Developing and using specific imaging technologies (e.g., micro-CT, MRI) allows for alternative methods for evaluating structural birth defects in animal models.
Developmental and Reproductive Toxicology (DART) Committee
Developmental and Reproductive Toxicology (DART) Committee
The DART committee provides a forum where scientists from industry, government and academia can exchange information and initiate activities to advance science related to DART, and to develop consensus on the appropriate use of experimental data for human health risk assessment.
The recently finalized Pregnancy Labeling and Lactation Labeling Rule changes the organization of the current Pregnancy and Nursing Mothers section of the US package insert of prescription drugs. In response to these changes in prescription drug labeling, the HESI Developmental and Reproductive Toxicology (DART) Technical committee sponsored a two-day workshop on this topic.
This satellite workshop was held in conjunction with the European Teratology Society Annual Meeting.
This workshop will consider new strategies to identify developmental hazards taking into account the current state of science which may include alternative possibilities or improvements to the current Segment 2 design. These considerations could include the use of new technology to overcome some of the limitations in predicting human response with current animal models or completely new radical approach to developmental toxicity hazard identification. These may range from having a critical paradigm to deciding when non-clinical studies are needed to the use of biotechnology and computational models or hazard characterization. Working groups can consider either strategy, or combinations of the two.
This satellite workshop to the 45th Annual Meeting of the European Teratology Society is addressed to participants working in industries or regulatory bodies who are involved in testing and assessment of the potential developmental toxicity of chemicals.
A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.
Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo–fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo–fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo–fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.
The Health and Environmental Sciences Institute (HESI) Developmental and Reproductive Toxicology Technical Committee sponsored a pharmaceutical industry survey on current industry practices for contraception use during clinical trials.
During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies.
Risk assessment for indirect exposure to small molecule pharmaceuticals in semen to the conceptus has traditionally been handled by calculations based on assumptions that any embryo-fetal exposure would be secondary to maternal absorption and redistribution.