Teratogenicity
Yet another response to toxicants is birth defects that may manifest
as either physical deformities, functional deficits, or behavioural changes.
The specific effect is dependent not only upon the chemical and its characteristics
but also upon the specific period of foetal development during which the
exposure occurred.
Normal Foetal Development follows four (4) general stages.
| Stage |
Time (Rat) |
Time (Human) |
Remarks |
| Implantation & Fertilisation |
8 days |
6 days |
|
| Embryonic Period |
14 days |
14 weeks |
If exposure occurs during weeks 3-7, death of the foetus or major morphologic/anatomic
changes may occur |
| Organogenesis |
17 days |
20 weeks |
Organs are differentiated at specific times. Exposure may result
in developmental or functional changes. Defects produced during organogenesis
may result in unbalanced growth (a pear-shaped kidney, for example). |
| Histogenesis |
21 days |
34 weeks |
Organ systems increase in mass and develop. Exposure results
in fewer morphological changes, but may produce retardation of growth and
functional deficits. |
| Parturition |
22 days |
36-40 weeks |
Birth |
The greatest risk of damage to the foetus occurs during the organogenesis
and early histogenesis phases. This increased sensitivity is due
to
1) rapid mitosis
2) differentiation of cell types
3) incomplete placental development, therefore less effective as a
barrier to entry of teratogens. Almost any chemical type may cross
the placenta. However, lipophilic compounds will readily cross the
placenta while those that are highly electronegative do not cross as well.
NOTE that the placenta possesses a P450 system that may detoxify
OR bioactivate a toxicant. (Thalidomide is bioactivated by the placental
P450 system.)
Some examples of the time-dependency of teratogenesis include thalidomide
which exerts its teratogenic effects if exposure occurs on days 34 - 50
of foetal development. Exposure on days 34-38 will result in ear
defects; 40-44, minor defects of the arm; and days 44-48, with phocomelia
or "seal-like" flippers or arms resulting. Absence of a particular
nutrient may also result in birth defects. The absence of folic acid
(required for closure of the palate) on day 70 will result in cleft palate,
as seen with many anti-convulsants (which may possess anti-folate activity).
Anti-convulsants may also produce other birth defects such as phenytoin,
which will produce deformities of the eyes and limbs on days 9-10 and facial
deformities on days 11-12. Exposure during the first week of foetal
development (implantation/fertilisation) most often results in death of
the foetus.
Teratogens DO exhibit a dose:response effect. Very low doses
of known teratogens may not produce any effect. Higher doses pose
a greater risk of defect and even higher doses may result in death of the
foetus.
Mechanisms of Teratogenesis
Many of the effects produced in teratogenicity are the same as those
that result in carcinogenicity. DNA of the developing foetus may
be directly altered via alkylation, intercalation, disarrangement of normal
repair enzymes (DNA polymerase), or base-pair abnormalities (as seen with
the anti-metabolite purine and pyrimidine antagonists). In addition
to these causes, teratogenicity may result from improper protein formation
within the cells (as seen with amino acid antagonists) and with spindle
poisons (such as colchicine) which inhibit mitosis and, subsequently, cell
and organ growth. NOTE that only 20% of birth defects are due to
mutagenesis. The remaining 80% of birth defects results from disarrangements
of chromatids and spindle effects, viz. changes in nucleic function.
Factors that affect whether or not and the degree to which teratogenesis
occurs include:
Stage of development of the foetus. The more advanced the foetus
at exposure, the less likely the risk for birth defects.
Route, dose, and interval of exposure to the toxicant, as discussed
previously in the course.
The placental state, whether or not the teratogen will cross it and
whether or not it is metabolised or bioactivated. (NOTE that the
foetus may also metabolise/bioactivate compounds, though not as effectively
as the mother or the placenta.)
The half-life of the chemical, as discussed previously.
The most dangerous teratogens are those that are tolerated by the mother
but cause harm to the foetus, i.e. thalidomide or Rubella infection.
Teratogenicity may present as either developmental or functional deficits.
Developmental defects of the organ may result in malformed organs, while
functional deficits may interfere only with its physiological role in homeostasis.
NOTE that either developmental or functional defects that affect the central
nervous system may result in many behavioural abnormalities, such as learning
and memory disability, behaviour, and co-ordination. For example,
Fetal Alcohol Syndrome results in a slow proliferation of numerous cells
causing altered and retarded growth and mental ability. FAS children
are very much like premature infants that do not recover.
Teratogenesis may result from nutritional deficits or excesses.
Deficiencies
Vitamins A, E, D, and Folic Acid
Hormones -- pituitary, thyroid, insulin, cortisol
Trace elements -- copper, zinc, manganese, chromium
Excess
Vitamin A
Nicotinic acid, galactose
Antibiotics -- streptomycin, tetracycline, penicillin, fluoroquinolones
Metals -- lead, thallium, methyl mercury, phenylmercuric acetate, mercuric
chloride
FDA Pregnancy Categories
These categories have been established to provide a guide of the relative
risk of potential harm if the drug is taken during pregnancy. They
should be used in evaluating the risk vs. the benefit that could
result from use of the drug. The categories are based primarily upon
existing studies in both animal models and humans and their scientific
integrity and reliability. The categories also attempt to classify
drugs based upon both the risk:benefit analysis and the reliability of
these studies. For example, a drug known to cause teratogenesis with
little benefit to the patient would be classified as contra-indicated during
pregnancy. (The table is adapted from the 1996 edition of Facts and
Comparisons.)
| Pregnancy Category |
Description |
| A |
Adequate studies in pregnant women have not demonstrated teratogenesis
during the 1st trimester. Additionally, no evidence exists that suggests
potential for harm in the 2nd or 3rd trimesters. |
| B |
Animal studies do not indicate a risk for teratogenesis but no human
studies have been performed OR animal studies have demonstrated a
risk but human studies have indicated no such risk during the 1st trimester
and no evidence for later trimesters. |
| C |
Animal studies indicate a potential for teratogenesis but there are
no adequate studies for humans OR there are no adequate animal or human
studies. Potential benefit may outweight potential risk. |
| D |
There is evidence for human teratogenesis but potential benefit may
outweight potential risk. |
| X |
Animal and/or human studies indicate teratogenesis or the potential
for abnormalities. Any potential benefits do not outweigh the risks
of exposure. |
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