Review of EPA's Integrated Risk Information System (IRIS) Process (2014) / Chapter Skim
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3 Problem Formulation and Protocol Development
3 Problem Formulation and Protocol Development
Pages 30-39
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From page 30... ...
Although the committee's review of the problem-formulation step focuses mainly on searching available literature, seeking stakeholder input and advice is an integral part of the process and should not be minimized. Evidence Used for IRIS Assessments As indicated in Figure 3-2, evidence typically used by EPA for IRIS assessments comes from human studies, animal studies, and mechanistic studies.
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. Experimental human studies with potentially toxic chemicals are performed infrequently, so most human studies of adverse outcomes are observational epidemiologic studies in which exposure is not controlled, but rather the consequences of inadvertent human exposures.
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Animal Studies Using laboratory animals, primarily rats and mice, to assess chemical hazard remains an essential component of toxicologic and chemical risk assessments (Beyer et al.
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For example, benzene and arsenic were identified as human carcinogens on the basis of epidemiologic data at a time when animal data failed to identify the carcinogenic risks; later refinement of animal models and a better mechanistic understanding of how these chemicals cause cancer have made it possible to explain the reasons for the disparate results of early studies. Mechanistic Studies For purposes of this report, mechanistic data come from a wide variety of studies that are not intended to identify an adverse outcome.
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Development of Systematic-Review Questions A major challenge in the problem-formulation step is determining what adverse outcomes are of potential concern.1 To identify the potentially relevant outcomes associated with exposure to a given chemical, the IRIS chemical-assessment team needs to conduct an initial broad search of the literature and toxicology databases by using the procedures described in the draft handbook for IRIS assessments (EPA2013b, Appendix F)
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Studiesa Animal (in vivo) Studies In vitro, Mechanistic Studies Genotoxicity or mutagenesis Oncogenesis Reproductive Developmental, teratogenesis Pharmacokinetics Neurologic and sensory systems Hepatic Renal Gastrointestinal Endocrine Metabolic disease Respiratory Cardiovascular Hematopoietic Immunologic Musculoskeletal Dermal Other a Human in vivo studies might embody an array of experimental designs, including controlled human exposure studies in chambers, case reports, and epidemiologic studies, including ecologic, cohort, crosssectional, and case-control studies.
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Decisions as to which specific outcomes should be further evaluated by specific systematic reviews require careful consideration of numerous factors, including whether the potential outcome is likely to occur at doses encountered by the general population and what the significance of the outcome will be if the potential association suggested in the screening review is real. Expert judgment will play an important role in this step of the IRIS process.
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Further discussion of protocol elements is provided where appropriate in the chapters that follow. FINDINGS AND RECOMMENDATIONS Finding: The materials provided to the committee by EPA describe the need for carefully constructed literature searches but do not provide sufficient distinction between an initial survey of the literature to identify putative adverse outcomes of interest and the comprehensive literature search that is conducted as part of a systematic review of an identified putative outcome.
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50 32-8) in Support of Summary Information on the Integrated Risk Information System (IRIS)
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1993. Interpretation of male rat renal tubule tumors.
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