scholarly journals Application of a combined aggregate exposure pathway and adverse outcome pathway (AEP-AOP) approach to inform a cumulative risk assessment: A case study with phthalates

2020 ◽  
Vol 66 ◽  
pp. 104855 ◽  
Author(s):  
Rebecca A. Clewell ◽  
Jeremy A. Leonard ◽  
Chantel I. Nicolas ◽  
Jerry L. Campbell ◽  
Miyoung Yoon ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Adverse Outcome ◽  
Cumulative Risk ◽  
Adverse Outcome Pathway ◽  
Exposure Pathway

Leveraging human genetic and adverse outcome pathway (AOP) data to inform susceptibility in human health risk assessment

2018 ◽  
Vol 29 (1-2) ◽  
pp. 190-204 ◽  
Author(s):  
Holly M. Mortensen ◽  
John Chamberlin ◽  
Bonnie Joubert ◽  
Michelle Angrish ◽  
Nisha Sipes ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Health Risk ◽  
Human Health ◽  
Health Risk Assessment ◽  
Adverse Outcome ◽  
Human Health Risk ◽  
Human Health Risk Assessment ◽  
Adverse Outcome Pathway

scholarly journals Example of Adverse Outcome Pathway Concept Enabling Genome-to-Phenome Discovery in Toxicology

2020 ◽  
Vol 60 (2) ◽  
pp. 375-384 ◽  
Author(s):  
Kurt A Gust ◽  
Qing Ji ◽  
Xiao Luo
Keyword(s):  
Biological Sciences ◽  
Weight Loss ◽  
Body Weight ◽  
Amino Acid ◽  
Adverse Outcome ◽  
Body Weight Loss ◽  
Energy Budgets ◽  
Adverse Outcome Pathway ◽  
Biological Organization

Synopsis The following article represents a mini-review of an intensive 10-year progression of genome-to-phenome (G2P) discovery guided by the adverse outcome pathway (AOP) concept. This example is presented as a means to stimulate crossover of this toxicological concept to enhance G2P discovery within the broader biological sciences community. The case study demonstrates the benefits of the AOP approach for establishing causal linkages across multiple levels of biological organization ultimately linking molecular initiation (often at the genomic scale) to organism-level phenotypes of interest. The case study summarizes a US military effort to identify the mechanism(s) underlying toxicological phenotypes of lethargy and weight loss in response to nitroaromatic munitions exposures, such as 2,4,6-trinitrotoluene. Initial key discoveries are described including the toxicogenomic results that nitrotoluene exposures inhibited expression within the peroxisome proliferator activated receptor α (PPARα) pathway. We channeled the AOP concept to test the hypothesis that inhibition of PPARα signaling in nitrotoluene exposures impacted lipid metabolic processes, thus affecting systemic energy budgets, ultimately resulting in body weight loss. Results from a series of transcriptomic, proteomic, lipidomic, in vitro PPARα nuclear signaling, and PPARα knock-out investigations ultimately supported various facets of this hypothesis. Given these results, we next proceeded to develop a formalized AOP description of PPARα antagonism leading to body weight loss. This AOP was refined through intensive literature review and polished through multiple rounds of peer-review leading to final international acceptance as an Organisation for Economic Cooperation and Development-approved AOP. Briefly, that AOP identifies PPARα antagonist binding as the molecular initiating event (MIE) leading to a series of key events including inhibition of nuclear transactivation for genes controlling lipid metabolism and ketogenesis, inhibition of fatty acid beta-oxidation and ketogenesis dynamics, negative energy budget, and ultimately the adverse outcome (AO) of body-weight loss. Given that the PPARα antagonism MIE represented a reliable indicator of AO progression within the pathway, a phylogenetic analysis was conducted which indicated that PPARα amino acid relatedness generally tracked species relatedness. Additionally, PPARα amino acid relatedness analysis using the Sequence Alignment to Predict Across Species Susceptibility predicted susceptibility to the MIE across vertebrates providing context for AOP extrapolation across species. Overall, we hope this illustrative example of how the AOP concept has benefited toxicology sows a seed within the broader biological sciences community to repurpose the concept to facilitate enhanced G2P discovery in biology.

scholarly journals Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles

2021 ◽  
Vol 3 ◽  
Author(s):  
Penny Nymark ◽  
Hanna L. Karlsson ◽  
Sabina Halappanavar ◽  
Ulla Vogel
Keyword(s):  
Lung Cancer ◽  
Risk Assessment ◽  
Adverse Outcome ◽  
Animal Experiments ◽  
Engineered Nanoparticles ◽  
Alternative Methods ◽  
Weight Of Evidence ◽  
Adverse Outcome Pathway ◽  
Alternative Mechanism

Lung cancer, one of the most common and deadly forms of cancer, is in some cases associated with exposure to certain types of particles. With the rise of nanotechnology, there is concern that some engineered nanoparticles may be among such particles. In the absence of epidemiological evidence, assessment of nanoparticle carcinogenicity is currently performed on a time-consuming case-by-case basis, relying mainly on animal experiments. Non-animal alternatives exist, including a few validated cell-based methods accepted for regulatory risk assessment of nanoparticles. Furthermore, new approach methodologies (NAMs), focused on carcinogenic mechanisms and capable of handling the increasing numbers of nanoparticles, have been developed. However, such alternative methods are mainly applied as weight-of-evidence linked to generally required animal data, since challenges remain regarding interpretation of the results. These challenges may be more easily overcome by the novel Adverse Outcome Pathway (AOP) framework, which provides a basis for validation and uptake of alternative mechanism-focused methods in risk assessment. Here, we propose an AOP for lung cancer induced by nanosized foreign matter, anchored to a selection of 18 standardized methods and NAMs for in silico- and in vitro-based integrated assessment of lung carcinogenicity. The potential for further refinement of the AOP and its components is discussed in relation to available nanosafety knowledge and data. Overall, this perspective provides a basis for development of AOP-aligned alternative methods-based integrated testing strategies for assessment of nanoparticle-induced lung cancer.

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