Biomedical Engineering Reference
In-Depth Information
TABLE 19.1
Selected Advantages and Limitations of Nonhuman Primate (NHP) Models for Developmental and
Reproductive Toxicity Testing
Advantage
Disadvantage
Cynomolgus monkey
Reasonable reference database
Litter size (default
¼
1)
Predominant NHP species in safety assessment
Fertility rate (35
45%/cycle, 60%/female)
e
Physiology/endocrinology similar to human
High pre- and postnatal loss rates compared to
nonprimates
Fertile throughout entire year
Supply of sexually mature animals
Noninvasive ovarian cycle monitoring (swabs)
Late attainment of puberty (36
72 months)
e
Rhesus monkey
Physiology/endocrinology similar to human
Comparatively large body size
Noninvasive ovarian cycle monitoring (swabs)
Distinct reproductive seasonality
Otherwise same as cynomolgus monkey
Incompatibility of sexually mature animals
Gradually replaced by cynomolgus monkey
Otherwise same as cynomolgus monkey
Marmoset
Small body size
Limited reference database
Litter size (default
¼
twin)
Male presence needed to maintain pregnancy
Fertility rate (70
80%/cycle)
Physiology/endocrinology different from human
e
Supply of sexually mature animals
Invasive ovarian cycle monitoring (progesterone)
Early attainment of puberty (12
18 months)
High pre- and postnatal loss rates compared to
nonprimates
e
Baboon
Physiology/endocrinology similar to human
Comparatively large body size
Limited reference database
Not commonly used in safety assessment
development, and similar responses to known human
teratogens, e.g. thalidomide and vitamin A (
Henck et al.,
1996; Buse et al., 2008
). For the safety evaluation of male
and female fertility a large battery of parameters can be
used that is basically identical to those used for gyneco-
logical and andrological diagnosis. From a regulatory
perspective, the most clinically relevant animal species
should be used for safety assessment. Reproductive and
developmental physiology studies have been described for
a number of nonhuman primate species, including Old
World monkeys and New World monkeys, and the cyn-
omolgus monkey currently is the predominant nonhuman
primate species used in nonhuman primate safety assess-
ment studies (
Weinbauer et al., 2008
).
On the other hand, the use of nonhuman primates poses
ethical and practical limitations. Pregnant nonhuman
primates are not available from breeders, but rather
a mating program is established at the site where the study
is conducted. Hence, animals enter studies as they become
pregnant, rendering study conduct complex and lengthy
with an overall study duration between 8 and 25 months
(
Chellman et al., 2009
). Default litter size in macaques is
one. Twin pregnancies/births are extremely rare in
macaques with an overall twin live births incidence around
0.1% (
Hendrie et al., 1996; van Esch et al., 2008
). Spon-
taneous fertility rates in macaques are clearly below 100%
(typically around 60% per animal but only 35
45% per
ovarian cycle;
Chellman et al., 2009
). It is pivotal to realize
that reproductive failure, e.g. post-implantation loss, is
significant among primates. A review of this aspect in nine
macaque species concluded that overall
e
reproductive
failure comprises
16.3% abortions, 9.9%
stillbirths, 21.9% neonatal deaths, and 15.2% infant deaths
(
Small, 1982
). In macaque breeding colonies, the annual
prenatal loss rates varied between 13% and 23% in the
rhesus monkey (seasonal breeder), 10% and 50% in the
bonnet monkey (seasonal breeder), and 8.6% and 28% in
the cynomolgus monkey (nonseasonal breeder) (
Hendrie
et al., 1996
). More recent work confirms that stillbirth rates
can attain 20% in the cynomolgus monkey (
Sesbuppha
on average
e
e
