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11 Aggregation
Pages 224-242

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From page 224...
... The aggregation problem is simplified when all end points of concern are believed to have dose-response thresholds or no-adverse-effect levels. Under this restriction, "acceptable," "allowable," or "reference" doses are typically calculated by dividing empirically determined threshold estimates (such as noobserved-adverse-effect levels, NOAELs)
From page 225...
... This chapter focuses on aggregation of different risks and different types of risk attributable to integrated, multiroute exposure to multiple chemicals that are assumed to have nonthreshold effects. EXPOSURE ROUTES Any comprehensive assessment of health risk associated with environmental exposure to any particular compound must consider all possible routes by which people might be exposed to that compound, even if expected applications in risk management are limited to some particular medium, such as air, or partic
From page 226...
... RISK-INDUCING AGENTS Quantitative environmental risk assessment is often needed for exposure to multiple toxic agents, for example, in the context of hazardous-waste, drinkingwater, and air-pollution control. The 1990 Amendments to the Clean Air Act in particular list 189 airborne pollutants of immediate regulatory concern that can be emitted singly or in combination from a variety of specified emission-source categories.
From page 227...
... . Although some cases of supra-additivity for acute toxicants are known, such as the synergistic interaction of organophosphate pesticide combinations in which one compound inhibits the detoxification of another compound, additivity has nevertheless been viewed as a reasonable expectation at the low doses at which detoxification enzymes are not expected to be saturated (NRC, 1988b; Calabrese, 19911.
From page 228...
... Highly nonlinear, supra-additive synergistic interaction of some types of nongenotoxic cancer promoters with genotoxic agents is predicted by "biomechanistic" multistage models of carcinogenesis. In those models, increased cell replication can play a pivotal role either by directly increasing the rates of production of premalignant or malignant lesions, by amplifying the incidence of malignant lesions through stimulated growth of spontaneously occurring premalignant lesions, or both (Armitage and Doll, 1957; Moolgavkar and Knudson, 1981; Moolgavkar, 1983;Bogen, 1989;Cohen and Ellwein, 1990a,b; l991;Ames and Gold, 1990a,b; Preston-Martin et al., 19904.
From page 229...
... Therefore, low-dose linearity has been recommended as a reasonable default assumption, even for agents known to increase cancer risk through nongenotoxic promotional mechanisms, in the absence of data establishing a pertinent, clearly defined, generally applicable threshold dose-response relation (Lutz, 1990; Perera, 1991~. Under this default assumption, the mechanistic type of cancer-risk model and the classical multistage cancer-risk model both predict that small amounts of increased risk will be approximately linearly proportional to the risk associated with small combined doses of genotoxic or nongenotoxic carcinogens, or both, and that their joint action will be approximately additive (Gibb and Chen, 1986; NRC, 1988a; Brown and Chu, 1989; Krewski et al., 1989; Kodell et al., l991b)
From page 230...
... to EPA's procedure for estimating aggregate cancer potency depends on the validity of the assumption that different tumor types occur independently within individual bioassay animals. If substantial interanimal heterogeneity exists in susceptibility to cancer, or if tumor types are positively correlated, the occurrence of multiple tumor types would be expected to cluster in the more susceptible individuals.
From page 231...
... Inherited genetic effects other than complex multifactorial effects have been found to occur spontaneously in roughly 2% of all liveborn people, appearing either at birth or thereafter; about 4080% often involve chromosomal anomalies or dominant or X-linked mutations ("CADXMs") (Mohrenweiser, 1991~.
From page 232...
... Such support of a default assumption of nonthreshold linearity in induced genetic risk has highlighted the uncertainty that exists in quantitative assessment of the total genetic risk to humans associated with exposure to ionizing radiation or genotoxic chemicals. That uncertainty, due particularly to problems in estimating possible increases in rates of human genetic disease, has led some to conclude that realistic assessment of total genetic risk associated with environmental exposure will not soon be possible (NRC, l990b; Mohrenweiser, 1991; Vogel, 1992~.
From page 233...
... However, individual genetic risk could be expressed as increased lifetime risk of expression of a serious inherited genetic end point in a person whose parents were both exposed from birth to a given relevant compound at a given effective dose rate. And addition of such a predicted risk to a corresponding magnitude of predicted somatic (cancer)
From page 234...
... MEASURES AND CHARACTERISTICS OF RISK Overall Characterization Goals An essential component of risk characterization is the aggregation of different measures and characteristics of risk; the risk assessor must communicate measures and characteristics of predicted risk in ways that are useful in risk management. The technical aspects of risk aggregation and characterization cannot and should not be separated from the design of useful, politically responsible, and legally tenable criteria of risk acceptability, because such criteria must generally be based on risk characterizations that follow some standard format, and the format must accommodate the criteria.
From page 235...
... The difficulty with this approach lies in ensuring that resulting semiquantitative characteristics are properly interpreted and communicated. For example, it would be illogical and potentially rnisleading to characterize a final risk estimate as a "plausible upper bound" on risk, if it were derived by aggregating component-specific point estimates that represent a mixture of best estimates and statistical upper confidence limits.
From page 236...
... The EPA guidelines for cancer-risk characterize the estimate produced by following the guidelines as a "plausible upper bound" on increased cancer risk. Such a risk estimation will generally involve a pertinent set of animal bioassay data, an animal-cancer potency estimate, and an interspecies dose-scaling factor.
From page 237...
... On the other hand, this risk management distinction between uncertainty and variability should not blind people to a central fact of environmental health risk assessment: that in general, risks are both uncertain and variable simultaneously. In the prototypical hazardous air pollutant risk assessment case, one can think of the source exposing each nearby resident to a different ambient
From page 238...
... may not be sufficient to pin down the mean with the precision desired. A group of 1000 workers observed in an epidemiologic study, for example, may have an average susceptibility to cancer significantly greater or less than the true mean of the entire population, if by chance (or due to a systematic bias)
From page 239...
... even when measurements are perfect, the amount of variability cannot be perfectly determined from any single data set random parameter uncertainty introduces the possibility that by chance, the population observed might be inherently less or more variable than the entire population; and (3) there may be "model uncertainty" in deciding what kind of probability distribution to fit to variable observations, and hence statistics such as the standard deviation or the upper confidence limit might be in error if they apply to a distribution that does not precisely describe the actual variability.
From page 240...
... EPA currently uses a specific procedure when analyzing animal bioassay data involving the occurrence of multiple tumor types (e.g., lung, stomach, etc.) to estimate the total cancer risk associated with exposure to a single compound.
From page 241...
... · EPA should continue to collect and use the data needed to evaluate the validity of the threshold assumption, and it should make any needed revisions in the proposed model so that human risks, particularly those of individuals with above-average sensitivity or susceptibility, are accurately estimated. "Upper-Bound Estimates" versus "Best Estimates" In a screening-level or semiquantitative risk characterization, component uncertainties associated with predicted cancer risk are not generally aggregated in a rigorous quantitative fashion.
From page 242...
... For screening-level analyses, the EPA (1992d) proposal to adopt a new interspecies doseequivalence factor is inconsistent with the 1986 guideline stipulation that risk estimated under the guidelines represents a "plausible upper bound" on increased cancer risk, and it is inconsistent with the corresponding stipulation that "upperbound" or health-conservative assumptions


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