Dose-response relationships deterministic responses

Risk Index for Mixtures of Hazardous Substances. For the purpose of developing a comprehensive and risk-based hazardous waste classification system, a simple method of calculating the risk posed by mixtures of radionuclides and hazardous chemicals is needed. The method should account for the linear, nonthreshold dose-response relationships for radionuclides and chemical carcinogens (stochastic effects) and the threshold dose-response relationships for noncarcinogenic hazardous chemicals (deterministic effects). 

Two types of responses from exposure to hazardous substances, called stochastic or deterministic,5 are of concern in risk assessment. The two types of responses are distinguished by the characteristic features of the dose-response relationship, i.e., the relationship between the dose of a hazardous substance and the probability (or frequency) of a response. 

The following sections present a comparison of approaches to estimating deterministic and stochastic dose-response relationships for radionuclides and hazardous chemicals. 

For purposes of health protection, the dose-response relationships for deterministic effects from exposure to radionuclides and hazardous chemicals are assumed to have a threshold. For either type of substance, the assumed thresholds are based on data for the most sensitive organ or tissue. However, there are potentially important differences in the way these thresholds are estimated and then applied in health protection of the public. 

First, the threshold for hazardous chemicals that cause deterministic effects is assumed for purposes of health protection to represent a lower confidence limit, taking into account uncertainties in the dose-response relationship (see Section 3.2.1.2.7). Depending, for example, on the slope of the dose-response relationship near the threshold, the chosen steps in the dosing regimen, and the magnitude of uncertainties in the data, the lower confidence limit of the assumed threshold can be substantially below MLE. In radiation protection, the estimated thresholds for deterministic effects are based on MLEs of dose-response relationships (ICRP, 1991). 

In contrast, risk management for substances that cause deterministic effects must consider unavoidable exposures to the background of naturally occurring substances that cause such effects. Based on the assumption of a threshold dose-response relationship, the risk from man-made sources is not independent of the risk from undisturbed natural sources, and the total dose from all sources must be considered in evaluating deterministic risks. In the case of ionizing radiation, thresholds for deterministic responses are well above average doses from natural background radiation (see Section 3.2.2.1)... 

The chemical paradigm for risk management also is used in regulating exposures to hazardous chemicals that cause deterministic effects and exhibit a threshold in the dose-response relationship. For these substances, RfDs, which are often used to define acceptable exposures, represent negligible doses, because RfDs usually are well below assumed thresholds for deterministic responses in humans and action to reduce doses below RfDs generally is not required. This interpretation is supported by cases where doses above an RfD are allowed when achieving RfD is not feasible. A particular example... 

Formulation of the risk index for mixtures of substances that cause deterministic effects is considerably more complex than in the case of substances that cause stochastic effects discussed in the previous section. The added complexity arises from the threshold dose-response relationship for these substances and the need to keep track of the dose in each organ or tissue at risk in evaluating whether the dose in each organ is less than the allowable dose in that organ. For substances that cause deterministic responses, the index T can refer not only to a specific organ or tissue (e.g., the liver or skin) but also to a body system that may be affected by a particular chemical, such as the immune or central nervous system. 

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. 

Use of the risk index in classifying waste requires that adequate data be available to allow estimation of dose-response relationships for substances that induce stochastic or deterministic responses. The availability of suitable data is a potential problem only for hazardous chemicals. If suitable data are not available for particular hazardous substances, there is no satisfactory approach that could be used to include these substances in classifying waste. However, this would be an important deficiency only if substances with inadequate data on dose-response posed an important hazard in the waste. NCRP does not expect that the most important hazardous substances in waste in regard to potential risks would be lacking information on the dose-response relationship. 

Approaches to Estimating Dose-Response Relationships for Substances That Cause Deterministic Responses. Most of the factors that must be considered in developing reasonably consistent approaches to estimating risk for radionuclides and chemicals that induce stochastic responses discussed in the previous section do not apply to substances that induce deterministic responses. For purposes of health protection, incidence generally is the appropriate measure of response for substances that cause deterministic responses. Furthermore, an accounting of deterministic responses... 

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... 

For radiation protection purposes, the biological effects of ionizing radiation are grouped into two main categories, the stochastic and deterministic effects. In both cases, the effects are related to the absorbed doses. Therefore, the knowledge on the dose-response relationships is essential for risk assessment. 

Deterministic responses are those for which the severity varies with dose and for which a threshold usually exists. In some toxicology texts, this type of response is called a graded response, to reflect both the increase in incidence of the response and the increase in its severity that usually are observed as the dose increases above the threshold. If the dose does not exceed a certain threshold, the probability of occurrence of a particular response is presumed to be zero. Deterministic responses often occur soon after exposure, and a causal relationship between dose and response in such cases is easily established if the dose is sufficiently high. Deterministic responses resulting from exposure to chemical toxicants include, for example, increased protein in the urine, birth defects and sterility,... 

Identification of Chemicals That Cause Deterministic Responses. Hazardous chemicals having a threshold in the dose-response relationship are identified using the following process ... 

Dose-Response Assessment for Chemicals That Cause Deterministic Effects. For hazardous chemicals that cause deterministic effects and exhibit a threshold in the dose-response relationship, the purpose of the dose-response assessment is to identify the dose of a substance below which it is not likely that there will be an adverse response in humans. Establishing dose-response relationships for chemicals that cause deterministic effects has proved to be complex because (1) multiple responses are possible, (2) the dose-response assessment is usually based on data from animal studies, (3) thousands of such chemicals exist, and (4) the availability and quality of data are highly variable. As a consequence, the scientific community has needed to devise and adhere to a number of methods to quantify the most important (low or safe dose) part of the dose-response relationship. 

There are two possible approaches to estimating the human safe dose for chemicals that cause deterministic effects the use of safety and uncertainty factors and mathematical modeling. The former constitutes the traditional approach to dose-response assessment for chemicals that induce deterministic effects. Biologically-based mathematical modeling approaches that more realistically predict the responses to such chemicals, while newer and not used as widely, hold promise to provide better extrapolations of the dose-response relationship below the lowest dose tested. 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

Section 6.3.2). Equation 6.4 is expressed in terms of dose, rather than risk, mainly because this form is consistent with the preferred form of the risk index for mixtures of substances that cause deterministic responses presented in the following section. Both ways of expressing the risk index are equivalent for substances that cause stochastic responses when a linear, nonthreshold dose-response relationship is assumed. 

By examination of the organ-specific ratios of calculated doses to allowable doses obtained in the previous step, the maximum value of these ratios is selected. Application of the MAX function to these organ-specific ratios is based on an assumption that induction of deterministic responses in any organ is independent of doses in any other organs or, equivalently, that the threshold in the dose-response relationship for any substance that causes deterministic responses is not affected by exposure to multiple... 

The order in which the summations over the responses (r) and substances (i) of concern are executed in the second and third steps above is arbitrary. However, these steps must be executed before the MAX and INTEGER functions are applied to the result. If the risk index for substances causing deterministic responses were based on calculations of health risk per se, rather than dose, the INTEGER function in Equation 6.5 would not be necessary, because the risk would be zero whenever a dose is below the threshold. Again, however, evaluation of the risk index for substances that cause deterministic responses based on dose is recommended when the dose-response relationship is assumed to have a threshold. The use of dose is supported by the observation that the dose-response relationship above the threshold generally is nonlinear. 

If the risk index for all substances that cause deterministic responses in the waste (RId) in Equation 6.5 is zero (i.e., the doses of all substances that cause deterministic responses are less than the allowable values), classification is determined solely by the risk index for all substances that cause stochastic responses (RP) in Equation 6.4 the latter must be nonzero based on the assumption of a linear, nonthreshold dose-response relationship. On the other hand, if the risk index for all substances that cause deterministic responses is unity or greater, the calculated risk exceeds the allowable risk for the waste class of concern without the need to consider the risk posed by substances that cause stochastic effects. The only advantage of the form of the composite risk index in Equation 6.6 is that it indicates more explicitly that the total risk posed by a given waste is the sum of the risks posed by the two types of hazardous constituents, however approximate that representation may be. 

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