Summary of the Workshop on Issues in Risk Assessment: Quantitative Methods for Developmental Toxicology

This report summarizes the proceedings of a conference on quantitative methods for assessing the risks of developmental toxicants. The conference was planned by a subcommittee of the National Research Council's Committee on Risk Assessment Methodology ⁴ in conjunction with staff from several federal agencies, including the U.S. Environmental Protection Agency, U.S. Food and Drug Administration, U.S. Consumer Products Safety Commission, and Health and Welfare Canada. Issues discussed at the workshop included computerized techniques for hazard identification, use of human and animal data for defining risks in a clinical setting, relationships between end points in developmental toxicity testing, reference dose calculations for developmental toxicology, analysis of quantitative dose-response data, mechanisms of developmental toxicity, physiologically based pharmacokinetic models, and structure-activity relationships. Although a formal consensus was not sought, many participants favored the evolution of quantitative techniques for developmental toxicology risk assessment, including the replacement of lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) with the benchmark dose methodology.     

Chemical and Radiation Environmental Risk Management: Differences, Commonalities, and Challenges

Driven by differing statutory mandates and programmatic separation of regulatory responsibilities between federal, state, and tribal agencies, distinct chemical and radiation risk management strategies have evolved. In the field this separation poses real challenges since many of the major environmental risk management decisions we face today require the evaluation of both types of risks. Over the last decade, federal, state, and tribal agencies have continued to discuss their different approaches and explore areas where their activities could be harmonized. The current framework for managing public exposures to chemical carcinogens has been referred to as a "bottom up approach." Risk between 10(-4) and 10(-6) is established as an upper bound goal. In contrast, a "top down" approach that sets an upper bound dose limit and couples with site specific As Low As Reasonably Achievable Principle (ALARA), is in place to manage individual exposure to radiation. While radiation risk are typically managed on a cumulative basis, exposure to chemicals is generally managed on a chemical-by-chemical, medium-by-medium basis. There are also differences in the nature and size of sites where chemical and radiation contamination is found. Such differences result in divergent management concerns. In spite of these differences, there are several common and practical concerns among radiation and chemical risk managers. They include 1) the issue of cost for site redevelopment and long-term stewardship, 2) public acceptance and involvement, and 3) the need for flexible risk management framework to address the first two issues. This article attempts to synthesize key differences, opportunities for harmonization, and challenges ahead.     

Recommended Reference Values for Risk Assessment of Oral Exposure to Copper

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) database, the authoritative source of U.S. risk assessment toxicity factors, currently lacks an oral reference dose (RfD) for copper. In the absence of such a value, various health-based reference values for copper are available for use in risk assessment. We summarize the scientific bases and differences in assumptions among key reference values for ingested copper to guide selection of appropriate values for risk assessment. A comprehensive review of the scientific literature best supports the oral RfD of 0.04 mg/kg body weight/day derived by EPA from their Drinking Water Action Level. This value is based on acute gastrointestinal effects but is further supported by broader analysis of copper deficiency and toxicity.     

Risk Assessment for Carcinogens Under California''s Proposition 65

Risk assessments for carcinogens are being developed through an accelerated process in California as a part of the state's implementation of Proposition 65, the Safe Drinking Water and Toxic Enforcement Act. Estimates of carcinogenic potency made by the California Department of Health Services (CDHS) are generally similar to estimates made by the U.S. Environmental Protection Agency (EPA). The largest differences are due to EPA's use of the maximum likelihood estimate instead of CDHS' use of the upper 95% confidence bounds on potencies derived from human data and to procedures used to correct for studies of short duration or with early mortality. Numerical limits derived from these potency estimates constitute "no significant risk" levels, which govern exemption from Proposition 65's discharge prohibition and warning requirements. Under Proposition 65 regulations, lifetime cancer risks less than 10(-5) are not significant and cumulative intake is not considered. Following these regulations, numerical limits for a number of Proposition 65 carcinogens that are applicable to the control of toxic discharges are less stringent than limits under existing federal water pollution control laws. Thus, existing federal limits will become the Proposition 65 levels for discharge. Chemicals currently not covered by federal and state controls will eventually be subject to discharge limitations under Proposition 65. "No significant risk" levels (expressed in terms of daily intake of carcinogens) also trigger warning requirements under Proposition 65 that are more extensive than existing state or federal requirements. A variety of chemical exposures from multiple sources are identified that exceed Proposition 65's "no significant risk" levels.     

Forty Years of Food Safety Risk Assessment: A History and Analysis

Before the founding of the Society for Risk Analysis (SRA) in 1980, food safety in the United States had long been a concern, but there was a lack of systematic methods to assess food-related risks. In 1906, the U.S. Congress passed, and President Roosevelt signed, the Pure Food and Drug Act and the Meat Inspection Act to regulate food safety at the federal level. This Act followed the publication of multiple reports of food contamination, culminating in Upton Sinclair's novel The Jungle, which highlighted food and worker abuses in the meatpacking industry. Later in the 20th century, important developments in agricultural and food technology greatly increased food production. But chemical exposures from agricultural and other practices resulted in major amendments to federal food laws, including the Delaney Clause, aimed specifically at cancer-causing chemicals. Later in the 20th century, when quantitative risk assessment methods were given greater scientific status in a seminal National Research Council report, food safety risk assessment became more systematized. Additionally, in these last 40 years, food safety research has resulted in increased understanding of a range of health effects from foodborne chemicals, and technological developments have improved U.S. food safety from farm to fork by offering new ways to manage risks. We discuss the history of food safety and the role risk analysis has played in its evolution, starting from over a century ago, but focusing on the last 40 years. While we focus on chemical risk assessment in the U.S., we also discuss microbial risk assessment and international food safety.     

Advancing Risk‐Informed Decision Making in Managing Defense Nuclear Waste in the United States: Opportunities and Challenges for Risk Analysis

An omnibus spending bill in 2014 directed the Department of Energy to analyze how effectively Department of Energy (DOE) identifies, programs, and executes its plans to address public health and safety risks that remain as part of DOE's remaining environmental cleanup liabilities. A committee identified two dozen issues and associated recommendations for the DOE, other federal agencies, and the U.S. Congress to consider, as well as other stakeholders such as states and tribal nations. In regard to risk assessment, the committee described a risk review process that uses available data, expert experience, identifies major data gaps, permits input from key stakeholders, and creates an ordered set of risks based on what is known. Probabilistic risk assessments could be a follow‐up from these risk reviews. In regard to risk management, the states, in particular, have become major drivers of how resources are driven. States use different laws, different priorities, and challenge DOE's policies in different ways. Land use decisions vary, technology choices are different, and other notable variations are apparent. The cost differences associated with these differences are marked. The net result is that resources do not necessarily go to the most prominent human health and safety risks, as seen from the national level.     

Consideration of Background Exposures in the Management of Hazardous Waste Sites: A New Approach to Risk Assessment

The current approach to health risk assessment of toxic waste sites in the U.S. may lead to considerable expenditure of resources without any meaningful reduction in population exposure. Risk assessment methods used generally ignore background exposures and consider only incremental risk estimates for maximally exposed individuals. Such risk estimates do not address true public health risks to which background exposures also contribute. The purpose of this paper is to recommend a new approach to risk assessment and risk management concerning toxic waste sites. Under this new approach, which we have called public health risk assessment, chemical substances would be classified into a level of concern based on the potential health risks associated with typical national and regional background exposures. Site assessment would then be based on the level of concern for the particular pollutants involved and the potential contribution of site contaminants to typical background human exposures. While various problems can be foreseen with this approach, the key advantage is that resources would be allocated to reduce the most important sources of human exposure, and site remediation decisions could be simplified by focussing on exposure assessment rather than questionable risk extrapolations.     

Engaging Expert Peers in the Development of Risk Assessments

The participation of external technical experts in the development of risk assessment documents and methodologies has expanded and evolved in recent years. Many government agencies and authoritative organizations have experts peer review important works to evaluate the scientific and technical defensibility and judge the strength of the assumptions and conclusions (OMB, 2004; IPCS, 2005; IARC, 2006; Health Canada, 2007; U.S. EPA, 2006). Expert advice has been solicited in other forms of peer involvement, including peer consultation in, for example, the U.S. EPA's Voluntary Children's Chemical Evaluation Program (VCCEP). This article discusses how the principles and practices of peer review can be extended to other types of peer involvement activities (i.e., peer input and peer consultation) to develop high-quality risk assessment work products. A comprehensive process for incorporating peer input, peer consultation, and peer review into risk assessment science is outlined. Four key principles for peer involvement-independence, inclusion of appropriate experts, transparency, and a robust scientific process-are discussed. Recent examples of peer involvement in the development of Health Canada's Priority Substances and Domestic Substance List (DSL) programs under the Canadian Environmental Protection Act (CEPA) serve to highlight the concepts.     

Evaluating the Risk of Liver Cancer in Humans Exposed to Trichloroethylene Using Physiological Models

Trichloroethylene (TCE) is a widespread environmental pollutant. TCE is classified as a rodent carcinogen by the U.S. Environmental Protection Agency (EPA). Using the rodent cancer bioassay findings and estimates of metabolized dose, the EPA has estimated lifetime exposure cancer risks for humans that ingest TCE in drinking water or inhale TCE. In this study, a physiologically based pharmacokinetic (PB-PK) model for mice was used to simulate selected gavage and inhalation bioassays with TCE. Plausible dose-metrics thought to be linked with the mechanism of action for TCE carcinogenesis were selected. These dose-metrics, adjusted to reflect an average amount per day for a lifetime, were metabolism of TCE (AMET, mg/kg/day) and systemic concentration of TCA (AUCTCA, mg/L/day). These dose-metrics were then used in a linearized multistage model to estimate AMET and AUCTCA values that correspond to liver cancer risks of 1 in 1 million in mice. A human PB-PK model for TCE was then used to predict TCE concentrations in drinking water and air that would provide AMET and AUCTCA values equal to the predicted mice AMET and AUCTCA values that correspond to liver cancer risks of 1 in 1 million. For the dose-metrics, AMET and AUCTCA, the TCE concentrations in air were 10.0 and 0.1 ppb TCE (continuous exposure), respectively, and in water, 7 and 4 μg TCE/L, respectively.     

The Use of PBPK Models to Inform Human Health Risk Assessment: Case Study on Perchlorate and Radioiodide Human Lifestage Models

Physiologically‐based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well‐defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium‐iodide symporter (NIS). In this analysis, a six‐step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer‐reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near‐term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.     

A Trichloroethylene Risk Assessment Using a Monte Carlo Analysis of Parameter Uncertainty in Conjunction with Physiologically-Based Pharmacokinetic Modeling

A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10^-6 lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10^-6 risk.     

Site-Specific Applications of Probabilistic Health Risk Assessment: Review of the Literature Since 2000

Whether and to what extent contaminated sites harm ecologic and human health are topics of considerable interest, but also considerable uncertainty. Several federal and state agencies have approved the use of some or many aspects of probabilistic risk assessment (PRA), but its site-specific application has often been limited to high-profile sites and large projects. Nonetheless, times are changing: newly developed software tools, and recent federal and state guidance documents formalizing PRA procedures, now make PRA a readily available method of analysis for even small-scale projects. This article presents and discusses a broad review of PRA literature published since 2000.     

Science and Decisions: Advancing Risk Assessment

At the request of the U.S. Environmental Protection Agency (EPA), the National Research Council (NRC) recently completed a major report, Science and Decisions: Advancing Risk Assessment, that is intended to strengthen the scientific basis, credibility, and effectiveness of risk assessment practices and subsequent risk management decisions. The report describes the challenges faced by risk assessment and the need to consider improvements in both the technical analyses of risk assessments (i.e., the development and use of scientific information to improve risk characterization) and the utility of risk assessments (i.e., making assessments more relevant and useful for risk management decisions). The report tackles a number of topics relating to improvements in the process, including the design and framing of risk assessments, uncertainty and variability characterization, selection and use of defaults, unification of cancer and noncancer dose‐response assessment, cumulative risk assessment, and the need to increase EPA's capacity to address these improvements. This article describes and summarizes the NRC report, with an eye toward its implications for risk assessment practices at EPA.     

Characterizing Dose-Response Relationships in Multiple Cancer Bioassays

In the evaluation of chemical compounds for carcinogenic risk, regulatory agencies such as the U.S. Environmental Protection Agency and National Toxicology Program (NTP) have traditionally fit a dose-response model to data from rodent bioassays, and then used the fitted model to estimate a Virtually Safe Dose or the dose corresponding to a very small increase (usually 10(-6)) in risk over background. Much recent interest has been directed at incorporating additional scientific information regarding the properties of the specific chemical under investigation into the risk assessment process, including biological mechanisms of cancer induction, metabolic pathways, and chemical structure and activity. Despite the fact that regulatory agencies are currently poised to allow use of nonlinear dose-response models based on the concept of an underlying threshold for nongenotoxic chemicals, there have been few attempts to investigate the overall relationship between the shape of dose-response curves and mutagenicity. Using data from an historical database of NTP cancer bioassays, the authors conducted a repeated-measures Analysis of the estimated shape from fitting extended Weibull dose-response curves. It was concluded that genotoxic chemicals have dose-response curves that are closer to linear than those for nongenotoxic chemicals, though on average, both types of compounds have dose-response curves that are convex and the effect of genotoxicity is small.     

Incorporating Risk Assessment and Benefit-Cost Analysis in Environmental Management1

Using data from interviews with a key set of individuals at the U.S. Environmental Protection Agency, this study examines intraagency views about the incorporation of risk assessment and benefit-cost analysis in environment management.     

Unconventional Gas Development in the USA: Exploring the Risk Perception Issues

Unconventional gas development (UGD) is growing rapidly in the United States. Drawing on insights from risk perception and risk governance theories and recent public opinion surveys, we find that UGD is an emerging technology that is likely to be perceived as risky, even though objective risk assessments suggest that risks are low and controllable through best risk management practices. Perceived risk varies significantly depending on the state and locality but perceptions of risk appear to be increasing as the technology is used more widely in the United States and as organized opponents of the technology intensify their efforts. Risk perceptions are attenuated somewhat because of the perceived benefits of UGD and compensation schemes for individuals and communities. The types of triggering events necessary for large‐scale social amplification and stigmatization have not yet occurred but awareness of UGD is growing and organized opposition has been sufficient to cause prohibitions of UGD in some U.S. states and localities. Additional directions for social science research on public reactions to UGD are recommended.     

Reducing Drinking Water Supply Chemical Contamination: Risks from Underground Storage Tanks

Drinking water supplies are at risk of contamination from a variety of physical, chemical, and biological sources. Ranked among these threats are hazardous material releases from leaking or improperly managed underground storage tanks located at municipal, commercial, and industrial facilities. To reduce human health and environmental risks associated with the subsurface storage of hazardous materials, government agencies have taken a variety of legislative and regulatory actions—which date back more than 25 years and include the establishment of rigorous equipment/technology/operational requirements and facility‐by‐facility inspection and enforcement programs. Given a history of more than 470,000 underground storage tank releases nationwide, the U.S. Environmental Protection Agency continues to report that 7,300 new leaks were found in federal fiscal year 2008, while nearly 103,000 old leaks remain to be cleaned up. In this article, we report on an alternate evidence‐based intervention approach for reducing potential releases from the storage of petroleum products (gasoline, diesel, kerosene, heating/fuel oil, and waste oil) in underground tanks at commercial facilities located in Rhode Island. The objective of this study was to evaluate whether a new regulatory model can be used as a cost‐effective alternative to traditional facility‐by‐facility inspection and enforcement programs for underground storage tanks. We conclude that the alternative model, using an emphasis on technical assistance tools, can produce measurable improvements in compliance performance, is a cost‐effective adjunct to traditional facility‐by‐facility inspection and enforcement programs, and has the potential to allow regulatory agencies to decrease their frequency of inspections among low risk facilities without sacrificing compliance performance or increasing public health risks.     

Probabilistic Risk Analysis and Terrorism Risk

Since the terrorist attacks of September 11, 2001, and the subsequent establishment of the U.S. Department of Homeland Security (DHS), considerable efforts have been made to estimate the risks of terrorism and the cost effectiveness of security policies to reduce these risks. DHS, industry, and the academic risk analysis communities have all invested heavily in the development of tools and approaches that can assist decisionmakers in effectively allocating limited resources across the vast array of potential investments that could mitigate risks from terrorism and other threats to the homeland. Decisionmakers demand models, analyses, and decision support that are useful for this task and based on the state of the art. Since terrorism risk analysis is new, no single method is likely to meet this challenge. In this article we explore a number of existing and potential approaches for terrorism risk analysis, focusing particularly on recent discussions regarding the applicability of probabilistic and decision analytic approaches to bioterrorism risks and the Bioterrorism Risk Assessment methodology used by the DHS and criticized by the National Academies and others.     

A Process for Incorporating Comparative Risk into Environmental Policymaking in Louisiana

The goal of Louisiana's 1990–1991 comparative risk project, also called the Louisiana Environmental Action Plan (LEAP), was to incorporate risk assessment into state environmental planning and policymaking. Scientists, government officials, and citizens were brought together to estimate the relative risk to human health, natural resources, and quality of life posed by 33 selected environmental issues. The issues were then ranked according to their relative estimated risks. It was hoped that this ranking of "comparative risks" would enable state policymakers to target the most important environmental problems and allocate scarce public resources more rationally and efficiently. As a result of the project, the governor issued an Executive Order forming a permanent Public Advisory Committee to continue this type of comparative risk assessment in Louisiana.