Integrated Risk Information System Database Research Articles

Leveraging Epidemiology to Improve Risk Assessment.

The field of environmental public health is at an important crossroad. Our current biomonitoring efforts document widespread exposure to a host of chemicals for which toxicity information is lacking. At the same time, advances in the fields of genomics, proteomics, metabolomics, genetics and epigenetics are yielding volumes of data at a rapid pace. Our ability to detect chemicals in biological and environmental media has far outpaced our ability to interpret their health relevance, and as a result, the environmental risk paradigm, in its current state, is antiquated and ill-equipped to make the best use of these new data. In light of new scientific developments and the pressing need to characterize the public health burdens of chemicals, it is imperative to reinvigorate the use of environmental epidemiology in chemical risk assessment. Two case studies of chemical assessments from the Environmental Protection Agency Integrated Risk Information System database are presented to illustrate opportunities where epidemiologic data could have been used in place of experimental animal data in dose-response assessment, or where different approaches, techniques, or studies could have been employed to better utilize existing epidemiologic evidence. Based on the case studies and what can be learned from recent scientific advances and improved approaches to utilizing human data for dose-response estimation, recommendations are provided for the disciplines of epidemiology and risk assessment for enhancing the role of epidemiologic data in hazard identification and dose-response assessment.

Medicinal Clay and Spiritual Healing

AbstractThe varied mineralogical composition of earthy materials and the quantity of elements extracted by simulated stomach acid substantiate the diversity of materials consumed by humans practicing geophagy. Direct consumption of ‘edible earths’ for medicinal and spiritual purposes occurs worldwide and is deeply rooted in ‘folk medicine’ and religion. The legends associated with the healing powers of the clay from Chimayo, New Mexico, provide an excellent example of the roots of geophagy. The clay mineral assemblages revealed by X-ray diffraction analysis of 22 samples from New Mexico, North America, and other parts of the world are highly variable. One might be monominerallic kaolinite or smectite, and another, a complex mixture of illite, kaolinite, smectite, and chlorite or vermiculite. The quantities of elements (Al, Si, K, Na, Ca, Mg, Fe, Mn, Ti, P, S, Ba, Sr, Pb, Zn, Cd, Co, Cu, Cr, Ni, V, Zr, Se, Mo, Be, Sb, and As) extracted by 0.12 M HCl varied from ∼1.0 mg/g to the limit of detectability, 0.0001 mg/g. Potential long-term human health effects were evaluated with the Reference Dose Ratio (RDR). It divides the quantity of the element extracted from 50 g of the total sample by the recommended reference dose (RfD) reported in the Environmental Protection Agency’s (EPA, USA) IRIS (Integrated Risk Information System) database. Median RDR values for Na, Cr, Sb, and As exceeded 1.0 indicating an abnormally high potential intake. Materials consumed by humans are so varied that caution should be used in comparing the results of one clay study with those of another without mineralogical and chemical data.

Use of epidemiologic data in Integrated Risk Information System (IRIS) assessments

In human health risk assessment, information from epidemiologic studies is typically utilized in the hazard identification step of the risk assessment paradigm. However, in the assessment of many chemicals by the Integrated Risk Information System (IRIS), epidemiologic data, both observational and experimental, have also been used in the derivation of toxicological risk estimates (i.e., reference doses [RfD], reference concentrations [RfC], oral cancer slope factors [CSF] and inhalation unit risks [IUR]). Of the 545 health assessments posted on the IRIS database as of June 2007, 44 assessments derived non-cancer or cancer risk estimates based on human data. RfD and RfC calculations were based on a spectrum of endpoints from changes in enzyme activity to specific neurological or dermal effects. There are 12 assessments with IURs based on human data, two assessments that extrapolated human inhalation data to derive CSFs and one that used human data to directly derive a CSF. Lung or respiratory cancer is the most common endpoint for cancer assessments based on human data. To date, only one chemical, benzene, has utilized human data for derivation of all three quantitative risk estimates (i.e., RfC, RfD, and dose-response modeling for cancer assessment). Through examples from the IRIS database, this paper will demonstrate how epidemiologic data have been used in IRIS assessments for both adding to the body of evidence in the hazard identification process and in the quantification of risk estimates in the dose-response component of the risk assessment paradigm.

Epidemiology and Risk Assessment: Examples From the US EPA Integrated Risk Information System

ISEE-184 Objective: The Integrated Risk Information System (IRIS) is a public use electronic database (www.epa.gov/iris) developed by the US Environmental Protection Agency. It currently receives more than 250,000 Web-page hits per month from public and private sector users in over 100 countries. This searchable database of 545 chemicals includes qualitative and quantitative health effects information pertaining to the hazard identification and dose-response components of the risk assessment process. Our objective was to identify assessments that used human data for qualitative and quantitative risk estimation. Material and Methods: Two reviewers independently abstracted information from the IRIS database pertaining to studies used to derive the reference dose and reference concentrations for oral and inhalation exposures for noncancer effects, cancer weight of evidence descriptors, and cancer inhalation unit risks and oral slope factors. Results: Data from human studies were used to derive a reference dose for 27 chemicals and a reference concentration for 12 chemicals. Twelve assessments (arsenic, acrylonitrile, asbestos, benzene, benzidine, beryllium, 1,3-butadiene, cadmium, chromium (VI), coke oven emissions, nickel refinery dust, and nickel subsulfide) used human data to estimate a cancer inhalation unit risk or oral cancer slope factor. The number of studies available pertaining to a specific chemical, the extent to which exposures to other carcinogens was able to be characterized, the available data on levels of exposure, and aspects of the data presentation were some of the key issues affecting use of the data from studies in humans. Conclusions: Epidemiology data have played an important role in the quantification of risk estimates in approximately 10% of the IRIS assessments to date. The role of epidemiology in risk assessment could increase, as specific issues regarding the design and presentation of data are incorporated into studies.

Vinyl Chloride and U.S. EPA Research

A commentary by Sass et al. (2005), “Vinyl Chloride: A Case Study of Data Suppression and Misrepresentation,” is itself a case study in misrepresentation. The inclusion of such an article in this peer-reviewed publication stands in contrast to its stated mission to publish “balanced” and “objective” information. Sass et al. (2005) did not include or address recent studies in characterizing the weight of the scientific evidence related to vinyl chloride and made inaccurate and unsupported allegations about the integrity of U.S. Environmental Protection Agency (EPA) scientists and the rigorous peer review process utilized by the U.S. EPA. Sass et al. (2005) asserted that there is a “scientific consensus that [vinyl chloride] is a multisite carcinogen in humans and experimental animals,” referencing 21 articles, only 3 of which were published during the past 15 years. They failed to mention or seriously discuss 7 articles noted below that were published in scientific journals since 1997 and update many of the studies Sass et al. cited and reach the opposite conclusion. These and other recent peer-reviewed studies and reviews fully support the U.S. EPA’s conclusion that “the association [between vinyl chloride and cancers other than the liver] is weak and any estimated increase in mortality from cancer at these sites is likely to be less than for liver cancer” (U.S. EPA 2000). Authors of these articles include Aaron Blair, the chief of the Occupational Studies Section of the National Cancer Institute (NCI), who stated that epidemiologic evidence shows a strong exposure–response relationship for angiosarcoma of the liver, but not for other types of cancer (Blair and Kazerouni 1997). In a more recent review, McLaughlin and Lipworth (1999) reached the same conclusion: Occupational vinyl chloride exposure has not been conclusively causally linked to any adverse health outcome, with the exception of angiosarcoma of the liver. Even more recently, Bosetti et al. (2003) stated that The aggregate data are reassuring in excluding any excess risk of death from lung, laryngeal, soft tissue sarcoma, brain and lymphoid neoplasms, as well as cirrhosis. Recently published updates of cancer incidence in European and American industry-wide cohorts of workers exposed to vinyl chloride provide a firm basis for the conclusion that vinyl chloride exposure is not causally associated with brain cancer and the other tumors mentioned by Sass et al. (2005). The European study (Ward et al. 2001) was conducted by scientists affiliated with the National Institute of Occupational Safety and Health (NIOSH) and the International Agency for Research on Cancer (IARC). The authors found no evidence of an increase in cancers other than the liver. Similar, though less definitive, results were published by Mundt et al. (2000) in an update of the American cohort. A recent meta-analysis of these cohorts by IARC scientists further supports the conclusion reached by the U.S. EPA (Boffetta et al. 2003). Given the strength and uniformity of the evidence supporting the U.S. EPA’s position, it is striking that Sass et al. (2005) did not address it. Instead, they claimed that the U.S. EPA yielded to advocacy by chemical manufacturers, implying that the U.S. EPA relied in part upon unpublished data. As noted above, however, the articles upon which the U.S. EPA placed primary reliance are published, in a few cases, by academic scientists sponsored by industry (e.g., Mundt et al. 2000), but for the most part by scientists affiliated with some of the most prestigious government-supported organizations engaged in cancer research (e.g., NCI, IARC, NIOSH). Finally, it is not accurate that industry unduly influenced the review process for vinyl chloride nor that the potency factors published in the IRIS (Integrated Risk Information System) database (U.S. EPA 2000) are insufficiently protective (Norman 2002). The former comment disparages the U.S. EPA scientists who spent 5 years and went through two external peer reviews to make sure that relevant current science was reflected. The latter fails to recognize that a pharmacokinetic (PK) approach to risk assessment was supported over 20 years ago by the National Academy of Sciences and that the PK model for vinyl chloride used by the U.S. EPA—which predicted the actual incidence of angiosarcoma of the liver in the early cohorts of exposed workers—has been peer-reviewed, published, and validated (Clewell et al. 2001; Reitz et al. 1996).

Development of an agricultural job-exposure matrix for British Columbia, Canada.

Farmers in British Columbia (BC), Canada have been shown to have unexplained elevated proportional mortality rates for several cancers. Because agricultural exposures have never been documented systematically in BC, a quantitative agricultural Job-exposure matrix (JEM) was developed containing exposure assessments from 1950 to 1998. This JEM was developed to document historical exposures and to facilitate future epidemiological studies. Available information regarding BC farming practices was compiled and checklists of potential exposures were produced for each crop. Exposures identified included chemical, biological, and physical agents. Interviews with farmers and agricultural experts were conducted using the checklists as a starting point. This allowed the creation of an initial or 'potential' JEM based on three axes: exposure agent, 'type of work' and time. The 'type of work' axis was determined by combining several variables: region, crop, job title and task. This allowed for a complete description of exposures. Exposure assessments were made quantitatively, where data allowed, or by a dichotomous variable (exposed/unexposed). Quantitative calculations were divided into re-entry and application scenarios. 'Re-entry' exposures were quantified using a standard exposure model with some modification while application exposure estimates were derived using data from the North American Pesticide Handlers Exposure Database (PHED). As expected, exposures differed between crops and job titles both quantitatively and qualitatively. Of the 290 agents included in the exposure axis; 180 were pesticides. Over 3000 estimates of exposure were conducted; 50% of these were quantitative. Each quantitative estimate was at the daily absorbed dose level. Exposure estimates were then rated as high, medium, or low based on comparing them with their respective oral chemical reference dose (RfD) or Acceptable Daily Intake (ADI). This data was mainly obtained from the US Environmental Protection Agency (EPA) Integrated Risk Information System database. Of the quantitative estimates, 74% were rated as low (< 100%) and only 10% were rated as high (>500%). The JEM resulting from this study fills a void concerning exposures for BC farmers and farm workers. While only limited validation of assessments were possible, this JEM can serve as a benchmark for future studies. Preliminary analysis at the BC Cancer Agency (BCCA) using the JEM with prostate cancer records from a large cancer and occupation study/survey has already shown promising results. Development of this JEM provides a useful model for developing historical quantitative exposure estimates where is very little documented information available.

Health Assessment of Polycyclic Aromatic Hydrocarbon Mixtures: Current Practices and Future Directions

The U.S. EPA's Integrated Risk Information System (IRIS) program has initiated a health assessment for polycyclic aromatic hydrocarbon (PAH) mixtures. The IRIS program develops EPA consensus scientific positions on potential human health effects from chronic exposure to chemicals. Currently, the IRIS database contains health assessments for the toxic effects of exposure to coke oven emissions, creosote, diesel emissions, and 15 individual PAH compounds. As a whole, these assessments do not consider issues related to the environmental occurrence of PAH compounds as complex mixtures. Risk assessment of PAH mixtures has been hindered by a lack of information on the composition and toxicity of specific mixtures, the components that contribute most to toxicity, and the interactions and differences in mode of action between components. The state-of-the-science has advanced considerably in the past decade and will play a key role in the development of the health assessment. Consideration of these issues led to an EPA-sponsored Workshop on Approaches to PAH Health Assessment in October 2001. The current practices of the EPA regarding the health assessment of PAH compounds and future directions of the agency are discussed in this article.

Health Assessment of Polycyclic Aromatic Hydrocarbon Mixtures: Current Practices and Future Directions

The U.S. EPA's Integrated Risk Information System (IRIS) program has initiated a health assessment for polycyclic aromatic hydrocarbon (PAH) mixtures. The IRIS program develops EPA consensus scientific positions on potential human health effects from chronic exposure to chemicals. Currently, the IRIS database contains health assessments for the toxic effects of exposure to coke oven emissions, creosote, diesel emissions, and 15 individual PAH compounds. As a whole, these assessments do not consider issues related to the environmental occurrence of PAH compounds as complex mixtures. Risk assessment of PAH mixtures has been hindered by a lack of information on the composition and toxicity of specific mixtures, the components that contribute most to toxicity, and the interactions and differences in mode of action between components. The state-of-the-science has advanced considerably in the past decade and will play a key role in the development of the health assessment. Consideration of these issues led to an EPA-sponsored Workshop on Approaches to PAH Health Assessment in October 2001. The current practices of the EPA regarding the health assessment of PAH compounds and future directions of the agency are discussed in this article.