Integrated Human Health and Ecological Risk Assessment for the South River, Virginia: a Bayesian Approach

Regional scale risk assessments can be used to determine the likelihood of effects from multiple stressors on ecological or human endpoints at multiple scales. The Relative Risk Model framework can incorporate ecosystem services as endpoints in this multiple stressor- multiple endpoint approach. Through this research, I aimed to demonstrate an approach to integrating ERA and HHRA that could be applied to assess risk to human health and ecosystem services using the South River, VA as a case study. I applied the Relative Risk Model with Bayesian networks (BN-RRM) to an integrated assessment of four ecosystem services of the South River, Virginia: Human health, Water quality, Recreation, and the Recreational fishery. The BN-RRM approach allowed for the calculation of relative risk to 14 human, biotic, and water quality endpoints from chemical and ecological stressors in the South River. Three separate conceptual models were developed for assessing risk to overall Ecosystem services, Human Health, and Recreation. The services at highest risk in the South River were Water quality and the Recreational fishery. Human health risk for users of the South River was low relative to the risk to other endpoints. Risk to Recreation in the South River was moderate with little spatial variation among the five risk regions. The sensitivity and uncertainty analysis of the BNs identified the parameters that influence risk for each endpoint in each risk region. Mercury concentrations in floodplain soils and river water influence human health risk. River temperature and E. coli bacteria were the main contributors of risk to water quality and recreational river uses. Lack of public access contributed risk to recreation and ecosystem services endpoints. This research is not meant to be a definitive assessment of human health risk to fulfill the regulatory requirements for the site. Rather, it is part of a larger effort to synthesize regional scientific research and better understand the effects of mercury contamination and other stressors in the South River watershed

Assessing the effects of chemical mixtures using a Bayesian network-relative risk model (BN-RRM) integrating adverse outcome pathways (AOPs) in three Puget Sound watersheds

Chemical mixtures are difficult to assess at the individual level, but more challenging at the population level. There is still little insight of the molecular pathway for numerous chemical mixtures. We have conducted a regional-scale ecological risk assessment by evaluating the effects chemical mixtures to populations with a Bayesian Network- Relative Risk Model (BN-RRM) incorporating a molecular pathway. We used this BN-RRM framework in a case study with organophosphate pesticide (OP) mixtures (diazinon, chlorpyrifos, and malathion) in three watersheds (Lower Skagit, Nooksack, Cedar) in the state of Washington (USA). Puget Sound Chinook salmon (Oncorhynchus tshawytscha) Evolutionary Significant Units (ESU) were chosen as population endpoints. These populations are a valuable ecosystem service in the Pacific Northwest because they benefit the region as a species that provide protection of biodiversity and are spiritually and culturally treasured by the local tribes. Laetz et al. (2009, 2013) indicated that organophosphate pesticide mixtures act synergistically to salmon and impair neurological molecular activity which leads to a change in swimming behavior and mortality, which then leads to changes in population productivity. Exposure response curves were generated for OP mixtures to connect the molecular pathway. Ecological stressors from dissolved oxygen and temperature were also included in our risk analysis. Synergism within the mixtures as well as increasing temperature and decreasing dissolve oxygen content lead to increasing risk to Puget Sound Chinook salmon populations. This research demonstrates a probabilistic approach with a multiple stressor framework to estimate the effects of mixtures through a molecular pathway and predict impacts to these valuable ecosystem services

Using metapopulation models to estimate the effects of pesticides and environmental stressors to Spring Chinook salmon in the Yakima River Basin, WA

Population-level endpoints provide ecological relevance to Ecological Risk Assessments (ERAs), because this is the level at which environmental management decisions are made. However, many population-level risk assessments do not reflect the spatial and temporal heterogeneity of the populations they represent, and thus preclude an understanding of how population dynamics and viability are affected by toxicants on a regional scale. We have developed a probabilistic ERA (specifically, a Bayesian Network-Relative Risk Model (BN-RRM)) that integrates an Adverse Outcome Pathway (AOP) framework, to quantify the sub-lethal and lethal effects of toxicants and environmental stressors on the metapopulation dynamics of salmonids. As a case study for developing this model, we have examined the impacts of organophosphate (OP) insecticides, water temperature, and dissolved oxygen on the Spring Chinook (Oncorhynchus tshawytscha) salmon metapopulation in the Yakima River Basin (YRB), Washington. A stochastic Matrix Metapopulation Model was developed using demographic data for three Spring Chinook salmon populations and one supplemental hatchery population in the YRB. Site specific data on OP contaminated habitats utilized by various salmonid life stages were incorporated into the metapopulation model by incrementally reducing survival parameters based on levels of exposure. Exposure scenarios were simulated for 200 replications of 50-year population projections using RAMAS Metapop©, and the results were incorporated into the BN-RRM. The results of this modeling effort indicated that small, wild Spring Chinook populations in the YRB have a greater probability of altered population dynamics when exposed to stressors than larger, supplemented populations. Additionally, the results indicated a seasonal effect of the stressors, with summer conditions posing a greater risk to salmon populations than winter conditions. This probabilistic ERA framework shows promise for estimating the spatiotemporal impacts of stressors on ESA-listed species (i.e., Pacific salmon) at the metapopulation level, where population dynamics and spatial structure create complex risk dynamics

Assessing the Effects of Chemical Mixtures using a Bayesian Network-Relative Risk Model (BN-RRM) Integrating Adverse Outcome Pathways (AOPs)

There are long-standing uncertainties about toxicity of chemical mixtures to populations. Laboratory toxicity tests have confirmed synergistic and antagonistic effects to individuals, but not to populations.We will conduct a regional scale ecological risk assessment by evaluating the effects chemical mixtures to populations with a new Bayesian Network- Relative Risk Model (BN-RRM) incorporating an Adverse Outcome Pathway (AOP). We started applying this new BN-RRM framework in a case study with organophosphate pesticide mixtures (diazinon, chlorpyrifos, and malathion). Acetylcholinesterase inhibition (AChE) was chosen the molecular initiating event and the Puget Sound Chinook salmon (Oncorhynchus tshawytscha) and Coho salmon (Oncorhynchus kisutch) Evolutionary Significant Units (ESU) were chosen as population endpoints. Dose-response equations will be generated from the mixtures, integrated into the new BN-RRM framework and then overall risk will be calculated for the populations. Preliminary results indicate that organophosphate pesticide mixtures act synergistically and impair olfactory function that lead to loss of antipredator, homing and reproductive behavior which lead to changes in population age structure and patch dynamics. Assessing mixtures through this new BN-RRM framework is an innovative method of predicting effects to populations. This research will demonstrate a probabilistic approach to synthesize the effects of mixtures and predict impacts to populations

Dataset for the Environmental Risk Assessment of Chlorpyrifos to Chinook Salmon in four Rivers of Washington State, United States

Data files available below. This data set is in support of Landis et al (in press) The integration of chlorpyrifos acetylcholinesterase inhibition, water temperature and dissolved oxygen concentration into a regional scale multiple stressor risk assessment estimating risk to Chinook salmon in four rivers in Washington State, USA. DOI: 10.1002/ieam.4199. In this research We estimated the risk to populations of Chinook salmon (Oncorhynchus tshawytscha) due to chlorpyrifos (CH), water temperature (WT) and dissolved oxygen concentrations (DO) in four watersheds in Washington State, USA. The watersheds included the Nooksack and Skagit Rivers in the Northern Puget Sound, the Cedar River in the Seattle -Tacoma corridor, and the Yakima River, a tributary of the Columbia River. The Bayesian network relative risk model (BN-RRM) was used to conduct this ecological risk assessment and was modified to contain an AChE inhibition pathway parameterized using data from chlorpyrifos toxicity datasets. The completed BN-RRM estimated risk at a population scale to Chinook salmon employing classical matrix modeling run up to 50 year timeframes. There were 4 primary conclusions drawn from the model building process and the risk calculations. First, the incorporation of an AChE inhibition pathway and the output from a population model can be combined with environmental factors in a quantitative fashion. Second, the probability of not meeting the management goal of no loss to the population ranges from 65 to 85 percent. Environmental conditions contributed to a larger proportion of the risk compared to chlorpyrifos. Third, the sensitivity analysis describing the influence of the variables on the predicted risk varied depending on seasonal conditions. In the summer, WT and DO were more influential that CH. In the winter, when the seasonal conditions are more benign, CH was the driver. Fourth, in order to reach the management-goal, we calculated the conditions that would increase in juvenile survival, adult survival, and a reduction in toxicological effects. The same process in this example should be applicable to the inclusion of multiple pesticides and to more descriptive population models such as those describing metapopulations. This research was supported by USEPA STAR Grant RD-83579501. Excel spreadsheet, model in Netica

Integration of Chlorpyrifos Acetylcholinesterase Inhibition, Water Temperature, and Dissolved Oxygen Concentration into a Regional Scale Multiple Stressor Risk Assessment Estimating Risk to Chinook Salmon

We estimated the risk to populations of Chinook salmon (Oncorhynchus tshawytscha) due to chlorpyrifos (CH), water temperature (WT), and dissolved oxygen concentration (DO) in 4 watersheds in Washington State, USA. The watersheds included the Nooksack and Skagit Rivers in the Northern Puget Sound, the Cedar River in the Seattle–Tacoma corridor, and the Yakima River, a tributary of the Columbia River. The Bayesian network relative risk model (BN‐RRM) was used to conduct this ecological risk assessment and was modified to contain an acetylcholinesterase (AChE) inhibition pathway parameterized using data from CH toxicity data sets. The completed BN‐RRM estimated risk at a population scale to Chinook salmon employing classical matrix modeling runs up to 50‐y timeframes. There were 3 primary conclusions drawn from the model‐ building process and the risk calculations. First, the incorporation of an AChE inhibition pathway and the output from a population model can be combined with environmental factors in a quantitative fashion. Second, the probability of not meeting the management goal of no loss to the population ranges from 65% to 85%. Environmental conditions contributed to a larger proportion of the risk compared to CH. Third, the sensitivity analysis describing the influence of the variables on the predicted risk varied depending on seasonal conditions. In the summer, WT and DO were more influential than CH. In the winter, when the seasonal conditions are more benign, CH was the driver. Fourth, in order to reach the management goal, we calculated the conditions that would increase juvenile survival, adult survival, and a reduction in toxicological effects. The same process in this example should be applicable to the inclusion of multiple pesticides and to more descriptive population models such as those describing metapopulations. Integr Environ Assess Manag 2020;16:28–42. © 2019 SETA

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

Risk factors in child maltreatment: a meta-analytic review of the literature

This review presents the results of a series of meta-analyses identifying the relative strength of various risk factors for child physical abuse and neglect. Data from 155 studies examining 39 different risk factors were included in the review. Large effect sizes were found between child physical abuse and four risk factors (parent perceives child as problem, parent anger, family conflict and family cohesion). Large effect sizes were also found between child neglect and six risk factors (child social competence, parent-child relationship, parent perceives child as problem, parent’s level of stress, parent’s level of anger, and parent’s self-esteem)