Ecological Risk Assessment Guidance and Procedural Documents: An Annotated Compilation and Evaluation of Reference Materials

The scientific approach toward ecological risk assessment (ERA) has advanced greatly during the 1990s. This growth has been accompanied by the development of ERA guidance by USEPA Headquarters, individual USEPA Regions, state environmental agencies, as well as international agencies. This compilation of ERA guidance and procedural documents identifies many of the existing ERA reference materials from the regulatory and/or governmental agency arena. In addition, this compilation provides annotations pertaining to the focus of each reviewed document, and compares/contrasts the approaches presented in the documents. As such, the evaluation provides insight into some of the qualities and levels of detail provided by each document. Examples of documents which are highlighted include recently published USEPA's “Guidelines for Ecological Risk Assessment;” USEPA's “Ecological Risk Assessment Guidance for Superfund;” the U.S. Army's “Procedural Guidelines for Ecological Risk Assessments;” and Environment Canada's “Ecological Risk Assessments Under the Canadian Environmental Protection Act.”     

Considerations Regarding the Use of Reference Area and Baseline Information in Ecological Risk Assessments

There has been debate in the recent literature as to whether a reference assessment should be included in ecological risk assessments (ERAs) of contaminated sites, and if so, how such an evaluation can be incorporated in a way that aids in decision making. It is our view that an assessment of reference conditions can be useful in the ERA process, for both prospective and retrospective ERAs, given adequate resources and acknowledgement and understanding of the limitations and uncertainties associated with this information. Suggestions and considerations for incorporating reference area information into an ecological risk assessment are discussed.     

Methodologies and special considerations for environmental risk analysis of genetically modified aquatic biocontrol organisms

Genetic biocontrol of invasive aquatic species proposes to introduce, for control purposes, a genetically modified (GM) version of an invasive fish species to a targeted aquatic environment. Safe deployment and long term use of such technologies will depend on identifying and managing possible unintended effects to the natural environment. Environmental risk analysis (ERA) is a method for identifying the likelihood and consequences of unintended impacts, and for developing risk management strategies. For the unique situation of genetically modified biocontrol organisms (GMBOs), we review the latest thinking in ERA methodologies for GM fish and explore how terminology and assumptions from ERAs of traditional, non-modified biocontrol organisms and GM fish will need to be recast in ERAs of GMBOs. We also outline some special considerations that an ERA of a GMBOs will have to contend with: non-intuitive potential hazards; uncertainty introduced by extrapolating from domestic systems to natural ecosystems; redundancy in risk management options; and challenges of stakeholder engagement related to new technologies.     

Protection goals in environmental risk assessment: a practical approach

Policy protection goals are set up in most countries to minimise harm to the environment, humans and animals caused by human activities. Decisions on whether to approve new agricultural products, like pesticides or genetically modified (GM) crops, take into account these policy protection goals. To support decision-making, applications for approval of commercial uses of GM crops usually comprise an environmental risk assessment (ERA). These risk assessments are analytical tools, based on science, that follow a conceptual model that includes a problem formulation step where policy protection goals are considered. However, in most countries, risk assessors face major problems in that policy protection goals set in the legislation are stated in very broad terms and are too ambiguous to be directly applicable in ERAs. This means that risk assessors often have to interpret policy protection goals without clear guidance on what effects would be considered harmful. In this paper we propose a practical approach that may help risk assessors to translate policy protection goals into unambiguous (i.e., operational) protection goals and to establish relevant assessment endpoints and risk hypotheses that can be used in ERAs. Examples are provided to show how this approach can be applied to two areas of environmental concern relevant to the ERAs of GM crops.     

The Changing Focus of the Ecological Risk Assessment of Aquaculture Operations: From Local to Cumulative Risk Assessment

Ecological risk assessment (ERA) methodologies must be continually improved so that resource managers, activity proponents, and stakeholders can better manage the environmental impacts of human activities. One of the largest challenges facing ERA methodologies and approaches is to develop the ability to encompass cumulative and far-field effects of human activities. It is argued here that the ERAs of industrial aquaculture activities have been an example of where ERA practitioners and researchers have responded to the challenge of managing the cumulative risks of a new and rapidly growing industry by developing innovative ERA approaches that can be applied elsewhere.     

How air pollution influences clinical management of respiratory diseases. A case-crossover study in Milan

Background

Environmental pollution is a known risk factor for multiple diseases and furthermore increases rate of hospitalisations. We investigated the correlation between emergency room admissions (ERAs) of the general population for respiratory diseases and the environmental pollutant levels in Milan, a metropolis in northern Italy.

Methods

We collected data from 45770 ERAs for respiratory diseases. A time-stratified case-crossover design was used to investigate the association between air pollution levels and ERAs for acute respiratory conditions. The effects of air pollutants were investigated at lag 0 to lag 5, lag 0–2 and lag 3–5 in both single and multi-pollutant models, adjusted for daily weather variables.

Results

An increase in ozone (O₃) levels at lag 3–5 was associated with a 78% increase in the number of ERAs for asthma, especially during the warm season. Exposure to carbon monoxide (CO) proved to be a risk factor for pneumonia at lag 0–2 and in the warm season increased the risk of ERA by 66%. A significant association was found between ERAs for COPD exacerbation and levels of sulphur dioxide (SO₂), CO, nitrate dioxide (NO₂), and particulate matter (PM₁₀ and PM_2.5). The multipollutant model that includes all pollutants showed a significant association between CO (26%) and ERA for upper respiratory tract diseases at lag 0–2. For chronic obstructive pulmonary disease (COPD) exacerbations, only CO (OR 1.19) showed a significant association.

Conclusions

Exposure to environmental pollution, even at typical low levels, can increase the risk of ERA for acute respiratory diseases and exacerbation of obstructive lung diseases in the general population.     

Problem formulation in the environmental risk assessment for genetically modified plants

Problem formulation is the first step in environmental risk assessment (ERA) where policy goals, scope, assessment endpoints, and methodology are distilled to an explicitly stated problem and approach for analysis. The consistency and utility of ERAs for genetically modified (GM) plants can be improved through rigorous problem formulation (PF), producing an analysis plan that describes relevant exposure scenarios and the potential consequences of these scenarios. A properly executed PF assures the relevance of ERA outcomes for decision-making. Adopting a harmonized approach to problem formulation should bring about greater uniformity in the ERA process for GM plants among regulatory regimes globally. This paper is the product of an international expert group convened by the International Life Sciences Institute (ILSI) Research Foundation.     

Bioavailability of Soil-borne Chemicals: A Regulatory Perspective

U.S. Environmental Protection Agency (USEPA) risk assessment guidance documents dating back to 1989 have articulated the principles for incorporating information on bioavailability into the risk assessment process. However, in the interim period both the methods for obtaining media or route specific measures of bioavailability and the corresponding guidance to incorporate these data have languished. Presently, USEPA is developing guidance to address both of these concerns. This article outlines the broad framework for systematically evaluating the role of bioavailability in site-specific risk assessment from a regulatory perspective. At the same time, in appreciation of the vast horizon of uncharted territory ahead, the focus of USEPA's draft guidance, and consequently this report, is on bioavailability adjustments for soil-borne metals. The article describes a two-stage process. The first stage outlines a paradigm for screening sites to determine if generating site-specific data on the bioavailability of a metal in soil is of technical utility and economically justifiable. The second stage focuses on the collection, analysis, and incorporation of these data into the risk assessment for decision-making purposes.     

Statistical Issues in Ecological Risk Assessment

Ecological risk assessment (ERA) is concerned with making decisions about the natural environment under uncertainty. Statistical methodology provides a natural framework for risk characterization and manipulation with many quantitative ERAs relying heavily on Neyman-Pearson hypothesis testing and other frequentist modes of inference. Bayesian statistical methods are becoming increasingly popular in ERA as they are seen to provide legitimate ways of incorporating subjective belief or expert opinion in the form of prior probability distributions. This article explores some of the concepts, strengths and weaknesses, and difficulties associated with both paradigms. The main points are illustrated with an example of setting a risk-based “trigger” level for uranium concentrations in the Magela Creek catchment of the Northern Territory of Australia.     

Environmental risk assessment of GE plants under low-exposure conditions

The requirement for environmental risk assessment (ERA) of genetically engineered (GE) plants prior to large scale or commercial introduction into the environment is well established in national laws and regulations, as well as in international agreements. Since the first introductions of GE plants in commercial agriculture in the 1990s, a nearly universal paradigm has emerged for conducting these assessments based on a few guiding principles. These include the concept of case-by-case assessment, the use of comparative assessments, and a focus of the ERA on characteristics of the plant, the introduced trait, and the receiving environment as well as the intended use. In practice, however, ERAs for GE plants have frequently focused on achieving highly detailed characterizations of potential hazards at the expense of consideration of the relevant levels of exposure. This emphasis on exhaustive hazard characterization can lead to great difficulties when applied to ERA for GE plants under low-exposure conditions. This paper presents some relevant considerations for conducting an ERA for a GE plant in a low-exposure scenario in the context of the generalized ERA paradigm, building on discussions and case studies presented during a session at ISBGMO 12.     

Identifying Uncertainty in Environmental Risk Assessments: The Development of a Novel Typology and Its Implications for Risk Characterization

Environmental risk analysts need to draw from a clear typology of uncertainties when qualifying risk estimates and/or significance statements about risk. However, categorizations of uncertainty within existing typologies are largely overlapping, contradictory, and subjective, and many typologies are not designed with environmental risk assessments (ERAs) in mind. In an attempt to rectify these issues, this research provides a new categorization of uncertainties based, for the first time, on the appraisal of a large subset of ERAs, namely 171 peer-reviewed environmental weight-of-evidence assessments. Using this dataset, a defensible typology consisting of seven types of uncertainty (data, language, system, extrapolation, variability, model, and decision) and 20 related sub-types is developed. Relationships between uncertainties and the techniques used to manage them are also identified and statistically evaluated. A highly preferred uncertainty management option is to take no action when faced with uncertainty, although where techniques are applied they are commensurate with the uncertainty in question. Key observations are applied in the form of guidance for dealing with uncertainty, demonstrated through ERAs of genetically modified higher plants in the European Union. The presented typology and accompanying guidance will have positive implications for the identification, prioritization, and management of uncertainty during risk characterization.     

Soil Microbial Communities and Ecological Risk Assessment: Risk Assessors’ Perspective

In the past, ecological risk assessments (ERAs) have generally overlooked the soil microbial community when evaluating the impacts of contaminants in soil. However, the soil microbial community, which includes bacteria and fungi, performs functions necessary for overall ecosystem health, including nitrogen fixation, nutrient cycling, and even degradation of contaminants. The incorporation of the soil microbial community into ERA requires the compilation of adequate toxicity data to complete the hazard assessment phase of the risk assessment. A variety of soil microbial toxicity tests exist that provide rapid and inexpensive results. Surveys of the microbial community at a contaminated site may also provide insight as to their functioning in the presence of contaminants. This paper explores the use of toxicity tests and surveys to evaluate chemical toxicity to microbes. However, many questions related to the best methodological approach to an ERA of the soil microbial community have yet to be answered.     

Ecological Risk Assessment for Terrestrial Ecosystems: The Summary of Discussions and Recommendations from the Adelaide Workshop (April 2004)

The Ecological Risk Assessment (ERA) workshop focused on the anthropogenic contaminants in the terrestrial environment, addressing various components of the ERA process. These included sources, exposure pathways, bioavailability, and toxicity to receptor organisms as well as risk communication. It was concluded that although the overseas experience on ERA for terrestrial ecosystems (e.g., International Standards or guidelines from the European Union and the United States) is very useful, it is not directly applicable to Australia due to the differences in receptor organisms, contaminants, soil, and environmental conditions. Workshop discussions stressed on the need for making ERA locally relevant (in terms of choice of receptor organisms, sampling strategy, and bioavailability considerations). The workshop discussions highlighted the need of better appreciation of both the similarities and the clear differences between aquatic and terrestrial ERAs. The availability of reliable data, problems with databases, estimation of bioavailability, and extrapolations from laboratory to field were noted among the key limitations. ERA—being inherently complex and involving a range of environmental compartments, target receptor, and exposure pathways—at a minimum requires a multidisciplinary approach to address the complexities. Bringing a multidisciplinary team together often proves a major challenge in ERA. The delegates called for continued efforts in this area and formation of a network or working group in Australia.     

Profile of past and current clinical trials involving endothelin receptor antagonists: the novel "-sentan" class of drug

Since its initial characterization in 1988, over 18,236 papers, including 2,485 reviews, have been published in the endothelin (ET) field. Over this period, several generations of selective and mixed (dual) ET receptor antagonists (ERAs), from peptidic backbones to orally active potent (subnanomolar) small molecular compounds, have been developed. These agents have been studied in many experimental animal models of various pathological conditions (cardiovascular, respiratory, and neuro-immunological). Continued basic research has led to a better understanding of the complex interactions between the ET axis and other biologic systems in human pathophysiology. The first clinical trial involved patients with idiopathic pulmonary arterial hypertension and led to approval of bosentan (Tracleer) for use in the United States and Europe in 2002. Since then, bosentan, the only currently approved dual (mixed) ERA, has been used in numerous other clinical trials. In addition, more selective ET(A) receptor antagonists (ambrisentan, atrasentan, avosentan, clazosentan, darusentan, and sitaxsentan) are undergoing clinical trials. Here we outline the ERAs undergoing development and summarize the standing of completed and ongoing trials at the time of the Ninth International Conference on Endothelin and even thereafter. This review is intended to provide a useful reference for those interested in the current state of clinical trials involving ERAs, and to identify lessons that might apply to the design of future trials.     

Pharmaceuticals in the environment: scientific evidence of risks and its regulation

During the past two decades scientists, regulatory agencies and the European Commission have acknowledged pharmaceuticals to be an emerging environmental problem. In parallel, a regulatory framework for environmental risk assessment (ERA) of pharmaceutical products has been developed. Since the regulatory guidelines came into force the German Federal Agency (UBA) has been evaluating ERAs for human and veterinary pharmaceutical products before they are marketed. The results show that approximately 10% of pharmaceutical products are of note regarding their potential environmental risk. For human medicinal products, hormones, antibiotics, analgesics, antidepressants and antineoplastics indicated an environmental risk. For veterinary products, hormones, antibiotics and parasiticides were most often discussed as being environmentally relevant. These results are in good correlation with the results within the open scientific literature of prioritization approaches for pharmaceuticals in the environment. UBA results revealed that prospective approaches, such as ERA of pharmaceuticals, play an important role in minimizing problems caused by pharmaceuticals in the environment. However, the regulatory ERA framework could be improved by (i) inclusion of the environment in the risk–benefit analysis for human pharmaceuticals, (ii) improvement of risk management options, (iii) generation of data on existing pharmaceuticals, and (iv) improving the availability of ERA data. In addition, more general and integrative steps of regulation, legislation and research have been developed and are presented in this article. In order to minimize the quantity of pharmaceuticals in the environment these should aim to (i) improve the existing legislation for pharmaceuticals, (ii) prioritize pharmaceuticals in the environment and (iii) improve the availability and collection of pharmaceutical data.     

The Applicability of Habitat Evaluation Methodologies in Ecological Risk Assessment

Traditionally, ecological risk assessments (ERAs) have emphasized risks to individual organisms or populations of species. Although habitats may be a potential target for chemical stressors, and are considered in the framework for ERAs, the actual use of habitat evaluation methods in this process is limited. Habitats obviously represent an important entity to protect since damaged aquatic and wildlife habitats may be totally irretrievable over a human life span compared to deleterious biochemical and physiological changes which may be reversible within the life cycle of an organism, if exposure is terminated. Habitat methods have been largely used as management tools to evaluate impacts of planned water and land development projects. Habitat evaluation methods represent a structured, systematic and logical approach to determine changes to habitats because they consider important life requisites and environmental variables limiting to species. Their use in the ERA process will provide a means to differentiate habitat changes resulting from physical, chemical and/or biological factors or a combination of such factors. In addition, minimal and optimum habitat suitability can be determined for different habitat variables under different chemical exposure scenarios. The objectives of this paper are to review several available habitat evaluation methods and discuss their use in risk assessment. Particular emphasis is given to USFWS's Habitat Evaluation Procedures (HEPs) and the Instream Flow Incremental Method (IFIM).     

Risk-Based Approaches to Managing Contaminants in Catchments

Risk-based methods promise improved decision-making for managing of contaminants, such as salinity, sediments, nutrients, and toxicants, that can adversely affect the ecological condition of aquatic ecosystems. Two aspects of ecological risk assessment (ERA) and management—stakeholder involvement and more quantitative approaches to risk analysis—are particularly challenging. Stakeholder involvement is crucial both in the risk assessment process and the development, acceptance, and implementation of a risk management plan. Additionally, a number of quantitative approaches (particularly Bayesian approaches and multi-criteria decision-making) have been identified as having the potential to include expert-based inputs into risk-based decision-making. These offer promise for better inclusion of stakeholder knowledge and preferences into the decision-making process, and for improving the links between stakeholder inputs and potential risks to the ecological condition of the system. A major challenge for ecologists and natural resource managers is to make the ERA process more quantitative. Most ERAs conducted to date have been qualitative assessments that suffer from a number of deficiencies, the most serious being the lack of transparency and a reliance on subjective judgments. This article argues that the most productive way forward may be to use Bayesian methods to couple existing process-based models, empirical relationships based on good data, and expert opinion, to make the analysis of ecological risks more robust, consistent, and repeatable.     

Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells

Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. Since the association and dissociation rates of G protein-coupled receptor antagonists can influence their pharmacological activity in vivo, we used human PASMC to characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium release and inositol-1-phosphate (IP₁) assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with K_b values of 0.14 nM, 0.12 nM and 1.1 nM, respectively. Macitentan, but not ambrisentan and bosentan, displayed slow apparent receptor association kinetics as evidenced by increased antagonistic potency upon prolongation of antagonist pre-incubation times. In compound washout experiments, macitentan displayed a significantly lower receptor dissociation rate and longer receptor occupancy half-life (ROt_1/2) compared to bosentan and ambrisentan (ROt_1/2∶17 minutes versus 70 seconds and 40 seconds, respectively). Because of its lower dissociation rate macitentan behaved as an insurmountable antagonist in calcium release and IP₁ assays, and unlike bosentan and ambrisentan it blocked endothelin receptor activation across a wide range of endothelin-1 (ET-1) concentrations. However, prolongation of the ET-1 stimulation time beyond ROt_1/2 rendered macitentan a surmountable antagonist, revealing its competitive binding mode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and they lacked inhibitory activity at high ET-1 concentrations. Thus, macitentan is a competitive ERA with significantly slower receptor dissociation kinetics than the currently approved ERAs. Slow dissociation caused insurmountable antagonism in functional PASMC-based assays and this could contribute to an enhanced pharmacological activity of macitentan in ET-1-dependent pathologies.     

Issues in Ecological Risk Assessment of Inorganic Metals and Metalloids

Ecological risk assessment (ERA) is a process that evaluates the potential for adverse ecological effects occurring as a result of exposure to contaminants or other stressors. ERA begins with hazard identification/problem formulation, progresses to effects and exposure assessment, and finishes with risk characterization (an estimate of the incidence and severity of any adverse effects likely to occur). Risk management initially sets the boundaries of the ERA and then uses its results for decision-making. Key information required for an ERA includes: the emissions, pathways and rates of movement of contaminants in the environment; and, information on the relationship between contaminant concentrations and the incidence and (or) severity of adverse effects. Because of specific properties and characteristics of metals in general and of certain metals in particular, a generalized ERA process applicable to organic substances is inappropriate for metals. First, metals are naturally occurring and can arise, sometimes in very high concentrations, from non-anthropogenic sources; organisms can and do adapt to a wide range of metal concentrations. Second, certain metals (e.g., copper, zinc) are essential for biotic health, which means there is an effect threshold for both deficiency and excess, and that standard body burden indices such as bioaccumulation factors (BCFs) can be misleading. Third, metals can occur in the environment in a variety of forms that are more or less available to biota but adverse biological effects can only occur if metals are or may become bioavailable. Fourth, whereas the bioavailability and hence the possibility of toxicity of persistent organic substances are mainly dependent on their intrinsic properties (i.e., lipophilicity), those of metals are generally controlled by external environmental conditions. Examples include pH and ligands, which affect the metal speciation and coexisting cations (e.g., H⁺, Ca²⁺) which compete with the metal ions. ERAs involving metals must include the above four major considerations; other considerations vary depending on whether the ERA is for a site, a region, or is global in scope.