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Federal Register / Vol. 86, No. 3 / Wednesday, January 6, 2021 / Rules and Regulations
studies and already identifies key or pivotal studies in some of its actions e.g., IRIS assessments. The EPA
intends to issue implementation guidelines and statute-specific rulemakings that will further describe these criteria and how the EPA will identify pivotal science in its assessments and rulemakings. In general, the EPA will rely on the highest quality, most relevant studies available in determining the potential for hazard due to exposure to a pollutant, contaminant, or substance. Where there is convincing and well substantiated evidence to support a relationship between exposure and effect, the EPA
will identify a subset of those studies based on the exposure situation being addressed, the quality of the studies, the reporting adequacy, and the relevance of the endpoints that would inform a doseresponse assessment for those effect endpoints and drive the requirements and/or quantitative analyses of an EPA
final significant regulatory action or influential scientific information will be identified as pivotal science.
Further, the EPA intends to promulgate regulations under the environmental statutes that the EPA
administers to further clarify how the Agency will apply the definition of pivotal science in specific programs authorized under those statutes e.g., CAA, CWA, SDWA, RCRA, FIFRA, TSCA, EPCRA. The specific criteria for determining pivotal science may necessarily be specific to the authorizing statute, as well as the significant regulatory action or the influential scientific information. The EPA intends to explain in each significant regulatory action and for influential scientific information how the pivotal studies were identified.
In response to comments on the meaning of drive the requirements and/or quantitative analysis, these are the studies that are integral to quantitatively characterizing doseresponse relationships for the toxicity endpoints that underlie the requirements or analyses of EPA
significant regulatory actions or influential scientific information. The EPA may further interpret the meaning of drive, and describe the process for designating key studies as pivotal science in subsequent implementation guidelines and/or statute-specific rulemakings.
Some commenters stated that the EPA
did not explain what was meant by other things being equal. Some of these commenters requested clarity on what factors in addition to transparency would be considered. Some specific suggestions from commenters include
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that EPA should give consideration to quality studies that evaluate a range of models, that are scientifically sound for the intended use, and that have study characteristics e.g., sample size, confidence intervals of results, or overall methods validity that may compensate for any lack of full transparency. In consideration of these and other public comments, the EPA
developed additional factors that clarify specific technical factors that it may consider in balancing study quality and data availability. Although the EPA is prioritizing transparency in pivotal science, the Agency also recognizes that there will be instances where the underlying dose-response data of pivotal science is unavailable for independent validation. In order to ensure that the Agency maintains a strong scientific basis for its decisionmaking, the availability of underlying dose-response data should be considered as long as other significant technical considerations can provide some level of certainty or confirmation of a studys conclusions, importance, and applicability, even in the absence of maximum transparency. Though EPAs list of factors herein is not exhaustive or exclusive, the EPA has identified several factors in 40 CFR 30.5d that balance some of the important technical considerations the EPA will consider in addition to data availability and that are particularly relevant to the stage of the analysis where dose-response data are used. These factors are intended to assist the EPA in determining the consideration to afford to pivotal science with underlying dose-response data that are not available for independent validation. The final rule requirements and the consideration of these factors apply to any data used in characterizing the relationship between the amount of dose or exposure to a pollutant, contaminant, or substance and an effect, regardless of the direction of that effect. Because study quality factors including soundness, applicability and utility, clarity and completeness, uncertainty and variability, and evaluation and review would have already been evaluated at an earlier stage in the assessment process see 40 CFR 30.5b, the EPA
envisions that at the stage of the evaluation that utilizes the factors described in 40 CFR 30.5d, the studies to be evaluated would generally be of the highest quality available.
Some of the factors in 40 CFR 30.5d are intended to be evaluated for pivotal science with underlying data that are not available for independent validation relative to pivotal science with
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underlying data that are available for independent validation. For example, when assessing studies, the EPA may determine that greater consideration should be given to a study with underlying data that are unavailable for independent validation when that study is of higher quality compared to a medium-quality study with underlying data that are available for independent validation factor 1, the conclusions of the significant regulatory action or influential scientific information are or are not highly sensitive to the exclusion of the study for which the underlying data are not available for independent validation factor 3, the study with data unavailable for independent validation was better fit for the purpose of the EPA
assessment factor 4, or the results of the study for which the underlying data are not available are supported by other scientific evidence, such as mechanistic data factor 6.
Importantly, the factors in 40 CFR
30.5d do not apply to other stages in the assessment process although they are relevant to determining whether to grant an exemption under 40 CFR 30.7, as further explained below. For example, the consideration for exposures that were conducted at more environmentally relevant exposure concentrations factor 5 does not suggest that epidemiological studies will automatically be given greater weight than laboratory studies. The EPA
will continue to use established guidelines for identifying and integrating evidence and will use the factors in 40 CFR 30.5d only when evaluating the data availability requirements of this rule or when determining whether to grant an exemption under 40 CFR 30.7, as further explained below. In addition, not all of these factors will be applicable to all studies or assessments. For example, some pollutants, chemicals, or substances may have unique scientific considerations factor 7, such as the valence state of a metal compound or endogenous contributions to internal concentrations, that may not be relevant for other pollutants, chemicals, or substances. Therefore, the weight afforded to each factor by the EPA may vary by assessment, and how those factors were considered will be documented in the assessment. If two studies, one with and one without available data and are relatively equal with respect to the study quality factors in 40 CFR 30.5b, the study where the underlying data is available will be given greater consideration and the weight of the other study will be based on an assessment of the factors in 40

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