Science and Decisions Advancing Risk Assessment (2009) / Chapter Skim
Currently Skimming:
6 Selection and Use of Defaults
6 Selection and Use of Defaults
Pages 188-212
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 188... ...
The specific inference options that now appear in EPA's risk-assessment guidelines, and that permeate risk assessments performed under those guidelines, have come to be called default options, or more simply defaults. The Red Book committee defined a default option as the inference option "chosen on the basis of risk assessment policy that appears to be the best choice in the absence of data to the contrary." As the authors of Science and Judgment in Risk Assessment (NRC 1994)
|
From page 189... ...
emphasize that the policy is consistent with EPA's mission and make clear that the general policy applies to cancer risk assessments: As an increasing understanding of carcinogenesis is becoming available, these cancer guide lines adopt a view of default options that is consistent with EPA's mission to protect human health while adhering to the tenets of sound science. Rather than viewing default options as the starting point from which departures may be justified by new scientific information, these cancer guidelines view a critical analysis of all of the available information that is relevant to assessing the carcinogenic risk as the starting point from which a default option may be invoked if needed to address uncertainty or the absence of critical information (p.
|
From page 190... ...
provides some statements regarding the need to identify key data gaps and avoid delays in the risk-assessment process in the planning and scoping phase, but it is concerned that such statements may not be adequate to address complications resulting from the current policy: Another discussion during the planning and scoping process concerns the identification of key data gaps and thoughts about how to fill the information needs. For example, can you fill the information needs in the near-term using existing data, in the mid-term by conducting tests with currently available test methods to provide data on the agents(s)
|
From page 191... ...
In short, this committee member sees most of the common risk assessment defaults not as "inferences retreated to because of the absence of information," but rather as "inferences generally endorsed on account of the information." Therefore, this committee member concluded that EPA's stated goal of "reducing reliance on defaults" per se is problematic; it begs the question of why a scientific-regulatory agency would ever want to reduce its reliance on those inferences that are supported by the most substantial theory and evidence. Worse yet, the committee member concluded, it seems to prejudice the comparison between default and alternative models before it starts -- if EPA accomplishes part of its mission by ruling against a default model, the "critical analysis of all available information" may be preordained by a distaste for the conclusion that the default is in fact proper.
|
From page 192... ...
The committee did not conduct a detailed evaluation, but a cursory examination of some recent assessments shows detailed presentations and analyses of the available data bearing on each assessment, explicit determinations that identified data that do not support an inference alternative to such defaults as low-dose linearity and the cross-species scaling of risk, but thus far not the wholesale reconsideration of generic defaults. No matter how one interprets EPA's current policy on defaults, an effective policy requires criteria to guide risk assessors on factors that would render data "not usable" or supportable of inference alternatives to a default, and therefore requiring that a default be invoked.
|
From page 193... ...
Tables 6-1 and 6-2 list some of the important defaults for carcinogen and noncarcinogen risk assessments. Missing Defaults In addition to explicitly recognized defaults, EPA relies on a series of implicit or "missing" defaults -- assumptions that may sometimes exert great influence on risk characterization.
|
From page 194... ...
Both explicit and missing defaults used by EPA are a cornerstone of the agency's approach to facilitating human health risk assessment in the face of inherent scientific limitations that may prevent verification of any particular causal model. Understanding of the complications introduced by EPA's policy and practice regarding defaults is central to evaluating EPA's management of uncertainty.
|
From page 195... ...
. Others have argued -- given the large scientific uncertainties surrounding risk assessment, human variability in both exposure to and response to toxic substances, and various missing defaults with "nonconservative" biases -- that risk overestimation might not be common in EPA's practices and that risk underestimation may occur (Finkel 1997; EPA SAB 1997, 1999)
|
From page 196... ...
. Integrated Risk Information System and provisional peer-reviewed toxicity values are then based on noncancer end points, and cancer risk estimates are not presented.
|
From page 197... ...
. Second, as part of its current practice of using defaults, EPA often does not quantify the portion of the total uncertainty characterized in the resulting risk estimate or RfD that is due to the presence of competing plausible causal models.
|
From page 198... ...
These recommendations include continued and expanded use of the best, most current science to choose, justify, and, when appropriate, revise EPA's default assumptions; development of a clear standard to determine when evidence supporting an alternative assumption is robust enough that the default need not be invoked and development of various sets of scientific criteria for identifying when an alternative has met that standard; making explicit the existing assumptions or developing new defaults to address the missing defaults, such as treatment of chemicals with limited information as though they pose risks that do not require regulatory action; and quantifying the risk estimates emerging
|
From page 199... ...
Best Use of Current Science to Define Defaults The defaults selected for EPA's risk assessments and described in the agency's guidelines should be periodically reviewed to determine their consistency with evolving science. The advance of scientific knowledge relevant to the selection of defaults is typically associated with studies of specific agents that provide insights into the applicability of alternative models to those agents (and perhaps also to related agents)
|
From page 200... ...
Comments included statements that EPA should always attempt to use real data instead of default factors and a statement that this use of clearance data is a significant step forward in the general EPA methodology for deriving uncertainty. The use of data-driven uncertainty factors was not without controversy, as reported in a 2004 Risk Policy Report: "environmentalists are concerned EPA is eroding its long-standing practice of us ing established safety factors when faced with scientific uncertainties.
|
From page 201... ...
In the case of criteria for setting aside the relevance of renal tumors that occurred after exposure to agents that act through the α2µ-globulin MOA, EPA developed clear criteria for departure from the default assumption that animal tumors are relevant to human risk.
|
From page 202... ...
For example, cancer bioassay data are needed from the mouse and the female rat to be able to demonstrate that the renal tumors are male-rat specific." EPA lists the type of data that are helpful, for example, data showing that the chemical in question does not cause renal tumors in the NBR rat (which does not produce substantial quantities of α2µ-globulin) , evidence that the substance's binding to α2µ-globulin is reversible, sustained cell division of the P2 renal tubule segment that is typical of the α2µ-globulin renal-cancer mode of action, structure-activity relationship data similar to those on other known α2µ-globulin MOA substances, evidence of an absence of genotoxicity, and the presence of positive renal-carcinogenicity findings only in male rats and negative findings in mice and female rats (EPA 1991b)
|
From page 203... ...
In the absence of data to derive a quantitative, chemical-specific estimate of toxicity, EPA treats such chemicals as though they pose risks that do not require regulatory action in its air, drinking-water, and hazardous-waste programs. In the case of carcinogens, EPA assigns no potency factor to a chemical and thus implicitly treats it as though it poses no cancer risk, for example, chemicals whose evidence meets the standard of "inadequate information to assess carcinogenic potential" in the carcinogen guidelines (EPA 2005a, p.
|
From page 204... ...
Full implementation of such a system will require about 10-20 years of data and method development. The committee urges EPA to begin to develop the methods for such a system by using existing data and the wealth of intermediate toxicity data being generated
|
From page 205... ...
Performing Multiple Risk Characterizations FOR Alternative Models The current management of defaults resembles an all-or-none approach in that EPA often quantifies the dose-response relationship for one set of assumptions -- either the default or whatever alternative to the default the agency adopts. Model uncertainty is discussed qualitatively; EPA discusses the scientific merits of competing assumptions.
|
From page 206... ...
that encouraged EPA to report risk estimates corresponding to alternative assumptions in its risk assessments. The level of detail in and scientific support for the alternative risk estimates should be tailored to be appropriate for the type of questions that the risk assessment is addressing (see Chapter 3)
|
From page 207... ...
• EPA should work toward the development of explicitly stated defaults to take the place of implicit or missing defaults. Key priorities should be development of default approaches to support risk estimation for chemicals lacking chemical-specific information to characterize individual susceptibility to cancer (see Chapter 5)
|
From page 208... ...
The goal is not to present the multitude of possible risk estimates exhaustively but to present a small number of exemplar, plausible cases to provide a context for understanding the uncertainty in the assessment. The committee acknowledges the difficulty of assigning probabilities to alternative estimates in the face of a lack of scientific understanding related to the defaults and acknowledges that much work is needed to move toward a more probabilistic approach to model uncertainty.
|
From page 209... ...
67-66-3) In Support of Summary Information on the Integrated Risk Information System (IRIS)
|
From page 210... ...
Review of the Draft Revised Cancer Risk Assessment Guidelines.
|
From page 211... ...
2007. Empirically observed distributions of pharmacokinetic and pharmacodynamic variability in humans: Implications for the derivation of single point component uncertainty factors providing equivalent protection as existing RfDs.
|
From page 212... ...
1999. Replacing the default values of 10 with data-derived values: A com parison of two different data-derived uncertainty factors for boron.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.