Allowable dose or risk

It is not NCRP s intent to recommend specific boundaries between waste classes. Rather, the examples illustrate that the recommended framework has the potential to be practical and to result in an implementable waste classification system when a variety of plausible assumptions are used. Many assumptions are made in developing the examples. NCRP endorsement or disapproval should not be construed from the use or absence of specific assumptions about exposure scenarios and allowable doses or risks. It is the responsibility of the appropriate regulatory authorities to develop and guide implementation of any waste classification system. 

Assessment starts with a general calculation based on assumed service conditions and identification of the critical parameters and components, with particular regard to risk. Although relatively crude, this ranking of components is probably correct. It is followed by assessment of the actual service conditions experienced - data that should be available for process plant. This can identify the accumulated exposure or dose , or confirm that parameters lie below a threshold level. It can also identify unexpectedly large values, due for example to rapid transient variations, which would not be found in the planned service history. Such large parameters can have an exceptional effect on service lifetime. This is followed by inspection (materials, dimensions, etc.) of the critical components either on the plant or, if allowed, of the dismantled component, to provide a more confident... 

There are several large impediments to achieving the goal of more accurate risk assessments. First, it often requires a considerable investment in the research necessary to uncover the types of information needed to replace default assumptions in specific cases. If one hypothesizes that di-(2-ethylhexyl)phthalate (DEHP, a real and important chemical) produces liver tumors in rodents by mechanisms that either do not apply to humans at all, or that do not operate at low (human) doses, or both, then there arises the question of what type of research information is necessary to test the validity of such hypotheses If such research is actually carried out, then what type of results from that research would allow conclusions to be drawn about the validity of the hypotheses In many specific cases creative and knowledgeable scientists can hypothesize alternatives to the usual defaults and ways to test their validity. But it often turns out to be difficult to arrive at... 

Large increases in mercury levels in water can be caused by industrial and agricultural use and waste releases. The health risk from mercury is greater from mercury in hsh than simply from water-borne mercury. Mercury poisoning may be acute, in large doses, or chronic, from lower doses taken over an extended time period. The maximum amount of mercury allowed in drinking water by the standard is 0.002 mg/L of water. That level is 13% of the total allowable daily dietary intake of mercury. 

For non-thresholded contaminants some mechanism is required that will allow the benefits in terms of reduced risks and costs associated with control to be taken into account. The costs of control will include enforcement costs as well as costs to producers in reaching ever stricter standards. Ultimately these costs will be borne by consumers in taxes, increased prices or reduced choice. Economic theory dictates that there must be a point where the extra increase in the cost of control is not justified by the corresponding increase in benefit (reduction in risk). This optimal point will differ for each contaminant according to the technology needed to control it, the nature of the hazard, and the relationship between dose and risk. It is in this latter context that quantitative risk assessment (QRA) becomes critical (see section 2.3.4 of this chapter). 

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. 

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 the purpose of illustrating how the composite risk index in Equation 6.6 would be used to classify a hypothetical waste, it is helpful to simplify Equations 6.4 and 6.5. This is done by assuming that the summation over all responses (index r) has been calculated, that only one waste classification boundary represented by the index j is being considered (i.e., the boundary between exempt and low-hazard waste, based on a negligible risk, or the boundary between low-hazard and high-hazard waste, based on an acceptable risk), and that the modifying factor (F) is unity. Further, the calculated dose in the numerator of the risk index is denoted by D and the allowable dose in the denominator is denoted by L. Then, the composite risk index for all hazardous substances in the waste, expressed in the form of Equation 6.6, can be written as ... 

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. 

Similar considerations should apply to waste that contains small amounts of hazardous chemicals that might be sent to a disposal facility for nonhazardous waste. Allowable doses could correspond to a negligible lifetime risk of about 10 5 in the case of substances that induce stochastic effects or an intake at an RfD (Section 3.2.1.2) in the case of substances that induce deterministic effects. The considerations of exposure scenarios should be the same as in the case of radioactive wastes. 

The risk index normally is determined by computing the risk or by using dose as a surrogate for risk. In the example in Section 7.1.3.1, the calculated dose associated with intrusion into the waste is divided by the assumed maximum allowable dose to estimate the risk index. In the example in Section 7.1.3.2, limits on acceptable concentrations are developed as surrogates for the allowable risk. The concentrations in the waste are then divided by these allowable concentrations to determine the risk index. The same approach is used in the example in Section 7.1.3.3, except the allowable concentrations are lower because a less protective disposal option is evaluated. The consequences of alternative assumptions about intrusion scenarios on classification of the Hanford waste are considered in Section 7.1.3.4. 

Deterministic models use a single value for input variables and provide a point estimate of exposure or dose. Probabilistic models take into account the fact that most input variables will have a distribution of values. These models use probability distributions to develop a range of plausible exposures for the population of concern. Understanding exposure distributions will allow understanding of the range of exposures as well as prediction of risk for the entire population. It will also allow prediction of risk for the most highly exposed individuals. Sophisticated models can be used to develop distributions for different pathways and populations. They can also be used to develop information on interindividual variability and uncertainty in the estimated distributions and to predict the variables that are most important for both exposure and dose. 

The route of exposure is another aspect of exposure in which health-relevance must be considered. In Section One of this book, there is a detailed discussion of exposure assessment methodologies, including the importance of identification of the most prevalent route of exposure (dermal, inhalation or oral) and the necessity of knowing the absorption of the pesticide to allow calculation of the absorbed dose for risk assessment. For epidemiological purposes, exposure-assessment smdies are usually limited to assessing contact exposure levels. Since dermal absorption is not known for many pesticides or complex mixtures, uptake through the dermal route can often not be estimated and contact exposure data are a poor proxy of internal exposure (absorbed dose) (Schneider et al., 1999). 

The efficacy of intravenous paricalcitol and calcitriol and the risks of hypercalcemia and hyperphosphatemia have been studied in an international, randomized, doubleblind comparison in 38 patients in dialysis units (3). The end points were a reduction of at least 50% in basehne parathyroid hormone concentration and the occurrence of hypercalcemia and hyperphosphatemia. Paricalcitol was started at a dose of 0.04 micrograms/kg and increased in 0.04 micrograms/kg increments every 4 weeks to a maximum allowable dose of 0.24 micrograms/kg or until there was at least a 50% fall in serum parathyroid... 

As shown previously, PBPK models allow the conversion of potential dose or exposure concentration to tissue dose, which can then be used for risk characterization purposes. The choice of an internal dose metric is based principally on an understanding of the mode of action of the chemical species of concern. The internal dose metric (sometimes called the biologically effective dose) is often used in place of the applied dose in quantitative dose-response assessments, in order to reduce the uncertainty inherent in using the applied dose to derive risk values. 

Of course, this restriction has caused some consternation among herbalists or Chinese practitioners who still believe that within the context of traditional use, Ma Huang has its merits. In Canada, the ephedrine alkaloid is limited to levels well below the excesses seen in U.S. products, a policy that allows the continued sale of traditional Chinese Ephedra products. Canada also allows Ephedra to be included in products used for nasal congestion in the following small doses 8 mg/dose or 32 mg/day of ephedrine and 400 mg/ dose or 1600 mg/day. However, Health Canada has issued several warnings regarding the illegal sale of Ephedra and the potential risks that are involved, particularly when it is combined with caffeine or other stimulants. 

Since nonstochastic effects have a threshold, all that is needed to satisfy requirement 2 is to set the exposure limits below that threshold. For nonstochastic effects, the maximum allowed dose is set at 0.5 Sv (50 rem) for any tissue, except for the lens of the eye, for which the limit is set at 0.15 Sv (15 rem). For stochastic effects the limits are set at an acceptable level of risk. Ideally, the limit should be zero, since any exposure is supposed to increase the probability for stochastic effects to occur. Obviously, a zero limit is not practical. For stochastic effects the 10CFR20 sets the limiting exposure on the basis that the risk should be equal regardless of whether the whole body is irradiated uniformly or different tissues receive different doses. Recognizing the fact that different tissues have different sensitivities and, therefore, the proportionality constant between dose and effect is not the same for all tissues, the limit is expressed in terms of the effective dose equivalent (Ffg), defined as... 

Dermal Exposure Opportunity In assessing dose and risk for PCB s and PCDD s/PCDF s, a critical variable is the opportunity for dermal exposure. In determining dermal exposure opportunity it is customary to differentiate between areas within a given space that are readily assessable for high level contact such as exterior vertical and horizontal surfaces vs. areas less directly accessible. In these areas the person with potential exposure was high probability of dermal contact. This is in contrast to areas inside mechanical systems or in areas that because of height or inaccessibility allow for less opportunity for dermal exposure. 

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