TERATOLOGY 50:97-98 (1994)
Letters
"Proof" of Human Teratogenicity
To the Editor:
More and more teratologists are being asked what
criteria do we use for "proof" of human teratogenicity.
The law profession is particularly interested in our answers, but among ourselves we do not seem to have a
very active dialogue on this important question. In order to highlight this subject, I am writing this letter
with the intent of educating other teratologists and
myself. I have tried to summarize and amalgamate the
work of others on the criteria for establishing human
teratogenicity (Shepard, '86a,b) in Table 1.
TABLE 1. Amalgamation of criteria for proof of
human teratogenicity'
1. Proven exposure to agent at critical time(s) in prenatal
development (prescriptions, physicians' records, dates).
2. Consistent findings by two or more epidemiologic studies
3.
4.
5.
6.
7.
-
of high quality
a. control of confounding factors,
b. sufficient numbers,
c. exclusion of positive and negative bias factors,
d. prospective studies, if possible, and
e. relative risk of six or more (?I.
Careful delineation of the clinical cases. A specific defect
or syndrome, if present, is very helpful.
Rare environmental exposure associated with rare
defect. Probably three or more cases (e.g., oral
anticoagulants and nasal hypoplasia, methimazole and
scalp defects(?), and heart block and maternal
rheumatism).
Teratogenicity in experimental animals important but
not essential.
The association should make biologic sense.
Proof in an experimental system that the agent acts in
an unaltered state. Important information for
prevention.
'Note: Items 1-3 or 1, 3 , and 4 are essential criteria. Items
5-7 are helpful but not essential. From Brent ('78), Stein
et al. ('84),Hemminki and Vineis ('85); Wilson ('771, and
Shepard ('86a,b,'89,'92).
As emphasized, there are a t least two modes for establishing human teratogenicity. The rare malformationirare exposure or case report method is far easier,
less expensive, and more common than full epidemiologic studies. Examples of this rare defectirare exposure
0 1994 WILEY-LISS, INC.
"proof" (or better stated strong association) are congenital rubella, diethylstilbestrol, rheumatic disease (and
congenital heart block), cyclophosphamide, and retinoic
acid. A discussion and examples of these two methods
have been published (Shepard, '91). The epidemiologic
approach is expected to be more productive in the figure
and has been elaborated on by Stein et al. ('841, Hemminki and Vineis ('85),and Corder0 and Oakley ('83).
Several lists of criteria for human teratogenicity
have included the dose (or concentration) response relationship (Brent, '86a,b; Beckman and Brent, '92;
Holmes, '93).Although a dose response may be considered essential in establishing teratogenicity in animals
it is extremely uncommon to have sufficient data in
human studies. This is fortunate. As examples where a
dose response has not been detected among humans, I
would cite thalidomide, diethylstilbestrol, and retinoic
acid. With the viral teratogens, a dose would be almost
impossible to establish. I find i t impossible to cite a
human teratogen that fits this criterion. Perhaps Brent
o r Holmes can furnish one.
Another criterion which is comforting to have but
often not fulfilled is biologic plausibility for the cause.
We have no biologically plausible explanation for thalidomide embryopathy. Without going into detail here,
I would suggest that at least one half of all human
teratogens do not fit this criterion.
Not all human teratogens will fit the exact criteria
outlined in Table 1. There have been and will be exceptions. Fetal thyroidectomy from therapeutic
amounts of maternal radioiodine is a n example of biologic plausibility which strongly reinforced the association with the rare occurrence of congenital absence of
the thyroid. Only a single case report might suffice.
Chronic villus sampling before the end of embryogenesis (about 60 days from fertilization) associated with
limb reduction is a rare event, but a number of epidemiologic studies tend to support it. This would be a n
example of both discovery modes.
There is need for a multiauthored scholarly discussion of the weight of evidence that leads us to the assignment of human teratogenicity. Perhaps this could
be undertaken by the Teratology Society's Public Af-
98
T.H. SHEPARD
fairs Committee. If this is done we should acknowledge
our historic dependence on Koch’s postulates and writing of Bradford Hill (’65).
THOMAS H. SHEPARD, M.D.
Department of Pediatrics
University of Washington
Seuttle, WA 98195
LITERATURE CITED
Beckman, D.A., and R.L. Brent (1992) Basic principles of teratology.
In: Medicine of the Fetus and Mother. E.A. Albert, J.C. Hobbins,
M.J. Mahoney, and R.H. Petrie, eds. Lippincott, Philadelphia, pp.
297-298.
Brent, R.L. (1978) Editor’s not,e. Teratology, 17t183.
Brent, R.L. (1986ai Evaluating the alleged teratogenicity of environmental agents in clinics. In: Perinatology. R.L. Brent and D.A.
Beckman, eds. W.B. Saunders, Philadelphia, Vol. 13, pp. 609-613.
Brent, R.L. (1986b) Methods of evaluating the alleged teratogenicity
of environmental agents. In: Teratology in Teratogen Update: Environmentally Induced Birth Defect Risks. J.L. Sever, and R.L.
Brent, eds. Alan R. Liss, Inc., New York, pp. 199-201.
Cordero, J.F., and J.P. Oakley (1983) Drug exposure during pregnancy: Some epidemiologic considerations. Clin. Obstet. Gynecol,
26:418-428.
Hemminki, K., and P. Vineis (1985) Extrapolation of the evidencc on
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Hill, B.H. (1965) The environment and disease: Association or causation? Proc. R. Soc. Med., ,58295-300.
Holmes, L.B. (1993)Report of National Institute of Child Health and
Human Development Workshop on chronic villus sampling and
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Sever, J.L. and R.L. Brent, eds. Alan R. Liss, Inc., New York, pp.
199-201.
Shepard, T.H. (1986a) Human teratogenicity. In: Advances in Pediatrics. L. Barness, ed. Year Book Medical Publishers, Chicago, Vol.
33. pp. 225-268.
Shepard, T.H. (1986b, 1988, 1992) A Catalog of Teratogenic Agents.
Johns Hopkins University Press, Baltimore, Eds. 5-7.
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brainstem vascular etiology’”: Case observation vs. epidemiology
studies. Teratology, 43.559-560.
Stein, Z., J. Kline, and M. Kharrazi (1984) What is a teratogen? Epidemiologic criteria. In: Issues and Reviews in Teratology. H. Kalter, ed. Plenum Press, New York, Vol. 2, pp. 23-66.
Wilson, J.G. (1977) Embryotoxicity of drugs in man. In: J.G. Wilson
and F.C. Fraser, eds. Handbook of Teratology. Plenum Press, New
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