Temporal Concordance Between Apical and Transcriptional Points of Departure for Chemical Risk Assessment

Abstract

The number of legacy chemicals without toxicity reference values combined with the rate of new chemical development is overwhelming the capacity of the traditional risk assessment paradigm. More efficient approaches are needed to quantitatively estimate chemical risks. In this study, rats were dosed orally with multiple doses of six chemicals for 5 days and 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points of departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with eight additional chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two, suggesting that for the current chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a practical framework for application of transcriptomic data to chemical risk assessment.

BMDExpress Data Viewer ‐ a visualization tool to analyze BMDExpress datasets

“…To illustrate the features and functionality of BMDExpress Data Viewer, BMDExpress output datasets were obtained from two case studies, i.e., (1) hepatic gene expression (Agilent) profiles of mice orally exposed to increasing doses of furan by oral gavage (Jackson et al ., 2014), and (2) thyroid gene expression (Affymetrix) profiles from rats that were orally exposed to increasing doses of the chemical MDMB (Thomas et al ., 2013b). …”

“…This observation was consistent with results of the Multiple Dataset Comparison analysis. The center values of overlaps for the timepoints were very similar to the 2‐year rodent cancer bioassay BMD of 381 ppm (Thomas et al ., 2013b). The higher BMDL‐BMD range of the hepatic fibrosis/hepatic stellate cell activation pathway in 14, 28 and 90 days may indicate that the pathway requires a higher dose to be activated than the other pathways.…”

“…In the second dataset (GSE45892), rats were exposed to increasing doses of one of six chemicals for 5, 14, 28 and 90 days. Affymetrix HT RG‐230 PM microarrays were used to examine transcriptional profiles for these rats (Thomas et al ., 2013b). We obtained the datasets for the chemical 4,4′‐methylenebis( N , N ‐dimethyl)benzenamine (MDMB), which examined transcriptional changes in the thyroid following exposure to 50, 200, 375, 500 and 750 ppm in drinking water.…”

“…2007). This approach has already been applied to a variety of chemicals (Bhat et al ., 2013; Moffat et al ., 2015; Thomas et al ., 2013b). Importantly, these studies have shown concordance between the BMD values modeled for transcriptional and apical endpoints.…”

A foresight study on emerging technologies: State of the art of Omics technologies and potential applications in food and feed safety

“…Results of these studies are informative about the modes of action of these toxicants, but do not add to risk assessment evaluations (National Research Council (NRC), 2013). Examples of transcriptomics studies aiming to risk assessment have been published by Thomas et al, 2013). In these studies, rats were treated with carcinogenic compounds and target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays.…”