This chapter presents the committee’s review of the report Assessment of Potential Long-Term Health Effects on Army Human Test Subjects of Relevant Biological and Chemical Agents, Drugs, Medications and Substances: Literature Review and Analysis (the Report) (Ho-Chunk Technical Solutions, 2016). The Report was reviewed in the context of the performance work statement in the contract for the Report and in the context of whether best practices in performing literature reviews and weight-of-evidence analyses were used to the support the identification and characterization of long-term health effects.
The contract for the Report was for a literature review and assessment of potential long-term health effects from more than 100 agents the Army tested on human subjects. Three objectives were specified: (1) performance of literature searches, (2) evaluation of information, and (3) preparation of a report. For the first objective, a list of relevant biological and chemical agents, drugs, medications, and substances was provided by the Army. The contract specified that literature searches be performed on all of the agents, the searches be conducted on studies published after June 30, 2006 (the last date when test subjects were provided information about their participation in the testing), and the search strategy and results documented. For the second objective, the contractor was to compare the results of the literature searches with information from records about the test subjects to characterize the significance of the new literature in understanding potential long-term health effects. Finally, a report was to be prepared that summarized the findings and their significance. An evaluation of how the Report meets these objectives is provided below.
The contract for the Report listed certain databases to be searched and specified that the databases, search parameters, and results be documented. The only information provided in the Report was the date range of the searches, and two reference lists, one for references cited and one for references consulted. Thus,
the Report did not provide the necessary documentation describing how the literature was searched and screened to meet the contract requirements. Because of this, the committee was unable to determine whether the searches were adequately designed or whether the most relevant references were selected for the analyses. The reason that omission of the literature strategies and screening criteria from the Report is problematic is described in the section below on Best Practices in Hazard Identification.
Evaluation of Information
The contractor was asked to describe the potential long-term health effects from the test agents. Potential long-term health effects were to be identified by comparing information from the literature search on an agent with what is known about the circumstances under which test subjects were exposed to the agent. The circumstances of exposure were to be obtained from records on the human test subjects, such as the agent they were exposed to, dates of exposure, and routes of exposure. A matrix also was to be prepared that would indicate the significance of potential long-term health effects to subjects, if any.
The Report has two major sections: Agents and Substances with Evidence for Long-Term Sequelae (Section 1.0) and Agents and Substances with Little or No Evidence for Long-Term Sequelae (Section 2.0). Eighteen agents were identified has having potential long-term health effects. Short summaries of the evidence for each agent are provided, but individual studies are not critically evaluated and there is no substantive synthesis of the collective evidence to explain how an agent was judged to have adequate or inadequate evidence of long-term health effects. (The importance of evaluating study quality and having a defined weight-of-evidence approach is discussed later in this chapter.)
For the agents judged to have evidence of long-term health effects, the strength of the associations is discussed in a separate Conclusions section (Section 5.0). Table 18 in Section 5.0 appears to be the “matrix” specified in the contract that was to indicate the significance of potential long-term health effects to test subjects. The table lists the 18 test agents and classifies the strength of their associations with “sequelae” as high, medium, or low. The accompanying text provides only superficial reference as to how the categorizations were made. For example, generalizations are made that low associations are due to low prevalence in the population, uncertainty about the specific test agent, or methodological problems. A strong association is based on well-documented health effects from multiple authors, a large population study, or a high-quality meta-analysis. No indication is provided in the text about the specific circumstances that led to the classification of each test agent in Table 18. Another ambiguity is that the table lists only the test agent and not the specific health effect(s) being judged. Eleven of the 18 test agents had more than one long-term health effect linked to them, so it is unclear whether the strength-of-association determinations are applicable to all of the health effects.
The Report also contains sections on Military Exposures and Health Outcomes (Section 3.0) and Comparing Historical and Recent Information (Section 4.0). Section 3 summarizes military-specific information, including published information on certain testing programs of the Army and other services, past reviews of potential health effects from the testing, and reviews of relevant agents conducted for the Department of Veterans Affairs. The Report contains no information about the specific exposures to test subjects, so comparisons of the results of the literature review with exposure information are not described beyond generalizations. Section 4.0 is a comparison of historical and recent information on a small subset of agents. It was unclear to the committee whether or how the information provided in these sections was used in making any determinations.
Preparation of the Report
The contract specified that the Report was to be modeled after the format used for previous reports, and was to be written in a manner to allow the public to understand the significance of the information. The Report does not indicate what previous report it was modeled after to allow the committee to understand how it would be used in the context of previously drawn conclusions. If an updated literature review is not considered in context with the older literature, erroneous conclusions can be drawn (see the example of cyanide discussed later in this chapter). The committee also found that the Report was not written in a manner that would allow the public to understand the significance of the new information. For example, many of the findings from epidemiological studies are described statistically (e.g., using odds ratios, adjusted odds ratios, and incidence rate ratios) without explaining the terms or their significance in a manner that may be understood by the public. Furthermore, as noted earlier in reference to the conclusions in Table 18, simply classifying the evidence as high, medium, or low for an agent without reference to specific health effects is not useful.
Other Observations on the Report
The contract for the Report specifies that long-term health effects are to be the focus of the literature review and analysis. In the Report, health effects are referred to as “sequelae,” and conflicting descriptions of what constitutes sequelae are provided. The Report’s (p. 9) definitions include (1) “secondary symptoms that can persist for weeks or sometimes months or years after an original exposure or infection,” (2) “usually [arising] weeks or months that follow an exposure or infection,” and (3) “to be even considered as potential sequelae of exposure, the conditions experienced by the volunteers in the military human trials must have arisen in the weeks or months following exposure, not five to ten years (or more) after exposure. Given this timing, potential sequelae should have been detected in the follow-up health screenings given to test participants.” Since the test subjects were exposed in the 1970s or earlier, how a long-term health effect is defined is important to ensure that the appropriate health effects are considered.
Hazard identification, which is the determination of whether a particular agent has the potential to cause an adverse health effect(s), is performed by a number of governmental and nongovernmental agencies, including the Institute of Medicine (IOM), the U.S. Environmental Protection Agency (EPA), the National Toxicology Program (NTP), the International Agency for Research on Cancer (IARC), and the Agency for Toxic Substances and Disease Registry (ATSDR). Overviews of these approaches were presented at the committee’s information-gathering meeting on November 30, 2017 (Chiu, 2017). The specific frameworks used for hazard identification, the relative weighting of different lines of evidence (human, animal, and mechanistic), and the classification terminology used for causality vary according to the objective of the hazard identification and the organization conducting the evaluation. For example, in the hazard classification methodologies for cancer used by EPA (2005), IARC (2006), and NTP (2015), the evidence base consists of human, animal, and mechanistic data. These lines of evidence are evaluated separately and then integrated to make a determination about the strength of an association between the agent and cancer. Human evidence of carcinogenicity is weighted most heavily, but strong mechanistic data can play a pivotal role in the overall classification of an agent as a carcinogen. The hazard identification frameworks for noncancer health effects used by EPA, NTP, and the IOM also consider human, animal, and mechanistic evidence; however, in contrast to the cancer hazard identifications, mechanistic data are largely used to support classifications on the basis of human and animal data. The methods used to determine causality in noncancer hazard identification vary slightly between organizations; the IOM methods (e.g., IOM, 2000, 2012; NASEM, 2016) rely more heavily on epidemiological studies than on animal studies compared to NTP and EPA methods. Despite these differences, there are common elements across the frameworks that are considered to be best practices in hazard identification, including initial problem formulation, the subsequent systematic gathering and review of the publicly available scientific evidence according to predetermined criteria, and a weight-of-evidence evaluation of the scientific information by subject-matter experts to reach consensus classifications of causality.
A general framework for hazard identification that demonstrates best practices includes a stepwise process that begins with problem formulation that identifies the agent, the health effect, and the overall objective for the evaluation. This determines the strategy for the literature search and the screening criteria for selecting studies. The relevant information from each selected study is reviewed using predetermined criteria to assess quality and internal validity and the results of the studies are synthesized. Subsequently, different lines of evidence (e.g., human, animal, and mechanistic) are integrated and expert judgment is applied to draw conclusions regarding the strength of association between a risk agent and an adverse health effect. Critical to best practices in hazard identification is transparency and documentation at each step to ensure credibility and confidence in the conclusions. The specific components of best practices in hazard identification that are missing or deficient in the Report include the following:
- Problem formulation: The Report did not (1) provide an adequate description of the overall objective of the review; (2) specify the question(s) that were evaluated for specific test agents; (3) adequately define the types of populations, exposures, comparators, and outcomes (PECO statement) considered relevant to the objective of the study; or (4) specify the types of information considered in the review. As a result, it was not possible for the committee to determine whether the scope of the literature search was relevant to or completely captured the objective of the hazard identification, or whether the methods were used consistently for all test agents.
- Literature search and screening: The Report did not (1) define a literature search strategy that identified search terms and databases to be searched, (2) specify whether searches of human and animal literature were performed separately, (3) develop inclusion/exclusion criteria based on a PECO statement for screening studies, or (4) document the results of the literature searches and screening. As a result, there are concerns as to whether an objective or adequate literature search was conducted, and concerns as to whether the most relevant references were selected for analyses.
- Data analysis and evidence synthesis: The Report did not (1) provide consistent or comprehensive documentation of the types of data extracted from each study, (2) specify criteria used to evaluate the quality of individual studies, (3) provide a systematic reporting of study quality for the studies, (4) describe approaches used to synthesize the evidence, (5) specify whether data from different lines of evidence (human, animal, and mechanistic) were synthesized separately, or (6) provide a substantive synthesis of the evidence. As a result, the committee was not able to determine whether or how the Report factored study quality into the assessment of the literature. This raises concerns about the validity of the conclusions drawn in the Report.
- Integration of evidence and drawing hazard identification conclusions: The Report did not (1) define the approach(es) used to integrate different lines of evidence, (2) adequately or consistently define criteria used to categorize test agents, or (3) provide evidence of expert judgment in drawing hazard identification conclusions. These omissions and deficiencies significantly decrease the credibility of and confidence in the conclusions drawn in the Report.
Although the committee did not evaluate the completeness of the literature search for all test agents reviewed in the Report, committee members with subject-matter expertise had concerns that key studies were missing for a subset of test agents, specifically cyanide, the organophosphates sarin and diisopropylfluorophosphate (DFP), and sulfur mustard. To confirm that studies were missed in the Report, the committee searched the PubMed database from January 2006 to February 2016 (when the Report was issued) using the search terms “cyanide,”
“sarin,” “diisopropylfluorophosphate,” and “sulfur mustard.” The ATSDR website (https://www.atsdr.cdc.gov) and NTP website (https://ntp.niehs.nih.gov) were also searched using the same search terms. Articles identified in these searches and confirmed by the committee to be primary scientific articles on biological effects of these test agents were cross-referenced to articles cited in the Report. For each of the four test agents, the committee identified a number of studies that were missing from the Report (see Table 2-1). Because of the lack of documentation in the Report about whether exclusion/inclusion criteria were used to screen studies, it is not possible to determine whether the missing studies were excluded from the Report for a valid reason. Nonetheless, the results of this exercise raise questions regarding the completeness of the literature search.
The committee’s review of missed studies raised concerns that the Report may have also missed long-term health effects associated with specific test agents, as exemplified in Table 2-2 for cyanide, sarin, and sulfur mustard. Another concern, in the case of cyanide, is that the Report gives an inappropriate impression of the potential for hazard. For example, on pages 75-76 of the Report, a single case report on neurological sequelae from acute cyanide ingestion is cited, suggesting that sequelae are uncommon. However, it is well known that people who survive an acute episode of cyanide poisoning, for example from suicide attempts, frequently develop a delayed neurological syndrome that resembles Parkinson’s disease (e.g., Way, 1984; Uitti et al., 1985; Carella et al., 1988; Rosenberg et al., 1989; Salkowski and Penney, 1994; Borgohain et al., 1995; Rachinger et al., 2002). This syndrome occurs even in patients who appear to have had a full recovery from the acute exposure (e.g., Valenzuela et al., 1992; Rosenow et al., 1995; Rachinger et al., 2002; Riudavets et al., 2005). Symptoms generally appear a few weeks to months after the acute poisoning. Computed tomography and magnetic resonance imaging of the patients’ brains show lesions in the basal ganglia, globus pallidus, putamen, substantia nigra, and sometimes in the cerebral cortex. Injury to these brain areas has been confirmed in several cases at autopsy (Uitti et al., 1985; Carella et al., 1988). Chronic exposure to low amounts of cyanide has also been reported to induce similar changes, and, in Africa, eating improperly prepared cassava root—which releases cyanogenic compounds—results in a severe spastic paraparesis commonly referred to as “konzo” (Tylleskar et al., 1992; Di Filippo et al., 2008; Oluwole, 2015; Tshala-Katumbay et al., 2016). As noted in Table 2-2, several of these reports were published in the interval between July 2006 and December 2015, and thus should have been found in the literature review by the contractor. Moreover, the recent papers refer to previous papers. Thus, the Report fails to identify cyanide as having evidence of long-term sequelae.
Another concern with missing studies is that new findings are constantly published, and thus the conclusions regarding the human health effects of a particular substance may change as new evidence becomes available. Thus, best practices in hazard identification include specifying periodic reevaluation of agents. IARC’s reevaluation of potential carcinogens has resulted in greater certainty regarding the carcinogenic potential or lack thereof for many agents. Such ad-
vances are expected in an open, transparent, and evidence-based process. The potential importance to the Army of implementing a protocol for updated literature reviews of test agents is suggested by the committee’s search for studies describing the biological effects of DFP. Since the Report was issued in February 2016, there have been nine primary scientific papers published on the health effects of DFP (Flannery et al., 2016; Gao et al., 2016; Phillips and Deshpande, 2016; Rojas et al., 2016; Hobson et al., 2017, in press; Sisó et al., 2017; Koo et al., 2018; Liang et al., 2018), which is more than the number of studies on DFP included in the Report.
|Test Agent||Health Effect||Reference|
|Cyanide||Visual loss, amblyopia||Chen et al. (2011)|
|Konzo: spastic paraparesis, neurocognitive dysfunction||Boivin et al. (2013)|
|Bumoko et al. (2014)|
|Tshala-Katumbay et al. (2013)|
|Sarin||Ocular effects||Genovese et al. (2008)|
|Immune dysfunction||Chaubey et al. (2016)|
|Sulfur mustard||Poikiloderma||Emadi et al. (2012)|
|Atopic dermatitis||Amiri et al. (2013)|
|Meibomian gland dysfunction, blepharitis, punctal closure, trichiasis, tear break-up time, and tear meniscus layer abnormality||Ghasemi et al. (2009)|
The committee finds that the Report does not constitute a hazard-identification assessment. The Report did not provide the necessary documentation and analysis to address the performance requirements of the contract and did not follow standard best practices in performing literature reviews in support of hazard identification. The major concerns include failure to document the literature search and screening strategies; inadequate evaluation and synthesis of the literature to explain how an agent was judged to have evidence of long-term health effects; and insufficient information to understand how strength-of-association determinations were made. Thus, the Report should not be used as the sole scientific basis to assess the potential long-term health effects from exposure to biological and chemical agents, drugs, medications, and substances. The committee recommends that the Army develop a streamlined, scientifically rigorous approach to categorize health hazards and, given the number of agents to be reviewed, a strategy to prioritize the evaluations. The committee proposes a strategy in Chapter 4.
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