Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research

Abstract

1. The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.

2. Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.

3. Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.

Keywords:

• Thalidomide
• anticonvulsants
• retinoids
• alkylating agents
• maternal metabolism
• foetal metabolism
• stem cells
• concentration response

Acknowledgements

The author is very grateful for the help and discussion of the manuscript provided by Scott Obach.

Disclosure statement

The authors report no declarations of interest.

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Funding

The author(s) reported there is no funding associated with the work featured in this article.