n      The Developmental and Reproductive Toxicology Committee of the ILSI Health and Environmental Sciences Institute (HESI) sponsored a two-day workshop to foster improvements in alternative models of developmental toxicity.   Breakout groups covered stem cells, whole embryo culture, zebrafish, and the statistical methods used to turn short-term or in vitro observations into predictions of mammalian developmental toxicity.  The workshop was held Feb 27-28, 2007, at the Umstead Hotel, in Raleigh (Cary), North Carolina, USA.   For further information, contact Ms. Regina Graham at HESI (rgraham@hesiglobal.org), or click here to visit the Workshop webpage.

n       Behavioral Testing Project – Parts I and II:  the DART Technical Committee critically assessed the contribution of behavioral teratology to hazard identification by compiling and evaluating a significant database on these types of studies.  A report, “Neurobehavioral Assessment:  A Survey of Use and Value in Safety Assessment Studies,” was published in Toxicological Sciences in late 2003.  Agents evaluated in the studies impacted behavioral parameters less often than general toxicology parameters; however, their effects on F1 behavioral parameters contributed toward defining the no-effect level (NOEL) in 15%, and solely defined the NOEL in 2.6% of the studies.  A follow-up activity to the project has begun, and is anticipated to result in an opinion paper on the specific value of these types of tests, and on possible triggers for the tests.  DART is exploring the possibility of conducting an independent workshop or session at the annual meeting of the Teratology Society in 2008.

n       The Histopathology of Female Reproductive Physiology project was completed in 2005.  The resulting series of papers and case studies was published in Birth Defects Research – Part B in spring 2007.  It is anticipated that the series will provide a reference for industry and government veterinary pathologists and toxicologists, and provide the basis for characterizing various toxicities and biologic effects of different compounds as they relate to vaginal cytology, ovarian histology, and mammary gland histology in the most commonly used laboratory species (rat, dog, and primates).  Case studies in the series include atrazine and reproductive function, dietary effects on mammary tissue, qualitative and quantitative assessments of tibulone on the mammary gland, animal models for ovatoxicity using 4-vinylcyclohexane, histologic changes in reproductive organs of dogs treated with the SERM idoxifene, and identification of drug-induced hypo/hyperprolactinemia in the female rat. 

n       The Juvenile Animal Studies in Assessments of Pediatric Safety project was essentially completed with the publication of proceedings from the committee’s November 2003 workshop, “Juvenile Animal Studies:  Testing Strategies and Design” (published in the journal Birth Defects Research-Part B, in mid-2004).  Workshop participants, including industrial, academic, and regulatory scientists from the United States and the European Union, agreed that case-by-case determinations should be made as to when juvenile animal studies are needed.  Key considerations for each case should include the patient population, the relevant adult organ toxicity, the mechanism(s) of action, and class effects.  They also agreed that one species is sufficient for each study, and that the preferred species is generally the rat.  Toxicokinetics or pharmacokinetics should be part of the study.  Adding to the reviews of postnatal development of a range of organ systems already published as part of this project, a review of the gastrointestinal system was published in Birth Defects Research-Part B, in 2005.  Presentations of the outcome of this project were made at several venues in 2005, including a Drug Information Association conference in Washington, DC, and EUROTOX 2005 in Krakow, Poland. 

n       The committee is continuing its work to develop a Review of the Current State of the Science of Skeletal Variations and Malformations that occur during development as related to chemical perturbation.  Manuscripts are being finalized for submission to a peer-reviewed journal in mid-2007.  The manuscripts include an overview of the project as well as: 1) The molecular basis for skeletal variation; 2) Abnormal patterning; 3) Interpretation of skeletal variations for human risk assessment; and 4) Alternative experimental approaches for interpreting skeletal findings in safety studies

n       DART is re-addressing the Reproductive Endpoints project that was one of its first formal activities.  The committee focused its initial efforts on scientific issues related to the evaluation and interpretation of nontraditional reproductive endpoints.  The goal of the project was to assess and build consensus among the various sectors of the scientific community (academic, industry, and government) regarding the value, application, and interpretation of both commonly measured and nontraditional reproductive endpoints for the purposes of characterizing the potential reproductive toxicity to humans of various chemical agents.  The endpoints included oocyte quantitation and ovarian histology, sperm parameters and testis histology, vaginal cytology, circulating hormones, reproductive performance, and endpoints of reproductive system development.  The committee sponsored a workshop on the “Evaluation and Interpretation of Reproductive Endpoints for Human Health Risk Assessment” on November 12-14, 1997, in Washington, D.C.  A report was published in December 1998.

At the conclusion of the original project, it was determined that the endpoints evaluated should be re-evaluated after five years. The committee is now conducting a broad-based evaluation of the value of the endpoints, in three steps.  The first step was a request for data, followed by collation and analysis involving a statistician and blinded data.  These data have been collected from parties that have conducted EPA guideline studies.  The Steering Team (governmental, industrial, and academic scientists) is evaluating the findings.  Two manuscripts are planned for submission to peer-reviewed journals in fall 2007 – one providing detail on the data analysis, and one addressing the value of the endpoints. 

n       In vitro methods of evaluating or recapitulating developmental toxicity have existed for several decades.  Only relatively recently, however, has a concerted effort been made to apply some of these methods in a predictive capacity. Because there is never a perfect correlation between a syndrome in vivo and its truncated in vitro model, there will always be some uncertainty about the application of these models.  The DART committee conducted a workshop in February 2007 that convened users of in vitro models of developmental toxicity – focusing on zebrafish, whole embryo cultures, and stem cells - to share their experiences with the goal of maximizing the correct application of these assays.  Proceedings of the workshop will be submitted for publication in a peer-reviewed journal in fall 2007.

n       The DART committee is currently developing several new projects addressing maternal toxicity, developmental/reproductive studies pertaining to vaccines, and an assessment of new directions in developmental toxicity testing.