ToxRefDB v2.1: update to curated in vivo study data in the Toxicity Reference Database

Abstract

The Toxicity Reference Database (ToxRefDB) contains in vivo study data from over 5,900 guideline or guideline-like studies for over 1,100 chemicals. The database includes information regarding study design, chemical treatment, dosing, treatment group parameters, treatment-related (significantly different from control) and critical (adverse) effects, guided by a controlled effect vocabulary, as well as endpoint testing status according to health effects guideline requirements. ToxRefDB v2.1 is an update to address a compilation error found in ToxRefDB v2.0 that resulted in some effects being inadvertently omitted from the database. Though effect data has been recovered, no new studies were added. The recovered data improves the utility of ToxRefDB as a resource for curated legacy in vivo information, which enhances scientific confidence in vitro high-throughput screening of chemicals and supports retrospective and predictive toxicology applications for which outcomes in traditional regulatory toxicology studies serve as reference information.

Keywords: NAMs; curation; database; in vivo; reference; toxicity.

FIGURE 1

(A) To describe the ToxRefDB data landscape, this stacked bar chart displays the number of studies by study type and species. Study type abbreviations are as follows: Chronic (CHR), Prenatal-Developmental (DEV), Multigeneration Reproductive (MGR), Subacute (SAC), and Subchronic (SUB). (B) To demonstrate ToxRefDB’s hierarchical effect terminology, one effect example “postimplantation loss”, as commonly measured in reproductive exposure studies such as MGR and DEV, is described. The finding will be recorded as is in the “effect description free” field, which is the verbatim wording used in the study report. The remaining fields are part of the ToxRefDB controlled terminology. The endpoint category is reproductive, the endpoint type is reproductive performance, the endpoint target is postimplantation loss, the effect description is postimplantation loss, and the specific observation of “postimplantation loss” was made in the adult pregnancy life-stage at the specific target site, the uterus.

FIGURE 2

For each study and chemical in v2.0 and v2.1, the lowest LEL, lowest LOAEL, highest NEL, and highest NOAEL were identified for comparison. (A) The table shows the number of changed values across POD types. Options include: “No change”, or change in “One or more”, “Two or more”, “Three or more”, or “All four” POD types. Only 5% of all studies had a change in 1 or more PODs. (B) When data is stratified by study type, the study type with the most change were CHR and SUB study types with SAC showing the least amount of change. (C) 29% of chemicals across all study types had a change in 1 or more POD types, with only 2% showing change in 3 or more. These study-level comparisons do not consider the PODs added for the 594 studies with effects. Chemical-level change drastically decreases when subset to exclude the PODs added for the 377 DEV and 123 MGR studies that were most impacted by compilation error and have the most recovered data.