Event:1001

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Event Title

Developmental Defects, Increased

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
VEGF Signaling and Vascular Disruption Leading to Adverse Developmental Outcomes AO [[Aop:43#Essentiality of the Key Events|]]

Taxonomic Applicability

Name Scientific Name Evidence Links

Affected Organs

Synonym Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

The risks for chemical effects on the reproductive cycle are broadly defined into two categories for regulatory guidelines: reproductive (fertility, parturition, lactation) and developmental (mortality, malformations, growth and functional deficits). With respect to apical endpoints for developmental defects, the International Conference on Harmonization regulatory guidelines for embryo-fetal developmental toxicity testing (ICH 2005) require studies in both a rodent and a non-rodent species, usually rat and rabbit. The current paradigm was developed in response to the pandemic of phocomelia associated with maternal exposure to thalidomide during early pregnancy [Schardein 2000]; however, dose ranges of thalidomide that were teratogenic in the rabbit induced embryo-fetal loss in the rat [Janer et al. 2008]. This observation is consistent with current knowledge that the specificity of the manifestations of embryo-fetal toxicity may vary greatly between species, and even between strains within the same species [Hurtt et al. 2003; Janer et al. 2008; Knudsen et al. 2009; Rorije et al. 2012; Theunissen et al. 2016].

This event consolidates the four main types of developmental defects from regulatory studies (prenatal loss, malformations, low birth weight, and postnatal function) into one AO. Any or all four AOs within the same litter, and as noted by SR2 this is what one would expect in AOPs relevant in developmental toxicity.

Whereas it makes sense mechanistically to unravel pathways of developmental toxicity leading to specific types of defects, a fundamental principle is that all four types of endpoints are deemed important for hazard assessment. Even a simple MIE may cut the embryo in dozens of ways depending on the nature of the insult and timing of exposure. As such, we agreed to consolidate the AOs into one for 'developmental defects' which we believe can be ported to many AOPs for developmental processes. Individual rationale is given in each appropriate section.

We believe AOP43 now provides an excellent case example for the AOP community to embrace the complexity of developmental toxicity, with future spinoffs of multiple AOPs for individual developmental defects as the data becomes available.

How it is Measured or Detected

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Evidence Supporting Taxonomic Applicability

References

Janer G, Slob W, Hakkert BC, Vermeire T and Piersma AH. A retrospective analysis of developmental toxicity studies in rat and rabbit: what is the added value of the rabbit as an additional test species? Regul Toxicol Pharmacol. 2008 50: 206-217.

Hurtt ME, Cappon GD and Browning A. Proposal for a tiered approach to developmental toxicity testing for veterinary pharmaceutical products for food-producing animals. Food Chem Toxicol. 2003 41: 611-619.

Knudsen TB, Martin MT, Kavlock RJ, Judson RS, Dix DJ and Singh AV. Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA's ToxRefDB. Reprod Toxicol. 2009 28: 209-219.

Rorije E, van Hienen FJ, Dang ZC, Hakkert BH, Vermeire T and Piersma AH. Relative parameter sensitivity in prenatal toxicity studies with substances classified as developmental toxicants. Reprod Toxicol. 2012 34: 284-290.

Schardein J. Chemically Induced Birth Defects. 2000. New York, Marcel Decker Inc.

Theunissen PT, Beken S, Beyer BK, Breslin WJ, Cappon GD, Chen C, Chmielewski G, De Schaepdrijver L, Enright B, Foreman JE, Harrouk W, Hew KW, Hoberman AM, Hui JY, Knudsen TB, Laffan SB, Makris S, Martin M, McNerney ME, Siezen CL, Stanislaus DJ, Stewart J, Thompson KE, Tornesi B, Weinbauer G, Wood S, Van der Laan JW and Piersma AH. Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects. 2016 Chem Rev Toxicol (in revision).