4

Findings and Recommendations

This Institute of Medicine (IOM) committee was asked by the Department of Labor (DOL) to review and critique the scientific rigor of the Site Exposure Matrix (SEM) database used by DOL as one of many tools that support the claims process for Energy Employee Occupational Illness Compensation Program Act (EEOICPA) Part E (Public Law 106-398, Title XXXVI). The committee was specifically tasked with assessing the strengths and weaknesses of SEM with particular reference to the links between the toxic substances found at Department of Energy (DOE) nuclear facilities and occupational diseases that may result from exposure to them. Where possible, the committee was to identify any toxic substance—disease links missing from the database, to highlight other databases that might be used to supplement it, to comment on the review process for Haz-Map, and finally, to evaluate the National Library of Medicine’s peerreview process for the Haz-Map database, which is the sole source of the toxic substance—disease links in SEM.

Initially, the committee thought it would be a relatively straightforward process to review the links in Haz-Map and their incorporation into SEM, but this was not the case. The process by which toxic substances are determined to be the cause of an occupational disease in Haz-Map was not straightforward and the committee spent many hours attempting to identify the specific sources of the toxic substance—occupational disease links in Haz-Map. Furthermore, the information in only one of its fields, “Diseases” is imported into SEM, which contains more than 13,500 toxic substances, Haz-Map has more than 7,000—and not all of its substances are in SEM and vice versa. Therefore, much of the committee’s deliberations centered around whether to focus on the information in the Haz-Map, SEM, or both. The committee was also cognizant that it had not been



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4 Findings and Recommendations T his Institute of Medicine (IOM) committee was asked by the Department of Labor (DOL) to review and critique the scientific rigor of the Site Exposure Matrix (SEM) database used by DOL as one of many tools that support the claims process for Energy Employee Occupational Illness Compensa- tion Program Act (EEOICPA) Part E (Public Law 106-398, Title XXXVI). The committee was specifically tasked with assessing the strengths and weaknesses of SEM with particular reference to the links between the toxic substances found at Department of Energy (DOE) nuclear facilities and occupational diseases that may result from exposure to them. Where possible, the committee was to identify any toxic substance–disease links missing from the database, to highlight other databases that might be used to supplement it, to comment on the review process for Haz-Map, and finally, to evaluate the National Library of Medicine’s peer- review process for the Haz-Map database, which is the sole source of the toxic substance–disease links in SEM. Initially, the committee thought it would be a relatively straightforward process to review the links in Haz-Map and their incorporation into SEM, but this was not the case. The process by which toxic substances are determined to be the cause of an occupational disease in Haz-Map was not straightforward and the committee spent many hours attempting to identify the specific sources of the toxic substance–occupational disease links in Haz-Map. Furthermore, the information in only one of its fields, “Diseases” is imported into SEM, which contains more than 13,500 toxic substances, Haz-Map has more than 7,000—and not all of its substances are in SEM and vice versa. Therefore, much of the com- mittee’s deliberations centered around whether to focus on the information in the Haz-Map, SEM, or both. The committee was also cognizant that it had not been 95

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96 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE asked to comment on any aspect of the EEOICPA claims process other than the toxic substance–occupational disease information in SEM. The committee was also aware that approval of an EEOICPA claim is based on more than information in the SEM “Specific Health Effects” field and that each claim is considered on a case by case basis. HAZ-MAP FINDINGS In Chapter 2, the committee reviewed the approach used by the Haz-Map developer for linking toxic substances to occupational diseases. This approach was compared with those used by other authoritative organizations including the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences and the International Agency for Research on Cancer (IARC). These organizations also attempt to determine what, if any, diseases may be associated with exposure to toxic substances. The committee did not review every substance–disease link in Haz-Map or even all of the links that are imported into the DOL SEM. However, the committee has attempted to highlight areas where the Haz-Map “Disease” links are ambiguous or where the process for making those links is unclear. Although the committee is appreciative of the enormous amount of work that has gone into the development and maintenance of Haz-Map to assist health pro- viders in identifying and possibly preventing occupational disease, the committee identified several limitations to the database links in the Haz-Map “Diseases” field that is imported into SEM. These include the lack of transparency in data sources used for determining each toxic substance–occupational disease link and the criteria for establishing those links, particularly for noncancer endpoints; the lack of a clear weight-of-the-evidence approach; the lack of peer review; over- reliance on textbooks such that information may be neither comprehensive nor up-to-date; and the lack of clarity on which toxic substances and fields have been updated by the Haz-Map database developer. The committee finds that there is no formal oversight or review process for the Haz-Map “Disease” links and that such review is critical for ensuring the scientific rigor of and user confidence in the database, irrespective of its use in SEM. In particular, the committee finds that the scientific evidence base used for the Haz-Map toxic substance–disease links should be documented so that a user can verify the information and determine its accuracy, validity, and credibility, and its use of the most comprehensive and current information. Without identification of all sources of the underlying infor- mation, the accuracy and timeliness of the links cannot be determined. SEM FINDINGS SEM serves a key function in the EEOICPA Part E claims process. It is one of many tools used by DOL claims examiners to assess whether exposure to a

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FINDINGS AND RECOMMENDATIONS 97 toxic substance at a DOE facility caused an occupational disease. In its evalua- tion of the database, the committee noted several strengths, including its devel- opment in consultation with DOE experts and former workers and its attempt to comprehensively list all toxic substances found at DOE sites. However, the committee also identified major weaknesses in SEM, including difficulties in accessing information; the lack of detailed exposure information; poor handling of complex exposures, e.g., exposures to mixtures; the lack of clarity for why certain links are missing; incomplete or inconsistent exposure profiles for par- ticular locations and jobs; disregard of epidemiologic studies of DOE workers; and the sole use of Haz-Map for toxic substance–occupational disease links as discussed in Chapter 3. In particular, the committee found that the use of Haz-Map as the sole source of disease causation in SEM to be problematic. The committee conducted an extensive exercise to identify examples of toxic substance–disease links that are not currently in SEM. The results of the exercise identified substances categorized by IARC as having sufficient evidence in humans for cancers and these links were not listed in it. In addition, the exercise identified agents considered by IARC to have “limited” evidence for cancer in humans, based on epidemiologic stud- ies. These links are also not listed in SEM, although the committee recognizes that, given the Haz-Map criterion of including only IARC Group 1 substances for cancer links, substances with limited evidence of carcinogenicity would not be included in Haz-Map and, therefore, would also not be in SEM. The exer- cise also identified links between toxic agents and noncancer health effects that were missing in SEM. Overall, the committee found that links may be missing in SEM for several reasons, including ambiguous criteria for establishing the links in Haz-Map (the source of the SEM links); lack of consistency between the Haz-Map “Diseases” field and the SEM “Specific Health Effects” field for some substances; an inability to deal with complex exposures, e.g., exposures to mixtures; and delays in updating links in Haz-Map and, thus, in SEM. There are no explanations for why some links are excluded from SEM. Many, if not all, of these weaknesses could be addressed with modifications to this database as discussed in the following sections. RECOMMENDATIONS TO IMPROVE SEM After its review of Haz-Map and SEM, the committee has several recom- mendations that should help ensure that the toxic substance–occupational disease links in SEM are current, comprehensive, and transparent. The committee notes that these recommendations focus only on changes to SEM, and can be imple- mented even if no changes are made to the Haz-Map database. The reasons for this are several:

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98 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE • Haz-Map is an independently developed database that was developed prior to SEM and for purposes unrelated to SEM. • Haz-Map has other users outside of DOL, and the integrity of the infor- mation for those users should not be compromised. • Although Haz-Map is published by the National Library of Medicine (NLM); neither NLM nor DOL is responsible for its content. Ultimately, the developer is responsible for its content. • Only one field (“Diseases”) from Haz-Map is imported into SEM and is used by DOL claims examiners. The committee found that focusing on only the “Specific Health Effects” field in SEM as imported from the Haz-Map database field “Diseases,” without consideration of the EEOICP claims process, was difficult because its review lacked context. Furthermore, the focus on the “Specific Health Effects” field precluded consideration of many other aspects of occupational health such as the potential for exposure (concentration, frequency, duration), strength of asso- ciation between exposures and health effects, and exposure to more than one chemical at a time. Nevertheless, the committee came to three overarching rec- ommendations for DOL to improve the toxic substance–disease links in SEM. 1. Add supplemental information sources to the health effects information imported from Haz-Map. 2. Improve the structure and function of SEM, including the addition of available exposure information. 3. Use an external advisory panel to review the health effects information in SEM. Although those three recommendations focus on improving SEM, recom- mendations 1 and 3 and portions of recommendation 2 are also applicable to Haz-Map. The committee believes that establishing a formal oversight and review process for the Haz-Map database and using a weight-of-evidence approach are critical for both maintaining and expanding the Haz-Map database and for its use in SEM. Expansion of the information used in Haz-Map and inclusion of cita- tions for all the information in each of its fields would greatly enhance its utility not only for SEM but also for other users. Peer review of the database would also increase public confidence in its accuracy and comprehensiveness and help ensure that it contains the most current information available, irrespective of its use for SEM. Each of these recommendations is discussed in greater detail in the follow- ing sections.

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FINDINGS AND RECOMMENDATIONS 99 RECOMMENDATION 1: Use supplemental information sources for the Site Exposure Matrix database. To improve SEM, the committee found that supplemental data sources, in addition to the health effects links imported from Haz-Map, are necessary to provide a more comprehensive picture of the adverse effects that may be associ- ated with exposure to the toxic substances found at DOE sites. Many information sources are used by Haz-Map to support the toxic substance–occupational disease links, as discussed in Chapter 2. However, the evidence used to support each link is not cited, nor are all available sources of information on adverse effects asso- ciated with a toxic substance necessarily used. Furthermore, because Haz-Map, for the most part, lacks transparency as to the criteria used to establish the causal links, it may be overly conservative in making the links for cancers by using only IARC Group 1 designations. The committee recommends that additional IARC classifications (e.g., IARC 2A “probably carcinogenic to humans” and 2B “pos- sibly carcinogenic to humans”) and additional information on noncancer effects of agents be considered for inclusion in SEM in separate fields. These fields may be structured as text fields that could capture the variety of adverse effects for each substance. This supplemental information should also be cited and refer- enced specifically in each SEM field. For example, IARC has determined that for some substances there is “limited evidence of cancer in humans” at specific organ sites. These designations might meet the statutory requirement that a toxic substance be more than likely than not to cause an occupational disease. See Chapter 2 for a more detailed discussion of the IARC cancer classifications. The committee emphasizes that any supplemental information in SEM should include appropriate references; such references will enhance the rigor, robustness, and transparency of each link. The committee suggests that there are two types of information that might be used to supplement the “Specific Health Effects” field in SEM—bibliographic information sources (e.g., PubMed and TOXLINE), and evaluative information sources, such as those found in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS) database and the NTP Office of Health Assessment and Translation (OHAT) toxicology reports. Bibliographic sources are typically databases such as those mentioned above that provide refer- ences that must be screened and assessed by the user (e.g., case reports, cohort studies, mechanistic studies). While helpful in collating large numbers of publi- cations and indentifying new studies, bibliographic databases are labor intensive to use for tools such as SEM database because they require knowledgeable staff to screen, retrieve, and assess the references before they are added. Therefore, although the committee finds that the use of such databases and the references they contain may be helpful in supplementing the information in SEM, but they are not the ideal sources for readily available information. Evaluative information is a more likely source of supplemental information

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100 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE for SEM. The committee acknowledges that some sources of evaluative informa- tion are already used to make the toxic substance–disease links in Haz-Map and are cited in its reference list. However, the use of these sources does not appear to be consistent and, in some cases (such as the use of NTP OHAT toxicology reports), is missing entirely. The advantage of using these evaluative databases and documents is that they typically use a weight-of-evidence approach to reach conclusions about the strength of association between exposure to a toxic sub- stance and a health effect. They also have a defined methodology, describe the evidence base for their conclusions and, for the most part, are periodically updated with new evidence used and documentation of any changes to the con- clusions. Among the databases and documents that evaluate health effects for individual toxic substances or groups of related chemicals is the EPA’s IRIS database and background documents, the Agency for Toxic Substances and Dis- ease Registry’s (ATSDR’s) toxicological profiles, NTP OHAT toxicology reports, the background document preamble for the Occupational Safety and Health Administration permissible exposure limits, IARC monographs, the California Environmental Protection Agency’s (Cal/EPA’s) toxicity criteria database and staff reports, documentation for the American Conference of Government Indus- trial Hygienists (ACGIH) threshold limit values (TLVs), documentation for the National Institute for Occupational Safety and Health (NIOSH) recommended exposure limits, and the NIOSH Pocket Guide to Chemical Hazards. For virtually all these information sources, a group of experts reaches a conclusion on a sub- stance’s toxicity by using established criteria and a weight-of-evidence approach. The inclusion of supplemental materials in SEM may be done by listing each source in an individual data field (e.g., separate fields for ACGIH, EPA, NTP) that would then be available to the claims examiner and the general public. This supplemental information might include descriptions of synergistic and other chemical–chemical interactions, as well as data from other sources, for example, additional IARC designations, NTP documents, and epidemiologic studies on DOE workers. However, it might be preferable to include a comment or text field where all the supplemental information could be given in paragraph form, similar to the format used by the Hazardous Substances Data Bank (HSDB). In either case, all sources of information (i.e., specific citations) and the conclusion reached by each source should be included so the user can find it in the original documentation. The committee appreciates that claims examiners should not be required to synthesize the supplemental information to reach a nuanced conclu- sion about the strength of the association between exposure to a toxic substance and a possible health effect. The committee recommends that such syntheses be done by an expert advisory panel, as discussed later in this chapter. The committee recognizes that the causal links between toxic substances and diseases in Haz-Map, as currently imported into SEM, are established in the absence of site-specific exposure information. These links are not representative of any judgment about whether an individual’s disease was caused by the toxic

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FINDINGS AND RECOMMENDATIONS 101 substance, or whether any site-specific factors contributed to his or her disease. Including site-specific exposure information in SEM such as the dates a toxic substance was used at a site, would increase its transparency. However, such information is not equivalent to conducting a site-specific exposure assessment for an individual or a group of workers or to determining the likelihood that an individual developed a disease as a result of his or her workplace exposures. Such exposure-outcomes determinations are made by DOL on a case-by-case basis. RECOMMENDATION 2: Improve the structure and function of the Site Exposure Matrix database. The committee has a number of specific recommendations that it believes will help both the public and claims examiners to navigate the SEM database and more effectively retrieve information. The committee has tried to be realistic about making modifications to the database and limited the number of suggested changes. Nevertheless, it firmly believes that such changes will not only greatly improve the usability of the database, but also the strength of the associations between exposures to toxic substances and possible health effects. First, the committee believes that the current links between a toxic substance and an occupational disease must be appropriately referenced whether in SEM, Haz-Map, or, preferably both databases. The committee spent considerable time in attempting to determine the sources and specific evidence used to make the links in Haz-Map, and therefore in SEM, and in many cases was largely unable to do so. The Haz-Map “Diseases” field does not indicate specific documentation on which the disease link was based, although some documentation is presented in its “Comments” field for a substance and by clicking on the specific disease and reading the explanation of that disease. There is no reason why SEM cannot contain such references. Including appropriate citations in it would increase user confidence that the links were accurate, up-to-date, and scientifically rigorous. Because the toxic substance–disease links in SEM are imported from Haz-Map it might be easier to modify the latter rather than ask DOL staff to research the evidence base for the imported Haz-Map database links. Alternatively, the Haz- Map author could provide the documentation to the DOL for uploading to SEM. The committee found several statements about NLM involvement in SEM to be misleading and recommends that they be corrected. First, the database homepage states The relationship between toxic substances and diagnosed illnesses shown in SEM is derived from records of research by recognized medical authorities maintained by the National Library of Medicine. DOL continually updates these relationships as new disease associations are recognized by NLM. The causal links provided by NLM do not represent an exclusive list of the pathways neces- sary for an affirmative Part E causation determination. (http://www.sem.dol.gov; accessed December 7, 2012)

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102 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE The NLM publishes the Haz-Map database on its website, but other than copyediting the agent profile fields, including the chemical identification field and physical properties, and making the links to other NLM databases such as the HSDB, the NLM does not review the other Haz-Map fields for content. DOL also states on its page for “Occupational illnesses and toxic substances” that it includes “Toxic substances with an established causal link to the diagnosed illness as accepted by NLM.” NLM does not “recognize” or “accept” any of the links in Haz-Map nor does it make any judgments on the accuracy of its “Diseases” field; rather, the toxic substance–disease links are made solely by the developer. If the implication is that the links come from evidence in NLM MED- LINE database, then this also is not accurate, as many of the information sources cited in Haz-Map are not in any NLM database (e.g., textbooks). Second, the committee was initially confounded in its attempts to retrieve from SEM a comprehensive list of all toxic substances identified at more than one DOE site. SEM search capabilities could be improved by providing a direct link on its homepage (http://www.sem.dol.gov) to the database (http://www. sem.dol.gov/expanded), without first requiring that a specific DOE site be cho- sen. The expanded database allows users to see a list of all the toxic substances and all the health effects in it, but this option is not immediately evident on the SEM homepage. The committee also notes that it is difficult to find toxic substances or diseases in the database if the user misspells a word or does not know the correct terminology, and possible alternatives are not suggested to help the user. Although records in SEM indicate when a record was last updated, there is no specification as to what information or which field was updated, added to, or revised. The lack of such information makes it extremely difficult for the user to know if and when the most current information has been incorporated into the database. The committee also notes other areas where an improved SEM search func- tion would be helpful. The user cannot generate a list of toxic substances that have been used at more than one site or that are associated with a general job category (e.g., plumber). This makes it difficult for workers who may have been at more than one site to identify all toxic substances to which they may have been exposed without cross referencing each substance individually and compiling an external list. This is also true for health effects. The committee suggests that the search capabilities of SEM be expanded so that the user could enter a job descrip- tion (e.g., plumber), site (e.g., Hanford), and a disease (e.g., lung cancer), and retrieve a list of toxic substances that were used at that site, in that job category, and that might cause that disease. The committee was asked to comment on the Haz-Map review process con- ducted by National Institutes of Health (NIH)/NLM and the Haz-Map developer. The committee finds that there are several levels of review that should be applied

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FINDINGS AND RECOMMENDATIONS 103 to both Haz-Map and SEM. The peer-review process is discussed in the follow- ing section on the external advisory panel but a quality control review of both databases is critical to ensuring their accuracy. The IOM committee recommends that DOL or its contractor conduct a quality control review of all records to ensure that the data abstracted from each information source are correctly cited, have no typographic errors, and are complete (that is, no important information has been omitted and the information is not taken out of context). Although NLM performs a quality control review of a portion of each Haz-Map record, it reviews only the chemical identification information. The NIH/NLM review might be expanded to include the entire Haz-Map record. Finally, the committee notes that although SEM is considered to be a site exposure matrix, information on possible exposures to toxic substances at each DOE site is incomplete. To help evaluate whether an individual’s disease might result from his or her occupational exposures requires information on the dura- tion, intensity, frequency, and route of exposure. None of this exposure informa- tion, such as air monitoring data, is currently in SEM, however, inclusion of such information, if available, would enhance the utility of the database for both claimants and claims examiners. The committee suggests that the DOL give consideration to conducting a feasibility study to determine if and what exposure information could be included in SEM. RECOMMENDATION 3: Establish an expert advisory panel for the Site Exposure Matrix database. To accomplish the two major recommendations given above, the committee recommends that DOL establish an expert advisory panel. This is not the first time that such a panel has been suggested (e.g., 2010 GAO report; H.R. 1030), and there is a precedent for such a panel as required for EEOICPA Part B, that is, the Advisory Board on Radiation and Worker Health (see Chapter 3). The proposed EEOICPA Amendment Act of 2011 (H.R. 1030) would have required the president to establish an Advisory Board on Toxic Substances and Worker Health to review and approve the SEM. An expert advisory panel could perform several important functions with regard to SEM, but the committee believes that the primary function of the advi- sory panel would be a peer review of its toxic substance–occupational disease links. The expert advisory panel should be broad based, external to DOL and its current SEM contractor, and its membership should include such expertise as epidemiology, occupational medicine, toxicology, and industrial hygiene. The committee also recommends that the advisory panel include claimants and advo- cacy organization representation. The expert advisory panel would have several immediate tasks:

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104 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE • Establish the criteria for the evidence base for causal links between exposure to a toxic substance and an occupational disease; criteria might be expanded to include a category of “evidence of no association” as is used by IOM and IARC. • Determine the information sources that might be reviewed to identify information on possible links. • Develop a worksheet or other documentation to capture the evidence taken from each information source, including Haz-Map. • Oversee revisions of SEM to add appropriate fields for capturing supple- mental information (such as, chemical interactions, route of exposure, and IARC 2A designations), supplemental information sources (such as NTP, ATSDR toxicological profiles, and IRIS), and update information (such as the date of the last revision of the record and the fields revised). Whatever criteria are established by the expert panel, this committee sug- gests that the criteria be expanded to include a category to capture “evidence of no association,” as done by IOM and IARC. The committee recognizes that the expert advisory panel may be the most appropriate body to decide whether the criteria for making toxic substance–cancer links in SEM should be expanded to include substances considered by IARC as having limited evidence of cancer in humans (Group 2), and whether information on possible structure-activity rela- tionships might be useful. Inclusion of such information would not necessarily require a change in Haz-Map but might require an additional field in SEM. The expert advisory panel would also have several ongoing responsibilities in support of EEOICPA Part E: • Peer review of all new links in SEM that are based on both Haz-Map and the supplemental information described earlier. This might include determining whether the appropriate references are screened and the data are accurately cited. • Assessment of occupational diseases that might result from complex exposures. • Identification of potential new links and tracking them for possible future inclusion in SEM, including those suggested by external sources. • As time permits, review of existing causal links in SEM that are based solely on Haz-Map. • Periodic review of a sample of the toxic substance–disease links from both accepted and rejected claims to determine whether SEM links are actually assisting in the claims process and, if not, what improvements could be made in the toxic substance–disease links or what other infor- mation might be added to the SEM that would help claimants and claims examiners, such as available monitoring information, disease terminol- ogy, or results of cohort studies of DOE workers.

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FINDINGS AND RECOMMENDATIONS 105 The committee recognizes that peer review is not a simple task nor is the recommended expert advisory panel likely to solve the complex problem of pro- viding clear-cut links between every toxic substance in SEM and occupational diseases. Nevertheless, the committee believes that such a panel is essential if the database is to meet the scientific standards needed to ensure that both the DOL claims examiners and claimants have access to balanced, comprehensive, accurate, and understandable information. DOL need not develop its peer review process de novo. Other federal agencies (EPA in 2006 and the Office of Manage- ment and Budget in 2004) have prepared guidance on the peer review process for scientific documents. DOL may use this guidance for the SEM or require that Haz-Map use a similar process before the agency can import Haz-Map informa- tion into SEM. The committee also acknowledges that there are several approaches that may be used to institute a peer review process for SEM, all of which have advantages and disadvantages. However, a major feature of each option is that all information and actions would be documented so that the evidence base used to make decisions on toxic substances–occupational disease links could be reviewed by others and would be easy to understand. Each of these options is discussed below: 1. DOL may use an expert advisory panel to review only the evidence used for those Haz-Map links that are incorporated into the SEM “Specific Health Effects” field. The expert advisory panel could review the refer- ences used for each Haz-Map record and direct the DOL SEM contractor to make any changes as necessary. No changes would be required for Haz-Map although the IOM committee believes that such changes would strengthen it as well. 2. A DOL contractor would prepare a comprehensive profile for each toxic substance in SEM. The profile would include the Haz-Map information and any supplemental health effects information deemed appropriate by the expert advisory panel (e.g., other database profiles or docu- ments, such as NTP toxicological reports). The contractor might then make an initial recommendation regarding the toxic substance–disease links that should be included in SEM. The expert advisory panel would review all the information in the substance profile, along with the con- tractor’s recommendation and either approve the recommendation or modify it as necessary. This final recommendation on the appropriate toxic substance–disease link would then be entered into SEM by the contractor. 3. A DOL contractor would prepare a profile for each toxic substance as described in Option 2, but would not make any recommendations regard- ing a plausible toxic substance–disease link. The expert advisory panel would review each profile and using a weight-of-evidence approach,

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106 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE comes to a conclusion about to the strength of the association between exposure to a toxic substance and the development of an occupational disease. This toxic substance profile and the conclusions reached by the expert advisory panel would then be reviewed by one or more outside peer reviewers. Outside peer review comments would be considered by the expert advisory panel and responses to them would be incorporated into the profile. The revised (if necessary) conclusions of the expert advisory panel would then be included in SEM. An expert advisory panel will increase claims examiner and claimant confi- dence in the toxic substance–disease links in the SEM database. Given the wealth of health effects information available on toxic substances, the IOM committee believes that a transparent process for identifying, screening, and evaluating this information must be done by a group of experts using a weight-of-evidence approach. The expert advisory panel would also be ideally situated to review the public submissions of disease-related information (and exposure-related if the panel has appropriate expertise) and could provide detailed responses to public submissions requesting that a link be added to SEM. The IOM committee finds that there are excellent prototypes that DOL might consider for establishing its expert advisory panel. First, in support of EEOICPA Part B, the law mandates that a review panel oversee the NIOSH radia- tion dose–reconstruction process, determine whether there should be additional special exposure cohorts, and develop guidelines to assess the likelihood that an employee’s cancer was caused by his or her work at a covered site. This Advisory Board on Radiation and Worker Health may provide the most relevant prototype for an expert advisory panel for Part E. Other federal agencies also use advisory panels. For example, the EPA Toxic Substances Control Act Interagency Testing Committee reviews toxicity and exposure information on numerous substances for possible inclusion on the EPA’s Priority Testing List. NIH has several study groups that review numerous grant applications. NLM also has a group of experts that periodically reviews information for HSDB records. Several of these panels are responsible for reviewing a wealth of information on a volume of substances in a timely manner, typically with contractor support to gather and abstract rel- evant information. In summary, the committee appreciates the need for and the utility of SEM as well as the urgency with which it was developed. However, as the EEOICP claims process has evolved and new claims continue to be submitted to DOL, the need for peer review of SEM (and Haz-Map) has increased. The committee believes that with implementation of its recommendations, DOL will improve its claims process for both claims examiners and claimants.

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FINDINGS AND RECOMMENDATIONS 107 STATEMENT OF TASK QUESTIONS AND RESPONSES In addition to offering recommendations to improve SEM, the committee provides here concise responses to the eight questions in its Statement of Task. 1. What, if any, occupational diseases that might have affected the DOE contractor workforce are missing from SEM? The committee examined the list of diseases in SEM and found that some diseases such as those of the cardiovascular system and ovar- ian cancer are not listed in it. Occupational diseases are listed in SEM only if they are associated with exposure to a toxic substance, so dis- eases associated with a particular job or worker population may not be included. Such organizations as IARC also look at associations between specific occupations (including painters and welders) and diseases in those workers without reference to exposure to specific toxic substances. DOL should consider those types of associations to identify other occu- pational diseases that may affect the DOE contractor workforce. Further- more, epidemiology studies conducted on DOE worker cohorts are not included in SEM. Given the opportunity to assess effects in the popula- tion of interest, results of those studies should be carefully considered by DOL and the recommended expert advisory panel. 2. What, if any, links between occupational diseases and toxic sub- stances present at DOE sites are missing from SEM? The committee notes that some links between toxic substances found at DOE sites and diseases associated with them are not in SEM, such as the link between asbestos and ovarian cancer. The committee notes, however, that given the lack of exposure information in SEM—including period of use and intensity and frequency of exposure—it is difficult to ascertain whether occupational exposures were acute or chronic and were sufficient to result in chronic occupational disease. The committee did not conduct a systematic review of all the substance–disease links in SEM, which includes more than 13,000 substances and more than 120 occupational diseases. 3. Is there additional literature (preferably human epidemiological in nature) that might be incorporated into SEM to strengthen or add to the existing links between toxic substances and occupational diseases? Are the existing links sufficiently robust? Because SEM incorporates toxic substance–occupational disease links only from Haz-Map, any information missing from Haz-Map is nec- essarily missing from SEM. Because Haz-Map does not adequately reference the evidence used to establish each toxic substance–disease

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108 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE link (except for cancer), the committee was unable to determine what additional literature might make the Haz-Map links more robust. The committee strongly recommends that evidence used to establish the Haz-Map links be clearly referenced in the Haz-Map “Diseases” field. Furthermore, the committee has commented on the information sources used for Haz-Map (see Chapter 2) and on the use of additional epide- miologic information in SEM (see Chapter 3), particularly the use of DOE worker cohort studies. Better and more comprehensive use of the existing data sources, such as IARC and ATSDR, and new ones—such as Cal/EPA OEHHA background documents, NTP, and IRIS—would substantially improve the robustness of the links in both Haz-Map and SEM. The recommended expert advisory panel could provide advice on the best way to incorporate the epidemiologic studies conducted in DOE worker populations; the exposures of these workers are directly relevant to the claimant populations. 4. What, if any, other occupational disease databases might be used to supplement the Haz-Map information in SEM? Haz-Map is used for SEM because it provides causal toxic substance– occupational disease links in an easily captured field. Haz-Map is a unique database, and the committee was unable to identify any other databases that explicitly link occupational exposures to toxic substances to occupational diseases. However, the committee does not believe that lack of such databases means that other sources of information might not be used to supplement either Haz-Map or SEM. The committee emphasizes that databases alone, whether occupational or other, are not sufficient resources to supplement Haz-Map information in SEM, and it recommends that such documents as ATSDR toxicological profiles, NTP reports, and EPA background documents be reviewed by the proposed expert advisory panel. Many of those documents contain information on health effects seen in worker populations that have been exposed to the substances of interest. Another database that might be used is EPA’s IRIS, which has clear documentation of the evidence on which EPA’s conclusions are based. 5. How scientifically rigorous are the disease links contained in SEM and Haz-Map? The toxic substance–disease links in Haz-Map, and thus in the SEM, for cancer are scientifically rigorous inasmuch as they are based solely on IARC’s determination that there is sufficient evidence that a given substance is carcinogenic in humans (Group 1). However, for noncan- cer health effects in Haz-Map and SEM, it is difficult to determine the evidence base for some of the links. Therefore, the committee is unable

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FINDINGS AND RECOMMENDATIONS 109 to state with certainty how rigorous the links are and finds that the rigor of links varies. In some cases disease links are based on one case report and in others on a substantial body of evidence. Furthermore, the links for mixtures are not robust. 6. What are the strengths and weaknesses of the NIH/NLM peer review process with regard to Haz-Map? How might this process be improved? There is no NIH or NLM peer review process for Haz-Map. The com- mittee finds that that is a critical weakness for the database. NLM indi- cated that its staff copyedits the toxic substance profiles for Haz-Map and makes the links to other NLM databases, such as the Hazardous Substances Data Bank (HSDB), but NLM does not conduct any peer review of the substance–disease links determined by the Haz-Map devel- oper. NLM also does not conduct peer review of any of the publications listed in PubMed; that is the responsibility of each journal. NLM does not conduct peer reviews of any external publications, even manuscripts. It is merely a platform for Haz-Map, and has little involvement in content. NLM does facilitate the peer review process for the HSDB, a database cited in Haz-Map, using an external group of experts. There are several options for a peer review process for both Haz-Map and SEM. 7. Can any known (epidemiologically significant) synergistic effects between chemicals/chemicals or chemicals/radiation be placed in SEM? If so, what are the sources of these links and are they occu- pational in nature? Research on synergism underscores that this type of chemical–chemical interaction is a valid scientific phenomenon. Such interactions, some of which are occupational, could be flagged in SEM for evaluation case by case. ATSDR and EPA conduct health assessments of chemical interac- tions, and these could be included in SEM in a new field as supplemen- tal information. The evidence base on chemical–radiation interactions is less robust, especially in humans. However, as more information becomes available, the proposed expert advisory panel could revisit this topic and determine whether such interactions should be flagged in SEM. 8. What consistent process or approach could be used to consider a disease or cancer established when studies are inconclusive, incon- sistent, or conflicted in some way? As discussed above, the committee strongly recommends that an expert advisory panel be established to review the evidence on any potential toxic substance–disease link. Such a panel, using a weight-of-evidence

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110 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE approach, could determine how to assess inconclusive, inconsistent, or conflicted studies for purposes of evaluating whether there is a causal link. The panel may wish to develop its own criteria for weighing evi- dence or use criteria established by other authoritative organizations, such as IARC, NTP, and IOM.