Deterministic responses

Negligible risks or doses used to classify exempt waste could be established based on a variety of considerations, consistent with the different approaches to risk management for radionuclides and hazardous chemicals described in Section 1.5.3. For noncarcinogenic hazardous chemicals, NCRP recommends that a negligible dose should be set at a small fraction (e.g., 10 percent) of a nominal threshold for deterministic responses in humans the recommended approach to estimating this threshold is described in Section I.5.5.3. For radionuclides, NCRP has recommended that an annual effective... 

As an alternative, multiples of RfDs established by EPA could be used to define acceptable (barely tolerable) doses of noncarcinogenic hazardous chemicals, because RfDs normally are intended to be well below nominal thresholds for deterministic responses in humans. However, the cautions about using RfDs discussed in the previous section, especially when RfDs are based on data of poor quality, also apply in establishing acceptable doses. As in establishing negligible doses of noncarcinogens, NCRP prefers an approach in which acceptable doses are based directly on nominal thresholds in humans and application of small safety factors, as appropriate, to promote transparency and consistency in waste classification. 

The risk index for any hazardous substance in Equation 1.1 or 1.2 (see Section 1.5.1) is calculated based on assumed exposure scenarios for hypothetical inadvertent intruders at near-surface waste disposal sites and a specified negligible risk or dose in the case of exempt waste or acceptable (barely tolerable) risk or dose in the case of low-hazard waste. Calculation of the risk index also requires consideration of the appropriate measure of risk (health-effect endpoint), especially for carcinogens, and the appropriate approaches to estimating the probability of a stochastic response per unit dose for carcinogens and the thresholds for deterministic responses for noncarcinogens. Given a calculated risk index for each hazardous substance in a particular waste, the waste then would be classified using Equation 1.3. 

In traditional toxicological methods of determining virtually safe doses of hazardous chemicals, nominal thresholds for deterministic responses in humans are estimated based on a NOAEL obtained in human or animal studies. In most high-quality studies, NOAEL is approximately the same as the lower confidence limit of the benchmark dose that corresponds to a 10 percent increase in the number of responses. Thus, as an alternative to the benchmark dose method, the nominal threshold in humans could be set at a factor of 10 or 100 lower than NOAEL obtained in a high-quality human or animal study. However, the benchmark dose method preferred by NCRP... 

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,... 

Characterization and classification of chemical toxicity is complex because of the many possible responses a chemical might induce and the variability of the dose required to yield a response. Toxic responses can include acute effects on the function of various organs or long-term effects such as cancer. Occurrence of a response may be deterministic or stochastic. EPA treats chemicals showing deterministic responses as if there is a threshold below which there is no... 

Although there is the potential for a complex, multi-dimensional discussion in this area, the identification of chemicals that cause deterministic responses is discussed first, followed by a discussion of identifying chemicals that cause stochastic responses. An additional complexity is that a material may be hazardous due to its physical and chemical form. Thus, an additional section discusses the identification of hazardous chemical wastes, as opposed to their hazardous chemical constituents per se. 

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

LOAEL, although a substantially smaller safety and uncertainty factor may be used when RfD is derived from a NOAEL obtained in a high-quality study in humans. The schematic relationship of NOAEL, LOAEL, and RfD is illustrated in Figure 3.5. Although RfDs are widely used in health protection of the public, it is important to understand that they do not represent thresholds for deterministic responses in humans. 

A third important assumption relates to selecting the critical response. EPA assumes that if the dose is below that required to cause the most sensitive response, then other deterministic responses will not occur. However, if other responses have shallower slopes in the dose-response curves near their thresholds, estimating RfD on the basis of the critical response may not be sufficiently protective to preclude a noncritical response from occurring. For this reason, EPA may use information on the slopes of dose-response curves to determine the critical response and the number of safety factors to be applied, although EPA rarely does so. 

EPA does not consider data on developmental toxicity, standing alone, as an adequate basis for estimating RfD. Investigators use acute or short-term exposures for these studies. Therefore, they are of limited use in estimating the threshold for deterministic responses. However, if developmental toxicity is the critical response for a chemical with a complete database, EPA will derive RfD from that study. 

RfD is useful as a reference point for identifying whether a particular dose to humans poses a significant health hazard. Doses below RfD are not likely to cause any deterministic responses and are of little regulatory concern. As the frequency of exposure that exceeds RfD increases, the chance increases that the dose may cause a response. However, EPA cannot conclude that doses below RfD will not result in a response in a few individuals, or that doses above RfD will result in a response in any individual. 

Deterministic Responses. Prevention of deterministic responses is a basic principle of health protection for both radionuclides and hazardous chemicals the goal is to achieve zero probability of such responses. Incidence is the primary measure of deterministic response for any hazardous substance, although prompt fatalities also are of concern at sufficiently high doses. In risk assessments and in establishing deterministic dose limits, no adjustments are made to take into account, for example, the relative severity of different responses with regard to consequent reductions in the quality of life. 

Second, in radiation protection of the public, deterministic dose limits are based mainly on data in humans and normally are set at a factor of 10 below the assumed thresholds. This safety factor is intended to ensure that deterministic responses would be precluded... 

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... 

In setting limits on exposure intended to prevent the occurrence of deterministic responses, the safety and uncertainty factors that are applied to the assumed thresholds for hazardous chemicals that cause deterministic effects usually are considerably larger (by at least a factor of 10) than the safety factor normally applied to the thresholds for deterministic responses from exposure to radiation. Furthermore, the assumed threshold usually is more conservative for hazardous chemicals than for radiation (i.e., a lower confidence limit of the threshold often is used for... 

Deterministic responses from exposure to hazardous chemicals generally are of concern in health protection of the public because many of the exposure limits derived from the assumed thresholds and the applied safety and uncertainty factors fall within the range of potential routine exposures. However, the possibility that the large safety and uncertainty factors normally used in setting exposure limits are quite conservative (pessimistic) could be taken into account in developing a risk-based waste classification system. Deterministic responses from exposure to radionuclides should not be of concern in health protection of the public or in classifying waste, because the dose limits intended to prevent deterministic responses are substantially higher than the dose limit intended to limit the occurrence of stochastic responses. 

Measures of Response for Substances Causing Deterministic Responses. For purposes of health protection in routine exposure situations, incidence has been the primary measure of deterministic response for both radionuclides and hazardous chemicals. Fatalities also are of concern for substances that cause deterministic responses, but only at doses substantially above the thresholds for nonfatal responses. Given that the objective of standards for health protection is to prevent the occurrence of deterministic responses, incidence is not modified by any subjective factors that take into account, for example, the relative severity of different nonfatal responses with respect to a diminished quality of life. Judgments about the importance of deterministic responses are applied only in deciding which responses are sufficiently adverse to warrant consideration in setting protection standards. 

For the purpose of developing a risk-based hazardous waste classification system, prevention of deterministic responses should be of concern only for hazardous chemicals, but not for radionuclides. Deterministic responses from exposure to radionuclides can be ignored because radiation dose limits for the public intended to limit the occurrence of stochastic responses are sufficiently low that the doses in any organ or tissue would be well below the thresholds for deterministic responses (see Section 3.2.2.1). 

Deterministic Responses. At the low levels of exposure of concern to waste classification, deterministic responses generally are important only for hazardous chemicals, but not for radionuclides. 

Estimated thresholds for deterministic responses in virtually all humans based on lower confidence limits of benchmark doses or NOAELs, as described above, would be used as points of departure in establishing allowable doses of chemicals that induce deterministic responses for purposes of waste classification. NCRP s recommendations on the magnitude of safety and uncertainty factors that should be applied to benchmark doses or NOAELs in classifying waste are described in Section 6.3.1.1. 

NCRP believes that use of a risk index expressed in terms of dose is acceptable and desirable as long as (1) the units of the numerator and denominator are consistent at a conceptual level, (2) the assumptions embodied in the proportionality constants between dose and response for substances that cause stochastic responses are clearly stated, and (3) the allowable doses are adjusted when the proportionality constants between dose and response for substances that cause stochastic responses or the thresholds for substances that cause deterministic responses change significantly. 

Establishing Allowable Doses of Substances That Cause Deterministic Responses. The risk index for substances that cause deterministic responses normally should be expressed in terms of dose, rather than risk, given the assumption of a threshold dose-response relationship. The allowable dose of substances that cause deterministic responses in the denominator in Equation 6.3 should be related to thresholds for induction of deterministic responses in different organs or tissues. 

The use of multiples of RfDs established by EPA to define acceptable (barely tolerable) doses of chemicals that cause deterministic responses also could be considered because RfDs normally are intended to be well below nominal thresholds for deterministic... 

Hazardous wastes can contain mixtures of substances that cause stochastic or deterministic responses, or a single substance can cause both types of responses (e.g., arsenic, uranium). The two types of... 

The implication of the difference described above is that the mathematical form of the risk index for the two types of hazardous substances must be different. Thus, while NCRP believes that it is appropriate to develop a single risk index that accounts for mixtures of substances that cause stochastic or deterministic responses, separate risk indexes for these two types of substances are formulated first. 

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. 

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 each substance, the organ or organs (including tissues or body systems) in which deterministic responses can be induced are identified. If a substance can induce responses in more than one organ, all such organs are included in calculating the risk index. 

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