
been equivocal, showing either a slight (Rothman et al.,
1979) or no (Mitchell et al., 1981) association. If Bendectin
were to induce VSD in humans in a similar fashion to that
reported in prenatal nonhuman primates, one would expect
that the vast majority of defects would close prior to birth.
The small number that might persist to term would be
difficult, if not impossible, to separate from the back-
ground rate of spontaneous defects. The incidence of VSD
in the USA has risen threefold since the early 1970s. If
Bendectin use were a significant factor in this increase, one
would expect a sharp decrease in the number of reported
VSD beginning several months after June 1983, when the
drug ceased to be manufactured, and as women who were
currently on Bendectin treatment completed their preg-
nancies.
Rubella virus
The initial definition of the rubella syndrome, the first
human teratogen to be recognized, consisted of congenital
heart disease, deafness and cataracts (Gregg, 1941). The
constellation of defects has been expanded to include
growth retardation, encephalitis, thrombocytopenia, radio-
graphic changes in long bones and persistence of virus
postnatally (Shepard, 1986). The teratogenic effects of the
rubella virus have been studied in the baboon and cynomol-
gus monkey (Hendrickx, 1966; Delahunt, 1966). Prelimi-
nary experiments to determine the effects of the rubella
virus during organogenesis demonstrated a high incidence
of abortion , stillbirths and early postnatal death. No other
abnormalities were noted. Cataracts were induced in the
cynomolgus monkey by exposure of the conceptus to the
virus in early pregnancy. The combined effects observed in
these two primate species only partially mimic the human
syndrome, characterized by prenatal loss, growth retarda-
tion and malformations, including eye defects, heart dis-
ease and deafness. These results were due, in part, to the
inability to determine accurately viral titres at the time of
the nonhuman primate experiments.
Comparative features
Table III summarizes the results of teratology studies car-
ried out in baboons and comparative information in hu-
mans and macaques. Overall, the presence/absence of
malformations in nonhuman primate studies has generally
reflected the situation in humans as derived from epide-
miological studies and case reports. The exception to this
trend is the lack of concordance, particularly in baboon,
with the rubella virus syndrome reported in human infants.
As mentioned previously, this may be due to the prelimi-
nary nature of these nonhuman primate studies. As indi-
cated in Table III, there is also some consistency in the
occurrence of death/abortion and growth retardation be-
tween macaques and baboons for the agents listed. Lack of
adequate information on these two endpoints in humans
prevents meaningful comparisons for all of these com-
pounds.
Protocols for safety evaluation
With the development and subsequent safety evaluation of
biotechnology products, the role of nonhuman primates
has changed from that of an alternate test species to that of a
preferred or essential test subject because many of these
products are bioactive only in species phylogenetically and
physiologically close to man (Henck et al., 1996). In stan-
dard teratology studies in both baboons and macaques,
females are inseminated in the ovulatory phase of the men-
 Baboon embryology and teratology 589

strual cycle, and pregnancy confirmation is performed be-

tween GD 18 and 20 using an assay for either serum or
urine chorionic gonadotrophin and progesterone and/or ul-
trasound. In the studies performed to date, treatment with
the test article on varying schedules (daily, weekly) en-
compasses the entire period of organogenesis (GD 20–50)
and may be extended for 20 or 30 additional days into the
fetal period (Figure 9). Under some conditions of testing,
shorter treatment periods of 1–15 days at various times
during organogenesis may be preferred due to the chemical
or physical characteristics of the test substance (Wilson,
1973). A Caesarean section is usually performed on GD
100, approximately two-thirds of the way through the
165-day gestation period for rhesus and cynomolgus ma-
caques and the 175-day gestation period for baboons. Nu-
merous studies have demonstrated that satisfactory
anatomical evaluation for external, skeletal and visceral
malformations, as well as for growth retardation, can be
performed at this time point. A variety of maternal end-
points have been studied and may include clinical signs, Figure 9. Standard experimental design for a teratology study in ba-
body temperature, haematology and blood pressure. boons or macaques.

Table III. Comparative teratogenicity

Agent/species Malformations Death/abortion Growth retardation

Thalidomide
Human +
Baboon + +
Macaques + +/– +/–
Sex hormones
Human +a
Baboon +a +/– –
Macaques +a +/– –
Triamcinolone acetonide
Human – –
Baboon + – +
Macaques + + +
Bendectin
Human – – –
Baboon –b –
Macaques –b – –
Rubella virus
Human + +/– +
Baboon – + –
Macaques + + –

+ = positive effect; – = negative effect; +/– = variable results (i.e., questionable or conflicting data); blank
space = not evaluated or reported.
aTarget organs only.
bDelay in closure of ventricular septum.
590 A.G.Hendrickx and P.E.Peterson

Spontaneous malformations baboon teratology studies at the CRPRC following expo-

The first known report on spontaneous congenital mal-
formations in baboons was provided by Lapin and Ya-
kovleva (1963) for the large colony in Sukhumi, Georgia of
the former USSR (Table IV). They reported a combined
incidence of 0.48% for baboons (multiple species) and
rhesus monkeys. A similar incidence (0.53%) was found in
the Southwest Foundation Colony (San Antonio, TX,
USA). The two malformations, congenital blindness at
birth and left diaphragmatic hernia in a 14-week old fetus,
were observed in 375 cases. Data obtained from necropsy
cases at the California Regional Primate Research Center
(CRPRC), Davis, USA between 1969 and 1982 indicated
only one case of VSD in 61 cases reviewed (1.6%) (Hen-
drickx and Prahalada, 1986). Additional spontaneous de-
fects in various species of baboon reported in the literature
are summarized in Table V. In contrast to these malforma-
tions, which primarily affect one organ system, was the
case of multiple defects that was observed in one of the
sure to Bendectin. Due to the isolated nature of the mal-
formation; i.e. lack of dose relationship, and the lack of a
biologically plausible mechanism for teratogenicity, this
case was considered spontaneous or due to unknown
causes, rather than a drug-induced abnormality. The over-
all incidence of <1% malformations in baboons is similar
to that reported for other commonly used primates (Hen-
drickx, 1966; Hendrickx and Prahalada, 1986; Peterson et
al., 1997).
In summary, studies conducted over the past 30 years
have clearly demonstrated the contribution that the ba-
boon, as a surrogate simian model, has made to our under-
standing of both normal and abnormal embryonic
development. The many similarities shared with early
human pregnancy have enabled direct comparisons with
known human teratogens and provided a valuable model
for screening new drugs/chemicals prior to human expo-
sure.

Table IV. Spontaneous malformations in baboon colonies

Colony/location No. cases examined No. cases malformed % Reference

Sukhumi Colony –a –a 0.48 Lupin & Yakovleva (1963)
Southwest Foundation 375 2 0.53 Hendrickx (1966)
California Regional Primate 61 1 1.6 Hendrickx & Prahalada (1986)
Research Center

aNo cases reported.

Table V. Summary of spontaneous malformations in baboons

Species Malformations (no.) References

Papio sp. Craniofacial deformity (1) Pruzansky (1975)
Unilateral renal aplasia (1) Kim and Kalter (1972)
Diaphragmatic hernia (1) Hendrickx and Gasser (1967)
Papio anubis Male pseudohermaphroditism (1) Wadsworth et al. (1978)
Unilateral renal aplasia (1) McCraw et al. (1973)
Papio cynocephalus Supernumerary nipple (1) Buss and Hamner (1971)
Papio doguera Coloboma (2) Schmidt (1971)
Papio hamadryas Arnold–Chiari malformation (1) Cameron and Hill (1955)
Patent ductus arteriosus, aortic hypoplasia, arotic Krilova and Yakovleva (1972)
and pulmonary valvular deformities (1)
Ventricular septal defect, overriding aorta, aortic and pulmonic
stenosis (1)
Ventricular septal defect, mitral and tricuspid
valvular deformities, left ventricular hypoplasia (1)
Papio sphinx Hand anomaly (1) Schultz (1944)
Papio ursinus XY gonadal dysgenesis (1) Bielert et al. (1980)
Retrocaval right ureter (1) Hesse (1969)
Pygathrix nemaeus Pectus excavatum (1) Sedgwick (1981)

Acknowledgements
This research was supported in part by NIH grant RR00169.
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Received on April 3, 1997; accepted on July 8, 1997