2018 Toxicological Sciences Papers of the Year

Decisions, decisions. Each year the Board of Publications selects a paper published over the previous July-June 12-month period as the Paper of the Year. It is always a difficult task. This year the Board decided 2 papers were deserving of the honor of the award. In no particular order, the Toxicological Sciences Paper of the Year Award was awarded to:

Collaborative Cross Mouse Population Enables Refinements to Characterization of the Variability in Toxicokinetics of Trichloroethylene and Provides Genetic Evidence for the Role of PPAR Pathway in Its Oxidative Metabolism

Abhishek Venkatratnam, Shinji Furuya, Oksana Kosyk, Avram Gold, Wanda Bodnar, Kranti Konganti, David W. Threadgill, Kevin M. Gillespie, David L. Aylor, Fred A. Wright, Weihsueh A. Chiu, and Ivan Rusyn

https://doi.org/10.1093/toxsci/kfx065

General toxicological evaluation of chemical biotransformation has relied on a limited number of animal models with selected tests of known genetic pathways. Venkatratnam and colleagues adapted a novel approach to use the Collaborative Cross mice, which are derived from 50 crossing multiple strains of mice, to investigate how genetic variations, beyond a single strain of animals, may influence the metabolism of environmentally toxic chemicals. In this paper the authors examined trichloroethylene (TCE). Significant variation was observed in the metabolism of TCE to trichloroacetic acid that was not explained by enzymes known to metabolize TCE; but rather, an association of PPARα-dependent genes was strongly associated with TCE metabolism. Results from these studies demonstrate the utility of Collaborative Cross mice to investigate differences in metabolism of chemicals, in addition to correlating with genetic pathways that may differ within diverse populations. This work provides an elegant model to study the linkages between genes and biological effects, in a way that more accurately reflects the diversity of the human genome. This well-written manuscript has made a significant contribution to the field of toxicology. The Board of Publications proudly confers the Paper of the Year Award to Dr Rusyn and his research team.

An Impaired Immune Tolerance Animal Model Distinguishes the Potential of Troglitazone/Pioglitazone and Tolcapone/Entacapone to Cause IDILI

Alastair Mak, Ryuji Kato, Kyle Weston, Anthony Hayes, and Jack Uetrecht

https://doi.org/10.1093/toxsci/kfx219

Identification of the potential for idiosyncratic drug-induced liver injury (iDILI) is a significant problem for drug development. Mak et al. have recently established a novel animal model of iDILI based on impaired immune tolerance that mimics many aspects of the human condition. In this paper the authors further tested the predictive power of this animal model by comparing drug pairs with similar structure but different iDILI potential. This included the antidiabetic drugs troglitazone (iDILI in humans) and pioglitazone, as well as the antiParkinson’s drugs tolcapone (iDILI in humans) and entacapone. Prolonged treatment with troglitazone or tolcapone in the animals with impaired immune tolerance induced liver injury and activation of various inflammatory cells in the liver; these were not observed in normal animals. Further studies demonstrated that treatment with troglitazone or tolcapone caused caspase-1 activation and IL-1β formation, indicative of inflammasome activation by damage-associated molecular patterns. This work provides a sound validation of a novel immune-deficient animal model as a useful tool to test for iDILI candidates. This well-written manuscript has made a significant contribution to the field of toxicology. The Board of Publications proudly confers the Paper of the Year Award to Dr Uetrecht and his research team.

The Board of Publications has also identified 3 honorable mentions:

A 3D Human Airway Model Enables Prediction of Respiratory Toxicity of Inhaled Drugs In Vitro

Kinga Balogh Sivars, Ulf Sivars, Ellinor Hornberg, Hui Zhang, Lena Brändén, Rosy Bonfante, Song Huang, Samuel Constant, Ian Robinson, Catherine J. Betts, and Per M. Åberg

https://doi.org/10.1093/toxsci/kfx255

Respiratory tract toxicity commonly occurs with inhalation of volatile chemicals, drugs and toxic metals. The lack of reliable and predictive in vitro systems has become a roadblock for early detection of respiratory toxicities. Sivars and colleagues in this study developed a physiologically relevant in vitro 3D human airway model and tested the model’s relevance and value in experimental assessment of toxicities in respiratory tract. By repeated administration of a set of compounds with or without respiratory toxicity following inhalation in vivo, researchers evaluated the predictability of the new model for respiratory toxicity in a set of critical parameters such as cytotoxicity, barrier integrity, viability, morphology, ciliary beating frequency, mucociliary clearance, and cytokine release. Their data show that in vivo toxicity can be predicted in vitro by studying cell barrier integrity by transepithelial electrical resistance and cell viability in this 3D airway models. Their approach may point toward a novel direction for evaluation of respiratory toxicity.

Base Excision Repair Variants and Pesticide Exposure Increase Parkinson’s Disease Risk

Laurie H. Sanders, Kimberly C. Paul, Evan H. Howlett, Hakeem Lawal, Sridhar Boppana, Jeff M. Bronstein, Beate Ritz, and J. Timothy Greenamyre

https://doi.org/10.1093/toxsci/kfx086

The study by Sanders and colleagues reports a novel gene-environment interaction between exposure to mitochondrial toxic pesticides and single nucleotide polymorphisms (SNPs) in the base excision repair enzymes (oxoguanine DNA glycosylase and apurinic/apyrimidinic endonuclease I). Utilizing a large sample size (619 PD patients and 854 population-based controls), the researchers discovered that 2 specific SNPs, which are functionally associated with an impaired capacity for oxidative DNA damage repair, can individually or synergistically increase PD risk among subjects exposed to pesticides, whereas expression of these BER variants itself is not a risk factor. Although the molecular mechanism of this interaction remains unknown, their finding highlights the possibility that genetic variations in DNA-repair pathways could influence PD risk.

Evaluating In Vitro-In Vivo Extrapolation of Toxicokinetics

John F. Wambaugh, Michael F. Hughes, Caroline L. Ring, Denise K. MacMillan, Jermaine Ford, Timothy R. Fennell, Sherry R. Black, Rodney W. Snyder, Nisha S. Sipes, Barbara A. Wetmore, Joost Westerhout, R. Woodrow Setzer, Robert G. Pearce, Jane Ellen Simmons, and Russell S. Thomas

https://doi.org/10.1093/toxsci/kfy020

The high-throughput in vitro data are important in prioritizing chemical risk assessment. The refinement of higher throughput toxicokinetic (HTTK) approach with improved data collection and mining and refined statistical models can greatly improve confidence in in vitro-in vivo extrapolation (IVIVE).

The study by Wambaugh et al. reports on the analysis of new in-vivo TK data from rats on 26 nonpharmaceutical chemicals. Authors compared the TK parameters derived from these data, coupled with additional data in published studies, with HTTK modeling outcomes. This IVIVE approach allows directly to address key issues in IVIVE, eg, oral bioavailability, underestimation of clearance, volume of distribution expected uncertainty (ie, predictive error), and to identify areas for improvement in HTTK-based IVIVE, including the prediction of bioavailability.

These papers represent the quality of the work published in the pages of Toxicological Sciences. We encourage you to use these papers in journal clubs as examples of the most influential research in the field of toxicology.

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