Review of EPA's Integrated Risk Information System (IRIS) Process (2014) / Chapter Skim
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6 Evidence Integration for Hazard Identification
6 Evidence Integration for Hazard Identification
Pages 85-109
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From page 85... ...
Evidence integration is understood to be the process of combining different kinds of evidence relevant to hazard identification. In a typical assessment developed for the Integrated Risk Information System (IRIS)
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From page 86... ...
. As described in previous chapters, the committee uses the phrase systematic review to describe a process that ends before evidence integration and hazard identification (Figure 6-1)
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From page 87... ...
ORGANIZING PRINCIPLES FOR INTEGRATING EVIDENCE One challenge that EPA and other regulatory agencies face when attempting to establish guidelines for integrating evidence is that the amount and quality of the various types of evidence can vary substantially from one chemical to another. For example, a small number of environmental contaminants -- such as arsenic, dioxins, polychlorinated biphenyls, and formaldehyde -- have extensive human data, often from relatively well-designed cohort studies, substantial animal data from several animal models, and mechanistic information.
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From page 88... ...
vitro mechanistic data might allow better selection of the most appropriate animal model for predicting human response. High-dose to low-dose extrapolation HE: Often better suited for considering actual range of HE: Occupational exposure is often higher than that seen in the population exposures.
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From page 89... ...
EA: Shorter animal lifespans allow for more rapid evaluation of EA: Multiple extrapolations required. Variable cost.
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From page 90... ...
In other words, in cases in which extensive human data strongly support a causal association between exposure and disease and the studies are judged to have a relatively low risk of bias, the human evidence can outweigh animal and other evidence, no matter what it is. Furthermore, a judgment of "carcinogenic to humans" can be justified when human studies show only an association (not a causal association)
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From page 91... ...
THE BRADFORD HILL GUIDELINES Common considerations (or quasicriteria) used in many frameworks in which various bodies of evidence must be integrated to reach a causal decision are the "Hill criteria for causality," a set of guidelines first articulated by Austin Bradford Hill in 1965 to deal with the problem of integrating evidence on environmental exposure and disease, particularly with respect to smoking and lung cancer.
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From page 92... ...
CURRENT ENVIRONMENTAL PROTECTION AGENCY APPROACH TO INTEGRATING EVIDENCE: THE AGENCY'S RESPONSE TO RECOMMENDATIONS IN THE NATIONAL RESEARCH COUNCIL FORMALDEHYDE REPORT The 2011 NRC formaldehyde report made several recommendations for evidence integration in IRIS assessments (see Box 6-1)
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From page 93... ...
gives extensive guidelines for synthesizing evidence within each stream but no guidelines for integrating evidence among streams. The guidelines and the summary descriptors offered for epidemiologic and other studies are reasonable, and similar ones have been used in many other organizations that have similar aims and problems, such as IARC and the National Toxicology Program (NTP)
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From page 94... ...
For example, observational studies show an association but co-exposures are difficult to address or other lines of evidence are limited or inconsistent; or multiple animal studies from different laboratories demonstrate effects and there are limited or no human data. Suggestive of a causal relationship At least one high-quality epidemiologic study shows an association but other studies are inconsistent.
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From page 95... ...
More specifically, the report notes that informative human studies of methanol are limited to acute exposures, but "the relatively small amount of data for subchronic, chronic, or in utero human exposures are inconclusive. However, a number of reproductive, developmental, subchronic, and chronic toxicity studies have been conducted in mice, rats, and monkeys" (EPA 2013b, p.
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From page 96... ...
The options are divided into qualitative approaches and quantitative approaches. A qualitative approach is a process whose output is a categorization of the overall evidence, for example, "the evidence suggests that it is likely that chemical X is immunotoxic." A quantitative approach is a process that produces a quantitative output, for example, "the evidence suggests that there is at least a 75% chance that chemical X is immunotoxic." Qualitative Approaches for Integrating Evidence Several approaches have been taken by the scientific and regulatory communities for integrating diverse evidence for hazard identification.
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From page 97... ...
In addition, EPA has established a Systematic Review Implementation Group whose primary purpose is to coordinate the implementation of systematic review in the IRIS program. Evidence integration done internally by EPA experts is (or can be)
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From page 98... ...
The Hill criteria require a prospective temporal relationship between the exposure and outcome and note that experimental evidence strengthens causation. Similarly, the GRADE criteria give greater weight to randomized clinical trials, although such studies are rarely available for environmental chemicals.
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From page 99... ...
b Includes Hill criteria of specificity, biologic plausibility, and coherence. c Rated under "other." d A formal dose-response assessment is typically performed, depending on the outcome of the hazard identification.
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From page 100... ...
A number of quantitative approaches can be used for hazard identification. Three approaches are meta-analysis, probabilistic bias analysis, and Bayesian analysis.3 In the case of meta-analysis and probabilistic bias analysis, the natural targets of the analyses are not qualitative yes-no questions but rather quantitative estimates of an effect size.
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From page 101... ...
Probabilistic Bias Analysis In all studies that seek to estimate causal effects, there are two broad sources of uncertainty: systematic bias and random error from sampling. In the famous poll that predicted that Thomas Dewey had beaten Harry Truman in the 1948 presidential election, there was systematic bias related to the sampling and the external validity of the survey; it was a telephone poll, telephone ownership was not ubiquitous at that time, and telephone ownership was heavily skewed toward Dewey supporters.
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From page 102... ...
= 0.65. In hazard identification, which is essentially a qualitative yes-no answer to a causal question, one would use the Bayesian approach to assess the probability of hazard, that is, the degree of belief in a causal proposition, after seeing all the evidence (human, animal, and mechanistic)
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From page 103... ...
In the present chapter, the discussion is restricted to a Bayesian approach to hazard identification, which involves a yesno proposition: Does chemical X cause outcome Y? To combine evidence from disparate studies, a Bayesian approach needs to model the likelihood of data or evidence from different kinds of studies, given the hypothesis that a chemical is hazardous to humans.
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From page 104... ...
Comparison of Quantitative Methods Meta-analysis is appropriate for situations in which there are a number of similar statistical studies involving experiments on humans or animals or similar epidemiologic studies. Probabilistic bias analysis is appropriate when the risk of bias in observational studies is substantial, and there is information that makes estimating or at least bounding such bias feasible.
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From page 105... ...
That technique could be helpful in modeling assumptions about the relevance of a variety of animal models to each other and to humans, in incorporating mechanistic knowledge to model the relevance of animal models to humans and the relevance of human data for similar but distinct chemicals, and in providing a general framework within which to update scientific knowledge rationally as new data become available. The committee emphasizes that the capacity for quantitative modeling should be developed in parallel with improvements in existing IRIS evidence-integration procedures and that IRIS assessments should not be delayed while this capacity is being developed.
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From page 106... ...
For example, the draft IRIS preamble provided to the committee states that "to make clear how much the epidemiologic evidence contributes to the overall weight of the evidence, the assessment may select a standard descriptor to characterize the epidemiologic evidence of association between exposure to the agent and occurrence of a health effect" (EPA 2013a, p.
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From page 107... ...
50 32-8) in Support of Summary Information on the Integrated Risk Information System (IRIS)
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From page 108... ...
2011. Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde.
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From page 109... ...
2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial.
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