Exposure-response relationship 1200 INDEX

Risk Index for Multiple Substances That Cause Deterministic Responses. The risk index for mixtures of substances that cause deterministic responses should be expressed in terms of dose, rather than risk, because risk is not proportional to dose and the goal of risk management is to limit doses to less than the threshold in the dose-response relationship (see discussion of Equation 6.2 in Section 6.3). As noted previously, deterministic responses from exposure to radionuclides should not be of concern in classifying waste, in which case only the risk index for chemicals that induce deterministic responses needs to be considered. 

For substances that cause stochastic effects, the risk index can be expressed in terms of risk, rather than dose. In this case, the risk per unit dose would be incorporated in the calculated risk in the numerator, based on the assumed exposure scenario, rather than in the denominator. However, the effective dose provides a convenient surrogate for risk for radionuclides, because all organs at risk and all stochastic responses of concern are taken into account, and the use of dose for all substances that cause stochastic effects is consistent with the form of the risk index for substances that cause deterministic effects, which generally should be expressed in terms of dose based on the assumption of a threshold dose-response relationship. 

The boundaries between different waste classes would be quantified in terms of limits on concentrations of hazardous substances using a quantity called the risk index, which is defined in Equation 6.1. The risk index essentially is the ratio of a calculated risk that arises from waste disposal to an allowable risk (a negligible or acceptable risk) appropriate to the waste class (disposal system) of concern. The risk index is developed taking into account the two types of hazardous substances of concern substances that cause stochastic responses and have a linear, nonthreshold dose-response relationship, and substances that cause deterministic responses and have a threshold dose-response relationship. The risk index for any substance can be expressed directly in terms of risk, but it is more convenient to use dose instead, especially in the case of substances that cause determinstic responses for which risk is a nonlinear function of dose and the risk at any dose below a nominal threshold is presumed to be zero. The risk index for mixtures of substances that cause stochastic or deterministic responses are given in Equations 6.4 and 6.5, respectively, and the simple rule for combining the two to obtain a composite risk index for all hazardous substances in waste is given in Equation 6.6 or 6.7 and illustrated in Equation 6.8. The risk (dose) that arises from waste disposal in the numerator of the risk index is calculated based on assumed scenarios for exposure of hypothetical... 

Using the Cd concentration in rice as an index of exposure and the prevalence of proteinuria with glucosuria as an index of health effect, a significant dose-response relationship was demonstrated between the two indices. The allowable values of Cd concentration in rice were estimated to be in the range of 0.05-0.20 mg/kg, representing values lower than the 0.4 mg/ kg provisionally adopted by the Japanese government [84]. 

The relationship of Pb exposure and anemia in terms of dose—response relationships and thresholds indexed by various exposure markers has been recorded. In children, the thresholds in the older literature for onset of Pb-derived anemia with reference to Hb reduction are lower, i.e., <40 pg/dl than it is in adults, s40—50 p-g/dl. At levels above these thresholds, studies typically identified an inverse relationship with PbB levels in children (Pueschel et al., 1972) and Pb workers (Baker et al., 1979). Several Pb worker epidemiological studies evaluated the percentage population response for a selected Hb reduction at varying levels of PbB. In the U.S. study of smelter workers by Baker et al. (1979), employing an Hb level <14.0 g/dl, 5% of workers had a Hb reduction at 40—59 pg/dl PbB, 14% at 60—79 pg/dl PbB, and 36% at s80 p-g/dl PbB. A similar analysis by Grandjean (1979), however, showed much higher frequencies at a somewhat different Hb cutoff of <14.4 g/dl 17% showed an Hb reduction at <25 pg/dl PbB, 26% at... 

The dose—response relationships for EP change with Pb exposure, including thresholds, are logarithmic and appear to show that children are more sensitive than adults, while women are somewhat more sensitive than men (Table 16.6). For children, the dose—response relationship persists down to a threshold in blood lead on the order of 15—20 xg/dl, and in adults across gender, 25—35 p-g/dl. The dose—response relationship of EP and PbB is affected by the time course of EP s accumulation with increase in Pb exposure indexed through PbB. 

The term dose—response in environmental epidemiology is typically understood to mean that quantitative relationship in which adverse effect severity and multiplicity increase in proportion to the intensity of exposure or dose indexed externally (intake/uptake quantities) or internally (exposure biomarkers). In the case of experimental animal exposures, reference is often to the administered dose, but biomarkers can also be available. Dose—response has also been employed to denote impacts at some selected effect level of a toxicant in terms of increasing affected fractions of some population as exposure increases. In this case, a dose—population response label is more precise. 

Part 2 and its chapters presented the topic of human lead exposure in global and categorical terms, addressing the technical areas of lead intakes, uptakes (absorption), toxicokinetics, integration of toxicokinetics into in vivo disposition in a manner allowing quantitative assessments of lead exposure, etc. In contrast to these broadly descriptive aspects of human Pb exposme, the applied health discipline of quantitative risk assessment requires prescriptive approaches for site-specific, case-specific, and environmental scenario-specific lead exposure characterizations. Data from such specific exposure characterizations are combined with available data for lead dose—response relationships to arrive at some quantitative risk characterization indexed as some endpoint for human health risk. 

There are several ways one can quantify human health risk characterization for humans at risk through lead exposure. The first and simplest examines the prevalences or incidences of blood lead levels above some health risk threshold, with frequencies of exceedance identifying those at more risk (compared to those with PbB values below the risk threshold). Expressions of health risk in terms of elevated PbB occurrences (e.g., 10 jig/dl) do not simultaneously provide quantitative estimates of organ- or system-specific toxic harm, such as actual loss of IQ points or increases in SBP or DBP. A health risk threshold indexed in terms of a PbB level, however, represents the synthesis of numerous empirical dose—toxic response relationships, as developed and discussed in previous chapters. 

PbB has long been used as the standard index of dose in estimating dose-effect and dose-response relationships. Some would argue that it is perhaps less valid than certain other measurements which reflect in quantitative fashion the bioavailable fraction of PbB, much as erythrocyte cholinesterase inhibition reflects the toxic impact of exposure to organophosphate insecticides. Indeed, it has been reported that inhibition of erythrocyte membrane Na, K-ATPase activity is better correlated with lead toxicity than erythrocyte lead concentration (Raghavan ei al, 1981). This was attributed to the fact that the subjects had variable concentrations of a low molecular weight lead binding protein which influenced the bioavailable fraction of PbB. It is possible that EP reflects bioavailable lead in a similar fashion. 

Weaver et al. (2003) showed a significant interaction of worker age and kidney disease in effect modification for the relationship of serum uric acid levels to either bone Pb or PbB in a mixed cohort of Korean current and former Pb workers (N = 803). While negative data for exposure-kidney endpoint associations were determined for the entire group, the oldest age tercile showed worsening kidney disease (increased uric acid) with increased exposure indexed as bone Pb and PbB, while the youngest subset had evidence of hyperfiltration responses. 

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