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Key Event Title
Increased, Developmental Defects
|Level of Biological Organization|
Key Event Components
|anatomical structure morphogenesis||morphological change|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Developmental Vascular Toxicity||AdverseOutcome||Tom Knudsen (send email)||Open for citation & comment||EAGMST Under Review|
Key Event Description
Key Event Description: The risks for chemical effects on the reproductive cycle in mammals are broadly defined in two categories for regulatory purposes: reproductive (fertility, parturition, lactation) and developmental (mortality, malformations, growth and functional deficits). Many advances in our knowledge of fundamental human embryology derives from model organisms such as zebrafish and chick embryos [Beedie et al. 2016 and 2017]. The standard formulation of prenatal developmental toxicity for drug or chemical exposure underscores several dependencies: initiating mechanisms (targets); dose response (quantitative response); stage susceptibility (temporal response); species differences (concordance); chemical bioavailability (metabolism and kinetics); and apical endpoint (phenotype). These principles have continued to guide scientific research in teratology, are widely used in teaching [Friedman, 2010].
How It Is Measured or Detected
How it is Measured or Detected: Developmental defects are typically assessed by observational studies of animal models and by human epidemiological studies. For animal models, the apical endpoints derive from a litter-based evaluation of fetuses just prior to birth or beyond. A study design fit for the purpose of regulatory toxicology adheres to regulatory guidelines specified by OECD Test Guideline No. 414 (Prenatal Developmental Toxicity Study). Prenatal animal studies in mammalian species where exposure to a drug or chemical is administered to the dam describe the occurrence and severity of effects to the mother and fetuses and perform statistical evaluations on a litter basis since the dam is the exposure unit.
Domain of Applicability
Domain of Applicability: Maternal and fetal weight effects and viability were the most often affected parameters at the developmental lowest effect levels, followed by skeletal malformations [Knudsen et al. 2009; Rorije et al. 2012]. Specific endpoints such as phocomelia have critical value in setting regulatory decisions for drugs and chemicals; however, they are less frequently observed than fetal weight reduction or skeletal malformations. Latent effects that do not manifest at term or are not reliably diagnosed until postnatal development or subsequent generations, may be detected by OECD Test No. 415 (One-Generation Reproduction Toxicity Study) or Test No. 416 (Two-Generation Reproduction Toxicity). Viability after delivery is important outcome for human health concerns, as are other conditions that may be missed in OECD 414 (e.g., stillbirth and neonatal mortality, long-term neurologic handicap, and maternal mortality). Those relevant to AO:1001 may be captured in the one-or two-generation reproduction toxicity study designs (OECD 415 and 416, respectively).
Regulatory Significance of the Adverse Outcome
Regulatory Significance of the Adverse Outcome: 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 two-species testing paradigm was developed in response to the pandemic of phocomelia associated with maternal exposure to thalidomide during early pregnancy [Schardein 2000]. 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 specific manifestations of embryo-fetal toxicity may in general vary greatly between species, and even between strains within the same species [Hurtt et al. 2003; Janer et al. 2008; Theunissen et al. 2016].
Friedman JM. The principles of teratology: are they still true? Birth Defects Res A. 2010 Oct;88(10):766-8. doi: 10.1002/bdra.20697.
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. Chem Rev Toxicol. 2016 (in revision).