Deterministic effects

Filipy RE, Toohey RE, Kathren RL, et al. 1995. Deterministic effects of 241 Am exposure in the Hanford americium accident case. Health Phys 69(3) 338-345. 

This Section is limited to a general discussion on the number and location of personal monitors eind other devices used to monitor deep dose equivalent. Other devices are commonly used to monitor dose equivalents in the extremities, skin and lens of the eye, for demonstrating compliance with the separate dose limits for deterministic effects in those tissues. These latter devices are not germane to this Report. 

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. 

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). 

Use of the composite risk index in classifying waste. Given the risk indexes for mixtures of substances causing stochastic or deterministic effects calculated using Equations 1.5 and 1.6, respectively, the composite risk index for all hazardous substances is calculated using Equation 1.4. This procedure assumes that induction of stochastic effects is independent of exposures to substances causing deterministic effects, and vice versa. 

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. 

Dose-response concepts. Dose-response assessment for hazardous chemicals that can cause deterministic effects begins with the toxicology data developed during the hazard identification step described in Section 3.1.4.1.2. In many cases, hazard identification and dose-response assessment occur simultaneously. For each chemical, the critical response (a specific response in a specific organ) is identified in the hazard identification process. Using the available data for the critical response, one of the following is established ... 

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). 

Selection of the database. The types of studies that make up a complete database for estimating an RfD of high confidence for chemicals causing deterministic effects from data in laboratory animals include ... 

Selection of uncertainty and modifying factors. The choice of an uncertainty factor for a chemical that can cause deterministic effects is based on case-by-case judgment. This factor should account for the shortcomings and uncertainties in the scientific data. 

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).

The rationale supporting use of EDi0 as the benchmark dose is that a 10 percent response is at or just below the limit of sensitivity in most animal studies. Use of the lower confidence limit of the benchmark dose, rather than the best (maximum likelihood) estimate (EDio), as the point of departure accounts for experimental uncertainty the difference between the lower confidence limit and the best estimate does not provide information on the variability of responses in humans. In risk assessments for substances that induce deterministic effects, a dose at which significant effects are not observed is not necessarily a dose that results in no effects in any animals, due to the limited sample size. NOAEL obtained using most study protocols is about the same as an LED10. 

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 benchmark dose method and MOE analyses are essentially the same for substances that cause stochastic or deterministic effects. For both types of substances, the point of departure in the dose-response curves for purposes of protecting human health is a dose at which some response is expected, either LED10 or some other human equivalent dose or concentration as the data support. For stochastic responses (e.g., cancers), the point of departure when animal data are used is a human equivalent dose or concentration... 

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). 

Based on these differences, the use of RfDs for hazardous chemicals that induce deterministic effects to define acceptable exposures of the public often may be considerably more conservative (provide a substantially larger margin of safety) than the dose limits for radiation induced deterministic effects. The likely degree of conservatism embodied in RfDs has important implications for establishing limits on allowable exposures to substances causing deterministic effects for the purpose of developing a risk-based waste classification system. Dose limits for deterministic effects for radiation should not be important in classifying waste (see Section 3.2.2.1). 

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... 

Incidence is the common measure of response for all substances that cause a deterministic effect, including radionuclides, used in routine health protection, and there is no evident reason to change this. As indicated by the discussions in the previous sections, arguments can be advanced in favor of using either incidence or fatalities as the common measure of stochastic response. Use of ICRP s total detriment appears to be disadvantageous, compared with either incidence or fatalities, and is not considered further. 

As an alternative to using the benchmark dose method, the more traditional approach of estimating threshold doses of substances that cause deterministic effects based on NOAELs could be used. In... 

The ALARA principle also has been used in decisions about risk management for chemicals that cause deterministic effects. RfDs often are used to define acceptable exposures to such substances. However, given the large safety and uncertainty factors often used in deriving RfDs from a NOAEL or LOAEL (see Section 3.2.1.2.4), RfDs generally correspond to doses considered negligible, and doses above an RfD may be permitted in particular situations if RfD is not achievable at a reasonable cost (see Section 3.3.2). 

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. 

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