2

Haz-Map Database

The Haz-Map database contains health effects information on hazardous agents found in the workplace. Haz-Map uses the term “hazardous agents” to refer to physical, chemical, and biologic substances that occur in the workplace. The original concept for Haz-Map asked the question: “Why can’t we have a relational database of toxic chemicals and occupational diseases to store and query information similar to ones used by companies to manage data about employees, products, and customers?” (Brown, 2008b). The database was designed “for health and safety professionals and for consumers seeking information about the adverse effects of workplace exposures to chemical and biological agents” (http://hazmap.nlm.nih.gov/about-us; accessed December 19, 2012). It was not designed for compensation purposes. One field in Haz-Map, “Diseases,” contains links between toxic substances and associated diseases, illnesses, or other adverse health outcomes. This field is incorporated into the Department of Labor’s (DOL’s) Site Exposure Matrix (SEM) database as a tool to assist Energy Employees Occupational Illness Compensation Program (EEOICP) Part E claims examiners in assessing whether occupational exposure to a toxic substance present at a Department of Energy (DOE) facility is associated with an occupational disease (see Chapter 3).

DEVELOPMENT OF HAZ-MAP

Haz-Map was developed in 1991 by Jay Brown, a physician board certified in occupational medicine who has substantial clinical primary care experience (Brown, 2008a). The initial development effort was to collect and distill information needed to recognize and prevent both acute and chronic occupational



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2 Haz-Map Database T he Haz-Map database contains health effects information on hazardous agents found in the workplace. Haz-Map uses the term “hazardous agents” to refer to physical, chemical, and biologic substances that occur in the workplace. The original concept for Haz-Map asked the question: “Why can’t we have a relational database of toxic chemicals and occupational diseases to store and query information similar to ones used by companies to manage data about employees, products, and customers?” (Brown, 2008b). The database was designed “for health and safety professionals and for consumers seeking informa- tion about the adverse effects of workplace exposures to chemical and biological agents” (http://hazmap.nlm.nih.gov/about-us; accessed December 19, 2012). It was not designed for compensation purposes. One field in Haz-Map, “Diseases,” contains links between toxic substances and associated diseases, illnesses, or other adverse health outcomes. This field is incorporated into the Department of Labor’s (DOL’s) Site Exposure Matrix (SEM) database as a tool to assist Energy Employees Occupational Illness Compensation Program (EEOICP) Part E claims examiners in assessing whether occupational exposure to a toxic substance pres- ent at a Department of Energy (DOE) facility is associated with an occupational disease (see Chapter 3). DEVELOPMENT OF HAZ-MAP Haz-Map was developed in 1991 by Jay Brown, a physician board certified in occupational medicine who has substantial clinical primary care experience (Brown, 2008a). The initial development effort was to collect and distill infor- mation needed to recognize and prevent both acute and chronic occupational 25

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26 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE diseases, thus only “the most useful information” was included (Brown, 2008b). It is a “decision-support relational database” designed to “map the knowledge domain of occupational exposures and diseases” for safety and health profession- als (Brown, 2008b). In this respect, Haz-Map is a major endeavor. It provides an important information resource for health care professionals as well as for the public. Although Haz-Map was initially developed and maintained privately, since 2002 the National Library of Medicine (NLM) has published Haz-Map on its website (http://hazmap.nlm.nih.gov). The database is updated quarterly for con- tent based on changes made by the developer (Brown, 2008a). In addition to Haz-Map, NLM publishes other databases that contain information on toxicology, hazardous chemicals, environmental health, and toxic releases, such as TOXNET, MEDLINE, PubMed, and ClinicalTrials.gov. NLM has a licensing agreement with the Haz-Map developer and NLM staff review the agent’s identity and physical properties (the chemical profile) and make the links to other NLM sponsored databases, such as the Hazardous Substance Data Bank (HSDB) and PubMed (Hakinnen, 2012). However, NLM has indicated that other information in the database, such as exposure assess- ment information and the toxic agent–disease links, are not reviewed or verified by NLM staff, although NLM occasionally identifies opportunities to add new substances to the database, e.g., isocyanates, that are of interest to the scientific community (Hakkinen, 2012). CONTENT OF HAZ-MAP The two major types of information in Haz-Map are lists of toxic substances (the industrial hygiene perspective) and lists of occupational diseases (the epi- demiological perspective). Information is contained in eight linked tables and numerous fields (see Figure 2-1). The database was not designed “to list every disease that could possibly be work related, but to focus on established occu- pational diseases and their causes” (Brown, 2008a). It should be noted that the database was developed to provide useful information to meet the needs of a wide range of health and safety professionals; therefore, the hazardous job tasks, industries, and occupations, and the industrial processes listed are broad and include many jobs and industries that may be unrelated to occupational activities that were performed at DOE sites (for example, bartender). The database originally began with the 700 chemicals listed in the National Institute for Occupational Safety and Health (NIOSH) Pocket Guide to Chemi- cal Hazards (available at http://www.cdc.gov/niosh/npg) and it has since been updated with additional chemical or biological agents associated with 235 occupational diseases, “using selected references from the scientific literature” (Brown, 2008b). As of December 2012, there were more than 7,000 hazardous agents listed. A description of the development of Haz-Map, the information

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HAZ-MAP DATABASE 27 Signs and Symptoms Industries Occupational Hazardous Diseases Job Tasks Occupations Industrial Processes Toxic Chemicals Home Activities FIGURE 2-1  Links between fields in the Haz-Map database. SOURCE: Brown, 2012c. Figure 2-1 contained in many of its fields (see Table 2-1), and how and why that information was selected is given at www.haz-map.com. Information is not always available for each field for every agent, particu- larly for the fields in the categories of Exposure Assessment and Adverse Effects. In part, this is because for many of the hazardous agents listed in Haz-Map, there is little or no industrial hygiene, toxicologic, or epidemiologic literature on the agent. The lack of information about a specific agent may be due to a number of factors, such as its low production, specialized use (that is, it is not com- monly used in industrial processes), transient nature in the environment, that it is a by-product or occurs in a closed system, or has not been tested for toxicity. Blank fields are not included in the database; for example, there is no biological exposure index (BEI) for formaldehyde, so that particular field is not listed in the formaldehyde record (see Box 2-1). The category of Adverse Effects includes several fields for those health effects that have been associated with the hazardous agent based on the developer’s review of selected references. See Box 2-1 for an example Haz-Map profile for kerosene.

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28 TABLE 2-1  Categories and Fields for Each Hazardous Agent Record in Haz-Map a Categories Links to Other NLM Agent Information Exposure Assessment Adverse Effects Databases Related Information in Haz-Map Fields Agent Name Skin Designation (ACGIH) Skin Sensitizer Health Studies Diseases (occupational diseases CAS Number BEI Asthma Toxicity Information associated with exposure to this Formula TIH Toxic Pneumonitis Chemical Information agent)b Major Category TLV (ACGIH) Dermatotoxin Biomedical References Symptoms/Findings (symptoms/ Synonyms Ceiling (ACGIH) IARC Carcinogen findings associated with this Category PEL (OSHA) Lacrimator disease) Description MAK Hepatotoxin Processes Sources/Uses IDLH and Excerpts from Neurotoxin Activities Comments Documentation for IDHLs Other Poison Restricted Vapor Pressure Methemoglobinemia Reference Link Odor Threshold (low and high) Anemia RD50 Reproductive Toxin Lethal Concentration Nephrotoxin WEEL Hematotoxin Explanatory Notes and Other Endpoints Half Life Reference Link Flammability (NFPA) NOTE: ACGIH = American Conference of Government Industrial Hygienists; BEI = biological exposure index; CAS = Chemical Abstracts Service; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or health concentrations; MAK = Maximale Arbeitsplatzkonzentrationen (German occupational exposure limit); NFPA = National Fire Protection Association; NLM = National Library of Medicine; OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; RD50 = exposure concentration producing a 50% respiratory rate decrease; TIH = toxic inhalation hazard; TLV = threshold limit value; WEEL = workplace environmental exposure level. aCategories and fields are based on those listed in agent profiles at http://hazmap.nlm.nih.gov. bThe “Diseases” field is the only one used by the SEM database. SOURCE: http://hazmap.nlm.nih.gov (accessed November 1, 2012).

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HAZ-MAP DATABASE 29 BOX 2-1 Haz-Map Profile for Kerosene Agent Name Kerosene CAS Number 8008-20-6 Major Category Solvents Synonyms  Fuel Oil No. 1; Range oil; [NIOSH] Deo- dourized kerosene; Deobase; Deodor- ized kerosine; Ultrasene; [CHEMINFO] UN1223 Category Petroleum, Refined Description  Colorless to yellowish, oily liquid with a strong, characteristic odor; [NIOSH] Sources/Uses  Used in jet, diesel, and tractor fuels; also used as a heating fuel and solvent; [Hawley] Comments  TSCA Definition 2008: A mixture of crude oil distillates with carbon numbers of C9 to C16 and boiling points of 180 deg C to 300 deg C; [ChemIDplus] Petroleum distillates, e.g., VM & P naphtha and kerosene, can cause anesthesia, slowing of reflexes, and dermatitis. They may con- tain n-hexane with the potential to cause peripheral neuropathy. [LaDou, p. 500-1] Kerosene is a refined petroleum solvent (predominantly C9-C16), which typically is 25% normal paraffins, 11% branched paraffins, 30% monocycloparaffins, 12% dicycloparaffins, 1% tricycloparaffins, 16% mononuclear aromatics, and 5% dinuclear aromatics. [NIOSH] Gasoline (C8-C10) causes trivial liver injury in animal studies; No known injury in human cases; [Haddad, p. 226t] See “Distillates (petroleum), hydrotreated light,” “Naphtha (petroleum), hydrotreated heavy,” and “Solvent naphtha (petroleum), heavy aliphatic.” Reference Link ATSDR - ToxFAQs - Fuel Oils / Kerosene continued

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30 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE BOX 2-1 Continued Exposure Assessment Skin Designation (ACGIH) Yes TLV (ACGIH)  200 mg/m3, total hydrocarbon vapor Vapor Pressure 0.48 mm Hg Odor Threshold Low 3 mg/m3 Lethal Concentration LC50 > 5,000 mg/m3/4h Explanatory Notes  Detection odor threshold from CHEMINFO; Flammability (NFPA)  High ambient temperature required 2: Adverse Effects Neurotoxin CNS Solvent Syndrome Hepatotoxin  Hepatotoxin, Secondary Links to Other NLM Databases Health Studies  Human Health Effects from Hazardous Substances Data Bank: •  EROSENE K Toxicity Information Search TOXNET Chemical Information Search ChemIDplus Biomedical References Search PubMed Related Information in HazMap Diseases  Occupational diseases associated with exposure to this agent: •  ncephalopathy, chronic solvent E •  olvents, acute toxic effect S Processes I ndustrial Processes with risk of exposure: •  etal Degreasing M • Painting (Solvents) • Petroleum Production and Refining Activities Activities with risk of exposure: • Intalagio printing NOTE: Only the “Diseases” field, in orange, is used in the Site Exposure Matrix database. SOURCE: http://hazmap.nlm.nih.gov/category-details?id=172&table=copytblagents (accessed December 5, 2012).

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HAZ-MAP DATABASE 31 HAZ-MAP INFORMATION SOURCES Information from numerous textbooks, journal articles, and electronic data- bases is cataloged and summarized to populate the Haz-Map database and to identify causal links between hazardous agents and occupational diseases (Brown, 2008a). The list of references used for the database is available at http://hazmap. nlm.nih.gov/references. As of December 2012, there were 35 online books and databases; 60 books, compact discs, and journal articles; 15 references specific to ionizing radiation; and 12 other websites used as data sources. Although some of the Haz-Map information sources, such as the HSDB, are available online to the general public, others, such as REPROTOX, are not. This makes it difficult to determine whether the most current information has been used for a database record, when a record was last updated, and what changes to the record were made. Furthermore, most of the cited textbooks are also not available online or in many libraries and reference collections, including DOL’s and many university medical libraries. With respect to journal articles, the Haz-Map developer informed the com- mittee that periodically, all journal articles in selected journals are reviewed. The last re- views were done in 2008 and 2011. The selected journals are: Am J Ind Med, Chest, Int Arch Occup Environ Health, J Occup Environ Hyg, J Occup Environ Med, Occup Environ Med, and Scand J Work Environ Health. (Brown, 2012c,d) There are no transparent selection criteria for the use of those particular journals or for the articles that are cited from them. The committee emphasizes that many other peer-reviewed journals (e.g., Allergy, Annals of Occupational Hygiene, British Medical Journal, Environmental Health Perspectives, Journal of Allergy and Clinical Immunology, Thorax) also publish studies on the health effects of occupational exposures to toxic substances. To be more comprehensive, these and other journals should also be reviewed for Haz-Map. TOXIC SUBSTANCE–DISEASE LINKS For EEOICPA Part E, the causation standard is “it is at least as likely as not that exposure to a toxic substance at a Department of Energy facility was a significant factor in aggravating, contributing to, or causing the illness; and it is at least as likely as not that the exposure to such toxic substance was related to employment at a Department of Energy facility” (Public Law 108-375 § 3161). The DOL claims examiners use the “Specific Health Effects” field in SEM, imported from the Haz-Map “Diseases” field, for an initial assessment of whether a claimant’s occupational exposure to a toxic substance at a DOE site is causally associated with the claimant’s diagnosed disease. Thus, SEM (and the links sup- plied by Haz-Map) has an impact on the claims examiner’s preliminary decision

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32 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE on whether a causal link between the claimant’s potential exposure and disease meets the causation standard. To assess the adequacy of the evidence for causal links between toxic substances and diseases given in the Haz-Map “Diseases” field requires a more general discussion of how scientific data are used to assess association and causality. The committee recognizes that concepts of association and causality for the assessment of the impact of agents on human health are complex. This section provides a brief primer on the concepts of strength of association and causality; more information on these topics may be found from a number of organiza- tions, e.g., the Institute of Medicine (IOM), the U.S. Environmental Protection Agency (EPA), the International Agency for Research on Cancer (IARC), and the National Toxicology Program (NTP). How an organization addresses these concepts may depend on factors such as public perception, ethical approaches to the common good, or the purpose for which the information is to be used (e.g., regulatory, guidance). Regardless of the goal, determining a causal association must be based on a careful review of all the available evidence. For example, the EPA and the Occupational Safety and Health Administration (OSHA) might rely on the same animal and human toxicity data for a toxic substance, however, each agency might apply the information differently to determine an association or causation, or to conduct quantitative risk assessments. Determining a causal link is challenging and often requires decision making in the face of uncertainty. Relationships between exposure and health effects can be obtained from in vivo studies in humans or animals, or from ex vivo and in vitro studies in tissues or cells. To determine whether a hazardous agent is likely to be causally associated with a specific health effect, scientists evaluate the relationship between exposure to the substance and any subsequent biological responses. Observing a greater response (e.g., a greater number of individuals with a specific disease or increased severity of effect) at higher exposure levels provides evidence that a toxic substance may cause the observed response. Types of health effects observed following exposure to a toxic substance can be broadly categorized as acute effects (i.e., the effects occur within 24 hours following exposure) or chronic effects (i.e., long-term) and in terms of whether effects occur at the point of contact with the toxic substance (i.e., local effects) or elsewhere in the body, following absorption (i.e., systemic effects). The result of many human epidemiologic studies is a measure of strength of the association between an exposure and a health outcome. Association is primar- ily a statistical concept referring to the quantification of the relationship (positive, negative, or none) between two variables (e.g., the exposure and the outcome). The observational nature of epidemiologic studies means that causality cannot generally be established directly using only one epidemiologic study because there may be other reasons for the positive association, including random error (chance), systematic error (bias), and reverse causality (where the outcome itself may have influenced the chance of exposure). Therefore, different approaches

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HAZ-MAP DATABASE 33 have been developed for evaluating causality, all of which involve considering a body of evidence and confounding factors. In the following sections, the committee comments briefly on the use of vari- ous types of evidence—epidemiologic studies, animal studies, and mechanistic studies—used in assessing associations between exposure and outcomes. It then presents an overview of various approaches used by several scientific organiza- tions such as IARC and IOM for assessing causality and other levels of associa- tion. The committee concludes with a discussion of the Haz-Map approach to causal links and its implementation. Types of Evidence Many types of evidence can be considered when looking at the relationship between exposure to a toxic substance and health effects or disease. This evidence can include large, well-conducted clinical controlled trials such as those used for pharmaceutical agents; epidemiologic studies where groups of humans are evalu- ated to see if exposures have an impact on health; animal studies to determine the toxicity of an agent; and mechanistic studies, often conducted in vitro or at the subcellular level to determine the biological mechanisms by which an agent produces an outcome. Each of these studies is described briefly below to highlight the wealth of information that may be considered when evaluating the impact of an agent on the health of an organism. The committee notes that this section is not intended to be a comprehensive description of epidemiology, toxicology, or occupational medicine. Epidemiological Studies Most epidemiological studies are observational rather than experimental. Three study designs commonly used for epidemiologic research are cohort, case- control, and cross-sectional (IOM, 2010). A cohort study follows a defined group over a period of time. Using data from a cohort study, investigators can test hypotheses about whether a specific exposure is related to the development of one or more health outcomes. A cohort study starts with people who are free of a disease (or other outcome) and clas- sifies them according to whether they have been exposed to the agent of interest and, usually, the level of exposure. The rate of the occurrence of a health outcome in the group over a specific period of time is determined (incidence rate) (IOM, 2010). Cohort studies can be prospective or retrospective. In a retrospective cohort study, investigators usually rely on records to determine past exposures for the cohort and another record system (e.g., medical records, death certificates, ques- tionnaires) to ascertain the occurrence of disease. In a prospective cohort study, both the exposure and the disease assessment methods can be designed by the

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34 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE investigator rather than relying on existing records. However, this study design will not be able to provide sufficient data on chronic disease risk factors until a number of years, if not decades, of follow-up time have accrued. This is because many exposure–disease associations have a long induction and latency period; that is, a protracted time interval between exposure to a toxic substance and the diagnosis of a resultant health outcome. For some exposure–disease associa- tions, often involving chronic diseases that can occur at older ages (such as some cancers and cardiovascular disease), this induction and latency period can be 20 years or more. A hazard ratio or a rate ratio greater than 1.0 indicates that there is a potential association between exposure to the agent and the disease, and the further from 1.0, the stronger the association, whether the association is positive or negative. Statistical analysis methods allow the investigator to control for other factors that might influence the risk of the disease or the relationship between the exposure and the disease (e.g., age, sex, smoking status). Therefore, results are usually adjusted for these factors (IOM, 2010). In a case-control study, subjects (cases) are selected on the basis of hav- ing a disease, and controls are selected on the basis of not having the disease. Information about cases and controls is collected from available records. Such potential factors as age, sex, and socioeconomic status that may affect results can be assessed in the epidemiologic analysis or by appropriately matching case and controls for those factors. An odds ratio is used in case-control studies to statisti- cally describe the odds of having exposure among those with disease relative to the odds of having the exposure in the comparison group without disease. As with the epidemiologic parameters for a cohort study, an odds ratio of greater than 1.0 indicates that there is a positive association between exposure to an agent and the disease (IOM, 2010). Case-control studies are especially useful and efficient for studying rare dis- eases and multiple exposures, and these have the advantages of ease, speed, and relatively low cost. However, they are vulnerable to several types of bias, such as recall (when reporting of an exposure is influenced by whether the participant has the outcome of interest), which can enhance (or dilute) apparent associations between disease and exposure. Other difficulties include the ability to identify representative groups of cases, choose suitable controls that represent the same population that gave rise to the cases, and collect comparable exposure informa- tion for both cases and controls (IOM, 2010). In cross-sectional studies, exposure and disease information is collected at a point in time. The selection of people for the study—unlike selection for cohort and case-control studies—is independent of both the exposure to the agent under study and the disease characteristics. In such studies, disease or symptom prevalence (the proportion of people with the disease at a specific time) between groups with and without exposure to the specific agent is compared using a risk ratio or risk difference. For example, workers in one facility that used a chemical may be compared with workers at another facility that did not use the chemical.

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HAZ-MAP DATABASE 35 The major difference between prevalence and incidence (as calculated in a cohort study), is that the latter is a measure of the new cases occurring over a given period of time (IOM, 2010), rather than a mere count of all cases in existence at a particular point in time. Cross-sectional studies are easier and less expensive to perform than cohort studies and they can identify the prevalence of diseases and exposures in a defined population. They are not very useful for determining cause and effect relation- ships, because disease and exposure data are collected simultaneously (Monson, 1990). For this reason, it may be difficult to determine the temporal sequence of exposures and symptoms or disease (IOM, 2010). Case reports of exposure to a chemical with resulting disease in one or more individuals, while not formally research studies, may provide additional support for causal links. Case reports by themselves rarely provide enough information to describe a causal association between exposure and disease that is free of bias and uncertainty (IOM, 2010). Toxicological Studies In animal toxicologic studies, it is possible to define and control exposures and factors such as diet and ancillary exposures that may influence response to a chemical much more precisely than in human studies. Thus, in animal studies it is much easier to identify substance-specific effects. Effects observed in ani- mals, however, may differ both quantitatively and sometimes qualitatively from effects in humans. For example, rats are much more susceptible to the effects of perchlorate, which inhibits uptake of iodine by the thyroid, than are humans (Lewandowski et al., 2004). Conversely, rats and mice do not exhibit the same hemolytic toxicity to naphthalene seen in humans, and even the two species differ in their susceptibility to the chemical (Wakefield, 2007). Such toxicologic differ- ences reflect species differences in how substances are distributed, modified, and eliminated once they enter the body. Because of these differences, results from animal studies alone are generally not sufficient to establish that exposure to a substance causes a specific health outcome in humans. Rather, animal studies can be used to support observations from human studies, to identify potential links between exposure and specific health outcomes in humans, or to provide hypotheses about what exposure and outcome relationships should be of concern. Furthermore, animal studies are often the best approach for understanding the mechanism of a toxic effect and for demonstrating interaction between substances (discussed in Chapter 3). The investigator must be aware that there may be sub- stantial differences due to physiology and other factors inherent in any animal model. Animal studies are also useful when it is unethical or impractical to study potentially harmful exposures in humans.

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40 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE When a judgment has been reached that there is sufficient evidence that an agent causes disease, it means that a working group of subject matter experts has evalu- ated and judged the body of evidence and concluded that a relationship has been observed between the exposure and cancer in studies in which chance, bias, and confounding could be ruled out with reasonable confidence (IARC, 2006). National Toxicology Program The NTP Office of Health Assessment and Translation (OHAT) of the National Institute of Environmental Health Sciences also reviews data to describe the health effects caused by exposure to a toxic substance. As with many other government agencies, the process used by OHAT to develop its monographs on substances includes a “methods” section that explicitly indicates how the litera- ture search was conducted, how studies were selected and reviewed, how the evidence was evaluated and weighed to come to the conclusions in the reports, and the peer review process (including the names of peer reviewers) used for each report. The NTP evaluates toxic substances using categories of association similar to those of IARC, IOM, and other organizations—sufficient evidence of association, limited evidence of association, inadequate evidence of an associa- tion, and evidence of no association. These categories of evidence and association are described in the methods section of each NTP report, for example, Health Effects of Low-level Lead Evaluation (HHS, 2012). Institute of Medicine Many IOM committees use a formal system similar to those of IARC and NTP to assess the weight-of-evidence and determine the strength of association between exposure to a hazardous agent and a health outcome (IOM, 2010). As with other approaches to assessing cause and effect, the IOM uses committees of experts who first evaluate the available evidence (typically from peer-reviewed studies). All committee members then reach a consensus on the conclusion and assign a category of association for each health outcome based on the number and quality of studies and expert judgment (see Box 2-3). The committees do not use a formulaic approach to assign a specific category of association; rather they have found that each health outcome requires a more considered and nuanced approach (IOM, 2010). EPA has used the IOM approach for its integrated scientific assess- ments for criteria air pollutants since 2008. Establishing Hazardous Agent–Occupational Disease Links in Haz-Map The committee’s understanding of the Haz-Map database approach to link- ing hazardous agents and occupational diseases is based on information provided by its developer and found at www.haz-map.com. The committee notes that this

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HAZ-MAP DATABASE 41 BOX 2-3 Categories of Associations Used by Several IOM Committees • Sufficient Evidence of a Causal Relationship: Evidence is sufficient to conclude that a causal relationship exists between an exposure and a health outcome. The evidence fulfills the criteria for sufficient evidence of a causal association in which chance, bias, and con- founding can be ruled out with reasonable confidence. The asso- ciation is supported by several of the other considerations used to assess causality: strength of association, dose-response relation- ship, consistency of association, temporal relationship, specificity of association, and biologic plausibility. • Sufficient Evidence of an Association: Evidence suggests an asso- ciation, in that a positive association has been observed between an exposure and a health outcome in humans; however, there is some doubt as to the influence of chance, bias, and confounding. • Limited/Suggestive Evidence of an Association: Some evidence of an association between an exposure and a health outcome in humans exists, but this is limited by the presence of substantial doubt regarding chance, bias, and confounding. • Inadequate/Insufficient Evidence to Determine Whether an Associa- tion Exists: The available studies are of insufficient quality, validity, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between an exposure and a health outcome in humans. • Limited/Suggestive Evidence of No Association: There are several adequate studies, covering the full range of levels of exposure that humans are known to encounter, that are consistent in not show- ing an association between an exposure and a health outcome. A conclusion of no association is inevitably limited to the conditions, levels of exposure, and length of observation covered by the avail- able studies. In addition, the possibility of a very small increase in risk at the levels of exposure studied can never be excluded. SOURCE: IOM, 2010. information is not provided on the NLM Haz-Map website—located at http:// hazmap.nlm.nih.gov—although there is a link for direct users to more informa- tion at www.haz-map.com. The developer told the committee that he tries to answer the following questions when determining whether exposure to a hazard- ous agent may cause an occupational disease: “Is there consensus in occupational medicine textbooks that this occupational disease is caused by these hazardous

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42 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE agents? Can the disease be prevented by good occupational hygiene practices?” (Brown, 2012d). The Haz-Map developer has determined that linkage between a chemical or biological agent and a disease indicates that sufficient exposure to the agent is associated with increased risk of developing the disease. For chronic diseases, links between an agent and a disease means that a causal relationship has been determined based on human case reports or epidemiological studies. (Brown, 2012b) He further states that In Haz-Map, there is a distinction between adverse effects (includes animal toxicology and human poisonings by ingestion cases) and occupational dis- eases (cases of workers made ill after inhalation or skin absorption). Therefore, chemicals are linked to the diseases “Asphyxiation, chemical” and “Hemolytic anemia” only if occupational cases (and not just ingestion cases) have been reported. Likewise, all chronic occupational diseases in Haz-Map are based on reports of occupational cases. (Brown, 2012d) The www.haz-map.com website provides more information on some of the hazardous agent–occupational disease links in the database: The only exceptions to the rule that linkage indicates human disease known to be caused by the agent are the following diseases: Solvents, acute toxic effect (linked to all organic solvents); Encephalopathy, chronic solvent (linked to all organic solvents used in paints or varnishes); Encephalopathy, acute toxic effect (linked to other potential causes of acute encephalopathy excluding solvents, asphyxiants, fumigants, and insecticides); and Pneumonitis, toxic (caused by chemicals corrosive to the skin, eyes, and respiratory tract). The occupational disease “pneumonitis, toxic” is defined as noncardiogenic pulmonary edema induced by acute exposure to metal fumes or toxic gases and vapors after a spill or confined space accident. The “major irritant inhalants” are ammonia, bromine, chlorine, chlorine dioxide, diborane, ethylene oxide, formaldehyde, hy- drogen chloride, hydrogen fluoride, methyl isocyanate, nitrogen dioxide, ozone, phosgene, and sulfur dioxide [LaDou, p. 523]. While human cases have been documented for the major irritant inhalants, there are many chemicals with similar properties that can cause acute lung injury. Haz-Map flags 560 chemicals that have the potential to cause toxic pneumonitis as an adverse effect in heavily exposed workers or in animal experiments. Of these 560 chemicals, 142 with the designation of “toxic inhalation hazard” by ERG 2008 are linked to the oc- cupational disease “Pneumonitis, toxic.” (Brown, 2012b) More specifics on what constitutes a consensus, what evidence is reviewed in making the links, and how the Haz-Map developer determines that good industrial hygiene practices would prevent the disease are not provided on the database website. Toxic substance–disease links are presented in the field “Diseases” under the

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HAZ-MAP DATABASE 43 category “Related Information in Haz-Map” (see Table 2-1 and Box 2-1). The determination of what diseases are associated with the agent is based on a review of the literature by the developer, although much of the reviewed literature is of secondary sources rather than primary studies. Furthermore, the developer does not indicate the criteria he uses to determine “sufficient exposure,” “increased risk,” or a “causal relationship.” The evidence used to determine associations or causal links is not provided for specific agents or generally for the database, so it is unclear how the developer made each determination and how robust the agent–disease link actually is. For example, it is unknown if the basis of a par- ticular toxic substance–disease link is one well-conducted epidemiologic study, five adequate epidemiologic studies, three case studies, conflicting studies, or a lack of studies. For noncancer health endpoints, however, there is no evidence that the developer uses a weight-of-evidence approach for determining causality, such as that used by NTP or IOM. The exception to this lack of specificity are those agents that are IARC Group 1 carcinogens (sufficient evidence in humans) as described in the chapter on occupation by Siemiatycki and colleagues in Schottenfeld and Fraumeni’s Cancer Epidemiology and Prevention, 3rd ed. (Brown, 2010; Schottenfeld and Fraumeni, 2006; Siemiatycki et al., 2006). This Haz-Map approach has recently been updated. Target site organs are determined by using IARC 2012 cancer site information. According to the developer, Prior to the 2012 IARC changes, the map of occupational cancer in Haz-Map was based on the “Occupation” chapter in Cancer Epidemiology and Prevention, 3rd Edition. New studies and new interpretations from IARC are now available. (Brown, 2012a) STRENGTHS AND WEAKNESSES OF HAZ-MAP Haz-Map has been favorably compared with other health information data- bases in terms of quality, number of chemicals, and usability (Laamanen et al., 2008). It has the advantage of providing basic health and safety information on more than 7,000 hazardous agents, and it can serve as a good initial resource for this type of information. There are important concerns, however, that preclude its use as a comprehensive resource for assessing the causal relationship between toxic substances and occupational diseases. In this section, the committee comments on some of the problems in the hazardous agent-occupational disease links, that is the “Diseases” field. Although there are numerous other fields in the database (see Figure 2-1), the validity of the information in those fields, including the “Adverse Effects” category is beyond the scope of the committee’s task and is not discussed in this report. In particular, the committee discusses the lack of transparency in how the links are established and the criteria used to select and weigh the evidence for each link.

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44 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE Selection and Interpretation of Information Sources There are several areas where Haz-Map lacks transparency. The most critical is the lack of formal criteria for determining the hazardous agent–occupational disease links. However, even before such criteria could be applied to the evidence selected by the developer, there is a lack of transparency about what information is reviewed, its sources, and how it is evaluated for each hazardous agent, with the exception of IARC classifications for carcinogens. For example, there are four noncancer diseases causally associated with formaldehyde—asthma, occu- pational; contact dermatitis, allergic; contact urticaria; and fumigants, acute toxic effect. The sources of the information for contact urticaria and fumigants, acute toxic effect are not given in the “Diseases” field, but rather must be deciphered from the earlier “Comment” field in the “Agent information” category. Further references can also be found by clicking on the specific disease link and reading the entry in the “Comment” field for that specific disease. Although sources for the information on asthma, contact urticaria, and allergic contact dermatitis are provided, the casual user would not easily find the supporting evidence for these agent–disease links in the database. Criteria for Determining Agent–Disease Links The rules and criteria used by the Haz-Map developer to determine whether the evidence is sufficient for a causal association between an agent and an occu- pational disease are not clear, with the exception of the very strict criteria of using only IARC Group 1 cancer designations. Furthermore, there appear to be discrepancies in using even this approach for carcinogens. Although IARC has designated asbestos as a known human carcinogen for ovarian cancer, this is not indicated in the asbestos record. However, cancer of the larynx, which was designated by IARC as caused by asbestos at the same time as ovarian cancer, is listed in the database as an asbestos-caused occupational disease. For chronic noncancer occupational diseases, the database appears to favor evidence from epidemiological studies and reports of occupational illness. How- ever, in the absence of human information, it does not consider other types of information (e.g., animal and mechanistic data) that may support a link between an agent and occupational disease. For acute occupational diseases, the developer states that animal data is sufficient if the routes of entry correspond. Examples of such acute occupational diseases include poisoning by pesticides, solvents, simple asphyxiation, hydrofluoric acid, and toxic pneumonitis. A special rule is applied to toxic pneumonitis. Any corrosive substance has the potential to produce toxic pneumonitis as an adverse effect. Any of these substances designated as “TIH” (Toxic Inhalation Hazards) in the 2008 Emergency Response Guidelines are also listed in Haz-Map as the occupational disease “Pneumonitis, toxic.” Other

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HAZ-MAP DATABASE 45 acute diseases with special rules are “Asphyxiation, chemical” and “Hemolytic anemia.” In Haz-Map, there is a distinction between adverse effects (includes animal toxicology and human poisonings by ingestion cases) and occupational diseases (cases of workers made ill after inhalation or skin absorption). There- fore, chemicals are linked to the diseases “Asphyxiation, chemical” and “Hemo- lytic anemia” only if occupational cases (and not just ingestion cases) have been reported. Likewise, all chronic occupational diseases in Haz-Map are based on reports of occupational cases. (Brown, 2012d) The stringent criteria for establishing hazardous agent and cancer links and the uninterpretable criteria for establishing noncancer disease links present substantial obstacles for the effective use of Haz-Map as the sole source of toxic substance–occupational disease links in SEM as discussed in detail in Chapter 3. Peer Review Concerns for Haz-Map Peer review is a commonly used process for scientific and technical articles submitted to scholarly journals. The goal of peer review is to help ensure that the reviewed documents are accurate, comprehensive, and, in some cases, adhere to the authoring organization’s policy guidelines. Peer review has been defined by the National Research Council as a documented, critical review performed by peers [defined in the U.S. Nuclear Regulatory Commission report as “a person having technical expertise in the subject matter to be reviewed (or a subset of the subject matter to be reviewed) to a degree at least equivalent to that needed for the original work”] who are independent of the work being reviewed. The peer’s independence from the work being reviewed means that the peer, a) was not involved as a participant, supervisor, technical reviewer, or advisor in the work being reviewed, and b) to the extent practical, has sufficient freedom from funding considerations to assure the work is impartially reviewed. (NRC, 1997) Typically, organizations have established criteria against which reviewers are asked to judge the document. Numerous organizations, including virtually all biomedical journals (e.g., Journal of the American Medical Association, the Lancet, New England Journal of Medicine), and other organizations such as the IOM and the National Research Council, NTP, ATSDR, EPA, IARC, and the Organisation for Economic Co-operation and Development, use peer review to ensure their documents meet scientific standards. Many government and other organizations have developed and documented their peer review process. Some organizations, such as NTP and IARC, publish their review guidelines so the public has an understanding of the level of rigor the organization has applied to its review process. For example, EPA has developed the Peer Review Handbook that provides guidance to EPA staff on how and when to conduct peer reviews of scientific documents and the types of peer review that are applicable to different documents (EPA, 2006). The Office of Management and Budget issued its “Final

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46 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE Information Quality Bulletin for Peer Review” that established federal guidance for the peer review of government science documents (OMB, 2004). The peer reviewers’ names are identified in many documents, although their reviews may be anonymous to the documents’ authors during the review process. Although the NLM publishes the database, Haz-Map lacks adequate over- sight or content review by external, independent experts because the Haz-Map developer is solely responsible for its content. Furthermore, there is no disclaimer on the Haz-Map home page at NLM indicating that it is not peer-reviewed or that NLM is not responsible for its content. Thus, the user may be unaware that this database has not been peer-reviewed nor has it been reviewed by anyone at NLM for accuracy, bias, or comprehensiveness. In contrast, NLM’s HSDB prominently displays a notice on its home page that the database has been peer- reviewed (NLM, 2011). The current Haz-Map process for determining toxic substance–occupational disease links is based on the developer identifying “textbooks, journal articles, the Documentation of the Threshold Limit Values (published by ACGIH), and electronic databases such as NLM’s Hazardous Substances Data Bank (HSDB).” The developer then “classifies, summarizes, and regularly updates the information found in the database” (http://hazmap.nlm.nih.gov/about-us; accessed January 2, 2013). The developer of Haz-Map extracts information from these sources and uses his own expertise and judgment to determine whether there is sufficient evidence from his sources to determine whether there is a causal link between a toxic substance and an occupational disease. The substance–disease links receive no further review for accuracy or comprehensiveness. Ideally, appropriate review of a database such as Haz-Map would include both a technical review and a quality assurance component. A technical review would ensure that the correct information from each source was cited accurately. The quality assurance component would determine that all fields are complete, that the cited information is not taken out of context, and that all the relevant information is included. The failure to list asbestos as a cause of ovarian cancer is one of the examples that the committee was able to identify during the course of the study that show why technical and quality control reviews are needed. The reason for excluding this cancer from the asbestos record is unclear. With good technical review and quality assurance of the database entries, users can make informed judgments about the validity of the links between a toxic substance and an occupational disease. Haz-Map relies heavily on textbooks and standardized reference books to determine agent–disease link. These books include Cancer Epidemiology and Prevention (Schottenfeld and Fraumei, 2006), the source of the database’s ref- erences to Siemiatycki et al. (2006) reference in Haz-Map; Textbook of Clini- cal Occupational and Environmental Medicine (Rosenstock et al., 2004); and Contact and Occupational Dermatology (Marks et al., 1997). Databases such

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HAZ-MAP DATABASE 47 as HSBD and REPROTOX are also used. Haz-Map cites only IARC for cancer designations. Although some of the referenced databases, such as HSDB, are peer- reviewed, this is not necessarily true for textbooks and other information sources, including some databases. Textbooks are typically written as educational tools and are not designed to be either all-encompassing or used for compensation purposes. While subject to the scrutiny of editors, they are not peer-reviewed to determine if the authors’ conclusions about the literature on a subject are accurate, comprehensive, or objective. Furthermore, although the information in many textbooks and, thus, in Haz-Map is presumably based on information from peer-reviewed and published documents, textbook chapters typically represent the interpretation of a limited number of authors who select which studies to review, evaluate, and summarize. Different conclusions about a chemical agent may be reached by different authors, depending on their purpose and their resources. Many of the references used for Haz-Map are not easily accessible to the general public either in hard copy or electronically, which makes it difficult to check the information from them to complete a quality assurance and technical review. Updating Toxic Substance–Disease Links Haz-Map is updated quarterly on the NLM website with some agents selected preferentially for review and updating (Brown, 2012d). Formal update informa- tion is not provided in the NLM version of Haz-Map making it impossible to ascertain which agents may be considered for review and updating and whether any changes have been made to the “Diseases” field. The developer provides some information on database updates at http://www.haz-map.com/wotsnu.htm, but this information can be difficult to interpret, such as the entry for January 7, 2013. Updates to hazardous agent records in Haz-Map occur when a new edition of a textbook or other reference is published with revised information on that agent. In 2010, 2,400 substances listed in HSDB were added to Haz-Map, with another 600 chemicals and 10 diseases added in 2011 (Brown, 2012c). Further revisions to Haz-Map were made in December 2012. Hazardous agents may also be added to the database at the instigation of DOL. The SEM contractor is required to “develop a list of toxic substances whose Haz-Map profiles are to be prioritized for updating by the DOL Project Medical Consultant,” subject to approval by the DOL (see Chapter 3). Although the committee was not informed as to the identity of the DOL project medical consultant, the DOL contractor stated that “funding is provided to Dr. Brown for research of toxic substances of interest to DOL” (Stalnaker, 2012). DOL refers substances on the SEM list to the Haz-Map developer for priority consideration. He also occasionally reviews proposed agent–disease links that have come to the attention of DEEOIC staff,

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48 REVIEW OF THE DOL’S SITE EXPOSURE MATRIX DATABASE often from EEOICP claimants or their representatives (Karoline Anders, DOL DEEOIC, personal communication, October 9, 2012). SUMMARY In this chapter the committee has reviewed the approach by which Haz-Map links exposure to toxic substances to occupational diseases. Haz-Map was devel- oped “for health and safety professionals and for consumers seeking information about the adverse effects of workplace exposures to chemical and biological agents.” The committee restricted its review to the selection and evaluation of the information in the “Diseases” field, as that is the only field used by DOL to provide the substance–disease links in the SEM “Specific Health Effects” field. As of December 2012, there were more than 7,000 substances listed in Haz-Map. The committee has not reviewed every substance–disease link in Haz-Map or all the links imported into SEM. However, the committee has attempted to high- light areas where the Haz-Map “Diseases” links are ambiguous and where the process for making those links is unclear. Although the committee appreciates the enormous amount of work that has gone into the development and maintenance of the database, the committee identified several limitations to the “Diseases” field as used by SEM in the context of the EEOICP compensation system. The limitations include the lack of transparency in data sources used for determining each toxic substance–occupational disease link and in the criteria for establish- ing these links, particularly in connection with noncancer diseases; the lack of a clear weight-of-evidence approach; the lack of peer review; the overreliance on textbooks such that information may be neither comprehensive nor up to date; and the lack of clarity on what toxic substances and fields have been updated by the Haz-Map database developer. REFERENCES Brown, J. A. 2008a. Haz-Map: A useful tool for SH&E professionals. Professional Safety 53(3):24-28. Brown, J. A. 2008b. An internet database for the classification and dissemination of information about hazardous chemicals and occupational diseases. American Journal of Industrial Medicine 51(6):428-435. Brown, J. A. 2010. Database Overview. http://www.haz-map.com/overview.htm (accessed February 15, 2012). Brown, J. A. 2012a. Causal Agent-Cancer Links in Haz-Map. http://www.haz-map.com/cancer.htm (accessed October 11, 2012). Brown, J. A. 2012b. Database Overview. http://www.haz-map.com/overview.htm (accessed December 5, 2012). Brown, J. A. 2012c. Haz-Map: A Process to Map Occupational Toxicology Information into a Re- lational Database. Presentation at the First Committee Meeting, January 23, Washington, DC. Brown, J. A. 2012d. Questions Posed by IOM Committee and Subsequent Answers from Dr. Brown, February 22, 2012. http://www.iom.edu/Activities/PublicHealth/SEMDatabaseReview/2012- MAR-16.aspx.

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HAZ-MAP DATABASE 49 Cogliano, V. J. 2006. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. http:// oehha.ca.gov/prop65/public_meetings/pdf/IARCVJCogliano121206.pdf (accessed March 18, 2012). EPA (Environmental Protection Agency). 2006. Peer Review Handbook, 3rd Ed. Washington, DC. www.epa.gov/peerreview/pdfs/peer_review_handbook_2006.pdf (accessed January 23, 2013). EPA. 2012. A Chronological History of Causation for Environmental Scientists. http://www.epa.gov/ caddis/si_history.html (accessed July 27, 2012). Hakkinen, P. 2012. Presentation to the IOM Committee Covering NLM Databases and Review Pro- cesses for Haz-Map. Presentation at the Second Committee Meeting, March 16, Washington, DC. HHS (Department of Health and Human Services). 2012. NTP Monograph on the Health Effects of Low-Level Lead Evaluation. National Toxicology Program, Office of Health Assessment and Translation. http://ntp.niehs.nih.gov/NTP/ohat/Lead/Final/MonographHealthEffectsLowLevel Lead_prepublication_508.pdf (accessed July 23, 2012). Hill, A. B. 1965. The environment and disease: Association or causation? Proceeding of the Royal Society of Medicine 58:295-300. IARC (International Agency for Research on Cancer). 2006. Preamble. IARC Monographs on the Evaluation of Carcinogenis Risks to Humans: Preamble. Lyon, France: World Health Organization. IARC. 2012. Chemical Agents and Related Occupations: A Review of Human Carcinogens, Volume 100F. Lyon, France: World Health Organization. IOM (Institute of Medicine). 2010. Gulf War and Health. Volume 8, Update of Health Effects of Serv- ing in the Gulf War. Washington, DC: The National Academies Press. Laamanen, I., J. Verbeek, G. Franco, M. Lehtola, and M. Luotamo. 2008. Finding toxicological infor- mation: An approach for occupational health professionals. Journal of Occupational Medicine and Toxicology 3:18. Lewandowski, T. A., M. R. Seeley, and B. D. Beck. 2004. Interspecies differences in susceptibility to perturbation of thyroid homeostasis: A case study with perchlorate. Regulatory Toxicology and Pharmacology 39(3):348-362. Marks, J. G., and V. A. DeLeo. 1997. Contact and Occupational Dermatology. 2nd ed. St. Louis: Mosby-Year Book. Monson, R. 1990. Occupational Epidemiology. 2nd ed. Boca Raton, FL: CRC Press. NLM (National Library of Medicine). 2011. Hazardous Substances Data Bank (HSDB): Compre- hensive, Peer-Reviewed Toxicology Data for about 5,000 Chemicals. http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB (accessed February 15, 2012). NRC (National Research Council). 1997. Peer Review in the Department of Energy–Office of Science and Technology: Interim Report. Washington, DC: National Academy Press. OMB (Office of Management and Budget). 2004. Final Information Quality Bulletin for Peer Review. http://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdf (accessed January 23, 2013). Rosenstock, L., and M. Cullen. 2004. Textbook of Clinical Occupational and Environmental Medicine. 2nd ed. London: Elsevier Inc. Schottenfeld, D., and J. F. Fraumeni. 2006. Cancer Epidemiology and Prevention. 3rd ed. New York: Oxford University Press. Siemiatycki, J., L. Richardson, and P. Boffetta. 2006. Occupation. In Cancer Epidemiology and Pre- vention. 3rd ed., edited by D. Schottenfeld and J. F. Fraumeni. New York: Oxford University Press. Pp. 322-354. Stalnaker, K. 2012. U.S. DOL Site Exposure Matrices, EEOICPA Part E. Presentation at the First Committee Meeting, January 23, Washington, DC. Wakefield, J. C. 2007. Napthalene: Toxicological Overview. Health Protection Agency. http://www. hpa.org.uk/webc/HPAwebFile/HPAweb_C/1203084377981 (accessed July 23, 2012).

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