Innovation in regulatory approaches for endocrine disrupting chemicals: The journey to risk assessment modernization in Canada.

Globally, regulatory authorities grapple with the challenge of assessing the hazards and risks to human and ecosystem health that may result from exposure to chemicals that disrupt the normal functioning of endocrine systems. Rapidly increasing number of chemicals in commerce, coupled with the reliance on traditional, costly animal experiments for hazard characterization - often with limited sensitivity to many important mechanisms of endocrine disruption -, presents ongoing challenges for chemical regulation. The consequence is a limited number of chemicals for which there is sufficient data to assess if there is endocrine toxicity and hence few chemicals with thorough hazard characterization. To address this challenge, regulatory assessment of endocrine disrupting chemicals (EDCs) is benefiting from a revolution in toxicology that focuses on New Approach Methodologies (NAMs) to more rapidly identify, prioritize, and assess the potential risks from exposure to chemicals using novel, more efficient, and more mechanistically driven methodologies and tools. Incorporated into Integrated Approaches to Testing and Assessment (IATA) and guided by conceptual frameworks such as Adverse Outcome Pathways (AOPs), emerging approaches focus initially on molecular interactions between the test chemical and potentially vulnerable biological systems instead of the need for animal toxicity data. These new toxicity testing methods can be complemented with in silico and computational toxicology approaches, including those that predict chemical kinetics. Coupled with exposure data, these will inform risk-based decision-making approaches. Canada is part of a global network collaborating on building confidence in the use of NAMs for regulatory assessment of EDCs. Herein, we review the current approaches to EDC regulation globally (mainly from the perspective of human health), and provide a perspective on how the advances for regulatory testing and assessment can be applied and discuss the promises and challenges faced in adopting these novel approaches to minimize risks due to EDC exposure in Canada, and our world.

Mercury and neurochemical biomarkers in multiple brain regions of five Arctic marine mammals.

Mercury is a neurotoxic chemical that represents one of the greatest pollution threats to Arctic ecosystem health. Evaluating the direct neurotoxic effects of mercury in free ranging wildlife is challenging, necessitating the use of neurochemical biomarkers to assess potential sub-clinical neurological changes. The objective of this study was to characterize the distribution and speciation of mercury, as well as exposure-associated changes in neurochemistry, across multiple brain regions (n = 10) and marine mammal species (n = 5) that each occupy a trophic niche in the Arctic ecosystem. We found consistent species differences in mean brain and brain region-specific concentrations of total mercury (THg) and methyl mercury (MeHg), with higher concentrations in toothed whales (narwhal, pilot whales and harbour porpoise) compared to fur-bearing mammals (polar bear and ringed seal). Mean THg (µg/g dw) in decreasing rank order was: pilot whale (11.9) > narwhal (7.7) > harbour porpoise (3.6) > polar bear (0.6) > ringed seal (0.2). The higher THg concentrations in toothed whales was associated with a marked reduction in the percentage of MeHg (<40 %) compared to polar bears (>70 %) that had lower brain THg concentrations. This pattern in mercury concentration and speciation corresponded broadly to an overall higher number of mercury-associated neurochemical biomarker correlations in toothed whales. Of the 226 correlations between mercury and neurochemical biomarkers across brain regions, we found 60 (27 %) meaningful relationships (r>0.60 or p < 0.10). We add to the growing weight of evidence that wildlife accumulate mercury in their brains and demonstrate that there is variance in accumulation across species as well as across distinct brain regions, and that some of these exposures may be associated with sub-clinical changes in neurochemistry.

Maximizing US nitrate removal through wetland protection and restoration.

Growing populations and agricultural intensification have led to raised riverine nitrogen (N) loads, widespread oxygen depletion in coastal zones (coastal hypoxia)1 and increases in the incidence of algal blooms.Although recent work has suggested that individual wetlands have the potential to improve water quality2-9, little is known about the current magnitude of wetland N removal at the landscape scale. Here we use National Wetland Inventory data and 5-kilometre grid-scale estimates of N inputs and outputs to demonstrate that current N removal by US wetlands (about 860 ± 160 kilotonnes of nitrogen per year) is limited by a spatial disconnect between high-density wetland areas and N hotspots. Our model simulations suggest that a spatially targeted increase in US wetland area by 10 per cent (5.1 million hectares) would double wetland N removal. This increase would provide an estimated 54 per cent decrease in N loading in nitrate-affected watersheds such as the Mississippi River Basin. The costs of this increase in area would be approximately 3.3 billion US dollars annually across the USA-nearly twice the cost of wetland restoration on non-agricultural, undeveloped land-but would provide approximately 40 times more N removal. These results suggest that water quality improvements, as well as other types of ecosystem services such as flood control and fish and wildlife habitat, should be considered when creating policy regarding wetland restoration and protection.

Improving quality of life in vasculitis patients.

Systemic vasculitis are a complex cluster of diseases with high associated morbidity. As disease-related mortality diminishes, the cumulative impact of poor health-related quality of life becomes more pertinent to patients than the initial pathological insult. In this article we explore health-related quality of life in ANCA-associated vasculitis, large-vessel vasculitis and therapeutic strategies that may enhance this critical outcome.

Response to Comment on "Legacy nitrogen may prevent achievement of water quality goals in the Gulf of Mexico".

Ballard et al argue that our prediction of a 30-year or longer recovery time for Gulf of Mexico water quality is highly uncertain, and that much shorter time lags are equally likely. We demonstrate that their argument, based on the use of a two-component regression model, does not sufficiently consider fundamental watershed processes or multiple lines of evidence suggesting the existence of decadal-scale lags.

Prognosis and future developments in vasculitis.

The prognosis of ANCA-associated vasculitis has been transformed in recent years. Once it was a set of invariably acute and fatal conditions, but these disorders are currently considered to be chronic diseases. This change is largely attributable to earlier diagnosis and the careful application of immunotherapeutics. However, patients still experience premature mortality, relapse, comorbid ill health and poor quality of life. Mortality rates in large-vessel vasculitis are not comparable; however, morbidity and poor patient outcomes prevail. Toxicity secondary to glucocorticoids represents a common driver of poor outcomes across systemic vasculitis. The main thrust of future treatment strategies is to reduce if not eliminate exposure to these agents.

Legacy nitrogen may prevent achievement of water quality goals in the Gulf of Mexico.

In August 2017, the Gulf of Mexico's hypoxic zone was declared to be the largest ever measured. It has been estimated that a 60% decrease in watershed nitrogen (N) loading may be necessary to adequately reduce eutrophication in the Gulf. However, to date there has been no rigorous assessment of the effect of N legacies on achieving water quality goals. In this study, we show that even if agricultural N use became 100% efficient, it would take decades to meet target N loads due to legacy N within the Mississippi River basin. Our results suggest that both long-term commitment and large-scale changes in agricultural management practices will be necessary to decrease Mississippi N loads and to meet current goals for reducing the size of the Gulf hypoxic zone.

An ecotoxicological view on neurotoxicity assessment.

The numbers of potential neurotoxicants in the environment are raising and pose a great risk for humans and the environment. Currently neurotoxicity assessment is mostly performed to predict and prevent harm to human populations. Despite all the efforts invested in the last years in developing novel in vitro or in silico test systems, in vivo tests with rodents are still the only accepted test for neurotoxicity risk assessment in Europe. Despite an increasing number of reports of species showing altered behaviour, neurotoxicity assessment for species in the environment is not required and therefore mostly not performed. Considering the increasing numbers of environmental contaminants with potential neurotoxic potential, eco-neurotoxicity should be also considered in risk assessment. In order to do so novel test systems are needed that can cope with species differences within ecosystems. In the field, online-biomonitoring systems using behavioural information could be used to detect neurotoxic effects and effect-directed analyses could be applied to identify the neurotoxicants causing the effect. Additionally, toxic pressure calculations in combination with mixture modelling could use environmental chemical monitoring data to predict adverse effects and prioritize pollutants for laboratory testing. Cheminformatics based on computational toxicological data from in vitro and in vivo studies could help to identify potential neurotoxicants. An array of in vitro assays covering different modes of action could be applied to screen compounds for neurotoxicity. The selection of in vitro assays could be guided by AOPs relevant for eco-neurotoxicity. In order to be able to perform risk assessment for eco-neurotoxicity, methods need to focus on the most sensitive species in an ecosystem. A test battery using species from different trophic levels might be the best approach. To implement eco-neurotoxicity assessment into European risk assessment, cheminformatics and in vitro screening tests could be used as first approach to identify eco-neurotoxic pollutants. In a second step, a small species test battery could be applied to assess the risks of ecosystems.

Geriatric hip fracture management: keys to providing a successful program.

BACKGROUND: Hip fractures are a common event in older adults and are associated with significant morbidity, mortality and costs. This review examines the necessary elements required to implement a successful geriatric fracture program and identifies some of the barriers faced when implementing a successful program. INTERVENTION: The Geriatric Fracture Center (GFC) is a treatment model that standardizes the approach to the geriatric fracture patient. It is based on five principles: surgical fracture management; early operative intervention; medical co-management with geriatricians; patient-centered, standard order sets to employ best practices; and early discharge planning with a focus on early functional rehabilitation. Implementing a geriatric fracture program begins with an assessment of the hospital's data on hip fractures and standard care metrics such as length of stay, complications, time to surgery, readmission rates and costs. Business planning is essential along with the medical planning process. CONCLUSION: To successfully develop and implement such a program, strong physician leadership is necessary to articulate both a short- and long-term plan for implementation. Good communication is essential-those organizing a geriatric fracture program must be able to implement standardized plans of care working with all members of the healthcare team and must also be able to foster relationships both within the hospital and with other institutions in the community. Finally, a program of continual quality improvement must be undertaken to ensure that performance outcomes are improving patient care.

Attitudes to contralateral risk reducing mastectomy among breast and plastic surgeons in England.

INTRODUCTION: Rates of contralateral risk reducing mastectomy (CRRM) are rising despite a paucity of data to support this practice. Surgeons work as part of the multidisciplinary team (MDT). They may counsel women on these requests without the benefit of established guidelines or agreed protocol. This study assessed the practices and perceptions of breast and plastic surgeons in England on CRRM. METHODS: A postal questionnaire was sent to 455 breast and 364 plastic surgeons practising in England. Basic demographics, trends in CRRM, risk assessment, role of the MDT and knowledge base were assessed. RESULTS: The response rate among breast surgeons was 48.3% (220/455) and 12.6% (46/364) among plastic surgeons. Nearly half (44%) of the respondents felt there had been an increase in rates of CRRM over the last three years. Seventy-one per cent of those surveyed performed 1-5 CRRMs annually while sixteen per cent did not perform this procedure at all. A third (32%) of respondents correctly quoted their patients an annual risk of 0.5-0.7%. Funding was refused in 4% of cases and 43% of the surgeons felt that in the future they would have to apply to relevant clinical commissioning groups. Over half (58%) of all respondents reported that decisions for CRRM are always discussed in the MDT meeting but 6% stated that these cases are never discussed by the MDT. BRCA mutation was perceived as the main risk factor for contralateral breast cancer by 81% of respondents. Surgeons felt that women requested CRRM mainly to alleviate anxiety. The next most common reasons were carriage of BRCA mutation and a desire to have reconstructions match. CONCLUSIONS: A wide variation of surgical practices and perceptions exist in assessing women for CRRM. Guidelines to standardise practices are required.

Uptake of selenium and mercury by captive mink: Results of a controlled feeding experiment.

Captive, juvenile, ranch-bred, male mink (Neovison vison) were fed diets containing various concentrations of methyl-mercury (MeHg) and selenium (Se) for a period of 13 weeks and then sacrificed to determine total Hg levels in fur, blood, brain, liver and kidneys and total Se concentrations in brain tissue. As MeHg concentrations in the diet increased, concentrations of total Hg in the tissues also increased with the highest level occurring in the fur > liver = kidney > brain > blood. Concentrations of Hg in the fur were correlated (r(2) > 0.97) with liver, kidney, blood and brain concentrations. The addition of Se to the mink diet did not appear to affect most tissue concentrations of total Hg nor did it affect the partitioning of Hg between the liver:blood, kidney:blood and brain:blood; however, partitioning of Hg between fur and blood was apparently affected.

Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis.

BRCA1 and BRCA2 mutation carriers have an increased risk of contralateral breast cancer after primary breast cancer. Risk reduction strategies are discussed after assessment of risk factors for developing contralateral breast cancer. We assessed potential risk factors that could be of use in clinical practice, including the novel use of single nucleotide polymorphisms (SNP) testing. 506 BRCA1 and 505 BRCA2 mutation carriers with a diagnosis of breast cancer were observed for up to 30 years. The risk of a contralateral breast cancer is approximately 2-3% per year, remaining constant for at least 20 years. This was similar in both BRCA1 and BRCA2 carriers. Initial breast cancer before age 40-years was a significant risk factor, which was more pronounced in BRCA1 patients. The effect of risk-reducing oophorectomy on contralateral breast cancer risk may be overestimated because of bias. No significant association was found between overall breast cancer risk SNP score and contralateral breast cancer development. Young mutation carriers, particularly those with BRCA1 mutations, who develop breast cancer have a significantly higher risk of developing contralateral breast cancer, remaining constant for over 20 years. Contralateral risk-reducing mastectomy should be considered in this group, in particular as there is a survival benefit. Caution is advised when counselling women considering risk-reducing oophorectomy as, after accounting for statistical bias, the associated risk reduction was found to be non-significant, and potentially smaller than has been previously reported. SNP testing did not add any further discriminatory information when assessing contralateral breast cancer risk.

Contralateral risk-reducing mastectomy: review of risk factors and risk-reducing strategies.

Rates of contralateral risk-reducing mastectomy have increased substantially over the last decade. Surgical oncologists are often in the frontline, dealing with requests for this procedure. This paper reviews the current evidence base regarding contralateral breast cancer, assesses the various risk-reducing strategies, and evaluates the cost-effectiveness of contralateral risk-reducing mastectomy.

Sentinel lymph node biopsy in a patient with ruptured poly implant prothese (PIP) implants: A case report.

INTRODUCTION: Around 400,000 silicone gel breast implants produced by the French company poly implant prothese (PIP) were used worldwide. Following revelations that the company were using non- medical grade silicone for the production of their implants there has been growing concern over the increased rupture rate of these implants and the implications this may have on patients. PRESENTATION OF CASE: We report the case of a 57-year old lady with ruptured bilateral cosmetic PIP breast implants in whom a right breast lesion was detected on screening mammograms. Biopsies demonstrated a grade 1 tubular carcinoma. Histology from the sentinel lymph node biopsy showed axillary silicone granulomas but no evidence of metastatic disease. DISCUSSION: To our knowledge, this is the first reported case to describe SLNB in the presence of ruptured PIP implants, although SLNB in ruptured non-PIP implants has been previously described. CONCLUSION: We conclude that SLNB can be utilised even in the context of concurrent PIP implant rupture and the presence of silicone granulomas in the axillary lymph nodes.

Morphological changes during annealing of polyethylene nanocrystals.

Polymer crystals are metastable and exhibit morphological changes when being annealed. To observe morphological changes on molecular scales we started from small nanometer-sized crystals of highly folded long-chain polymers. Micron-sized stripes consisting of monolayers or stacks of several layers of flat-on oriented polyethylene nanocrystals were generated via evaporative dewetting from an aqueous dispersion. We followed the morphological changes in time and at progressively higher annealing temperatures by determining the topography and viscoelastic properties of such assemblies of nanocrystals using atomic force microscopy. Due to smallness and high surface-to-volume ratio of the nanocrystals, already at 75 °C, i.e. about 60 degrees below the nominal melting point, the lateral size of the crystal coarsened. Intriguingly, this occurred without a noticeable reduction in the number of folds per polymer chain. Starting at around 110 °C, chain folds were progressively removed leading to crystal thickening. At higher temperatures, but still below the melting point, prolonged annealing allowed for surface diffusion of molten polymers on the initially bare substrate, leading eventually to the disappearance of crystals. We compared these results to the behavior of the same nanocrystals annealed in an aqueous dispersion and to bulk samples.

Temporal trends and future predictions of mercury concentrations in Northwest Greenland polar bear (Ursus maritimus) hair.

Hair samples from 117 Northwest Greenland polar bears (Ursus maritimus) were taken during 1892-2008 and analyzed for total mercury (hereafter Hg). The sample represented 28 independent years and the aim of the study was to analyze for temporal Hg trends. Mercury concentrations showed yearly significant increases of 1.6-1.7% (p < 0.0001) from 1892 to 2008 and the two most recent median concentrations from 2006 and 2008 were 23- to 27-fold higher respectively than baseline level from 1300 A.D. in the same region (Nuullit). This indicates that the present (2006-2008) Northwest Greenland polar bear Hg exposure is 95.6-96.2% anthropogenic in its origin. Assuming a continued anthropogenic increase, this model estimated concentrations in 2050 and 2100 will be 40- and 92-fold the baseline concentration, respectively, which is equivalent to a 97.5 and 98.9% man-made contribution. None of the 2001-2008 concentrations of Hg in Northwest Greenland polar bear hair exceeded the general guideline values of 20-30 µg/g dry weight for terrestrial wildlife, whereas the neurochemical effect level of 5.4 µg Hg/g dry weight proposed for East Greenland polar bears was exceeded in 93.5% of the cases. These results call for detailed effect studies in main target organs such as brain, liver, kidney, and sexual organs in the Northwest Greenland polar bears.

Mercury and selenium content of Taiwanese seafood.

Fish consumption is avid in Taiwan (and other Asian nations), but little is known about the mercury and selenium content in local seafood. This paper reports on total mercury, methylmercury and selenium levels from 14 commonly consumed seafood items obtained from Taichung, Taiwan. Mean total mercury concentrations varied nearly 100-fold across species. Fifty per cent of the marlins sampled and 35% of the sharks exceeded the 0.3 µg g(-1) US Environmental Protection Agency (USEPA) guideline. Methylmercury comprised a majority of the total mercury in all species. In all species studied there was a molar excess of selenium over mercury. The rank order of mean selenium-mercury molar ratios was red tilapia (166.8) > abura (87.9) > river prawn (82.4) > whiteleg shrimp (64.2) > butterfish (44.6) > milkfish (37.0) > tuna (15.6) > grouper (13.9) > ayu (13.4) > coral hind (13.0) > weever (11.8) > saury (9.0) > shark (7.8) > marlin (4.2).