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Environmental Protection Agency's ToxCast project is profiling the in vitro bioactivity of chemicals to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesized that developmental toxicity in guideline animal studies captured in the ToxRefDB database would correlate with cell-based and cell-free in vitro high-throughput screening (HTS) data to reveal meaningful mechanistic relationships and provide models identifying chemicals with the potential to cause developmental toxicity. To test this hypothesis, we built statistical associations based on HTS and in vivo developmental toxicity data from ToxRefDB. Univariate associations were used to filter HTS assays based on statistical correlation with distinct in vivo endpoint. This revealed 423 total associations with distinctly different patterns for rat (301 associations) and rabbit (122 associations) across multiple HTS assay platforms. From these associations, linear discriminant analysis with cross-validation was used to build the models. Species-specific models of predicted developmental toxicity revealed strong balanced accuracy (> 70%) and unique correlations between assay targets such as transforming growth factor beta, retinoic acid receptor, and G-protein-coupled receptor signaling in the rat and inflammatory signals, such as interleukins (IL) (IL1a and IL8) and chemokines (CCL2), in the rabbit. Species-specific toxicity endpoints were associated with one another through common Gene Ontology biological processes, such as cleft palate to urogenital defects through placenta and embryonic development. This work indicates the utility of HTS assays for developing pathway-level models predictive of developmental toxicity.

As the primary source for regulatory developmental toxicity information, prenatal studies characterize maternal effects and fetal endpoints including malformations, resorptions, and fetal weight reduction. Results from 383 rat and 368 rabbit prenatal studies on 387 chemicals, mostly pesticides, were entered into the U.S. Environmental Protection Agency's (EPA) Toxicity Reference Database (ToxRefDB) using harmonized terminology. An initial assessment of these data was performed with the goal of profiling environmental chemicals based on maternal and fetal endpoints for anchoring in vitro data provided in the EPA's ToxCast research program. Using 30 years worth of standard prenatal studies, maternal and fetal effects were culled from the database and analyzed by target-description fields and lowest effect levels (LELs). Focusing on inter-species comparison, the complexity of fetal target organ response to maternal dosing with environmental chemicals during the period of major organogenesis revealed hierarchical relationships. Of 283 chemicals tested in both species, 53 chemicals (18.7%) had LELs on development (dLEL) that were either specific, with no maternal toxicity (mLEL), or sensitive (dLEL

Background: In several countries, risk classification systems have been set up to summarise the sparse data on drug safety during pregnancy. However, these have resulted in ambiguous statements that are often difficult to interpret and use with accuracy when counselling patients on drug use in pregnancy., Objectives: The objective of this study was to compare and analyse the consistency between and the criteria for risk classification for medications used during pregnancy included in 3 widely used international risk classification systems. All 3 systems use categories based on risk factors to summarise the degree to which available clinical information has ruled out the risk to unborn offspring, balanced against the drug's potential benefit to the patient., Methods: Drugs included in the risk classification systems from the US Food and Drug Administration (FDA), the Australian Drug Evaluation Committee (ADEC) and the Swedish Catalogue of Approved Drugs (FASS), were reviewed and compared on basis of the risk factor category to which they had been assigned. Agreement between the systems was calculated as the number of drugs common to all 3 and assigned to the same risk factor category. In addition, evidence on teratogenicity and adverse effects during pregnancy was retrieved using a MEDLINE search (from 1966 up to 1998) for common drugs classified as teratogenic., Results: Differences in the allocation of drugs to different risk factor categories were found. Risk factor category allocation for 645 drugs classified by the FDA, 446 classified by ADEC and 527 classified by FASS was compared. Only 61 (26%) of the 236 drugs common to all 3 systems were placed in the same risk factor category. Analysis of studies on the safety of common drugs during pregnancy of drugs classified as X by the FDA indicated that the variability in category allocation was not only attributable to the different definitions for the categories, but also depended on how the available scientific literature was handled., Conclusions: Differences in category allocation for the same drug can be a source of great confusion among users of the classification systems as well as for those who require information regarding risk for drug use during pregnancy, and may limit the usefulness and reliability of risk classification systems.

The Swedish system for the classification of fetal risk of drugs was the first of its kind and was implemented in 1978. Drugs for use in pregnant women are classified in 4 general categories--A to D. The US Food and Drug Administration (FDA) introduced a system in 1979 also using the letters A to D, together with an X category. However, the definitions differ considerably between the FDA system and the Swedish system, resulting in a very different allocation of drugs to the respective categories. In the Swedish system, category A includes drugs that have been extensively used and/or for which there are reliable clinical data indicating no evidence of disturbance of the reproductive process. Category B includes drugs for which data from pregnant women are insufficient for making any solid estimation of human teratogenic risk, and classification is therefore based on animal data, with allocation to 3 subgroups. For products in category C, the pharmacological action of the drug may have undesirable effects on the human fetus or newborn infant. Finally, category D contains drugs for which human data indicate an increased incidence of malformations. The categorisation statement is always followed by a short explanatory text. In contrast to the FDA system, the Swedish system has been well accepted, as judged by an interview study including 934 physicians and pharmacists. We believe that much of the American dissatisfaction may be a consequence of shortcomings in the category definitions of the FDA system. The FDA system requires an unrealistically high quality of data, e.g. the availability of controlled studies in pregnant women that fail to demonstrate a risk to the fetus are needed for a drug to be assigned to category A. Consequently, the majority of drugs on the US market are allocated to category C, interpreted as 'risk cannot be ruled out'. The distribution of drugs into the various categories is thus very different between the Swedish and FDA systems. We think that the issue of this debate reflects a fundamental problem related to public health information: how should a large, compounded, changing and difficult to evaluate databank be organised before it is made available to professionals and secondarily to lay people?

The Teratology Society believes that the current FDA Use-in-Pregnancy Ratings should be abandoned. The Society recommends that drug labeling should include narrative statements that summarize and interpret available data regarding hazards of developmental toxicity and provide estimates of potential teratogenic risk.

Classifications of carcinogenesis, mutagenesis and teratogenesis used by the National Toxicological Advisory Committee in Italy (CCTN), the Commission of the European Communities (CEC), the Environmental Protection Agency in the USA (EPA), the International Agency for Research on Cancer (IARC), and the National Toxicology Programme in the USA (NPT) are examined and commented on, with a synopsis of several allocations made by the above organizations. However, the authors consider it advisable to redefine the categories and create 5 groups of substances (designated C1 to C5), on the basis of given definitions, with the aim of rendering the allocations comparable. This procedure is used solely for carcinogenesis and excludes the NTP. From such comparison, good agreement was found between CCTN and EPA and between CCTN and CEC, whereas agreement between IARC and other organizations was poor.

Published data regarding the human teratogenic potential of 157 drug components that are frequently prescribed to outpatients in the United States were evaluated according to a protocol developed for TERIS, an automated clinical teratology resource. This protocol stipulates that a bibliographic search be performed on each agent, a brief narrative summary of the available teratologic information prepared, and a risk rating assigned. The ratings are determined by consensus of five clinical teratologists, who independently assess the magnitude of teratogenic risk associated with each agent under usual therapeutic conditions as "none," "minimal," "small," "moderate," "high," and "undetermined." Forty-nine percent of the components of these frequently prescribed drugs had insufficient published information available to assess the risk of human teratogenicity. Of the agents that could be rated, the teratogenic risk in usual therapeutic doses was considered to be minimal or less in 92.5%. Many of these agents have also been assigned Pregnancy Categories by the United States Food and Drug Administration (FDA) according to a system designed to provide therapeutic guidance. There was no more agreement than that expected by chance between TERIS ratings and the FDA Pregnancy Categories for 83 agents that were classified according to both systems. We believe that the FDA Pregnancy Categories should not be used to provide counseling regarding the risk of teratogenic effects to women who have taken medication during pregnancy. Such counseling should be based on a more comprehensive evaluation of the teratologic literature and clinical situation, but need not involve consideration of the therapeutic benefit of the agent.