Regulatory Community Research Articles

The mercury science-policy interface: History, evolution and progress of the Minamata Convention

Mercury (Hg) pollution is an important environmental and public health issue that has garnered significant interest from policy makers and the global regulatory community. Consumption of seafood is the primary mechanism of methyl Hg (MeHg) exposure in humans, globally, and marine fish represent an important linkage between atmospheric dynamics, aquatic biogeochemistry and trophic transfer of this highly neurotoxic and easily assimilated form of Hg. Hg policies and management are highly interdisciplinary and at their foundation are relatively well established scientific principles related to Hg methylation, MeHg cycling and bioaccumulation, and subsequent trophic transfer to humans; however, certain fine-scale aspects of these processes remain poorly understood. After several years of intergovernmental negotiations the Minamata Convention on Mercury (MCM) entered into force in August 2017. Anthropogenic releases (water) and emissions (air) of Hg, human exposure, and environmental health are of considerable importance within the framework and policies outlined in the MCM. Additionally, the overall risk of Hg from artisanal and small-scale gold mining (ASGM) is considered a significant source of human exposure and commonly occurs in low and middle income countries, where miners use elemental Hg to extract gold from ore. Here I outline the history, evolution and progress of the MCM as it relates to the science-policy interface and offer a brief synthesis of the state of Hg science in the context of modeling, temporal assessments of Hg trends and global environmental change and ecosystem sensitivity.

Recommendations for further revisions to improve the International Agency for Research on Cancer (IARC) Monograph program

In 2019, the International Agency for Research on Cancer (IARC) "Preamble to the IARC Monographs" expanded guidance regarding the scientific approaches that should be employed in its monographs. These amendments to the monograph development process are an improvement but still fall short in several areas. While the revised Preamble lays out broad methods and approaches to evaluate scientific evidence, there is a lack of specificity with regard to how IARC Working Groups will conduct consistent evaluations in a standardized, objective, and transparent manner; document systematic review and evidence integration actions, and substantiate how these actions and decisions inform the ultimate classifications. Furthermore, no guidance is provided to ensure Working Groups consistently incorporate mechanistic evidence in a robust manner using a defined approach in the context of 21st century knowledge of modes of action. Nor are the conclusions of the working groups subjected to outside, independent scientific peer review. Continued improvements and modernization of the procedures for evaluating, presenting, and communicating study quality, and in the methods used to conduct and peer-review evidence-based decision making will benefit the Working Group members, the IARC Monographs Programme overall, and the international regulatory community and public who rely upon the monographs.

Implementing a globally harmonized risk assessment-based approach for regulatory decision-making of crop protection products.

A global, harmonized evaluation system for crop protection chemicals based on exposure and risk will improve the ability to inform risk management decisions and better support innovation. This would be achieved through harmonized risk assessment-based regulatory decision-making realized through the application of the best available science, via integration of new methods and traditional data to create tailored exposure-driven risk assessments. A requirement to achieve success is a structure that encourages direct communication between the regulatory community and the regulated industry, which would enable a more rapid incorporation of new technologies and advancing science. An approach that emulates the International Conference of Harmonization (ICH) for pharmaceuticals would bring together regulatory authorities and the regulated industry along with relevant experts from academia and Non-Governmental Organizations to discuss scientific and technical advances and their implementation. These discussions would also encourage the elimination of outmoded practices that no longer serve a purpose resulting in more uniform testing requirements and best practices for data evaluation to support safe use and scientifically defensible human health and environmental risk assessments. New and developing technologies offer exciting opportunities to improve the current toxicity testing paradigms to provide better solutions and diminish animal testing. Implementation of a harmonized approach will increase the speed, efficiency and accuracy of regulatory decision-making for human health and environmental protection while increasing the efficiency of providing safe and effective innovative products to the agriculture community. © 2020 Society of Chemical Industry.

Tsunami or Squall?

More than a decade ago, it was realized that the workforce in North America and many developed areas was getting older, leading to fears of a “silver tsunami” of retirements that would critically upend our workforce. However, the Great Recession dampened that forecast, as people worldwide were more concerned about keeping their jobs than trading them in. Fast forward to 2020 and some areas are again anticipating or already experiencing the effects of increasing retirements. Some utilities report nearly half of their workforce may be eligible to retire in the next five to 10 years. While some are facing this potential “brain drain,” unemployment levels are near record lows in North America and the market for talent feels tighter than normal. Professional expectations within the industry are higher than ever as the complexities of water systems grow along with reporting and regulatory requirements and community involvement. However, eligible doesn't necessarily mean inevitable, and another big storyline these days is that too many folks aren't prepared to retire. Underfunded retirements and fewer pensions likely mean more will work longer. But within the water industry, many often translate their experience and knowhow into new careers. For example, when a consultant becomes a utility leader (or vice versa), knowledge is transferred back and forth within the water industry and throughout the various networks. Many still have a lot to share and will want to stay engaged and give back. The real trouble for the water industry will be if a wave of experienced workers leave their positions before transferring their institutional knowledge. Rural and smaller utilities will take the brunt of this, as they usually do, because this group already faces trouble finding qualified workers as there is always upward momentum to higher paying/better jobs at larger utilities. Outside of urban centers, it's especially hard to replenish the loss of certified and skilled operators who want to grow, even in the best of times. The next generation of water professionals must be strengthened by proactive plans to recruit new members and strengthen the capabilities of those already employed. Whether the tsunami comes or if it turns out to be a steady stream, the water industry needs to recruit more diversity so that it better represents our communities. We need to combine all of our lived experience into guidance and practice to ensure that current and future generations continue to deliver safe and clean water. This month's Journal AWWA features articles on managing lead and copper, chromium, groundwater, and resilience. If you are interested in submitting an article, contact me at [email protected].

Advancing ‘Environmental Subjectivity’ in the realm of neoliberal forest governance: Conservation subject creation in the Lokkere Reserve Forest, India

State-based governance mechanisms, such as the ‘fortress model’ and ‘regulatory community’, have proven to be ineffective to overcome forest degradation. Neoliberal interventions adopted by NGOs that provide economic incentives for communities to govern forests are presented as an alternative approach. This article suggests that different neoliberal interventions produce different modes of governance and may involve multiple environmentalities. The work of the NGO ‘Junglescapes’ in the Lokkere Reserve Forest was examined through its community engagement in, (a) lantana craft making in the village and, (b) restoration in the forest. Interviews, focus group discussion, and shadowing research took place during ten field-visits between June 2017 and June 2019. Within the neoliberal governance domain, communities engaged in village occupations were provided with economic incentives through a top-down ‘neoliberal NGO apparatus’. ‘Environmental subjects’ resulted, by which individuals regulate their actions by reducing their dependence on the forest but not necessarily inculcating environmental norms or values. In contrast, actors employed in the forest exhibited independence, effected their own strategies, incorporated local knowledge, and achieved improved ecosystem conditions. This occurred due to the facilitation of local social interaction and leadership through a non-hierarchical ‘conservation network’. An advanced form of environmental subjects emerged and are proposed as ‘conservation subjects’. The latter argued as actors that are produced within a neoliberal conservation model, and are empowered and self-mobilised to act independently to conserve the ecosystem, thereby achieving more-sustainable conservation. Research results have the potential for replication across similar ecosystems, particularly within severely-degraded landscapes in India and globally.

The detection and analysis of differential regulatory communities in lung cancer

The tumorgenesis process of lung cancer involves the regulatory dysfunctions of multiple pathways. Although many signaling pathways have been identified to be associated with lung cancer, there are little quantitative models of how inactions between genes change during the process from normal to cancer. These changes belong to different dynamic co-expressions patterns. We quantitatively analyzed differential co-expression of gene pairs in four datasets. Each dataset included a large number of lung cancer and normal samples. By overlapping their results, we got 14 highly confident gene pairs with consistent co-expression change patterns. Some of they, such as ARHGAP30 and GIMAP4, had been recorded in STRING network database while some of them were novel discoveries, such as C9orf135 and MORN5, TEKT1 and TSPAN1 were positively correlated in both normal and cancer but more correlated in normal than cancer. These gene pairs revealed the underlying mechanisms of lung cancer occurrence.

Rodent Sperm Analysis: A rationale for and path toward acceptance and use in ecological risk assessment

The Rodent Sperm Analysis method was devised some two decades ago to advance ecological assessment science for mammals, one of two groups of terrestrial receptors routinely evaluated at chemically contaminated sites. In part, this method recognizes that sufficient time has elapsed at sites, such that a need to anticipate or predict impacts to ecological receptors is an obsolete task. The method therefore, recommends evaluating the very receptors that occupy sites for evidence today of their displaying compromised reproduction, a toxicological endpoint of great concern within the regulatory community. Critically, Rodent Sperm Analysis is not a risk assessment method but rather a direct health status assessment method, a distinction that ecological risk assessors may fail to recognize or appreciate. Further, the method is not intended as a replacement for the conventional approach to ecological assessment, but rather a method to be run in tandem with it, where it may likely reveal that site mammals are commonly free of impacts and that conventional assessments are fully unnecessary. This Discussion paper is a cautious analytical review of ecological assessor perceptions about the vetted and recently ASTM International certified Rodent Sperm Analysis method. The review identifies potential impediments to the method gaining broader acceptance by professionals in the field, prominently among these, resistance to adopting a new ecological assessment paradigm that may be more helpful than the one presently in place.

Developmental biology meets toxicology: contributing reproductive mechanisms to build adverse outcome pathways.

An adverse outcome pathway (AOP) is a simplified description of the sequence of mechanistic events that lead to a particular toxicological effect, from initial trigger to adverse outcome. Although designed to inform regulatory risk assessors, the AOP framework also provides a platform for innovative collaborations between experts from relevant research fields and the regulatory community. The underpinning for any AOP is basic knowledge about molecular and developmental processes; such knowledge can only be attained by solid bioscientific research. Starting with this fundamental knowledge, the objective is to devise novel testing strategies that focus on key events in a causative pathway. It is anticipated that such a knowledge-based approach will ultimately alleviate many of the burdens associated with classical chemical testing strategies that typically involve large-scale animal toxicity regimens. This hails from the notion that a solid understanding of the underlying mechanisms will allow the development and use of alternative test methods, including both in vitro and in silico approaches. This review is specifically targeted at professionals working in bioscientific fields, such as developmental and reproductive biology, and aims to (i) inform on the existence of the AOP framework and (ii) encourage new cross-disciplinary collaborations. It is hoped that fundamental biological knowledge can thus be better exploited for applied purposes: firstly, an improved understanding of how our perpetual exposure to environmental chemicals is causing human reproductive disease and, secondly, new approaches to screen for harmful chemicals more efficiently. This is not an instructional manual on how to create AOPs; rather, we discuss how to harness fundamental knowledge from the biosciences to assist regulatory toxicologists in their efforts to protect humans against chemicals that harm human reproductive development and function.

Arguments for a Different Regulatory Categorization and Framework for Stromal Vascular Fraction.

Although adipose tissue and cells show considerable promise for clinical translation in the emerging field of regenerative medicine, they present a challenge to the regulatory community both nationally and internationally. This commentary evaluates the status of adipose-derived therapeutics and considers regulatory approaches designed to maximize patient safety while advancing clinical translation in accordance with evidence-based medical science.

Making better use of toxicity studies for human health by extrapolating across endpoints.

To develop and evaluate scientifically robust and innovative approaches for the safety assessment of chemicals across multiple regulatory sectors, the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) has started a project to explore how to better use the available information, including that from existing animal studies. The aim is to minimize reliance on in vivo testing to avoid redundancy and to facilitate the integration of novel non-animal methods in the regulatory setting with the ultimate goal of designing sustainable testing strategies. In this thought-starter paper, we present a number of examples to illustrate and trigger further discussions within the scientific and regulatory communities on ways to extrapolate useful information for predicting toxicity from one toxicity endpoint to another or across endpoints based on mechanistic information.

Outbreaks of Lumpy Skin Disease of Cattle in Bangladesh: What to Know and What to Do

Lumpy Skin Disease (LSD) is a transboundary disease of cattle originated in Africa. In recent years it has emerged in different countries with a severe impact on production. Bangladesh has now encountered the second consecutive year’s outbreak of LSD. The first outbreak occurred in 2019 while disease manifested with high fever, skin nodules and edema. The reported morbidity rate was 10 to 20% with a 1-5% mortality rate. Sharp decrease in milk production, long time treatment cost and reproductive difficulties lead to the widespread financial loss of farmers. But the scarcity of literature on the epidemiology, vector and genetic characteristic of the virus in Bangladesh cause delay in diagnosis and reporting which make the situation become worst. The author provides baseline data for enhancing future research and advocates preventive measures focusing on vector control. Quarantine and mass vaccination are efficient tools to halt the epidemic. However, extensive entomological surveillance might initiate a cost-effective measure through vector control. This paper might raise concerns to push the regulatory bodies and research communities for taking collaborative actions to prevent the serial outbreaks of LSD.

Regulatory Status of Genome-Edited Organisms Under the Japanese Cartagena Act.

The Japanese government recognizes the substantial values of genome-edited agricultural organisms and has defined in which cases these are covered by the existing regulatory framework to handle this technology. Genome-editing technologies could revolutionize and accelerate plant breeding owing to the simplicity of the methods and precision of genome modifications. These technologies have spread rapidly and widely, and various genome-edited crops have been developed recently. The regulatory status of genome-edited end products is a subject of controversy worldwide. In February 2019, the Japanese government defined genome-edited end products derived by modifications of SDN-1 type (directed mutation without using a DNA sequence template) as not representing “living modified organisms” according to the Japanese Cartagena Act. Here, we describe the classification and regulatory status of genome-edited end products in this decision. We hope that reporting the progress in Japan toward the implementation of this regulatory approach will provide insight for scientific and regulatory communities worldwide.

Fire control systems in forest reserves: An assessment of three forest districts in the Northern region, Ghana

Forest fires may have beneficial effects ecologically, but can also be damaging to the overall health and diversity of flora and fauna and may also result in loss of farm produce and livelihood base of local communities living around the forest reserves. In order to minimize damage from fires to the forest vegetation, information on frequency, timing and control of fire events is needed for decision making at the district and regional management levels of the Forestry Commission. However, not much of such information exists, particularly for northern Ghana. Therefore, this research sought to ascertain occurrences of forest fires and how they are controlled in three (3) Forest Districts in the northern region of Ghana namely: the Tamale, Yendi and Walewale Forest Districts. Respondents comprised staff of Ghana Forestry commission, members of fringe communities and personnel from the Ghana National Fire Service. A mixed method research design involving structured interview schedule, in-depth interviews and quantitative review of secondary data was employed for data collection. Quantitative data was analyzed using descriptive statistics such as frequencies and percentages while qualitative data was analyzed using simple narratives. The study revealed that detection by smoke was the dominant means of detecting fires within the forest reserves. December and January were the months with the most fire occurrences and periods between 2 and 4 h and greater than 8 h were the dominant timeframes within which fires were controlled. Inadequate firefighting equipment and lack of effective cooperation between regulatory institutions and community members were identified as major constraints to effective control of forest fires. Active collaboration between regulatory agencies and members of fringe communities among others are recommended for effective control of wildfires in forest reserves in northern region of Ghana.

Floodplain inundation spectrum across the United States

Floodplain inundation poses both risks and benefits to society. In this study, we characterize floodplain inundation across the United States using 5800 stream gages. We find that between 4% and 12.6% of a river’s annual flow moves through its floodplains. Flood duration and magnitude is greater in large rivers, whereas the frequency of events is greater in small streams. However, the relative exchange of floodwater between the channel and floodplain is similar across small streams and large rivers, with the exception of the water-limited arid river basins. When summed up across the entire river network, 90% of that exchange occurs in small streams on an annual basis. Our detailed characterization of inundation hydrology provides a unique perspective that the regulatory, management, and research communities can use to help balance both the risks and benefits associated with flooding.

Monitoring Aspergillus flavus Genotypes in a Multi-Genotype Aflatoxin Biocontrol Product With Quantitative Pyrosequencing.

Aflatoxins pose significant food security and public health risks, decrease productivity and profitability of animal industries, and hamper trade. To minimize aflatoxin contamination in several crops, a biocontrol technology based on atoxigenic strains of Aspergillus flavus is commercially used in the United States and some African countries. Significant efforts are underway to popularize the use of biocontrol in Africa by various means including incentives. The purpose of this study was to develop quantitative pyrosequencing assays for rapid, simultaneous quantification of proportions of four A. flavus biocontrol genotypes within complex populations of A. flavus associated with maize crops in Nigeria to facilitate payment of farmer incentives for Aflasafe (a biocontrol product) use. Protocols were developed to confirm use of Aflasafe by small scale farmers in Nigeria. Nested PCR amplifications followed by sequence by synthesis pyrosequencing assays were required to quantify frequencies of the active ingredients and, in so doing, confirm successful use of biocontrol by participating farmers. The entire verification process could be completed in 3–4 days proving a savings over other monitoring methods in both time and costs and providing data in a time frame that could work with the commercial agriculture scheme. Quantitative pyrosequencing assays represent a reliable tool for rapid detection, quantification, and monitoring of multiple A. flavus genotypes within complex fungal communities, satisfying the requirements of the regulatory community and crop end-users that wish to determine which purchased crops were treated with the biocontrol product. Techniques developed in the current study can be modified for monitoring other crop-associated fungi.

The Use and Misuse of Historical Controls in Regulatory Toxicology: Lessons from the CLARITY-BPA Study.

For many endocrine-disrupting chemicals (EDCs) including Bisphenol A (BPA), animal studies show that environmentally relevant exposures cause harm; human studies are consistent with these findings. Yet, regulatory agencies charged with protecting public health continue to conclude that human exposures to these EDCs pose no risk. One reason for the disconnect between the scientific consensus on EDCs in the endocrinology community and the failure to act in the regulatory community is the dependence of the latter on so-called "guideline studies" to evaluate hazards, and the inability to incorporate independent scientific studies in risk assessment. The Consortium Linking Academic and Regulatory Insights on Toxicity (CLARITY) study was intended to bridge this gap, combining a "guideline" study with independent hypothesis-driven studies designed to be more appropriate to evaluate EDCs. Here we examined an aspect of "guideline" studies, the use of so-called "historical controls," which are essentially control data borrowed from prior studies to aid in the interpretation of current findings. The US Food and Drug Administration authors used historical controls to question the plausibility of statistically significant BPA-related effects in the CLARITY study. We examined the use of historical controls on 5 outcomes in the CLARITY "guideline" study: mammary neoplasms, pituitary neoplasms, kidney nephropathy, prostate inflammation and adenomas, and body weight. Using US Food and Drug Administration-proposed historical control data, our evaluation revealed that endpoints used in "guideline" studies are not as reproducible as previously held. Combined with other data comparing the effects of ethinyl estradiol in 2 "guideline" studies including CLARITY-BPA, we conclude that near-exclusive reliance on "guideline" studies can result in scientifically invalid conclusions.

Potential Use of Artificial Intelligence for Regulatory Intelligence: Biopharmaceutical Industry's Views.

Pharmaceutical companies rely on regulatory intelligence (RI) to analyze information from internal and external sources. To facilitate RI activities, companies are seeking ways to harness technology to optimize their capabilities. Specifically, there is a growing interest for artificial intelligence (AI) to enhance RI activities. However, exploration of the potential utility of AI and related technologies will be key to begin unlocking these tools for the regulatory community. To identify potential development paths for these technologies, we interviewed over 30 global regulatory leaders at 22 pharmaceutical companies and 3 leading companies in RI and AI technologies. Thirteen of the 22 pharmaceutical companies also provided responses to a subsequent informational survey. This study elucidated potential value proposition, barriers, and risks to integrating AI into the RI field. Twenty of the 22 participating companies consider that AI offers significant opportunity for RI activities of data processing (mining, searching, monitoring, alerting). Thirty-two percent of companies envisage use in data synthesis (combining different types of information across formats), 36% in data analysis (trends, patterns, predictive analytics), and 23% in decision making. Additionally, results of this research provided insights about the potential role of precompetitive consortia, which may enhance future actualization. Opportunity presents for AI to enhance quality, speed, and efficiency of RI activities. This assessment of the current technology landscape revealed a lack of fully developed AI tools; however, the RI community demand is beginning to be recognized. Therefore, now more than ever, the timing to advance AI within the RI field is right.

T1000: a reduced gene set prioritized for toxicogenomic studies.

There is growing interest within regulatory agencies and toxicological research communities to develop, test, and apply new approaches, such as toxicogenomics, to more efficiently evaluate chemical hazards. Given the complexity of analyzing thousands of genes simultaneously, there is a need to identify reduced gene sets. Though several gene sets have been defined for toxicological applications, few of these were purposefully derived using toxicogenomics data. Here, we developed and applied a systematic approach to identify 1,000 genes (called Toxicogenomics-1000 or T1000) highly responsive to chemical exposures. First, a co-expression network of 11,210 genes was built by leveraging microarray data from the Open TG-GATEs program. This network was then re-weighted based on prior knowledge of their biological (KEGG, MSigDB) and toxicological (CTD) relevance. Finally, weighted correlation network analysis was applied to identify 258 gene clusters. T1000 was defined by selecting genes from each cluster that were most associated with outcome measures. For model evaluation, we compared the performance of T1000 to that of other gene sets (L1000, S1500, Genes selected by Limma, and random set) using two external datasets based on the rat model. Additionally, a smaller (T384) and a larger version (T1500) of T1000 were used for dose-response modeling to test the effect of gene set size. Our findings demonstrated that the T1000 gene set is predictive of apical outcomes across a range of conditions (e.g., in vitro and in vivo, dose-response, multiple species, tissues, and chemicals), and generally performs as well, or better than other gene sets available.

Why Wait? The Case for Treating Tuberculosis with Inhaled Drugs.

The discovery of drugs to treat tuberculosis (TB) was a major medical milestone in the twentieth century. However, from the outset, drug resistance was observed. Currently, of the 10 million people that exhibit TB symptoms each year, 450,000 have multidrug or extensively drug resistant (MDR or XDR) TB. While greater understanding of the host and pathogen (Mycobacterium tuberculosis, Mtb) coupled with scientific ingenuity will lead to new drugs and vaccines, in the meantime 4000 people die daily from TB. Thus, efforts to improve existing TB drugs should also be prioritized. Improved efficacy and decreased dose and associated toxicity of existing drugs would translate to greater compliance, life expectancy and quality of life of Mtb infected individuals. One potential strategy to improve existing drugs is to deliver them by inhalation as aerosols to the lung, the primary site of Mtb infection. Inhaled drugs are used for other pulmonary diseases, but they have yet to be utilized for TB. Inhaled therapies for TB represent an untapped opportunity that the pharmaceutical, clinical and regulatory communities should consider.

The emerging radiographer's transient community service professional career pathway.

BackgroundPost-qualification regulatory 12-month community service (CS) was implemented in South Africa in 1998. Since the implementation, studies have been conducted in various disciplines to measure the impact on health services and on the affected professionals, but these did not include radiography professionals.AimThis study explored the expectations and experiences of student radiographers in respect of the CS concept as an integral transitional career pathway from the student radiographer role to that of a provisional practitioner in transit to acquiring registered radiographer practitioner status.Research methodsThe research design entailed a qualitative exploratory approach using a longitudinal data collection approach. That is, data collection from the purposefully selected student radiographers’ focus group discussions, as well as from placement institutions’ qualified professionals and managers, formed the triangulated data sources. In addition, individual interviews were conducted post-placement until data and thematic saturation had been reached. Tesch’s (1990) method was used for the data interpretation and analysis.ResultsThe themes that emerged reflected the preparedness of these students to fulfil the requirements, their experiences of their anticipated placement institution, preparedness for their roles and responsibilities and uncertainties about their readiness for the actual encounter. A golden thread throughout was critical self-reflection on their ability, adaptability and capability to meet the requirements of the system, namely the community placement institutions and appeasing the Department of Health.ConclusionThe study illustrates, by means of a framework, the student radiographers’ journey in transit to acquiring eligibility as registered radiography practitioners in a regulated career pathway.