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Event: 1001

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased, Developmental Defects

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
anatomical structure morphogenesis		morphological change

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Developmental Vascular Toxicity	AdverseOutcome	Undefined (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

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. 443 (Extended 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 the OECD TG 414 Prenatal Developmental Toxicity Study (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 443 and 416, respectively).

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

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].

OECD Test Guideline No. 414 (Prenatal Developmental Toxicity Study) and Test Guideline No. 443 (Extended One-Generation Reproduction Toxicity Study) test for the endpoints relevant to this AOP. TG 414 is an OECD validated developmental toxicity test designed to provide general information concerning the effects of prenatal exposure on the pregnant test animal and on the developing organism. It is intended for use with rodents (rat, preferably) and non-rodent (rabbit, preferably). Exposure is administered to pregnant animals at least from implantation through organogenesis.

OECD Test Guideline 443 is an extended one generation toxicity test that looks for developmental and reproductive effects after chemical exposure administered pre- and postnatal. Systemic toxicity in pregnant and lactating females in addition to young and adult offspring is also evaluated.

The full text of the guidelines can be found at https://www.oecd-ilibrary.org/environment/test-no-414-prenatal-development-toxicity-study_9789264070820-en and https://www.oecd-ilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicity-study_9789264185371-en .

References

List of the literature that was cited for this KE description. More help

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).

OECD (2018), Test No. 414: Prenatal Developmental Toxicity Study, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, https://doi.org/10.1787/9789264070820-en.

OECD (2018), Test No. 443: Extended One-Generation Reproductive Toxicity Study, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, https://doi.org/10.1787/9789264185371-en.