Comparison of Risk Assessments of Boron: Alternate Approaches to Chemical-Specific Adjustment Factors

Health risk assessments of boron (B) have been performed in recent years by seven well-respected regulatory and scientific organizations, including the Institute for Evaluating Health Risks, European Centre for Ecotoxicology and Toxicology of Chemicals, International Programme on Chemical Safety, World Health Organization, National Academy of Sciences Food and Nutrition Board, U.K. Expert Group of Vitamins and Minerals (draft) and U.S. Environmental Protection Agency (draft). Of interest, all of these risk assessments employed chemical-specific adjustment factors, resulting in total uncertainty factors in the range of 25–62 and estimates of tolerable intake levels ranging from 10 to 24 mg B/day. These risk assessments are particularly instructive because they all used the same critical developmental toxicity study and the same NOAEL (10 mg B/kg/day). Therefore, the primary differences among these risk assessments reside in the choice of chemical-specific adjustment factors. It is generally agreed that renal clearance is the primary determinant of B pharmacokinetic variability, both within and among species. However, the methods used to select chemical-specific adjustment factors for pharmacokinetics vary among B risk assessments. Several have estimated intraspecies pharmacokinetic variability based on glomerular filtration rates (GFR) in pregnant women. Based on the results of renal clearance studies of B, the use of GFR is scientifically appropriate to estimate the intraspecies pharmacokinetic variability in B renal clearance. B homeostasis in humans appears to be primarily regulated by the kidney, and at typical low doses in humans, there is evidence of tubular reabsorption of B in the kidneys. Human studies indicate that urinary B excretion is a sensitive indicator of recent dietary intake. The major source of B exposure in humans is consumption of fruits, vegetables, nuts and legumes, which are naturally rich in B. Human dietary consumption of B is below the estimated tolerable intake levels established in these recent risk assessments. Considering the growing evidence of the nutritional role of B, it is important to consider both the benefits and risks of B consumption. By legitimately reducing the uncertainty factor for toxicity, the margin of safety is effectively increased to protect against the possibility of insufficient dietary intake. Risk assessments of B provide valuable lessons regarding how chemical-specific adjustment factors may be selected.     

Case Studies of Categorical Data-Derived Adjustment Factors

Investigations were performed on representative compounds from five different therapeutic classes to evaluate the use of categorical data-derived adjustment factors to account for interindividual variability. The five classes included antidepressants, angiotensin converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDS), cholesterol lowering agents, and antibiotics. Each of the case studies summarized the mode of action of the class responsible for both the therapeutic and adverse effects and the key pharmacodynamic (PD) and pharmacokinetic (PK) parameters that determine the likelihood of these responses for individual compounds in the class. For each class, an attempt was made to identify the key factors that determine interindividual variability and whether there was a common basis to establish a categorical default adjustment factor that could be applied across the class (or at least across specific subclasses within the class). Linking the PK and PD parameters to the critical endpoint used to establish a safe level of exposure was an important underlying theme throughout the investigations. Despite the wealth of PK and PD information in the published literature on the surrogate compounds representing these classes, it was difficult to derive a categorical adjustment factor that could be applied broadly within each class. The amount of information available may have hindered rather than helped the evaluations. Derivation of categorical defaults for different classes of “common” chemicals may be more straightforward if sufficient data are available. In a few cases (e.g., tricyclic antibiotics, ACE inhibitors and selected antiinflammatory agents) categorical defaults could be proposed, although it is unclear whether the reduction in uncertainty resulting from their application would be offset by the additional uncertainties that may have resulted from their application. Residual uncertainties may remain depending on the level of confidence in the underlying assumptions used to support the categorical defaults. Regardless of the conclusions on the utility of categorical defaults, these investigations provided further support for the use of data-derived adjustment factors on a compound-specific basis.     

Uncertainty/Safety Factors in Health Risk Assessment: Opportunities for Improvement

This paper presents the results of deliberations from participants who met on the second day of the Fourth Annual Workshop on the Evaluation of Uncertainty/Safety Factors in Health Risk Assessment. The group reviewed the previous day's presentations and implications for improvement in risk assessment. After much discussion, the group concluded that, in the short term, significant improvements could be made in the pharmacokinetic component of the inter-species uncertainty factor and developed a series of default options for this factor. These defaults consider route of exposure (oral or inhalation), and the form of the active compound (parent, metabolite, or very reactive metabolite). Several assumptions are key to this approach, such as a similar oral or inhalation bioavailability across species. We believe this method represents a useful default approach until more compound-specific information is available.     

Synergism between Metarhizium anisopliae (Deuteromycota: Hyphomycetes) and Boric Acid against the German Cockroach (Dictyoptera: Blattellidae)

Mortality of German cockroaches, Blattella germanica (L.), caused by Metarhizium anisopliae (Metschnikoff) Sorokin strain AC-1 alone and in combination with different formulations of boric acid, was evaluated in laboratory bioassays. Topical application of M. anisopliae alone (8.96 × 10⁹ conidia/m²) required 28 days to cause >92% cockroach mortality (LT₅₀ = 10 days). In contrast, in combination with boric acid (topically applied as a dust or in drinking water), M. anisopliae killed cockroaches significantly faster than without boric acid. M. anisopliae conidial dust (8.96 × 10⁸ conidia/m²) with either 12.5% (w/w) boric acid dust or 0.1% (w/v) boric acid in drinking water killed 100% of the cockroaches in only 8 days (LT₅₀ = 5 days) and 10 days (LT₅₀ = 6 days), respectively, without compromising the fungus emergence from cadavers. Replacement of M. anisopliae with flour dust or heat-killed M. anisopliae conidia eliminated this effect, demonstrating that it was not the consequence of greater boric acid ingestion due to more extensive cockroach grooming upon exposure to M. anisopliae conidia. Moreover, injections of a low dose of M. anisopliae, which caused only 30% mortality, together with sublethal concentrations of boric acid into the cockroach hemocoel resulted in a doubling of mortality. Statistical analysis demonstrated a synergistic interaction between these two insecticides.     

Asexual Reproduction and Segmental Regeneration, but not Morphallaxis, are Inhibited by Boric Acid in Lumbriculus variegatus (Annelida: Clitellata: Lumbriculidae)

Body fragmentation, in some animal groups, is a mechanism for survival and asexual reproduction. Lumbriculus variegatus (Müller, 1774), an aquatic oligochaete worm, is capable of regenerating into complete individuals from small body fragments following injury and reproduces primarily by asexual reproduction. Few studies have determined the cellular mechanisms that underlie fragmentation, either regenerative or asexual. We utilized boric acid treatment, which blocks regeneration of segments in amputated fragments and blocks architomic fission during asexual reproduction, to investigate mechanistic relationships and differences between these two modes of development. Neural morphallaxis, involving changes in sensory fields and giant fiber conduction, was detected in amputated fragments in the absence of segmental regeneration. Furthermore, neural morphallactic changes occurred as a result of developmental mechanisms of asexual reproduction, even when architomy was prevented. These results show that fragmentation in L. variegatus, during injury or asexual reproduction, employs developmental and morphallactic processes that can be mechanistically dissociated by boric acid exposure. In regeneration following injury, compensatory morphallaxis occurred in response to fragmentation. In contrast, anticipatory morphallaxis was induced in preparation for fragmentation during asexual reproduction. Thus, various forms of regeneration in this lumbriculid worm can be activated independently and in different developmental contexts.     

Intra-Species Extrapolation in Risk Assessment of Different Classes of Antimicrobials

The risk assessment process for non-carcinogens incorporates all available scientific information, including toxicokinetic and toxicodynamic data. A 10-fold uncertainty factor (UF) is most commonly used to account for underlying variability within the human species. The purposes of this investigation are to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharma-codynamic data are incorporated to characterize interindividual variability and whether another UF is needed for the children group. An extensive literature search was conducted on seven antimicrobials in order to incorporate information on kinetics and dynamics to allow extrapolation among susceptible humans. The drugs are cefaclor, cefuroxime, erythromycin, clarithromycin, ampicillin, gentamicin and amikacin. The composite factor was calculated using the highest ratio for appropriate parameters and default subfactor. According to the data, we concluded that when relevant kinetic and dynamic data are available, replacing the default factors with actual data-derived values was possible for the antimicrobials evaluated and that there is no need to add another UF to the children group.     

Boric acid‐induced immunotoxicity and genotoxicity in model insect Galleria mellonella L. (Lepidoptera: Pyralidae)

Boric acid (BA) is widely used in various industrial process and can be accessed to nontarget organisms. This study aimed to investigate the insecticidal effects of BA and its toxic activities with respect to immunologic and genotoxic effects using Galleria mellonella larvae as a model. BA concentrations (78.125–10,000 ppm) were administrated to the larvae using the feeding method. Concentration‐dependent mortality was observed in all larval groups. Probit analysis revealed LC₃₀, LC₅₀, and LC₇₀ values to be 112.4, 320.1, and 911.4 ppm, respectively. These concentrations were used in all bioassays. Drastic reductions in total hemocyte counts along with changes in differential hemocyte counts were observed following BA treatment. Cell viability assays showed dose‐dependent reductions in viable cells and an increase in the necrotic and apoptotic ratios after BA treatment. However, mitotic indices of larval hemocytes did not change at all BA concentrations. The cytotoxic effect of BA led to a significant reduction in cellular immune responses such as encapsulation, melanization, and nodulation activities of treated larvae. While BA increased micronucleus ratios at the highest concentration, comet parameters indicating DNA damage increased in G. mellonella larval hemocytes at all concentrations. These report that BA suppresses the immune system of G. mellonella and also poses risks of genotoxicity at high concentrations.     

Developing A Regional Ecological Risk Assessment: A Case Study of a Tasmanian Agricultural Catchment

A regional ecological risk assessment was conducted for the Mountain River catchment in Tasmania, Australia. The Relative Risk Model was used in conjunction with geographic information systems interpretations. Stakeholder values were used to develop assessment endpoints, and regional stressors and habitats were identified. The risk hypotheses expressed in the conceptual model were that agriculture and land clearing for rural residential are producing multiple stressors that have potential for contamination of local waterbodies, eutrophication, changes in hydrology, reduction in the habitat of native flora and fauna, reductions in populations of beneficial insects in agricultural production systems, increased weed competition in pastures, and loss of aesthetic value in residential areas. In the risk analysis the catchment was divided into risk regions based on topography and land use. Stressors were ranked on likelihood of occurrence, while habitats were ranked on percentage land area. Risk characterization showed risks to the maintenance of productive primary industries were highest across all risk regions, followed by maintenance of a good residential environment and maintenance of fish populations. Sensitivity analysis was conducted to show the variability in risk outcomes stemming from uncertainty about stressors and habitats. Outcomes from this assessment provide a basis for planning regional environmental monitoring programs.     

Uncertainty Estimation in a Remediation Process: A Case Study

A case study concerning the reclamation of a brownfield for residential purposes is presented. Because a high contamination of Polycyclic Aromatic Hydrocarbons (PAHs) was detected in soil, a remediation process is necessary. Bench-scale treat-ability tests were carried out in order to evaluate performances of some remediation technologies on this specific matrix, and particularly for the removal of high-molecular-weight PAHs. Biodegradation studies allowed the evaluation of PAH abatement in a slurry phase treatment, the amount of abiotic losses and the effect of macronutri-ents and bioaugmentation on the removal efficiency. The experimental study was performed in compliance with a Quality System, based on ISO 9001:2000 and ISO/ EC 17025:1999; validation of the analytical method provided the expanded uncertainty of the removal efficiency, varying from nearly 13 to 21%, depending on the compound considered. Experimental results showed a high removal efficiency for all PAHs; the addition of nitrogen and phosphorous increased the removal rate and the efficiency for high-molecular-weight PAHs, whereas no remarkable differences were observed in total (abiotic + biotic) removal of light compounds.     

The Health Risk Assessment Performed in California for the Herbicide Simazine: A Case Study

Simazine, a member of the triazine group, is registered in California for weed control in soils where a wide range of crops will be (or are) planted. The health risks from simazine use in California were recently assessed by the California Department of Pesticide Regulation (CDPR) for all potential (acute and long-term) exposure scenarios relevant to Californian residents and workers. The results of the CDPR risk assessment indicate that current exposure levels in many of the scenarios under consideration are not health protective for the people in California. The main objective of the present summary report (i.e., case study) was two-fold, both for offering a forum to advance further scientific discussion: (1) to highlight the toxicity and exposure data as well as the assumptions used in the CDPR simazine risk assessment and then (2) to systematically requalify the uncertainties and complexities involved in terms of the toxicity and exposure appraisals given in that risk assessment. In both attempts, the focus was more on residential exposures for young children and women of child-bearing age in that simazine was reportedly seen to exhibit neuroendocrine effects across a variety of species.     

Extrapolation in Risk Assessment: Improving the Quantification of Uncertainty,and Improving Information to Reduce the Uncertainty

Risk assessments inevitably extrapolate from the known to the unknown. The resulting calculation of risk involves two fundamental kinds of uncertainty: uncertainty owing to intrinsically unpredictable (random) components of the future events, and uncertainty owing to imperfect prediction formulas (parameter uncertainty and error in model structure) that are used to predict the component that we think is predictable. Both types of uncertainty weigh heavily both in health and ecological risk assessments. Our first responsibility in conducting risk assessments is to ensure that the reported risks correctly reflect our actual level of uncertainty (of both types). The statistical methods that lend themselves to correct quantification of the uncertainty are also effective for combining different sources of information. One way to reduce uncertainty is to use all the available data. To further sharpen future risk assessments, it is useful to partition the uncertainty between the random component and the component due to parameter uncertainty, so that we can quantify the expected reduction in uncertainty that can be achieved by investing in a given amount of future data. An example is developed to illustrate the potential for use of comparative data, from toxicity testing on other species or other chemicals, to improve the estimates of low-effect concentration in a particular case with sparse case-specific data.     

Derivation of Population-Level Ecological Remedial Action Objectives: Tualatin River Case Study

In 1997, Oregon enacted rules that define an unacceptable population-level risk as a >10% chance of >20% of the total local population receiving an exposure greater than the toxicity reference value. This rule applies to populations of plants and animals not listed as threatened or endangered. An operational procedure was developed to perform such population-level ecological risk assessments. This case study describes how this procedure was used to develop site-specific groundwater remedial action objectives for resident aquatic populations at a site in Northwest Oregon, where an upland petroleum pipeline released gasoline-range hydrocarbons (TPH-G) into soils and groundwater immediately upgradient of the Tualatin River. With an interim response in place, the goal was to proactively establish a remedial action objective that would equate to an acceptable risk level for populations of aquatic receptors potentially threatened by future groundwater discharges to the river. Approximately 10 and 32% dilutions of the water-soluble fraction of pure product produced an acceptable risk level for zooplankton and forage fish populations, respectively. The proposed population-level remedial action objective, based on zooplankton as the most sensitive receptor, was a TPH-G groundwater concentration of 17.4?mg/L.     

Extrapolation in Human Health and Ecological Risk Assessments: Proceedings of a Symposium

A symposium was conducted in April 1998 by the U.S. Environmental Protection Agency's National Health and Environmental Effects Research Laboratory (NHEERL) to explore issues of extrapolation in human health and ecological risk assessments. Over the course of three and one half days, leading health and ecology experts presented and discussed research methods and approaches for extrapolating data among taxa and across levels of biological organization, through time, and across spatial scales. The intended result of this symposium was enhanced interaction among a diverse array of scientists, policymakers, and risk assessors to promote identification of approaches for reducing the uncertainties of extrapolation in risk assessment.     

Environmental Implications of Consumer Convenience: Coffee as a Case Study

Products of convenience are playing an increasingly large role in today's society. These products provide a competitive advantage over their conventional counterparts by requiring less time and effort to produce a similar service or experience. At the same time, these products are often also more materials intensive to produce and create a greater amount of waste. A comparative midpoint life cycle assessment of different coffee brewing systems is presented in order to explore the comparative impact of three different systems: drip filter, french press, and pod style (a product of convenience). Utilizing a comparative functional unit, the drip filter system method was found to have the greatest environmental impact in all impact categories, whereas the pod style had the least in six of the impact categories (with the french press having the least in two of the impact categories, and a tie between pod style and french press in a single impact category). This suggests that contrary to popular belief, the pod style coffee may be the more environmentally friendly option. The two most significant contributors to environmental impact in all of the categories considered was the amount of dry coffee utilized and the energy needed to brew the coffee, although in some categories considered transportation was also significant. There is the potential for the environmental impact of coffee brewing to shift if coffee wastage occurs (likely in the case of the drip filter and french press system) or if substantial changes in materials or energy consumption were to occur (in the case of the pod‐style brewing system). From the perspective of industrial ecology, this analysis suggests that, in regard to products of consumer convenience, the convenient alternative may not have a significantly greater environmental impact than its conventional counterpart, and that it may be time to question that often‐held assumption.     

Analysis and Portrayal of Uncertainty in a Food-Web Exposure Model

The results of quantitative risk assessments are key factors in a risk manager's decision of the necessity to implement actions to reduce risk. The extent of the uncertainty in the assessment will play a large part in the degree of confidence a risk manager has in the reported significance and probability of a given risk. The two main sources of uncertainty in such risk assessments are variability and incertitude. In this paper we use two methods, a second-order two-dimensional Monte Carlo analysis and probability bounds analysis, to investigate the impact of both types of uncertainty on the results of a food-web exposure model. We demonstrate how the full extent of uncertainty in a risk estimate can be fully portrayed in a way that is useful to risk managers. We show that probability bounds analysis is a useful tool for identifying the parameters that contribute the most to uncertainty in a risk estimate and how it can be used to complement established practices in risk assessment. We conclude by promoting the use of probability analysis in conjunction with Monte Carlo analyses as a method for checking how plausible Monte Carlo results are in the full context of uncertainty.     

A Weight-of-Evidence Framework for Assessing Sediment (Or Other) Contamination: Improving Certainty in the Decision-Making Process

A basic framework is presented for the ecological weight-of-evidence (WOE) process for sediment assessment that clearly defines its essential elements and will improve the certainty of conclusions about whether or not impairment exists due to sediment contamination, and, if so, which stressors and biological species (or ecological responses) are of greatest concern. The essential “Certainty Elements” are addressed in a transparent best professional judgment (BPJ) process with multiple lines-of-evidence (LOE) ultimately quantitatively integrated (but not necessarily combined into a single value). The WOE Certainty Elements include: (1) Development of a conceptual model (showing linkages of critical receptors and ecosystem quality characteristics); (2) Explanation of linkages between measurement endpoint responses (direct and indirect with associated spatial/temporal dynamics) and conceptual model components; (3) Identification of possible natural and anthropogenic stressors with associated exposure dynamics; (4) Evaluation of appropriate and quantitatively based reference (background) comparison methods; (5) Consideration of advantages and limitations of quantification methods used to integrate LOE; (6) Consideration of advantages and limitations of each LOE used; (7) Evaluation of causality criteria used for each LOE during output verification and how they were implemented; and (8) Combining the LOE into a WOE matrix for interpretation, showing causality linkages in the conceptual model. The framework identifies several statistical approaches for integrating within LOE, the suitability of which depends on physical characteristics of the system and the scale/nature of impairment. The quantification approaches include: (1) Gradient (regression methods); (2) Paired reference/test (before/after control impact and ANOVA methods); (3) Multiple reference (ANOVA and multivariate methods); and 4) Gradient with reference (regression, ANOVA and multivariate methods). This WOE framework can be used for any environmental assessment and is most effective when incorporated into the initial and final study design stages (e.g., the Problem Formulation and Risk Characterization stages of a risk assessment) with reassessment throughout the project and decision-making process, rather than in a retrospective data analysis approach where key certainty elements cannot be adequately addressed.     

A Human Health Risk Assessment Software for Facilitating Management of Urban Contaminated Sites: A Case Study: The Massa Site,Tuscany, Italy

The goal of this article is to present the Human Health Risk Assessment (HRA) software developed as one of the NORISC ^{1 1}NORISC is the acronym of the project “Network Oriented Risk assessment by In-situ Screening of Contaminated sites” realized under under the 5th European Union Community Framework Programme for Research, Technological Development and Demonstration Activities. View all notes decision support software system components that could be used as a tool for facilitating management of urban contaminated sites. The NORISC-HRA software provides sufficient technical and procedural support to conduct a simple site-specific risk assessment. The employed HRA methodology is generally based on U.S. Environmental Protection Agency (USEPA) procedures. The software determines the level and spatial distribution of human health risks at a given site and sets up site-specific preliminary Health-Based Remedial Goals (HBRGs)/Risk-Based Concentrations (RBCs) for soil and groundwater. The NORISC-HRA software is recommended for use when national soil and groundwater limit values are exceeded. Exposure pathways considered in this software are associated with three land use patterns—residential, industrial/commercial, and recreational. The aricle also presents the software testing results obtained at one of the NORISC test sites—the Massa site (Avenza-Carrara, Tuscany, Italy). Findings of the HRA indicated that the contaminated soil at the Massa test site might pose potential cancer and non-cancer risks to industrial workers in its present condition. Arsenic was the dominant substance responsible for most of the baseline risk and at the RBC of 1.77 mg/kg it was the primary driver of remedial decisions at the Massa site.     

Potential Distribution and Risk Assessment of an Invasive Plant Species: A Case Study of Hymenachne amplexicaulis in Australia

Given the limited resources available for weed management, a strategic approach is required to give the “best bang for your buck.” The current study incorporates: (1) a model ensemble approach to identify areas of uncertainty and commonality regarding a species invasive potential, (2) current distribution of the invaded species, and (3) connectivity of systems to identify target regions and focus efforts for more effective management. Uncertainty in the prediction of suitable habitat for H. amplexicaulis (study species) in Australia was addressed in an ensemble-forecasting approach to compare distributional scenarios from four models (CLIMATCH; CLIMEX; boosted regression trees [BRT]; maximum entropy [Maxent]). Models were built using subsets of occurrence and environmental data. Catchment risk was determined through incorporating habitat suitability, the current abundance and distribution of H. amplexicaulis, and catchment connectivity. Our results indicate geographic differences between predictions of different approaches. Despite these differences a number of catchments in northern, central, and southern Australia were identified as high risk of invasion or further spread by all models suggesting they should be given priority for the management of H. amplexicaulis. The study also highlighted the utility of ensemble approaches in indentifying areas of uncertainty and commonality regarding the species’ invasive potential.