Primer for evaluating ecological risk at petroleum release sites

Increasingly, risk-based approaches are being used to guide decision making at sites such as service stations and petroleum product terminals, where petroleum products have been inadvertently released to the soil. For example, the API Decision Support System software, DSS, evaluates site human health risk along six different routes of exposure. The American Society for Testing and Materials' Risk-Based Corrective Action (RBCA) standard, ASTM 1739, establishes a tiered framework for evaluating petroleum release sites on the basis of human health risk. Though much of the risk assessment focus has been on human health risk, regulatory agencies recognize that protection of human health may not fully protect the environment; and EPA has developed guidance on identifying ecological resources to be protected through risk-based decision making. Not every service station or petroleum product terminal site warrants a detailed ecological risk assessment. In some cases, a simple preliminary assessment will provide sufficient information for decision making. Accordingly, the American Petroleum Institute (API) is developing a primer for site managers, to assist them in conducting this preliminary assessment, and in deciding whether more detailed ecological risk assessments are warranted. The primer assists the site manager in identifying relevant ecological receptors and habitats, in identifying chemicals and exposure pathways of concern, in developing a conceptual model of the site to guide subsequent actions, and in identifying conditions that may warrant immediate response.     

Calculation of human health risk-based screening levels (RBSLs) for petroleum

Hazardous waste site managers and regulators can decide easily whether site contamination requires remediation to protect human health, but defining the extent of cleanup is often an enormous challenge. When is the site clean enough for human access and use? Risk assessment tools can be used to help answer this question. One can calculate chemical-specific risk-based screening levels (RBSLs) in environmental media (e.g. soil, water, and food) that correspond to "acceptable" levels of risk. RBSLs can be calculated for individual chemicals and chemical mixtures, specific to various exposure pathways. In calculating RBSLs, one must account for the fact that people may be exposed to more than one chemical by more than one exposure pathway. Fate and transport models may be needed to predict how people might become exposed to site contamination in the future. Examples RBSLs for non-cancer effects are calculated to illustrate the utility and limitations of RBSLs for making risk-based decisions at petroleum release sites.     

Sociodemographic aspects of human susceptibility to toxic chemicals: Do class and race matter for realistic risk assessment?

Susceptibility is well-recognized as a potentially important aspect of health risk assessment, particularly for groups such as pregnant women and their fetuses, infants, children, the elderly, and the infirm, that are known or suspected to be more vulnerable to environmental insults. More recently, it has become apparent that economically disadvantaged groups are likely to be systematically both more exposed and more susceptible to environmental pollution. This article reviews the reasons why low-income communities and many racial minorities are at an increased risk because they are more susceptible to the adverse health effects of toxic chemicals. The scientific challenges of quantifying the magnitude of environmental health risks for these groups are discussed, emphasizing ramifications for risk assessment and risk management decisions. Problems incorporating susceptibility into risk-based decision making are identified, and specific actions are recommended to address these deficiencies.     

THE ANNAPOLIS ACCORDS ON THE USE OF TOXICOLOGY IN RISK ASSESSMENT AND DECISION-MAKING: AN ANNAPOLIS CENTER WORKSHOP REPORT

The Annapolis Center, in partnership with the Society of Toxicology and the American College of Clinical Pharmacology, convened a workshop to draft a series of accords (or principles) to help guide the interpretation and use of data from toxicology studies in human health-risk assessment and risk management. Workshop participants included 12 toxicologists from the fields of environmental health assessment, food safety, and pharmaceutical development. The participants hope that the accords set forth here will serve as guideposts for the purposes of evaluating the strengths and weaknesses of past risk analyses, and of improving the quality of future analyses. The accords are the product of the workshop participants' consensus and do not necessarily represent the opinions of the participants' employers.     

Development of Toxicity Criteria for Petroleum Hydrocarbon Fractions in the Petroleum Hydrocarbon Criteria Working Group Approach for Risk-Based Management of Total Petroleum Hydrocarbons in Soil

ABSTRACT

The Total Petroleum Hydrocarbon Criteria Working Croup (TPHCWG) was formed in 1993 based on the observation that widely different clean-up requirements were being used by states at sites that were contaminated with hydrocarbon materials such as fuels, lubricating oils, and crude oils. These requirements were usually presented as concentration of total petroleum hydrocarbon (TPH), and ranged from 10 to over 10,000 mg TPH/kg soil. Members of this multi-disciplinary group, consisting of representatives from industry, government and academia, jointly recognized that the numerical standard was not based on a scientific assessment of human health risk and established the following goal for the effort: To develop scientifically defensible information for establishing soil cleanup levels that are protective of human health at hydrocarbon contaminated sites. The approach developed by the TPHCWG for TPH hazard assessment consisted of dividing the petroleum hydrocarbon material into multi-chemical-containing fractions with similar fate and transport characteristics. These fractions were then assigned fate and transport properties (volatilization factor, soil leaching factor, etc.) and toxicity values (RfDs/RfCs) representative of the fraction. The actual site specific hazard assessment and derivation of cleanup levels is accomplished by analyzing sites to determine which fraction(s) is present and applying the appropriate fate, transport and toxicity factors.

The method used by this group to determine TPH Faction specific toxicity criteria is a surrogate approach intended to supplement the indicator approach. Indicators are single, carcinogenic hydrocarbon compounds which are evaluated/regulated individually at either the federal or state level. The TPHCWG surrogate approach utilized all appropriate fraction specific toxicity data (single compound and mixture/product), minus the carcinogenic indicator compounds, to derive the fraction specific RfDs and RfCs. This hazard assessment method for petroleum contaminated sites would be utilized where indicator compounds are not present or are below/remediated to regulatory action levels. Derivation of the RfD/RfC values for the n-hexane containing aliphatic C5 - Cs fraction is examined in detail to illustrate the underlying assumptions and use of existing data employed by the TPHCWG to develop fraction specific toxicity criteria. Toxicity RfDs/RfCs for all of the model fate and transport based fractions are also presented.     

Dopamine D1/D2 Receptor Activity in the Nucleus Accumbens Core But Not in the Nucleus Accumbens Shell and Orbitofrontal Cortex Modulates Risk-Based Decision Making

Background:

It is well known that brain dopamine (DA) signals support risk-based decision making; however, the specific terminal regions of midbrain DA neurons through which DA signals mediate risk-based decision making are unknown.

Methods:

Using microinfusions of the D1/D2 receptor antagonist flupenthixol, we sought to explore the role of D1/D2 receptor activity in the rat orbitofrontal cortex (OFC) and core and shell regions of the nucleus accumbens (AcbC and AcbS, respectively) in the regulation of risky choices. A risk-discounting task was used that involves choices between a certain small-reward lever that always delivered 1 pellet or a risky large-reward lever which delivered 4 pellets but had a decreasing probability of receiving the reward across 4 subsequent within-session trial blocks (100%, 50%, 25%, 12.5%). To validate task sensitivity to experimental manipulations of DA activity, we also examined the effects of systemic amphetamine and flupenthixol.

Results:

Systemic amphetamine increased while systemic flupenthixol reduced risky choices. Results further demonstrate that rats that received intra-AcbC flupenthixol were able to track increasing risk associated with the risky lever but displayed a generally reduced preference for the risky lever across all trial blocks, including in the initial trial block (large reward at 100%). Microinfusions of flupenthixol into the AcbS or OFC did not alter risk-based decision making.

Conclusions:

Our data suggest that intra-AcbC D1/D2 receptor signaling does not support the ability to track shifts in reward probabilities but does bias risk-based decision making. That is, it increased the rats’ preference for the response option known to be associated with higher risk-related costs.     

PIC/S及欧美基于风险制定GMP检查计划对我国药品检查的启示

目的：将我国GMP药品检查管理要求与药品检查合作计划（PIC/S）进行比较研究,为提高我国药品GMP检查管理的规范性、系统性,提升检查排查风险的能力提供对策建议。方法：通过文献研究分析PIC/S及欧美药品监管机构执行基于风险制定药品GMP检查计划情况,探索我国实施基于风险制定GMP检查计划的路径。结果与结论：基于风险制定GMP检查计划的理念已在PIC/S和欧美药品监管检查体系中广泛实施,并形成当地适用的较为成熟的模型,发挥了集约检查资源、有效排查隐患的效能。本文结合我国药品监管法规体系中对检查程序的相关要求,分析我国基于风险制定GMP检查计划的实施现状和挑战,从制定基于风险的检查计划、明细检查程序、保障检查资源等方面提出对策建议,以统一规范药品监管机构药品检查运行机制和标准,提高药品检查效能。     

Risk indicator taxonomy for supervision of clinical trials on medicinal products

Aim: To facilitate a risk-based approach for the supervision of clinical trials on medicinal products, we identified and categorized indicators that may present an elevated safety and/or ethical risk for participants, and/or for data integrity. The indicators are relevant for all stakeholders including participants, regulatory bodies, health care inspectorates, sponsors and trial sites.

Methods: The sources of indicators included Medline (using the search terms risk-based/-triggered/-driven oversight/monitoring/inspection), relevant documents from websites of regulatory authorities in Europe, North America and Australia, and results of a brainstorm session organized for experts working in the field. Indicators were classified according to risk area (safety and ethical, data integrity, or both).

Results: In total, we identified 69 risk indicators that were categorized into six branch-levels of the taxonomy. We visualized the taxonomy in a tree structure to clearly distinguish individual indicators. In addition to readily detectable risk indicators, more context-related aspects determine the final impact of the trial and constitute further components in risk assessment. Context-related aspects include potential high media attention, consequences for the reputation of medical research, and the socioeconomic situation in the geographic region and have to be considered on a case-by-case basis.

Conclusions: We identified a wide array of risk indicators for clinical trials on medicinal products and we used a tree structure to incorporate the indicators identified to clearly distinguish individual indicators and to enable efficient use of the indicators. The overview of indicators may facilitate multiple stakeholders in developing structured risk assessment (identification and analysis) for supervising clinical trials on medicinal products. Stakeholders can interpret and prioritize the indicators from their own perspective.     

Exposure assessment and the health of deployed forces

The risk assessment process is a critical function for military Deployment Toxicology research objectives, emphasizing improved health protection of deployed forces. Reliable risk assessment methodology is essential for decision making related to risk reduction procedures during combat deployment, as well as during routine occupational activities. Such decision making must be based upon quality science that both guides sound judgments in risk characterization and management, and provides necessary health protection tools. The health and fitness of deployed forces must be considered for both acute and long-term issues. Exposure assessment specifies populations that might be exposed to injurious agents, identifies routes of exposure, and estimates the magnitude, duration, and timing of the doses that personnel may receive as a result of their exposure. Acute or short-term catastrophic risks for deployed forces are of immediate concern and must be addressed on a risk prioritization basis using Operational Risk Management (ORM) procedures. However, long-term effects of exposure to the same agents must be considered as part of the overall health concerns for deployed forces. In response to these needs, a number of military, federal government, academic and private sector organizations are currently developing new classes of biologically-based biosensors with the programmed capacity to detect the presence of virtually any environmental chemical or biological stressor with the capacity to induce health consequences in deployed personnel. A major objective of this engineering effort is development of biosensor systems that detect novel (previously unresearched) chemical or biological agents that might be used during international combat or terrorist attacks to induce acute or long-term health effects on military or civilian populations. A large portion of the discussion in this paper is devoted to describing the development, testing, and implementation of tissue-based biosensors (TBBs) that utilize small samples of living tissue from laboratory small animals for a wide range of human risk assessment applications.     

Ecological and health risk assessment of heavy metals in the Hattar industrial estate,Pakistan

Abstract

This study aimed to determine the heavy metals (HMs) contaminations in soil of the Hattar industrial estate (HIE), Haripur, Khyber Pakhtunkhwa. For this purpose, various types of soils were collected in HIE and analyzed for the HMs concentrations. The HMs showed highest contamination levels in wastewater irrigated agriculture soil (WWIAS), followed by waste dump site soil (WDSS), and the lowest in range land soil (RLS). Determined HMs concentrations were used for pollution quantification factors, including contamination factors (CFs), pollution load index (PLI), ecological risk factor (ER), and potential health risk assessment, including chronic or non-cancer and cancer risk levels.     

Resources for global risk assessment: the International Toxicity Estimates for Risk (ITER) and Risk Information Exchange (RiskIE) databases

The rate of chemical synthesis and use has outpaced the development of risk values and the resolution of risk assessment methodology questions. In addition, available risk values derived by different organizations may vary due to scientific judgments, mission of the organization, or use of more recently published data. Further, each organization derives values for a unique chemical list so it can be challenging to locate data on a given chemical. Two Internet resources are available to address these issues. First, the International Toxicity Estimates for Risk (ITER) database (www.tera.org/iter) provides chronic human health risk assessment data from a variety of organizations worldwide in a side-by-side format, explains differences in risk values derived by different organizations, and links directly to each organization's website for more detailed information. It is also the only database that includes risk information from independent parties whose risk values have undergone independent peer review. Second, the Risk Information Exchange (RiskIE) is a database of in progress chemical risk assessment work, and includes non-chemical information related to human health risk assessment, such as training modules, white papers and risk documents. RiskIE is available at http://www.allianceforrisk.org/RiskIE.htm, and will join ITER on National Library of Medicine's TOXNET (http://toxnet.nlm.nih.gov/). Together, ITER and RiskIE provide risk assessors essential tools for easily identifying and comparing available risk data, for sharing in progress assessments, and for enhancing interaction among risk assessment groups to decrease duplication of effort and to harmonize risk assessment procedures across organizations.     

Site contamination health risk assessment case study involving tenant relocation from a former gasworks site

An Adelaide suburban public-housing residential site with 16 apartments was investigated after complaints of odor in some yard areas. A distinct 0.5-m layer of dark, odorous (tarry), contaminant material, which in some areas had been covered with plastic sheeting, was subsequently found beneath the topsoil across most of the site. This material appeared to extend beneath the apartments. Analysis indicated high levels of cyanide and polycyclic aromatic hydrocarbons (PAHs), consistent with gasworks waste. Historical investigation revealed that the site was originally owned by a gas company and that a large gasometer (gas-storage tank) existed in one corner of the site. This finding of significant soil contamination precipitated a decision by the health and housing authorities to notify tenants immediately and to plan for their relocation. In addition to tending to the consequent personal disruption and logistical difficulties this posed, a detailed risk assessment process was developed. Urine samples were collected before and after relocation and analyzed for 1-hydroxypyrene (1-OHP), a biomarker for polycyclic aromatic hydrocarbon (PAH) exposure. In addition, samples of tap water, indoor and outdoor air, indoor and ceiling dust, carpets, and soil from tillage areas were analyzed for PAHs. Data indicated a low health risk associated with tenancy on the site. This report presents details of the health risk assessment process undertaken and discusses vindicative reasons for tenant relocation.     

Identification and characterization of adverse effects in 21st century toxicology

The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.     

Ecological risk assessment of sediment management areas: application to Sado Estuary, Portugal

The purpose of this work was to integrate different methodologies to assess the potential ecological risk of estuarine sedimentary management areas, using the Sado Estuary in Portugal as case study. To evaluate the environmental risk of sediment contamination, an integrative and innovative approach was used involving assessment of sediment chemistry, sediment toxicity, benthic community structure, human driving forces and pressures and management areas organic load levels. The basis for decision-making for overall assessment was a statistical multivariate analysis appended into a score matrix tables, using a best expert judgment. The integrated approach allowed to identify from the 19 management areas analyzed, three with no risk but other three with high risk to cause adverse effects in the biota, related with the contaminants analyzed. The methodologies used showed to be effective as a support for decision making leading to future estuarine management recommendations.     

Assessing biomarker use in risk assessment--a survey of practitioners

Advances in molecular epidemiology and mechanistic toxicology have provided increased opportunities for incorporating biomarkers in the human health risk assessment process. For years, the published literature has lauded the concept of incorporating biomarkers into risk assessments as a means to reduce uncertainty in estimating health risk. For all the potential benefits, one would think that markers of effective dose, markers of early biological effects, and markers of human susceptibility are frequently selected as the basis for quantitative human health risk assessments. For this article, we sought to determine the degree to which this evolution in risk assessment has come to pass. The extent to which biomarkers are being used in current human health risk assessment was determined through an informal survey of leading risk assessment practitioners. Case studies highlighting the evolution of risk assessment methods to include biomarkers are also described. The goal of this review was to enhance the implementation of biomarker technology in risk assessment by (1) highlighting successes in biomarker implementation, (2) identifying key barriers to overcome, and (3) describing evolutions in risk assessment methods.     

Variability in toxic response - relevance to chemical safety and risk assessment at the global level

The aim of control limits for exposure to chemicals in air, food, water, and consumer products is to protect the whole human population, including the most susceptible individuals and ‘at risk’ groups. The existence of susceptible individuals is a factor that must be taken into account when quantitative chemical risk assessments are being made, and should be covered in the risk characterization. Classically, when extrapolating data derived from animal experiments using homogeneous, healthy test species for human health risk assessment uncertainty factors are applied. For inter-species extrapolation an uncertainty factor of up to 10 is applied. While it is evident that this procedure provides reasonable protection for the great majority of the population there are outlyers who may not be protected under all conditions. Within a population, individual susceptibility is influenced by genetic and environmental factors. These have regional and national differences. Environmental factors that are important in many countries include ‘life-style’ (e.g. tobacco and alcohol consumption, diet), nutritional and health status. In the case of environmental protection similar considerations apply but the emphasis is on species rather than individuals. The International Programme on Chemical Safety, as the global programme on identifying and assessing chemical risks to human health and the environment in order to assist countries in effective management, is constantly advancing the basic science and methodology for making chemical risk assessment.     

In silico approaches to explore toxicity end points: issues and concerns for estimating human health effects

The European Chemicals Bureau and the Organisation for Economic Cooperation and Development are currently compiling a sanctioned list of quantitative structure-activity relationship (QSAR) risk assessment models and data sets to predict the physiological properties, environmental fate, ecological effects and human health effects of new and existing chemicals in commerce in the European Union. This action implements the technical requirements of the European Commission's Registration, Evaluation and Authorisation of Chemicals legislation. The goal is to identify a battery of QSARs that can furnish rapid, reliable and cost-effective decision support information for regulatory decisions that can substitute for results from animal studies. This report discusses issues and concerns that need to be addressed when selecting QSARs to predict human health effect end points.     

Human milk surveillance and research of environmental chemicals: concepts for consideration in interpreting and presenting study results

This article describes issues related to the interpretation, presentation, and use of data from human milk surveillance and research studies. It is hoped that researchers conducting human milk studies in the future will consider these concepts when formulating study conclusions and presenting data. The key issues discussed are; (1) communication of information on human milk constituents to health care providers and the public; (2) complexities associated with assessing risks and benefits when comparing breast-feeding and formula-feeding; (3) use of human milk information for trends analysis and assessment of the efficacy of restrictions on use/release of chemicals in the environment; and (4) risk assessment and regulatory decision-making concepts regarding environmental chemicals in human milk. As researchers conduct surveillance and research involving human milk, it is of the utmost importance that the results of these studies are provided with information on risk and benefits that place the data in perspective, so that those involved in decision making regarding infant nutrition (e.g., expectant mothers, physicians, midwives, nurses, and lactation consultants) can appropriately interpret the research data.     

Assessing the Impact on Health of Pharmacovigilance Activities: Example of Four Safety Signals

Introduction

The impact of pharmacovigilance activities on public health remains under-investigated, and measuring the impact on health of pharmacovigilance activities for a specific safety signal is challenging.

Objective

To gain more insight into the methodological challenges and the data required, we assessed the impact of pharmacovigilance on public health for four identified product-specific safety signals using publicly available data in the Netherlands. The assessment was on the impact of the intertwined and complementary steps of the pharmacovigilance pathways.

Methods

The impact of pharmacovigilance on public health was assessed using the assessment support tool and ‘open data’ from the Netherlands for four different types of pharmacovigilance safety signals: (1) off-label use of cyproterone acetate/ethinyloestradiol (CPA/EE) and thrombotic risk after pharmacovigilance measures after 2014; (2) pergolide and the risk of cardiac valvulopathy after pharmacovigilance activities in 2003; (3) proton pump inhibitors and the risk of hypomagnesaemia after pharmacovigilance activities in 2011; (4) rosiglitazone withdrawal from the market because of cardiovascular effects in 2010.

Results

For the signals on CPA/EE and pergolide, a crude estimation of the impact could be made with varying degrees of assumptions based on the risk described in the literature and utilisation data.

Conclusion

This article highlights the methodological challenges and the data required to assess the impact of product-specific safety signals. A structured assessment support tool can be used as a guide for the necessary data elements and steps needed for the measurement or estimation of impact of pharmacovigilance activities on public health, provided that the appropriate data are available.