Use of Toxicological Data in Estimating Reference Values for Risk Assessment

A number of programs within the U.S. Environmental Protection Agency (USEPA) currently set less-than-lifetime exposure limits in addition to the chronic reference dose (RfD) and reference concentration (RfC). A review of procedures within the USEPA for setting reference values suggests that less-thanlifetime reference values should be more routinely developed and captured in the USEPA's online IRIS database where chronic RfDs and RfCs, as well as cancer slope factors, are currently available. A review of standard testing study protocols was conducted to determine what data were available for setting acute, short-term, and longer-term reference values, as well as chronic values. This review was done from the point of view of endpoints assessed for specific organ systems (both structural and functional), life stages covered by exposure and outcome, durations of exposure covered and the outcomes evaluated for each, and evaluation of latency to response and/or reversibility of effects. This review revealed a number of data gaps and research needs, including the need for an acute and/or short-term testing protocol that can be used to set acute and shortterm reference values, a strategy for when to conduct more extensive testing based on initial screening data or other information (e.g., chemical class, pharmacokinetics, mode of action), additonal standard testing guidlines protocols to allow more complete assessment of certain organ systems and life stages, development of pharmacokinetic data for different life stages, toxicity related to aging, and latency to response, particularly long-term latency as a result of developmental exposures. The implications of this review are discussed relative to characterizing hazard data for setting reference values, and the potential effects on uncertainty factors and low-dose extrapolation.     

Methyl Ethyl Ketone Safety Characterization for Infants and Children: Assessment in the USEPA Voluntary Children's Chemical Evaluation Program

A safety characterization specific to children was performed for methyl ethyl ketone (MEK) according to the guidelines of the Voluntary Children's Chemical Evaluation Program (VCCEP). The characterization indicates that MEK exposures are not expected to pose an acute or chronic risk to children. Hazard information, summarized as per the VCCEP Tier structure, indicated no need for additional studies. All exposure pathways potentially relevant to children were considered, including child contact with environmental media, food, drinking water, parental transfer to child (human milk or dermal contact), direct consumer product use, and presence during product use. The assessment found that exposures from anthropogenic sources that children may encounter on a daily basis are very low, and in particular well below the chronic inhalation and oral health benchmarks (RfC and RfD) derived by the U.S. Environmental Protection Agency (USEPA). Indoor uses of consumer products can result in higher acute exposures, but these are short-lived and also fall below chronic benchmarks adjusted to an acute timeframe. In addition, MEK is rapidly metabolized and excreted, thus acute exposures do not lead to an increase in body burden over time. The USEPA concluded the VCCEP submission sufficiently characterized potential risks to children, and that no additional toxicity tests were needed for MEK.     

Historical drinking water contamination at Camp Lejeune: Regulatory risk assessor and personal perspectives

Historical concentrations of trichloroethylene (TCE) and other chemicals in drinking water at the U.S. Marine Corps Base at Camp Lejeune, NC, were sufficiently elevated to raise potential health concerns. The 1952–1984 mean TCE concentration (138 µg/L) exceeded the U.S. Environmental Protection Agency's (USEPA's) current maximum contaminant level (MCL) of TCE by 28-fold, with the corresponding dose (3.9E–03 mg/kg-day) exceeding all three candidate USEPA reference dose (RfD) values by 8- to 11-fold. Today, TCE hazard quotients (HQs) of 8–11 compel immediate action by USEPA. The mean dose also exceeds the supporting RfD values for toxic nephropathy and increased kidney weight, as well as the point of departure (POD) for toxic nephropathy. Furthermore, the estimated doses for 34% of the 9-month rolling averages exceed the POD for the highest RfD value for fetal heart defects. The incidences of nephropathy and fetal heart defects should be thoroughly evaluated among those who were exposed. Long-term follow-up will be required to assess potential health effects for the 500,000 to 1 million people who may have used the contaminated water at Camp Lejeune or were exposed in utero. This should serve as a cautionary tale for the thousands of Department of Defense sites across the USA (and other similarly contaminated sites elsewhere in the world) that are commonly contaminated with chemicals such as those at Camp Lejeune, where necessary sampling should be conducted to identify and mitigate any likely ongoing (or future) exposures of potential health concern.     

Noncancer Risk Assessment: A Probabilistic Alternative to Current Practice

Based on imperfect data and theory, agencies such as the United States Environmental Protection Agency (USEPA) currently derive “reference doses” (RfDs) to guide risk managers charged with ensuring that human exposures to chemicals are below population thresholds. The RfD for a chemical is typically reported as a single number, even though it is widely acknowledged that there are significant uncertainties inherent in the derivation of this number.

In this article, the authors propose a probabilistic alternative to the EPA's method that expresses the human population threshold as a probability distribution of values (rather than a single RfD value), taking into account the major sources of scientific uncertainty in such estimates. The approach is illustrated using much of the same data that USEPA uses to justify their current RfD procedure.

Like the EPA's approach, our approach recognizes the four key extrapolations that are necessary to define the human population threshold based on animal data: animal to human, human heterogeneity, LOAEL to NOAEL, and subchronic to chronic. Rather than using available data to define point estimates of “uncertainty factors” for these extrapolations, the proposed approach uses available data to define a probability distribution of adjustment factors. These initial characterizations of uncertainty can then be refined when more robust or specific data become available for a particular chemical or class of chemicals.

Quantitative characterization of uncertainty in noncancer risk assessment will be useful to risk managers who face complex trade-offs between control costs and protection of public health. The new approach can help decision-makers understand how much extra control cost must be expended to achieve a specified increase in confidence that the human population threshold is not being exceeded.     

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.”     

Improving Risk Assessment: Research Opportunities in Dose Response Modeling to Improve Risk Assessment

Substantial improvements in dose response modeling for risk assessment may result from recent and continuing advances in biological research, biochemical techniques, biostatistical/mathematical methods and computational power. This report provides a ranked set of recommendations for proposed research to advance the state of the art in dose response modeling. The report is the result of a meeting of invited workgroup participants charged with identifying five areas of research in dose response modeling that could be incorporated in a national agenda to improve risk assessment methods. Leading topics of emphasis are interindividual variability, injury risk assessment modeling, and procedures to incorporate distributional methods and mechanistic considerations into now-standard methods of deriving a reference dose (RfD), reference concentration (RfC), minimum risk level (MRL) or similar dose-response parameter estimates.     

Methods for evaluating variability in human health dose–response characterization

Abstract

The Reference Dose (RfD) and Reference Concentration (RfC) are human health reference values (RfVs) representing exposure concentrations at or below which there is presumed to be little risk of adverse effects in the general human population. The 2009 National Research Council report Science and Decisions recommended redefining RfVs as “a risk-specific dose (for example, the dose associated with a 1 in 100,000 risk of a particular end point).” Distributions representing variability in human response to environmental contaminant exposures are critical for deriving risk-specific doses. Existing distributions estimating the extent of human toxicokinetic and toxicodynamic variability are based largely on controlled human exposure studies of pharmaceuticals. New data and methods have been developed that are designed to improve estimation of the quantitative variability in human response to environmental chemical exposures. Categories of research with potential to provide new data useful for developing updated human variability distributions include controlled human experiments, human epidemiology, animal models of genetic variability, in vitro estimates of toxicodynamic variability, and in vitro-based models of toxicokinetic variability. In vitro approaches, with further development including studies of different cell types and endpoints, and approaches to incorporate non-genetic sources of variability, appear to provide the greatest opportunity for substantial near-term advances.     

The Value of Human Testing of Pesticides

Recently, the issue of using human volunteers as subjects for studying the potential toxicity of pesticides has received public attention through the media and subsequently in the regulatory arena. The debate has focused on whether such studies are ethical per se and if data from these investigations should be used for regulatory decisions. The precipitating event that prompted the current debate was the enactment of the Food Quality Protection Act (FQPA) of 1996. The FQPA, which amended the two laws governing the regulation of pesticides in the United States, requires the Environmental Protection Agency to reassess all of the nearly 10,000 tolerances (maximum allowable residues in food) and exemptions from tolerances that were in place when the law went into effect. When reassessing tolerances the U.S. Environmental Protection Agency (USEPA) reviews the data, including toxicology, available on each pesticide to determine if they are adequate to allow the Agency to make the necessary safety finding. Historically, it had been considered acceptable to conduct and use data from studies of exposure to chemicals (including pesticides) of human volunteers if these studies were conducted according to specific criteria as outlined in the Helsinki Declaration and Common Rule. Now this philosophy is being challenged and the USEPA is faced with answering the question of whether pesticides should be viewed as different, from an ethical standpoint, from other chemicals, and how such data should be used in the risk assessment process. The following paper makes an argument for the use of human volunteer testing of pesticides applying the logic that, if one wants to protect humans from the potential harm that may occur from eating foods containing pesticides, one must use the best possible data available. There can be little doubt that the best data for predicting the toxicity of a chemical in humans is to obtain and use human data, as long as it is obtained in an ethical manner.     

Risk of Ill-Informed Decision-Making When Choosing Your Favorite Fish

Risk to children of women who choose a favorite fish without regard to its methylmercury or omega-3 content was estimated under three consumption scenarios: (1) current fish consumption rate by U.S. women if limited to orange roughy (Hoplostethus atlanticus), (2) 12 oz of roughy per week, and (3) roughy consumption to meet docosahexaenoic acid (DHA) requirements. Risks were similarly assessed if king mackerel (Scomberomorus cavalla) were eaten. Based on mercury concentrations in fillets purchased from 2004–2007 (0.73 ± 0.29 mg Hg/kg; n = 45), women would have an 85% probability of exceeding USEPA's reference dose (RfD) if they ate only roughy. Based on literature-derived concentrations, they would have a 91% probability of exceeding the RfD if they ate only mackerel. Increasing consumption of either fish to 12 oz per week would increase their probability of exceeding the RfD to 100%. Attempting to meet DHA requirements through eating these fish also results in a 100% probability of exceeding the RfD; however, owing to its very low DHA content, roughy consumption would result in exceedance by 100-fold. These results highlight recommendations of others that benefits and risks of fish consumption should be presented together to enable consumers to make informed decisions.     

Some Comments on the Selection of Human Intraspecies Uncertainty Factors

The Reference Dose (RfD) is used in the risk assessment of non-carcinogenic chemicals. It is derived by dividing a point of departure by the product of the uncertainty (UFs) and modifying factors (MFs). Separate UFs are used for different variables, e.g., intraspecies variation and, in general, each UF is an order of magnitude (10-fold). On the other hand, the MF is usually based on some known variable such as differences in absorption of a chemical from food and water and its default value is one. The USEPA's Integrated Risk Information System (IRIS) has 14 chemicals that have RfDs based on human studies. We examined those IRIS files to determine the rationale for setting human intraspecies uncertainty factors (UF_H). The first consideration was that the chemical had an adequate peer-reviewed human database. Without such, it would not be possible to derive an RfD based on human data. Ten of the 14 chemicals had an UF_H of 1 or 3; four of these were essential trace elements (ETEs). The rationales for using less than a 10-fold UF_H for the ETEs included; 1) nutritional data, 2) large human exposure groups, 3) minimal effect levels and/or 4) several studies with similar effect levels. For the other compounds, reasons included; 1) large human exposure groups, 2) a critical effect that was not adverse (cosmetic), 3) the most sensitive population was exposed, 4) the compound was on the FDA's “generally regarded as safe” (GRAS) list, 5) database uncertainties and 6) less-than-lifetime exposure adjusted for 70 years exposure. It is important to understand the reasons for selecting a UF_H of 1, or 3 as they will apply to future chemicals considered by the USEPA and other agencies.     

Annotated reference compilation: Conducting qualitative and quantitative ecological risk assessments at hazardous waste sites

As the field of ecological risk assessment (ERA) broadens, scientists from various disciplines are called upon to become assessors at hazardous waste sites. Although a United States Environmental Protection Agency (USEPA) Framework for ERAs exists, the guidance is unlike the detailed USEPA guidance available for human risk assessments. Currently, the quality of an ERA is dependent upon the assessor's scientific acumen, professional experience, and recognized reference documents. This annotated reference compilation encompasses published documents which have provided useful and important information for qualitative and quantitative ERAs.     

Setting Pesticide Reference Doses: A Retrospective Analysis Examining Key Data and Choices

Toxicity tests are widely used to set “acceptable” levels of chemical exposure. Different organizations have identified a base set of tests specifying a mix of endpoints, durations, and species to be tested. A specific test and endpoint is chosen as the basis for calculation of human health risk values like reference doses (RfDs). This study empirically evaluates the data and choices made in setting acute and chronic RfDs for 352 conventional pesticides. The results suggest that for Acute, Acute-Female Specific, and Chronic RfDs one test is used far more than others. Ninety-six percent of the 116 Acute Female-Specific RfDs relied on a developmental toxicity test and 78% of Chronic RfDs used the chronic bioassay. Tests in rats were used far more often than other species in all RfD calculations. For all types of RfDs a total uncertainty factor of 100 was most common although values as low as 1 and as high as 3000 were seen. These results provide insights not only into the science policy frameworks used, but also into ways toxicity testing and risk assessment may be streamlined and made more efficient.     

Ethical Concerns Over Testing on Human Subjects

A Joint Subcommittee of the Scientific Advisory Board and the FIFRA Scientific Advisory Panel recently issued a report to the U.S. Environmental Protection Agency (USEPA) concerning the use of data derived from testing on human subjects. The authors address both scientific and ethical issues pertaining to such research and conclude that as long as certain conditions are met, the deliberate exposure of voluntary subjects to potentially dangerous levels of pesticides can be both scientifically and ethically sound. I argue that there are further ethical problems not adequately addressed in the report. In particular, there are serious concerns about fairness and exploitation in connection with paid volunteers, which also raise questions about the degree to which the conditions of non-coercion and informed consent are likely to be met. The primary aim of this paper is to bring these issues more fully into the discussion. I also consider briefly the constraints placed on legitimate justifications of human studies by the requirement that the promotion of public safety be the ultimate purpose of the studies. This will help to clarify which reasons in support of human studies are in principle legitimate, which will in turn better enable us to weigh them against the ethical concerns about fairness and exploitation.     

Strategies for Protecting and Restoring Rhode Island's Watersheds on Multiple Scales

The Clean Water Act has traditionally preserved the quality and quantity of a region's water by focusing resources on areas with known or anticipated problems. USEPA Region 1 is taking the supplemental, longer-range approach of protecting areas of New England where natural resources are still healthy. As part of Region 1 's “New England Resource Protection” approach, stakeholders participate in an open process that identifies healthy ecosystems and characterizes how well they support aquatic life and human health. Since the concerns of stakeholders are usually local, the process also displays areas of nonattainment within individual watersheds and determines their likely causes. One of the most powerful ways to display these types of information on multiple scales is to use a geographic information system (GIS). The case of phosphorus in southern Rhode Island's Tucker Pond illustrates how a GIS can help integrate concerns from the public, data from Clean Water Act monitoring, and information from the New England Resource Protection Project to identify types of environmental assessment questions on scales ranging from states to subwatersheds. By involving the public at all stages of the process and better informing them about their watersheds, this new approach makes them better stewards of their environment.     

When Domestic Environmental Policy Meets International Trade Policy: Venezuela's Challenge to the U.S. Gasoline Rule

The role of the World Trade Organization (WTO) in the setting and enforcement of international and domestic environmental policy continues to evolve. This paper reviews the first case that focused clearly on environmental issues that involved WTO mediation: the case of Venezuela's challenge of the legality of United States restrictions on the importation of gasoline based on requirements to reduce health risks under the Clean Air Act. In this case, the WTO deemed the U.S. Environmental Protection Agency's policy as a barrier to free trade and this has important implications for future policies. We explore the underlying issues of the decision and its implications for future cases that focus on environmental risks.     

Evaluating the Melbourne Strategic Assessment—Elegant on process,currently failing on implementation

This paper provides a critical analysis of the development and current outcomes of Australia's first endorsed strategic assessment under the Environment Protection and Biodiversity Conservation Act 1999, namely, the Melbourne Strategic Assessment. It covers progress towards protection of a number of Nationally Significant Species and Ecological Communities – most notably, the native grassland communities immediately adjacent to Melbourne's Urban Growth Boundary. The Commonwealth approval to protect biodiversity and allow urban development was made in 2010 and it aimed to achieve its outcomes by 2020. These outcomes included providing new land for homes, for new transport corridors, and for conservation of biodiversity. Natural Temperate Grassland (4,667 ha), Grassy Eucalypt Woodland (709 ha) and seven other Matters of National Environmental Significance will be impacted. Mitigation for this is establishment of 15,000 ha of grassland reserves, 1,200 ha of grassy woodland reserves, over 4,000 ha of other land zoned for conservation and 300 ha of wetland restoration. We conclude that the Melbourne Strategic Assessment has been a success in terms of the elegance and comprehensiveness of the approach, in cooperation between the levels of government, in the economic benefits, and in some aspects of social engagement of the agreement. However, the achievement of environmental outcomes must be currently considered a failure due to poor implementation. This failure includes not meeting the agreed 10 year deadline for land acquisition and management, poor monitoring and protection of set-aside areas, and in reporting. We offer suggestions for how these current shortcomings could be overcome. These align well with the recommendations of the review of the Environment Protection and Biodiversity Conservation Act 1999 (The independent statutory review of the Act in 2020) and include the establishment of the proposed Office of Compliance and Enforcement, the adoption of National Environmental Standards and the reforms regarding the role of Indigenous Australians in strategic assessments. If these were adopted, we conclude that the strategic assessment approach should be more widely used because of the more holistic approach and efficiencies that it envisages compared with site by site approaches.     

Assessing Children's Exposures and Risks to Drinking Water Contaminants: A Manganese Case Study

Background: Compared to adults, children maybe more highly exposed to toxic substances in drinking water because they consume more water per unit of body weight. The U.S. Environmental Protection Agency (USEPA) has developed new guidance for selecting age groups and age-specific exposure factors for assessing children's exposures and risks to environmental contaminants. Research Aim: To demonstrate the application and importance of applying age-specific drinking water intake rates, health reference values, and exposure scenarios when assessing drinking water exposures because these approaches illustrate the potential for greater potential for adverse health effects among children. Methods: manganese, an essential nutrient and neurotoxicant, was selected as a case study and chemical of potential concern for children's health. A screening-level risk assessment was performed using age-specific drinking water intake rates and manganese concentrations from U.S. public drinking water systems. Results: When age-specific drinking water intake rates are used to calculate dose, formula-fed infants receive the highest dose of manganese from drinking water compared to all other age groups. Estimated hazard quotients suggest adverse health effects are possible. Use of USEPA's standardized childhood age groups and childhood exposure factors significantly improves the understanding of childhood exposure and risks.     

北京市老年人肝肾功能参数的参考值范围调查

目的:观察北京市60岁以上不同年龄段健康老年人肝肾功能检验项目水平的差异,建立各自的参考值范围。方法:随机挑选600例60岁以上的北京市健康老人,按照不同年龄段分为三组,空腹采血,采用Modular仪器及原装试剂测定血清ALT(丙氨酸氨基转移酶)、AST(天冬氨酸氨基转移酶)、TP(总蛋白)、ALB(白蛋白)、Bun(尿素氮)、Crea(肌酐)、UA(尿酸)水平,结果利用SPSS11.0进行统计分析,根据统计学结果,判断参考值范围,并比较不同组间水平的差异。同时随机选择371例健康青年,与老年组进行这些项目水平的比较。结果:统计学结果显示,AST、TP、UA组间无显著差异;ALT、ALB随年龄增加而下降;Bun、Crea随年龄增加而升高。结论:通过上述实验,对老年人群的ALT、AST、TP、ALB、Bun、Crea、UA等项目的参考区间进行初步分析,对现行参考区间的设定提供建议与参考。各实验室应建立自己的参考值范围。