Effective dose defined

Median Effective Dose (ED) The statistically derived single dose of a substance that can be expected to cause a defined nonlethal effect in 50% of a given population of organisms under a defined set of e.xperimental conditions. 

The Fractional Effective Dose (FED) of toxicant received by an exposed person is defined by Hartzell (5.6) as... 

Figure 10. The percent probability of incapacitation or death as dependent on the corresponding Fractional Effective Dose (FED) defined by Equation 1.

Stochastic radiation effects are typically associated with those that occur over many months or years (i.e., are typically chronic instead of acute). Chronic doses are typically on the order of background doses (0.3 rem [0.003 Sv] or less) and are not necessarily associated with larger doses that could result from a terrorist attack with radiological weapons. However, stochastic health effects are defined here as effects that occur many years after chronic or acute exposure to radiological contaminants. Stochastic effects are categorized as cancers and hereditary effects. Because no case of hereditary effects (e.g., mutation of future generations) has been documented, this discussion focuses on cancer risk. 

By the Method of Frequency the stimulus range is selected in discrete intervals so that the frequency of positive answers is distributed over the range between 1% and 99%. In general, the frequency of positive responses either for an individual or for a group, is cumulatively normally distributed over a geometric intensity continuum. The absolute odor threshold can then be defined as the effective dose corresponding to an arbitrarily selected frequency of positive responses, ordinarily 50% ED50 Effective dose at the 50% level. 

Hunt et al. [6] demonstrated that the DTI is also equivalent to the ratio of the therapeutic index (abbreviated to TI in Hunt et al. s paper in this chapter TI is defined differently, see Section 13.4.3) of the drug-carrier conjugate and that of the free drug. The therapeutic index (also called the therapeutic ratio) is a statistical measure defined as the ratio of the median toxic dose to the median effective dose [22]. 

They suggested the effect parameter the Critical Effect Dose (CED, a benchmark dose. Section 4.2.5) derived from the dose-response data by regression analysis. This CED was defined as the dose at which the average animal shows the Critical Effect Size (CES) for a particular toxicological endpoint, below which there is no reason for concern. The distribution of the CED can probabilistically be combined with probabilistic distributions of assessment factors for deriving standards... 

Keeping the above principles in mind, Herscher et al. gives an excellent overview of the characteristics of an idealized radiation modifier (35). In the case of the radiation protector more dose can be delivered to the tumor and in the case of a sensitizer more effective dose can be delivered. In theory the ideal radiation enhancer will have selective systemic activity against malignant but not against nonmalignant cells, will reach the tumor in adequate concentrations to affect radiation, and will have been studied such that the ideal timing with relation to radiation treatment delivery will be defined. Such a compound will increase the effects of radiation in one of several ways (see Fig. 2) ... 

B.5.3 Effective Dose Equivalent and Effective Dose Equivalent Rate. The absorbed dose is usually defined as the mean absorbed dose within an organ or tissue. This represents a simplification of the actual problem. Normally when an individual ingests or inhales a radionuclide or is exposed to external radiation that enters the body (gamma), the dose is not uniform throughout the whole body. The simplifying assumption is that the detriment will be the same whether the body is uniformly or nonuniformly irradiated. In an attempt to compare detriment from absorbed dose of a limited portion of the body with the detriment from total body dose, the ICRP (1977) has derived a concept of effective dose equivalent. 

Both acute and chronic anxiety can be treated with benzodiazepines, although it is anticipated that for most anxiety disorders counseling will also play an important role. Benzodiazepines employed in the treatment of anxiety should be used in the lowest effective dose for the shortest duration so that they will provide maximum benefit to the patient while minimizing the potential for adverse reactions. For most types of anxiety, none of the benzodiazepines is therapeutically superior to any other. Choice of a particular agent is usually made on the basis of pharmacokinetic (Table 30.2) considerations. A benzodiazepine with a long half-life should be considered if the anxiety is intense and sustained. A drug with a short half-life may have advantages when the anxiety is provoked by clearly defined circumsfances and is likely to be of short duration. 

The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the specific and the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Table 5-1, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a specified toxic effect is not seen the minimum lethal dose—the smallest dose that is observed to kill any experimental animal and, if necessary, the median lethal dose (LD50)—the dose that kills... 

Several lipids A have been tested in cancer patients MPLA, SDZ MRL 953, and ONO-4007 were injected i.v. in phase I trials. The maximal tolerated dose found is lower than or close to the optimal dose defined in animals. Humans are more sensitive to lipid A than rodents so it is possible that similarly to the toxic dose, the effective dose is lower in humans than in animals. 

Laboratory test organisms should be representative of the four groups microorganisms, plants, invertebrates, and fish. The results are often reported as a lethal dose or concentration (LD or LC) with LCS0 the concentration where 50 % of the test organisms survived. The effective dose or concentration (ED or EC) is defined analogously where EC50 is used... 

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). 

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). 

The recommended dose limits for the public define limits on the probability of stochastic responses that are regarded as necessary for protection of public health. Doses above the limits are regarded as intolerable and normally must be reduced regardless of cost or other circumstances, except in the case of accidents or emergencies (see Section 3.3.1). For continuous exposure over a 70 y lifetime, and assuming a nominal probability coefficient for fatal cancers (i.e., the probability of a fatal cancer per unit effective dose) of 5 X 10 2 Sv 1 (ICRP, 1991 NCRP, 1993a), the dose limit for continuous exposure corresponds to an estimated lifetime fatal cancer risk of about 4 X 10 3. However, meeting the dose limits is not sufficient to ensure that routine exposures of the public to man-made sources would be acceptable. 

The biological effectiveness of dose depends on the type of radiation and also on the mass and sensitivity of the irradiated tissue. For alpha irradiation, a quality factor of 20 is assumed (ICRP, 1981), and the dose in Sieverts is 20 times the dose in Grays. In addition, ICRP recommends a weighting factor of 0.12 for irradiation of the whole lung and 0.06 for irradiation of bronchial epithelium only. Thus the effective dose equivalent , symbol HE, is defined as the dose to the whole body which carries the same risk as the given dose to the organ or tissue. This, for irradiation of bronchial tissue is 20 x 0.06 = 1.2 times the dose to the organ in Gy. 

After acceptable safety and pharmacokinetic data are observed in phase I trials, phase II studies are initiated with the goal of establishing efficacy, determining the effective dose range, and obtaining safety and tolerability data. In phase II, the dose and dosing interval to be employed in the patient population and the estimated noeffect dose are defined. Phase II studies may require 1-1.5 years to complete and may involve several hundred patients. 

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