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Part II Strategies for Improving Risk Assessment: 6 Default Options
Pages 79-105

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From page 79...
... · Data needs. Is enough information available to EPA to generate risk assessments that are protective of public health and are scientifically plausible?
From page 80...
... Hence, there are many uncertainties in the health risk assessments of those pollutants. Some of these can be referred to as model uncertainties for example, uncertainties regarding dose-response model choices due to a lack of knowledge about the mechanisms by which hazardous air pollutants elicit toxicity.
From page 81...
... The committee, as discussed in Chapter 6, believes that EPA has acted reasonably in electing to issue default options. Without uniform guidelines, there is a danger that the models used in risk assessment will be selected on an ad hoc basis, according to whether regulating a substance is thought to be politically feasible or according to other parochial concerns.
From page 82...
... They concluded that weighing societal values is properly left to those who have been chosen, directly or indirectly, to represent the public. Indeed, in the view of these members, any recommendation by the committee would give the false impression that the choice of principles is ultimately an issue of science; noting the sharp differentiation that Congress made between the tasks of this committee and those of the Risk Assessment and Management Commission established by Section 303 of the Clean Air Act Amendments of 1990.
From page 83...
... , it can often be quantified, as Chapter 9 suggests. Model uncertainties result from an inability to determine which scientific theory is correct or what assumptions should be used to derive risk estimates.
From page 84...
... THE ITERATIVE APPROACH One strategy component that deserves emphasis is the need for iteration. Neither the resources nor the necessary scientific data exist to perform a fullscale risk assessment on each of the 189 chemicals listed as hazardous air pollutants by Section 112 of the Clean Air Act.
From page 85...
... 63~. Default options are not rules that bind the agency; rather, as the alternative term inference guidelines implies, the agency may depart from them in evaluating the risks posed by a specific substance when it believes this to be appropriate.
From page 86...
... The guidelines, the report urged, should not be rigid, but instead should allow flexibility to consider unique scientific evidence in particular instances. The Red Book described the advantages of such guidelines as follows (pp.
From page 87...
... For instance, the default options indicate that, in assessing the magnitude of risk to humans associated with low doses of a substance, "in the absence of adequate information to the contrary, the linearized multistage procedure will be employed" (EPA, 1986a, p.
From page 88...
... In the absence of adequate human data, it is necessary to use laboratory animals as surrogates for humans. One advantage of guidelines, as already noted, is that they can articulate both the agency's choice of individual default options and its rationale for choosing all of the options.
From page 89...
... the assumptions that lead to risk estimates that, although plausible, are believed to be more likely to overestimate than to underestimate the risk to human health and the environment. EPA's risk estimates thus are intended to reflect the upper region of the range of risks suggested by current scientific knowledge.
From page 90...
... Better data and increased understanding of biological mechanisms should enable risk assessments that are less dependent on default assumptions and more accurate as predictions of human risk. In evaluating EPA's risk-assessment methods, we are aware that the agency's guidelines, to use the terminology of the earlier NRC report, are in part statements of science policy, rather than purely statements of scientific fact.
From page 91...
... Congress ought to be aware of the need for greater agency resources to carry out the mandates of the Clean Air Act and similar legislation. Even if a default option is not set aside, we believe that decision-makers ought to be informed in a narrative way of any specific information suggesting that, in specific cases, alternatives to the default options might have equal or greater scientific support, and believe that the characterization of risk should include a discussion of the effect of the alternative options on risk estimates.
From page 92...
... . The first four have been classified as hazardous air pollutants by the Clean Air Act Amendments of 1990.
From page 93...
... Classical kidney carcinogens, such as dimethylnitrosamine, induce renal tubule cancer in laboratory animals at a high incidence in both sexes after short periods of exposure, with a clear increase in kidney tumor incidence with increased dose. Thus, the classical kidney carcinogens and CIGAs appear to act via different mechanisms.
From page 94...
... In accord with the default options of EPA's guidelines, the carcinogenic potency of methylene chloride was estimated by scaling the laboratory animal data to humans with a body surface-area conversion factor. The resulting cancer risk estimate was 4.1 x 10-6 for exposure at 1 ~glm3 (Table 6-1~.
From page 95...
... Research with animal species used in the bioassays and human tissue has shed light on the metabolism of methylene chloride. Much of the research was conducted with the goal of providing input for physiologically based pharmacokinetic (PBPK)
From page 96...
... The process by which EPA arrived at the current risk estimate for methylene chloride with PBPK modeling involved use of peer-review groups and SAB review to achieve a scientifically acceptable consensus position on the validity of the alternative model. After EPA's re-evaluation, however, articles in the peer-reviewed literature began to focus attention on parameter uncertainties in PBPK modeling, which neither EPA nor the original researchers in the methylene chloride case had considered.
From page 97...
... One avenue of investigation was directed toward character TABLE 6-2 Incidence of Nasal Tumors in F344 Rats Exposed to Formaldehyde and Companson of EPA Estimates of Human Cancer Risk Associated with Continuous Exposure to Formaldehyde Exposure rate, ppma Incidence of Rat Nasal Tumors 14.3 5.6 2.0 o 94/140 2/153 0/159 0/156 Upper 95% Confidence Limit Estimates Exposure Concentration, ppm 1987 Risk Estimatesb 1991 Risk EstimatesC Monkey-Based Rat-Based 1.0 2 x 10-2 7 x 10 - 1 x 10-2 0 5 8 x 10-3 2 x 10 - 3 x 10-3 0.1 2x 10-3 3x 10-5 3x 10 Maximum Likelihood Estimates 1.0 1 x 10-2 1 x 10 - 1 x 10-2 0.5 5 x 10 ~ 1 x 10-5 1 x 10-3 0.1 5x 10-7 4x 10-7 3x 10-5 aExposed 6 hr/day, 5 days/week for 2 years. bEstimated with 1987 inhalation cancer unit risk of 1.6 x 1~2 per ppm, which used airborne concentration as measure of exposure.
From page 98...
... The SAB recommended that the agency attempt to develop an additional risk estimate using the epidemiological data and prepare a revised document reporting all the risk estimates developed by the alternative approaches with their associated uncertainties. The two examples just discussed used mechanistic data and modeling to improve the characterization of the exposure-dose link.
From page 99...
... It is anticipated that modeling will provide insight into the relative importance, at various exposure concentrations, of the two mechanisms that appear to have a dominant role in formaldehyde carcinogenesis: mutation and cell proliferation. Improved insight into their role could provide a mechanistic basis for selecting between the linearized multistage mathematical model now used for extrapolation from high to low doses and alternative models that might have more biologic plausibility.
From page 100...
... Peroxisome proliferation has been proposed as a causal mechanism for the liver tumors, and proponents have asserted that such tumors should receive treatment in risk assessments different from evaluation under EPA's default assumptions. In particular, human liver cells might be much less sensitive than mouse liver cells to tumor formation from this mechanism, and the dose-response relationship might be nonlinear at low doses.
From page 101...
... But the SAB review and the EPA response to it suggest that the carcinogenic risk associated with a specific cadmium compound could be overestimated or underestimated, because bioavailability has not been included in the risk assessment. A refined version of the risk assessment that includes bioavailability might be appropriate, especially if residual risks for cadmium compounds appear to be important under the Clean Air Act Amendments of 1990.
From page 102...
... In 1988, EPA asked the SAB to review a proposal to revise its risk estimate for TCDD. SAB agreed with EPA's criticism of the linearized multistage model and its assessment of the promise of alternative models based on the receptor mechanism.
From page 103...
... inducing canceri.e., if intake of even one molecule of a chemical has an associated probability for cancer induction that can be calculated the appropriate model for relating exposure-response relationships is a linearized multistage model. Of the 189 hazardous air pollutants, unit risk estimates are available for only 51: 38 with inhalation unit risks, which are applicable to airborne materials, and 13 with oral unit risks.
From page 104...
... EPA should have a means of filling the gap when scientific theory is not sufficiently advanced to ascertain the correct answer, e.g., in extrapolating from animal data to responses in humans. RECOMMENDATION: EPA should continue to regard the use of default options as a reasonable way to cope with uncertainty about the choice of appropriate models or theory.
From page 105...
... In particular, the agency should continue to make the greatest possible use of peer review, workshops, and other devices to ensure broad peer and scientific participation to guarantee that its risk-assessment decisions will have access to the best science available through a process that allows full public discussion and peer participation by the scientific community, Missing Defaults FINDING: EPA has not stated all the default options in each step in the riskassessment process, nor the steps used when there is no default. Chapters 7 and 10 elaborate on this matter and identify several possible "missing defaults." RECOMMENDATION: EPA should explicitly identify each generic default option in the risk-assessment process.


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