OVERVIEW OF THE COMMITTEE'S STRATEGY

The overall strategy envisioned by the committee for evaluating evidence of low-dose adverse human effects consists of three broad phases—surveillance, investigation and analysis, and actions (see Figure 2-1). The strategy recognizes that a toxicity testing program, no matter how sophisticated, cannot provide 100% assurance that all adverse effects will be identified and can be prevented. Even with pharmaceuticals, which are tested in human clinical trials, adverse effects are often not identified until after the drug has been marketed. Therefore, environmental chemicals, which are tested (if at all) in experimental systems only before use, require continued surveillance to protect public health given the expectation that false negatives will occasionally occur in testing.

Once a topic has been identified for additional investigation, the specific details of the investigation and analysis need to be planned so that they will support future agency actions. The results from the investigations and analyses are then used to select specific actions. In some cases, the only further action would be continued surveillance. In other cases where key uncertainties exist, further action could entail the generation of new data or models to address the uncertainties. If the results of an investigation suggest that adverse outcomes in humans are expected or might be occurring at low doses, the conclusions of previous toxicity testing or toxicity assessments for the chemicals that are under investigation might need to be updated to reflect the new evidence. Additionally, such evidence might support updates to specific toxicity-testing or assessment practices to reduce the false-negative rate in the future.

The first two phases, surveillance and investigation and analysis, are described in more detail below. As noted in Figure 2-1, completion of each phase could involve one or more approaches. Although the descriptions of the components are presented sequentially in the report, there is no requirement that each approach be used or that a specific order be followed. The last phase, actions, involves policy decisions, which are outside of the committee's charge and therefore are not discussed in detail in this report.

SURVEILLANCE

In the context of this report, surveillance refers to the process for detecting signals (indications that an adverse outcome in a human population or animal model might be related to exposure to an EAC at low doses) by searching, retrieving, and evaluating existing data. Surveillance also refers to the process for monitoring the literature for methods that could be used for toxicity testing of EACs. Types of data that could be considered in an active surveillance program include human, animal, or mechanistic data.

Actively Monitor for New Data

A surveillance program for identifying low-dose effects should have a process for actively monitoring for new data to help ensure that effects will be identified and analyzed on a regular basis. Three broad categories—chemical-specific data, information that could lead to modifications of toxicity-testing methods and best practices for EACs, and information on endocrine-related effects in animals and humans—should be considered in the surveillance program. Relevant information to monitor might include scientific literature, various databases, nontraditional information sources, stakeholder input, and human exposure information. Although monitoring scientific literature and databases and human exposure information might provide the most valuable information, nontraditional information sources and stakeholder input have recently been highlighted as potential sources that could lead to valuable insights. Which sources are selected for surveillance will clearly depend on the problem under consideration and the resources available to the agency. Each source is discussed in more detail in the following sections.

FIGURE 2-1

Strategy for evaluating evidence of adverse human effects from low-dose exposure to chemicals. The strategy includes three broad phases: surveillance, investigation and analysis, and actions. Each phase includes multiple options that may be employed alone (more...)

Monitoring the Scientific Literature

EPA has many ongoing literature-review activities for evaluating chemical hazards, such as the chemical-specific evaluations of the Office of Research and Development, the Office of Pesticide Programs, the Office of Water, and the Office of Air and Radiation. Chemical-induced effects on endocrine function might be considered in those assessments. Although the assessments typically rely heavily on animal data, human data also contribute to these assessments. Whether human studies are concordant or discordant with the animal data is an important consideration.

In addition to chemical-specific data, the scientific literature should be monitored to identify relevant end points that might need to be included in toxicity testing or risk assessment or to identify other changes to toxicity-testing practices that might be needed to improve assessment of EAC effects. For example, several assessments conducted by EPA, NTP, and international institutions have investigated various methodological issues, including addition of mammary gland assessment in regulatory guideline protocols (Makris 2011); adequacy of rodent models for detecting hormonally related cancers (Thayer and Foster 2007); study design issues for developmental reproductive toxicity (Blystone et al. 2010); and the question of biological thresholds for EACs (Haas et al. 2013). Furthermore, literature reviews of diabetes, breast cancer, and other diseases have identified biological processes and specific chemicals that appear to be involved in their etiology (Rudel et al. 2007, 2011, 2014; Macon and Fenton 2013; Schwarzman et al. 2015; Auerbach et al. 2016; Smith et al. 2016; Bruner-Tran et al. 2017), and these reviews might reveal effects that need to be integrated into toxicity-testing methods.

The study of endocrine-related human diseases, such as prostate cancer and endometriosis, might also identify adverse effects that are not readily detected in rodent studies. For example, endometriosis is a human disease that is difficult to assess in animal models because most nonprimate mammals do not menstruate and consequently do not develop ectopic lesions, which are the pathological hallmarks of endometriosis (Bellofiore et al. 2017; Bruner-Tran et al. 2017). Concerns about the possible role of chemical exposure in the development of endometriosis might therefore be difficult to assess in an animal model (see Box 2-2). Agencies that are involved in health surveillance and that have health registries (e.g., Centers for Disease Control and Prevention, National Center for Health Statistics) could also be a source of information about relevant human diseases. Thus, by reviewing endocrine-related human diseases, one could ensure that signals are not being missed because they are not recapitulated in animal models. Given that there will always be species differences in response to chemical exposure, a surveillance system should always include monitoring epidemiologic literature or research.

The committee notes that automated methods are being developed for monitoring the literature. For example, methods or tools have been developed to extract drug-safety information from the published literature and electronic medical records (Shetty and Dalal et al. 2011; Wang et al. 2011; Duke et al. 2012; Gurulingappa et al. 2012; Avillach et al. 2013; Pontes et al. 2014; Winnenburg et al. 2015), and these approaches might be relevant for monitoring literature on EACs. Other publicly available tools have been developed for supporting systematic reviews (ICASR 2015), and these might assist with searching and retrieving data related to new toxicity-testing methods, outcomes, exposure assessment, and biomonitoring.

Assessing Scientific Data

In addition to the published peer-reviewed scientific literature, data are being generated and made available to the scientific community through various other venues. For example, as described in Chapter 1, EPA's ToxCast program has generated substantial data that can potentially provide toxicity and mechanistic information on a variety of chemicals. The testing is typically conducted in in vitro assays and uses a broad range of testing concentrations, including ones found in human biological samples; thus the testing could have relevance to environmental or low-dose exposure. The data are made available through EPA's website.¹ Other information could come from databases developed to track mechanistic pathways for adverse outcomes.² These types of data could potentially help identify EACs, and their review might be considered important for a surveillance program.

Tracking Nontraditional Sources of Information

Some investigators have explored whether information extracted from such informal media sources as blogs and other various forms of social media could provide useful drug-safety surveillance data (Harpaz et al. 2012; Lardon et al. 2015; Nikfarjam et al. 2015; Sarker and Gonzalez 2015). Those efforts have proven challenging for drug surveillance programs because the language used to describe medical information in social media is often informal or descriptive (Nikfarjam et al. 2015). Applying those methods to surveillance of environmental chemical exposures could prove even more challenging because, unlike with drug surveillance, people are generally unaware of their environmental exposures. Despite the limitations, approaches for evaluating social media could be explored as a means to provide additional surveillance of potential health effects associated with chemical exposure.

Obtaining Stakeholder Input

A surveillance program could also include components from stakeholder input. EPA could evaluate recommendations or policy statements made by scientific societies or organizations or other academic groups. For example, several position papers have been published on the effect of EACs on human health (Diamanti-Kandarakis et al. 2009; Skakkebaek et al. 2011; Gore et al. 2015; Bennett et al. 2016). Another means of identifying a potential public-health problem is to consider input from advocacy groups, individual scientists, political leaders, chemical manufacturers, and other stakeholders. For example, NTP has a long-standing process that encourages nominations of chemicals of concern regarding human health (Heindel 1988). Similarly, EPA's Integrated Risk Information System (IRIS) program provides opportunities for EPA program and regional offices and other stakeholders to nominate chemicals for consideration. Nomination processes provide opportunities for stakeholder input and can help focus attention on societal concerns. Nomination processes are not without some limitations, however, including the possibility of reporting bias by the media, community action groups, or industry. Those groups might also be influenced by social activism or corporate product defense and might not be focused on longer-term public-health issues (Mihaylov and Perkins 2015; Zoller 2017). Guidance for engaging stakeholders has been provided in other National Academies reports (e.g., NRC 2009, 2014).

BOX 2-2

Endometriosis: An Example in Which Traditional Toxicity Testing Might Be Inadequate to Evaluate Endocrine Active Chemicals.

Monitoring Human Exposure Information

Biomonitoring data are an important information source that can help identify whether human exposure to EACs has occurred or changed over time (NRC 2006a, 2007, 2009, 2012) and are useful in defining low-dose exposures. They can also identify potential exposure sources and demographics of highly exposed groups. A previous NRC committee provided the following recommendations regarding the need to use biomonitoring data in surveillance programs: “Develop biomonitoring-based epidemiologic, toxicologic, and exposure-assessment investigations and public-health surveillance to interpret the risks posed by low-level exposure to environmental chemicals. Where possible, enhance existing exposure assessment, epidemiologic, and toxicologic studies with biomonitoring to improve the interpretation of results of such studies” (NRC 2006a, p. 9).

Box 2-3 illustrates how biomonitoring data from the US Centers for Disease Control and Prevention (CDC) National Health and Nutrition Examination Survey (NHANES) can help inform evaluations of EACs. Occupational exposure data might also provide information that could help define the range of human exposures to some chemicals.

In the absence of biomonitoring data, external exposure data can be used to estimate the range of potential human exposure to chemicals. Active air sampling devices have been used for several years to assess personal exposure to air pollutants, such as particulates, ozone, and polycyclic aromatic hydrocarbons (Geyh et al. 1999; Perera et al. 2003; Tsai et al. 2012; Oliveira et al. 2016). More recently, passive sampling devices have been developed to eliminate the need for cumbersome equipment that decreases compliance in human studies. Passive samplers are favored for personal monitoring because they are lighter and smaller and less likely to interfere with daily activities (NRC 1991). For example, silicone wristbands have been developed as personal passive samplers capable of sequestering polycyclic aromatic hydrocarbons, flame retardants, and pesticides as measures of an individual's external exposure (O'Connell et al. 2014; Donald et al. 2016; Hammel et al. 2016). Several funding agencies are supporting the development of sensor technologies for the 21st century, which includes wearable monitors that can be used in population studies to measure personal exposure in real time with high sensitivity and specificity and low cost.³

Another type of exposure data comes from efforts to measure chemicals in air, water, soil, and other environmental media (such as house dust), food, and consumer products, and extrapolate those measurements to human exposure. For example, EPA's Particulate Matter (PM) Supersites Program was established to obtain atmospheric measurements to address the research questions and scientific uncertainties about PM relationships between sources, receptors, exposures, and effects (Solomon and Sioutas 2008). A similar EPA program—the Clean Air Status and Trends Network (CASTNET)—is a national monitoring network established to assess trends in pollutant concentrations, atmospheric deposition, and ecological effects due to changes in air-pollutant emissions (Puchalski et al. 2015). Other air-monitoring programs have evaluated changes in urban ozone concentrations that have occurred over several decades (Sather and Cavender 2016).

BOX 2-3

NHANES: A Platform for Surveillance.

Surveillance of Endocrine-Mediated Drug Reactions Using Pharmacovigilance

The US Food and Drug Administration (FDA) has developed pharmacovigilance⁴ programs to monitor for adverse drug reactions (ADRs). Such programs are needed because human clinical trials use relatively small sample sizes; have shorter durations of exposure than usually occur; often lack diversity among study participants; and do not include pediatric and other susceptible subpopulations (McMahon et al. 2015). Those design features limit the ability of clinical trials to detect rare (1:1,000 to 1:10,000) ADRs that occur at therapeutic drug doses (Schotland et al. 2016).

Pharmacovigilance programs often consist of premarketing surveillance that identifies ADRs during preclinical screening and clinical trials and postmarketing surveillance in which data are accumulated throughout a drug's market life (Ibrahim et al. 2016). Voluntary reporting systems have historically served as the primary data collection system for postmarketing pharmacovigilance. Such passive surveillance systems primarily rely on the collection of reports of suspected ADRs from health care professionals, consumers, and pharmaceutical companies. Today, FDA has established the Office of Surveillance and Epidemiology to help coordinate its efforts in postmarket drug safety surveillance (see Box 2-4).

BOX 2-4

Overview of FDA's Efforts in Postmarket Drug Safety Surveillance.

Some drugs have been shown to demonstrate endocrine activity (see, for example, Friedman et al. 2009). In fact, the Institute of Medicine recommended that FDA “engage the pharmaceutical industry and scientific community in postmarketing studies or clinical trials for hormonally active prescription drugs for which the potential impact on breast cancer risk has not been well characterized” (IOM 2012, p. 21). Such an approach is also relevant for other endocrine-related effects. The committee concludes that methods that have been developed for pharmacovigilance programs might be adapted or help inform an EAC surveillance program. The committee notes, however, that EAC surveillance programs that are based solely on voluntary reporting might be limited because people often cannot self-report environmental exposures.

Formulate Questions to Address and Develop an Approach for the Investigation

Once a topic is selected for further analysis, the next step is to formulate the questions to address and develop an approach to the investigation, which will involve consideration of the scientific evidence, expert judgment, and relevant stakeholder perspectives. Questions and approaches are often targeted depending on the topic under investigation and potential actions that could be taken by the agency. For example, EPA might consider whether a new outcome measure should be included in regulatory toxicity tests. In that case, questions that might be posed include the following:

• Is the outcome an emerging concern?
• Are appropriate assays available or could they be developed?
• Is the outcome a more sensitive measure of adverse toxicity than currently used outcomes?
• Is the outcome of interest a reproducible effect after chemical exposure?
• Will including the new outcome in regulatory testing improve hazard identification—that is, improve sensitivity?

Box 2-5 provides a retrospective example of how the answers to these questions helped establish the measurement of anogenital distance as an outcome measure in regulatory toxicity tests.

Once the questions have been identified, the next step is to formulate the approach to the investigation and determine the types of data and analyses that are needed to answer the questions and provide the basis for agency actions. Figure 2-1 shows four types of investigation and analysis that could be considered: generation of new data or models to fill data gaps, targeted analysis of existing data, systematic review, and integration of the available evidence. The types of investigations or analyses might not be mutually exclusive because several related investigations or analyses might be needed to address the questions adequately. And, as noted above, they could be influenced by a number of factors, including the size of the population at potential risk, public-health significance, and available resources.

BOX 2-5

Anogenital Distance and Its Addition to Regulatory Toxicity Tests.

INVESTIGATION AND ANALYSIS

Integrate Available Evidence

This committee—as have other National Academies committees before it—emphasizes the need for evidence integration to be both transparent and standardized in its approach. Thus far, evidence integration has focused on the purpose of hazard identification: that is, determining whether a causal relationship exists. Causal frameworks, such as those developed by the International Agency for Research on Cancer, NTP, and EPA, can be adopted or adapted to provide transparency and consistency in conducting causal evaluations. See previous National Academies reports for additional guidance on such approaches (NRC 2014; NASEM 2015, 2017).

BOX 2-6

Bisphenol A: Generating Data to Address Uncertainty.

The committee recognizes, however, that for addressing low-dose adverse effects of chemical exposure, the question will often be more explicitly quantitative: that is, it specifically concerns the nature of the dose-response relationship at low doses. Although the evidence of causality is still important, the problem is that the causal evidence might include studies that exclusively include high exposures, such as experimental doses near the maximum tolerated dose. High-dose data alone are usually not useful for making inferences about response to exposures at low doses because of uncertainties in the shape of dose-response curves below the range of observation.

Therefore, it might be necessary to integrate the subset of evidence that includes low-dose toxicity data separately. Although not very informative for causal inferences, environmental exposure data, such as biomonitoring data, might nevertheless be useful for defining what subset of the data can be considered as low dose (see discussion earlier in this chapter). Some additional considerations include the following:

• In vitro–in vivo extrapolation or reverse toxicokinetics can help to determine what in vitro mechanistic data could be considered low-dose data.
• Incorporation of modeled dose-response relationships, including BMD estimates.
• Addressing toxicokinetic and toxicodynamic differences between species and populations.
• Biological plausibility given mechanistic data.
• Co-exposures that might act on the same end point.

Data integration can also be used to consider questions that are not about specific EACs but are broader, such as whether a new end point or new exposure or assessment window is relevant to determining low-dose effects. As noted earlier, some end points have been added to regulatory testing protocols in response to growing evidence that they are indicators of toxicity, and the duration of some tests has been extended to capture effects that might occur later in life. Signals identified during the surveillance step that have those types of implications about toxicity testing could be evaluated by integrating the available evidence. One example of such a signal is the growing concern about evaluations of mammary gland toxicity. Makris (2011) evaluated how the effects of environmental chemicals on the mammary gland are assessed in guideline studies of EPA, OECD, and NTP and made a number of recommendations for enhancing how the end point is assessed. She identified data gaps, issues, and challenges and noted that “to address these issues, a paradigm shift would be needed for the evaluation of [mammary gland] in guideline studies” (Makris 2011, p. 1050). Challenges identified with implementing such a shift were issues of species and strain sensitivity, the timing of exposure, and when the end point is evaluated. Evidence integration could help address such issues.

ACTIONS

The remaining step in the committee's strategy is to select the types of actions that are needed. As shown in Figure 2-1, several types of actions could result, including the need to update chemical assessments, to continue to monitor for new data, to require new data or models to reduce uncertainties, or to update toxicity-testing designs and practices. The type of actions that EPA takes could be influenced by a number of factors, including the size of the population at risk, the public-health significance of the investigation, and available resources. Specific recommendations on exactly what actions to take are beyond the scope of this report.

FINDINGS AND RECOMMENDATIONS

• To ensure adequate understanding of hazards and to inform regulatory decision making, EPA needs a general strategy for ongoing evaluation of evidence of low-dose effects from exposure to EACs. The committee proposes a strategy involving three phases: surveillance, investigation and analysis, and actions. EPA is already conducting many activities consistent with the proposed strategy, though not necessarily in the specific context of assessing low-dose exposure to EACs.
  Recommendation: EPA should develop an active surveillance program focused specifically on low-dose exposures to EACs. This program could include regularly monitoring published research and other information sources, gathering input from stakeholders, and collecting human exposure information. It might also involve data collection in collaboration with other agencies and outside parties. The surveillance program should periodically identify, scope, and prioritize potential areas of focus related to low-dose effects, such as particular chemicals and end points. Some approaches discussed in this chapter will require methods and tool development, such as automated methods for monitoring the literature.
  Recommendation: After a topic is selected for further evaluation, the agency should plan its investigation by identifying key questions to be addressed and determining the types of data and analyses needed to answer the questions and to support future agency actions.
• The four main approaches for investigation and analysis are targeted analysis of existing data, systematic review, generation of new data or models, and integration of evidence. The types of analyses used to investigate the questions are not mutually exclusive, and several approaches might be needed to address the questions adequately. Integration of evidence for low-dose adverse human effects of EACs involves consideration of both hazard identification and dose response.
  Recommendation: Environmental exposure data should be used, if available, to define what subset of the data should be considered as low dose.
• A robust strategy will provide the agency with a range of options to address questions of concern.
  Recommendation: The specific approaches and tools used to implement the strategy to address issues related to low-dose endocrine effects will need to be considered on a case-by-case basis and should be guided by the specific questions under study.
• The proposed strategy in this chapter will facilitate more regular consideration of the adequacy of toxicity testing. However, the agency will also be faced with questions about the amount of evidence needed to change traditional test methods, and these questions might be more appropriately addressed through policy decisions.

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