How well can in vitro data predict in vivo effects of chemicals? Rodent carcinogenicity as a case study.

A recent research article by the National Center for Computational Toxicology (NCCT) (Kleinstreuer et al., 2013), indicated that high throughput screening (HTS) data from assays linked to hallmarks and presumed pathways of carcinogenesis could be used to predict classification of pesticides as either (a) possible, probable or likely rodent carcinogens; or (b) not likely carcinogens or evidence of non-carcinogenicity. Using independently developed software to validate the computational results, we replicated the majority of the results reported.

Challenges in using the ToxRefDB as a resource for toxicity prediction modeling.

Developing and evaluating toxicity prediction models requires selection and use of datasets of known positive and negative agents for the endpoint(s) of interest. EPA's Toxicity Reference Database (ToxRefDB) is a publicly available dataset containing detailed study and effect information on more than 400 chemicals, and it has been used by EPA researchers to develop toxicity prediction models. During an initial evaluation of reproductive toxicity, however, limitations were uncovered in applying data from ToxRefDB that involved interpretation of toxicity effects and designation of toxicity endpoints, core attributes of the database that are critical to its use.

An enhanced tiered toxicity testing framework with triggers for assessing hazards and risks of commodity chemicals.

This paper presents an enhanced integrated testing framework based on tiered testing and endpoint-specific decision triggers envisioned for application to commodity chemical safety assessments. The framework has two tiers in which exposure information can be integrated with hazard data at each Tier. Tier 1 tests are used to screen chemicals for major toxic effects (i.

Tiered toxicity testing: evaluation of toxicity-based decision triggers for human health hazard characterization.

A set of biologically-based toxicity testing decision triggers was developed and analyzed within a tiered testing and decision-making framework for evaluating potential human health hazards and risks associated with chemical exposures. The proposed three-tiered toxicity testing approach starts from a base set of toxicity studies (acute toxicity, in vitro genetic toxicity, in vitro cytogenetics, repeat dose/subchronic toxicity, developmental toxicity, reproductive toxicity) and then uses the toxicity triggers to identify which specific additional tests are needed to adequately characterize a substance's hazard potential. The toxicity triggers were initially evaluated using published information for eight chemicals, representing diverse classes.

Humans appear no more sensitive than laboratory animals to the inhibition of red blood cell cholinesterase by dichlorvos.

Inhibition of red blood cell (RBC) cholinesterase is a consistent and sensitive indicator of exposure to dichlorvos (DDVP). Absent human data, default 10-fold adjustment factors for potential interspecies and intraspecies sensitivity differences would be used in developing a reference dose from the no observed effect levels for this endpoint obtained in toxicological assessments of laboratory animals. However, many studies of the cholinesterase-inhibiting effects associated with DDVP exposure have been conducted in humans, including healthy male volunteers, other healthy subpopulations, and diverse clinical subpopulations.