Thresholds for Deterministic Effects

For noncarcinogenic hazardous chemicals, NCRP believes that the threshold for deterministic effects in humans should be estimated using EPA s benchmark dose method, which is increasingly being used to establish allowable doses of noncarcinogens. A benchmark dose is a dose that corresponds to a specified level of effects in a study population (e.g., an increase in the number of effects of 10 percent) it is estimated by statistical fitting of a dose-response model to the dose-response data. A lower confidence limit of the benchmark dose (e.g., the lower 95 percent confidence limit of the dose that corresponds to a 10 percent increase in number of effects) then is used as a point of departure in establishing allowable doses. 

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 

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Fig. 3.6. Illustration of use of benchmark dose method to estimate nominal thresholds for deterministic effects in humans. The benchmark dose (EDio) and LEDi0 are central estimate and lower confidence limit of dose corresponding to 10 percent increase in response, respectively, obtained from statistical fit of dose-response model to dose-response data. The nominal threshold in humans could be set at a factor of 10 or 100 below LED10, depending on whether the data are obtained in humans or animals (see text for description of projected linear dose below point of departure).

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). 

The consequences of accidents are expressed in terms of dose, which can be calculated using standard atmospheric dispersion and dose calculation software, such as those based on the Canadian standard (CSA, 1991). Stochastic doses are usually expressed in terms of the effective and thyroid doses for emergencies that involve the release of radioactive iodine. For emergencies that do not involve iodine, the critical organ dose would be based on the main radionuclide most likely to be released. For the calculation of deterministic health effects, it is important to use organ-specific equivalent doses because the effective dose concept is not applicable to doses this high. It is also important to consider the rate at which the dose is received because the thresholds for deterministic effects vary with the exposure rate. 

This dose can be exceeded if justified but every effort shall be made to keep dose below this level and certainly below the thresholds for deterministic effects. The workers should be trained in radiation protection and understand the risk they face. They must be volunteers and be instmcted on the potential consequences of exposure. 

Management of Victims at the Scene of the Accident. At facilities with radioactive sources, trained personnel on every shift should normally provide any first aid required. In case of serious injury, medical personnel from suitable off-site medical centers should be available. The purposes of medical response on-site are to treat traumatic injuries, to assess contamination and perform limited decontamination. If anyone receives high doses exceeding threshold for deterministic effects, it is usually recommended that he or she be transported directly to a highly specialized medical hospital for complete medical examination, treatments, and assessment of the dose. 

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... 

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. 

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. 

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... 

For any justified interventions, the objective is achieved by keeping the individual doses lower than the threshold levels for deterministic effects and keeping all doses as low as reasonably achievable in the circumstances. 

Thresholds arise for deterministic effects because large numbers of cells usually must be simultaneously destroyed to produce such effects, which is highly unlikely at low doses. The threshold dose for a specific deterministic effect depends on the type of radiation, on the rate at which the dose is delivered (dose rate), and, for some effects, on other factors. 

Table 5 Thresholds (lower, central and upper estimates) for deterministic effects of exposure of the unborn embryo or fetus ...

If people of varying susceptibility are exposed to radiation, the threshold in a given tissue for deterministic effects of sufficient severity to be observable will be reached with smaller doses in more sensitive individuals. 

Obviously, any immediate protective actions should be directed toward meeting the first objective by keeping the dose below the thresholds for deterministic health effects. 

Accidents resulting in deterministic health effects will be very rare, and usually this will occur among employees or other professionals. However, in the case of a lost or stolen source, limited number of the general public may receive doses that can lead to deterministic health effects. Such a situation requires special medical care and supportive treatment for the early effects of acute radiation. In the event of internal exposure, especially by long-lived ra onuclides, decorporation might be considered, even if the dose is below the threshold for deterministic health effects. The decision about decorporation levels should be based on committed equivalent dose to the organs and the effective committed dose. 

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). 

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. 

Safety factor approach for chemicals that cause deterministic effects. Traditional toxicologic procedures for chemicals that can induce deterministic effects, which are assumed to have a threshold dose, define RfD for humans or animals as some fraction of NOAEL. This fraction is determined by establishing safety factors to account for weaknesses and uncertainties in the data and in the extrapolation from animals to humans. In the safety factor approach, doses below RfD are assumed not to result in a response because they are below the threshold of toxicity (Dourson and Stara, 1983 Renwick and Lazarus, 1998 Weil, 1972). 

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. 

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 ... 

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 of concern that causes deterministic effects (hazardous chemicals only), establish nominal thresholds for induction of deterministic responses in humans, taking into account all organs and tissues at risk. Then, establish organ-specific negligible and acceptable doses of each substance by applying appropriate safety and uncertainty factors to the assumed thresholds. 

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. 

In classifying waste, deterministic responses generally should be of concern only for hazardous chemicals (see Section 3.2.2.1). Therefore, the only important issue for risk assessment is the most appropriate approach to estimating thresholds for induction of responses in humans. The primary concern here is that consistent approaches should be used for all substances that induce deterministic effects. NCRP s recommendation that nominal thresholds in humans should be estimated using the benchmark dose method and a safety factor of 10 or 100, depending on whether the data were obtained in a study in humans or animals (see Section 6.1.2.1), is intended to provide consistency in estimating thresholds for all substances that cause deterministic effects. 

For most chemicals that induce deterministic effects, the nominal threshold in humans or animals has been estimated based on NOAELs or LOAELs. However, the benchmark dose method should provide more reliable estimates of thresholds (see Section 3.2.1.2.7). Therefore, whenever the nominal threshold in humans for an important chemical in waste that induces deterministic effects has been estimated based on NOAELs or LOAELs, NCRP believes that the data should be re-evaluated using the benchmark dose method to promote greater consistency in classifying waste. As in the case of chemicals that induce stochastic effects discussed in the previous section, NCRP believes that uncertainties in the data beyond those incorporated in the benchmark dose method should be taken into account, if need be, in setting allowable exposures, rather than in an estimate of the nominal threshold. 

In many respects, the foundations and framework of the proposed risk-based hazardous waste classification system and the recommended approaches to implementation are intended to be neutral in regard to the degree of conservatism in protecting public health. With respect to calculations of risk or dose in the numerator of the risk index, important examples include (1) the recommendation that best estimates (MLEs) of probability coefficients for stochastic responses should be used for all substances that cause stochastic responses in classifying waste, rather than upper bounds (UCLs) as normally used in risk assessments for chemicals that induce stochastic effects, and (2) the recommended approach to estimating threshold doses of substances that induce deterministic effects in humans based on lower confidence limits of benchmark doses obtained from studies in humans or animals. Similarly, NCRP believes that the allowable (negligible or acceptable) risks or doses in the denominator of the risk index should be consistent with values used in health protection of the public in other routine exposure situations. NCRP does not believe that the allowable risks or doses assumed for purposes of waste classification should include margins of safety that are not applied in other situations. 

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