Threshold dose-response, definition

Some aspects of degree of concern currently can be considered in a quantitative evaluation. For example, EPA considers human and animal data in the process of calculating the RfD, and these data are used as the critical effect when they indicate that developmental effects are the most sensitive endpoints. When a complete database is not available, a database UF is recommended to account for inadequate or missing data. The dose-response nature of the data is considered to an extent in the RfD process, especially when the BMD approach is used to model data and to estimate a low level of response however, there is no approach for including concerns about the slope of the dose-response curve. Because concerns about the slope of the dose-response curve are related to some extent to human exposure estimates, this issue must be considered in risk characterization. (If the MOE is small and the slope of the dose-response curve is very steep, there could be residual uncertainties that must be dealt with to account for the concern that even a small increase in exposure could result in a marked increase in response.) On the other hand, a very shallow slope could be a concern even with a large MOE, because definition of the true biological threshold will be more difficult and an additional factor might be needed to ensure that the RfD is below that threshold. 

Early blood lead measurements were used to assemble dose—response relationships for clinical toxic effects, and this was the case during the 1950s to the 1970s. With the availability of an accepted measure of body dose, one could be alerted to the likely degree of poisoning. With time and in more recent years, the clinical and scientific definitions of significant adverse effects of lead have been associated with lower and lower blood lead thresholds. 

The risk index in Equation 6.2 is expressed in terms of risk (i.e., the probability that an adverse response will occur during an individual s lifetime). This definition is consistent with the fundamental objective of developing a risk-based hazardous waste classification system. However, the use of health risk per se in calculating the risk index presents some difficulties because risk is not proportional to dose for substances that cause deterministic effects. For this type of substance, the risk is presumed to be zero at any dose below a nominal threshold. Since the allowable dose should always be less than the threshold in order to prevent the occurrence of adverse responses, expressing the risk index in terms of risk would result in an indeterminate value and, more importantly, a lack of distinction between doses near the nominal thresholds and lower doses of much less concern. For any hazardous substance, including carcinogens for which risk is assumed to be proportional to dose without threshold, it is generally useful to express the risk index as the ratio of a calculated dose [e.g., sieverts, mg (kg d)-1] to an allowable dose that corresponds to an allowable risk ... 

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