Science Inventory

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EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that are highly correlated with observed in vivo toxicity. We hypothesize that cell signaling pathways underlying development are primary targets f...

Environmental causes of birth defects include maternal exposure to drugs, chemicals, or physical agents. Environmental factors account for an estimated 3–7% of birth defects although a broader contribution is likely based on the mother’s general health status and genetic blueprin...

Xenobiotic exposures affect the maternal and/or in utero environment resulting in impairments in fetal development. During the period of rapid fetal growth, underdeveloped cardiovascular systems are especially vulnerable to their environment. Furthermore, fetal exposures can evok...

Sixty-five chemicals in the ToxCast high-throughput screening (HTS) dataset have been linked to cleft palate based on data from ToxRefDB (rat or rabbit prenatal developmental toxicity studies) or from literature reports. These compounds are structurally diverse and thus likely to...

High-throughput in vitro assays offer a promising alternative to pregnant animal studies for assessing developmental toxicity of chemicals. Varying cells used in high-throughput screening assays have unique properties of self-renewal, pluripotency, and self-organization which hel...

Summary: Congenital anomalies of the external genitalia (CAEG) are a prevalent and serious public health concern with lifelong impacts on the urinary function, sexual health, fertility, tumor development, and psychosocial wellbeing of affected individuals. Complications of treat...

Computational models can translate in vitro data from HTS testing platforms to potential in vivo outcomes. Much effort is being expended today to realize this challenge for the future. EPA’s Virtual Embryo research program is building and testing computational (in silico) models ...

The ToxCast paradigm for predictive toxicology utilizes in vitro data from automated high-throughput screening (HTS), coupled with in silico models for data mining and systems modeling. This chapter highlights recent progress with an HTS-driven approach for developmental toxicity...

ToxRefDB was developed to store data from in vivo animal toxicity studies. The initial focus was populating ToxRefDB with pesticide registration toxicity data that has been historically stored as hard-copy and scanned documents by the Office of Pesticide Programs. A significant p...

ToxRefDB was developed to store data from in vivo animal toxicity studies. The initial focus was populating ToxRefDB with pesticide registration toxicity data that has been historically stored as hard-copy and scanned documents by the Office of Pesticide Programs. A significant p...

Predicting and characterizing potential human teratogenic compounds remains a challenge as toxicology moves towards new approach methods (NAMs) for hazard identification with animal models remaining the ‘gold’ standard for assessing developmental toxicity in humans. Utilizing plu...

Cleft palate has been linked to both genetic and environmental factors that perturb key events during palatal morphogenesis. To characterize the potential molecular targets for chemical-induced cleft palate, we mined the ToxCast high-throughput screening (HTS) database for patter...

Cleft palate is a common human birth defect that has been linked to both genetic and environmental factors. To characterize the potential molecular targets and biological processes across mechanistically diverse teratogens that cause cleft palate, we mined the ToxCast high-throug...

Reflecting the numerous changes in the field since the publication of the previous edition, this third edition of Developmental Toxicology focuses on the mechanisms of developmental toxicity and incorporates current technologies for testing in the risk assessment process.

Discuss how the US EPA/NCCT is trying to solve the problem of too many chemicals, too high cost, and too much biological uncertainty

A major challenge to using in vitro high-throughput screening (HTS) data in risk assessment is the identification of toxicological “tipping points” between adaptation and adversity. Toxicological tipping points represent a systems threshold, or critical point, beyond which biolog...

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 adverse ef...

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 adverse ef...

A retrospective review of results from more than 800 embryo-fetal development (EFD) studies with 379 pharmaceutical compounds was performed to compare the utility of rats and rabbits for the detection of developmental toxicity of small molecule pharmaceuticals. A major advantage ...

Regulatory non-clinical safety testing of human pharmaceutical compounds typically requires embryo fetal developmental toxicity (EFDT) testing in two species, (one rodent and one non-rodent, usually the rat and the rabbit). The question has been raised whether under some conditio...

Congenital limb malformations are among the most frequent malformation occurs in humans, with a frequency of about 1 in 500 to 1 in 1000 human live births. ToxCast is profiling the bioactivity of thousands of chemicals based on high-throughput (HTS) and computational methods that...

Cellular agent-based models (ABMs) are a novel approach to: (i) visualize cellular trajectories; (ii) map toxicodynamics; and (iii) predict adverse phenotype (cybermorphs). In silico reconstitution of a self-organizing embryo from in vitro data (eg, embryogeny) remains a challeng...

Identification of mechanisms responsible for adverse developmental effects is the first step in creating predictive toxicity models. Identification of putative mechanisms was performed by co-analyzing three datasets for the effects of ToxCast phase Ia and II chemicals: 1.In vitro...

New approach methods (NAMs) are available for high-throughput screening (HTS) chemical inventories for profiling chemical-biological interactions in vitro. Adverse outcome pathways (AOPs) provide a framework for quantitative prediction of cellular and tissue responses to molecula...

Embryonic development entails a series of coordinated multicellular behaviors that evolve over time and space. Human cell-based synthetic microsystems (in vitro) and computational systems models (in silico) are emerging tools for predictive modeling of complex morphogenetic behav...