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By Anthony Scialli, MD
All compounds are harmless at one dose and toxic at another, and the same is true for so-called teratogens. Teratogenicity, like toxicity, is a relative concept. Just as all compounds are poisons at a high enough dose, all compounds should be expected to produce developmental toxicity at a high enough exposure level.
The risk of birth defects in humans for a given exposure cannot be extrapolated from embryo culture tests without considerable information on the exposure level anticipated in humans, and without an understanding of the kinetics of the compound in humans and in the test system. In vivo (whole animal) tests provide some predictive information on the risk of birth defects, because the dose level at which maternal toxicity is present serves as an intraspecies comparator of the sensitivity of the embryo.
Opioids are an example of the importance of exposure level in evaluating developmental toxicity potential. Although opioids increase developmental toxicity in whole animal teratology studies at a sufficiently high dose, these agents have not been associated with an increased incidence of congenital anomalies under conditions of clinical use for pain relief.
Rat whole embryo culture by itself cannot be used as a screening test for risks to human reproduction, although the technique can be designed to investigate mechanisms of toxicity when such toxicity has been identified in whole animal testing. Whole embryo culture is not recognized as an appropriate screen for human reproductive risk by the National Institute of Environmental Health Sciences (NIEHS), the National Center for Evaluating Health Risks to Reproduction (NCEHR), or the Environmental Protection Agency (EPA).
The finding that components of blue cohosh produce abnormal development of the rat embryo in culture cannot be interpreted without additional information:
• How do the concentrations in culture compare to human plasma concentrations under usual conditions of use of this drug?
• How rapidly is the agent being studied metabolized or excreted by the mother? Remember, in whole embryo culture, there is no maternal organism to get rid of the drug, so exposures tend to be longer and at higher levels than in real life.
• Is the developmental toxicity unique, or (more likely) a nonspecific consequence of general toxicity? High enough concentrations of any compound can be expected to prevent normal embryo flexion and neural tube closure, for example, because these events are the biggest things happening during the culture period.
Dr. Scialli is the Editor of Reproductive Toxicology and is on the editorial advisory board.