Fractional effective dose model

Hartzell, G.E. Emmons, H.W. "The Fractional Effective Dose Model for Assessment of Hazards Due to Smoke from Materials," J. Fire Sciences 1988, 6(5), 356-362. 

The general approach in generating toxic potency data from chemical analysis is to assume additive behavior of individual toxicants, and to express the concentration of each toxicant as its fraction of the lethal concentration for 50% of the population for a 30 min exposure (LC50). Thus an fractional effective dose (FED) equal to one indicates that the sum of concentrations of individual species will be lethal to 50% of the population over a 30 min exposure. Two equations have been developed for the estimation of the FED for lethality from the chemical composition of the environment in the physical fire model. Each begins with the precept that the fractional lethal doses of most gases are additive, as developed by Tsuchiya and Sumi.32... 

Although the pH-partition hypothesis and the absorption potential concept are useful indicators of oral drug absorption, physiologically based quantitative approaches need to be developed to estimate the fraction of dose absorbed in humans. We can reasonably assume that a direct measure of tissue permeability, either in situ or in vitro, will be more likely to yield successful predictions of drug absorption. Amidon et al. [30] developed a simplified film model to correlate the extent of absorption with membrane permeability. Sinko et al. [31] extended this approach by including the effect of solubility and proposed a macroscopic mass balance approach. That approach was then further extended to include facili-... 

Figure 10 The fraction of dose absorbed as a function of the effective human permeability. (---) Compartmental absorption and transit model (Eqs. (59) or (60)) (—) single-...

EUSES. As in the case of USEtox model, the present model provides outputs such as human intake fraction of a certain substance for different exposure pathways. In the present case study, estimation of the human intake doses for Guiyu was calculated. These results were compared with the incidence and severity of the effects (dose-response assessment). 

This inverse relationship between equilibrium factor and "unattached" fraction and their relationship to the resulting dose is important in considering how to most efficiently and effectively monitor for exposure. This inverse relationship suggests that it is sufficient to determine the radon concentration. However, it is not clear how precisely this relationship holds and if the dose models are sufficiently accurate to fully support the use of only radon measurements to estimate population exposure and dose. 

Then the unattached fraction was calculated in each measurement and was found to be between. 05 and. 15 without aerosol sources in the room and below. 05 in the presence of aerosol sources. The effective dose equivalent was computed with the Jacobi-Eisfeld model and with the James-Birchall model and was more related to the radon concentration than to the equilibrium equivalent radon concentration. On the basis of our analysis a constant conversion factor per unit radon concentration of 5.6 (nSv/h)/(Bq/m ) or 50 (ySv/y)/(Bq/m3) was estimated. 

The fraction of unattached daughters (fp), the equilibrium factor (F) and the activity median diameter (AMD) are plotted in Figure 6 for all the measurements. The AMD is derived from the aerosol measurements. These three parameters are important in the dosimetric models. At the top of Figure 6 the effective dose equivalent is plotted, computed with two models called the J-E (Jacobi-Eisfeld) and J-B (James-Birchall) models in the NEA-report (1983, table 2.9, linear interpolation between AMD=0.1 and 0.2 ym). The figure also shows the effective dose equivalent calculated from the equilibrium equivalent radon concentrations with the NEA dose conversion factor (NEA,1983, table 2.11). 

Typically, two types of error are recognized (a) measurement level error resulting from error in concentrations due to assays, time of measurement, and so on and (b) subject level error represented in the model by random effects, accounting for deviations in the PK parameters between subjects, that is, in absorption Ka), elimination Ke), and/or volume (V). V is usually expressed as T/Twhen the fraction of dose absorbed (F) is unknown. 

A nnmber of materials, such as tritium labelled compoimds, organic carbon compounds and compounds of iodine, can penetrate intact skin. In these cases, a fraction of the activity will enter the blood. Specific models need to be developed to assess doses from such intakes [35]. For example, the behaviour of tritiated organic compounds following direct absorption through the skin will be significantly dilFeient from that after inhalation or ingestion. For skin contamination, both the equivalent dose to the area of skin contaminated and the effective dose will need to be considered. 

FIGURE 3.6 Classical model of agonism. Ordinates response as a fraction of the system maximal response. Abscissae logarithms of molar concentrations of agonist, (a) Effect of changing efficacy as defined by Stephenson [24], Stimulus-response coupling defined by hyperbolic function Response = stimulus/(stimulus-F 0.1). (b) Dose-response curves for agonist of e = 1 and various values for Ka. 

The effect of incomplete absorption is that only a fraction of a single-dose D is made available to the central plasma compartment. The solution of the previous model needs, therefore, to be modified by replacing the term D by F D. Consequently the area under the curve AUCg under incomplete extravascular absorption will be smaller than the maximal AUC that results from complete absorption. The latter, as we have seen is equal to the AUC obtained from a single intravenous injection, which we denote by AUC,. These considerations can be summarized as follows ... 

Radon daughters are deposited on the surface of mucus lining the bronchi. It is generally assumed that the daughter nuclides, i.e. polonium-218 (RaA), lead-214 (RaB) and bismuth-214 (RaC), remain in the mucus and are transported towards the head. However, one dosimetric model assumes that unattached radon daughters are rapidly absorbed into the blood (Jacobi and Eisfeld, 1980). This has the effect of reducing dose by about a factor of two. Experiments in which lead-212 was instilled as free ions onto nasal epithelium in rats have shown that only a minor fraction is absorbed rapidly into the blood (Greenhalgh et al., 1982). Most of the lead remained in the mucus but about 30% was not cleared in mucus and probably transferred to the epithelium. 

Figure 11. Variation of unattached fraction of potential alpha-energy and equilibrium factor according to a model of room aerosol behaviour and the effect on bronchial dose rate per unit radon gas concentration.

Comparative Toxicokinetics. The metabolism and excretion of orally administered phenol in 18 animal species have been compared to metabolism and excretion in humans (Capel et al. 1972). The rat was the most similar to the human with respect to the fraction of administered dose excreted in urine in 24 hours (95%) and the number and relative abundance of the 4 principal metabolites excreted in urine (sulfate and glucuronide conjugates of phenol and 1,4-dihydroxybenzene). The rat excreted a larger fraction of the orally administered dose than the guinea pig or the rabbit (Capel et al. 1972) and appears to be the least susceptible of the three species to respiratory, cardiovascular, hepatic, renal, and neurological effects of inhaled phenol (Deichmann et al. 1944). More rapid metabolism and excretion of absorbed phenol may account for the lower sensitivity of the rat to systemic effects of phenol. More information on the relative rates of metabolism of phenol in various species is needed to identify the most appropriate animal model for studying potential health effects in humans. 

This model assumes that any dosage effect has the same mechanism as that which causes the background incidence. Low-dose linearity follows directly from this additive assumption, provided that any fraction of the background effect is additive no matter how small. A best fit curve is fitted to the data obtained from a long-term rodent cancer bioassay using computer programs. The estimates of the parameters in the polynomial are called Maximum Likelihood Estimates (MLE), based upon the statistical procedure used for fitting the curve, and can be considered as best fit estimates. Provided the fit of the model is satisfactory, the estimates of these parameters are used to extrapolate to low-dose exposures. 

Moved] Cranberry fruit of Early Black cultivar was fractionated chromatographically and fractions were analyzed for flavonoid content. The effects of the flavonoid fractions and ursolic acid, an abundant triterpenoid in cranberry peel, were assessed in two models of colon cancer and one model of breast cancer. Clonogenic soft agar assays were used to determine the effect of these compounds on tumor colony formation in HCT-116, HT-29 and MCF-7 cells. MTT and trypan blue assays were performed to assess their ability to inhibit tumor cell proliferation. TUNEL assays were performed to assess apop-totic response to the cranberry compounds. The proanthocyanidins inhibited tumor colony formation in HCT-116 and HT-29 cells in a dose-dependent manner, with greater effect on the HCT-116 cell line. Ursolic acid strongly inhibited tumor colony formation in both colon cell lines. These compounds also decreased proliferation in all three tumor cell lines with the HCT-116 cell line most strongly affected. (150 words)... 

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