PRINCIPLES OF TOXICOLOGY

ders, such as diabetes and phenylketonuria. In turn, genetically based developmental disorders still
surpass all of the environmental phenomena that can affect development in terms of proportional
importance within the population.
This section will cover the toxicology relevant to all stages of development from fertilization
onward. This will include the action of toxicants on the mother that affect the ability to establish and
maintain pregnancy, as well as direct actions on the fetus. The developmental stages can be divided
into 1) the preimplantation stage, where toxicity generally affects the entire organism and there is
typically an all or none response (i.e., there is repair or the developing organism is aborted), and 2) the
later embryonic and fetal stages, where specific structural defects can occur. The most sensitive period
for teratogenesis, the production of congenital defects, is during organogenesis in the embryonic
period.
Mammalian development can be thought of as an expansive flow diagram (Figure 11.5). Following
fertilization there is a very particular sequence of events that is followed, directed by the expression
of certain genes at certain times. From a toxicological point of view, disruptions during this relatively
linear phase generally derail the entire developmental sequence. Certain developmental steps serve as
branch points and once particular branches are followed, the occurrence of events on that branch will
not necessarily affect other branches. As development progresses, many smaller branches are reached,
which may each relate to the development of certain tissues, cell types, or regions of a structure.
Toxicologically, when specific sequences are affected, the response may be restricted to the features
that develop out of that particular sequence. This illustrates how very specific defects can occur in
response to toxicants or other environmental factors and exhibit clear time dependence.
Spontaneous Abortion and Embryonic Loss
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Recent improvements in the ability to measure human chorionic gonadotropin, a very early indicator
of the presence of an embryo, have allowed reasonable estimates of early pregnancy loss. Overall,
more than 50 percent of fertilized eggs/embryos are lost through spontaneous abortion. Around 30
percent are lost after implantation but before the first menstrual period is missed. An additional 20–25
percent are lost after they have been clinically recognized as a pregnancy. There are also probably
substantial pre-implantation losses, but these are much harder to accurately estimate. Presented another
way, it appears that the chance of achieving a full-term pregnancy for any one menstrual cycle in which
fertilization is likely to have occurred (based on non-contracepted intercourse with ovulation) is around
25 percent.
The preponderance of embryonic loss occurs during what was described as the linear phase of
development. Based on chromosomal analysis of spontaneously aborted embryos, approximately
two-thirds of this loss can be explained by gross genetic abnormalities. Around 10 percent can be
attributed to a known environmental cause, and a cause cannot be determined for the remainder. While
some of the genetically associated loss could be related to environmentally mediated DNA damage, it
is clear that most is due to major chromosomal aberrations associated with germ cell production and
fusion. Once again, the potentially chemically induced responses are hidden within an extremely high
background rate of embryonic loss.
In general, the response to toxicological insult during the early embryonic stage is considered
to be an all or none event, where damage up to minor cell death is completely repairable and major
cellular disruption or death results in abortion of the pregnancy. This is based on the flexibility
of the cells in the early embryo, which allows them to functionally replace a few lost cells. As
development progresses, most cell lines become committed to a particular fate and such compensation
is less likely.
The limited responses available during early embryogenesis mean that typically the endpoint of
concern for toxic exposures is spontaneous abortion. While this criterion has held over the years for
most toxicants, there are recent experimental results which suggest that very early exposure to ethylene
oxide and some other mutagens may cause responses that are manifest much later in development.
This implies that the exposure may result in a sublethal injury that is not repaired, nor are all of the