Candidate risk genes for bipolar disorder are highly conserved during evolution and highly interconnected.

OBJECTIVES: Bipolar disorder (BPD) is a highly heritable psychiatric disorder whose genetic complexity and pathogenetic mechanisms are still being unraveled. The main goal of this work was to characterize BPD risk-gene candidates (identified by Nurnberger et al., JAMA Psychiatry 71:657, 2014, and Stahl et al., Nat. Genet. 51:793, 2019) with respect to their evolutionary conservation, associated phenotypes, and extent of gene-gene interactions. METHODS: Database searches and BLAST were used to identify homologous counterparts of human BPD risk genes in C. elegans, zebrafish, and Drosophila. Phenotypes associated with the C. elegans genes were annotated and searched. With GeneMANIA, we characterized and quantified gene-gene interactions among members of the BPD gene set in comparison to randomly chosen gene sets of the same size. RESULTS: BPD risk genes are highly conserved across species and are enriched for essential genes and genes associated with lethality and altered life span. They are significantly more interactive with each other in comparison to random genes. We identified syntenic blocks of risk genes, which provided potential insights into molecular pathways and co-morbidities associated with BPD including coronary disease, obesity, and decreased life expectancy. CONCLUSIONS: BPD risk genes appear to be special in terms of their degree of conservation, interconnectedness, and pleiotropic effects that extend beyond a role in brain function. Key hub genes or pleiotropic regulatory components may represent attractive targets for future drug discovery.

Using publicly available information to create exposure and risk-based ranking of chemicals used in the workplace and consumer products.

Mandates that require the estimation of exposure and human health risk posed by large numbers of chemicals present regulatory managers with a significant challenge. Although these issues have been around for some time, the estimation of human exposure to chemicals from use of products in the workplace and by the consumer has been generally hindered by the lack of good tools. Logically and in the interest of cost-effective resource allocation and regulation one would typically and naturally first attempt to rank-order or prioritize the chemicals according to the human exposure potential that each might pose. We have developed an approach and systematic modeling construct that accomplishes this critical task by providing a quantitative estimate of human exposure for as many as several hundred chemicals initially; however, it could ultimately do this for any number of regulated chemicals starting only with the identity (Chemical Abstract Service number) for each chemical under consideration. These exposure estimates can then be readily linked to toxicological benchmarks for each item to estimate and rank the human health risk for the chemicals under consideration in a "worst things first" listing. This modeling construct, entitled Complex Exposure Tool (ComET) was developed by The LifeLine Group as a proof of concept under the sponsorship of Health Canada. ComET considers multiple routes of exposure, multiple subpopulations and different possible durations of exposure. A beta-version of ComET was issued and demonstrated in which users can change the assumptions in the model and see the impacts of these changes and the quality of information as they relate to the predicted exposure potential. We have advanced the operational elements of ComET into a tool entitled the Chemical Exposure Priority Setting Tool (CEPST) designed to provide quantitative estimation of the exposure potential of large groups of chemicals with little data and possibly multiple exposure scenarios. A basic feature of this tool is the utilization of an internally consistent approach and assumptions that are completely transparent. It uses publicly available information as critical input and is specifically designed to be continually reviewed, refined, expanded and updated using scientific peer review and stakeholder input.

A tiered approach to systemic toxicity testing for agricultural chemical safety assessment.

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Systemic Toxicity Task Force proposes an approach to systemic toxicity testing as one part of the overall assessment of a compound's potential to cause adverse effects on health. The approach is designed to provide more relevant data for deriving reference doses for shorter time periods of human exposure, and includes fewer studies for deriving longer term reference doses-that is, neither a 12-month dog study nor a mouse carcinogenicity study is recommended. All available data, including toxicokinetics and metabolism data and life stages information, are taken into account. The proposed tiered testing approach has the potential to provide new risk assessment information for shorter human exposure durations while reducing the number of animals used and without compromising the sensitivity of the determination of longer term reference doses.