Dose-fractionation experiments

At relatively high X-ray dose rates, the increase in aberration yield, namely dicentric and ring chromosomes (2 hit aberrations) is proportional to the square of the dose. Repair of chromosome breaks occurs within 4 hr after X-irradiation as measured by dose fractionation experiments (9). When a single radiation dose is fractionated into two smaller doses given 5 hr apart, there is time for breaks induced by the first dose to rejoin before the second dose is given. The yield of 2 hit aberrations observed in this case is the sum of the yields of each of the half doses rather than proportional to the total dose, i.e., four times the half dose (10). When, on the other hand, lymphocytes were cultured with 3AB (10), or in nicotinamide deficient medium (11) (thereby eliminating an essential precursor for polymer synthesis), the yield of chromosome dicentrics was proportional to the... 

Dmg metabolism is the main cause for the absence of correlation between permeability and bioavailability in low dose PK experiments, as illustrated in Figure 3.1. Refined aspects of metabolism are presented in Chapter 7. As a first approach one can use the following relation to connect the fraction bioavaUable with its basic components ... 

Few split-dose experiments have been performed with chemicals. Popescu et aL (1984) observed that with split doses of carcinogen separated by 2 to 24 hours only N-acetoxy-2-fluorenylacetamide enhanced transformation of Syrian hamster embryo ceUs while doses of N-methyl-N -nitro-N-nitrosoguanidine, mitomycin C or ultraviolet light were less effective than single doses, and no effect of dose fractionation was observed with methyl methanesulfonate. 

The fraction of the dose absorbed must be estimated in a separate study or from past experience. 

Recent studies provide evidence for rapid dermal absorption of inorganic lead in adults however, these studies have not quantified the fraction of applied dose that was absorbed (Stauber et al. 1994). The quantitative significance of the dermal absorption pathway as a contributor to lead body burden remains an uncertainty. In children who experience extensive dermal contact with lead in soil, sand, or surface water and suspended sediment (e.g., beach or shoreline exposure scenario), even a low percent absorption... 

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. 

Styrene was purified from stabiliser and rough-dried conventionally, then it was distilled i. vac. and a 60 vol% middle fraction was stored over calcium hydride at 0 °C in the dark in a reservoir attached to the vacuum line. It was dosed into the observation vessel from a burette which was filled freshly for each experiment by distillation from the reservoir. 

Figure 17 Volume dependent in vivo dissolution of micronized felodipine FCDNa indicates the dissolved fraction of felodipine aspirated at mid-jejunum of Labradors. The orally administered dose of 10 mg was suspended in 200 mL saline 0.9% (Experiments E and F) or glucose 20% (Experiments B, D, and S). VR represents the recovered fluid volume. Source From Ref. 10, Figure 16.12.

Some sophisticated guessing goes into dose selection. Knowledge of the minimum acutely toxic dose helps the toxicologist pick the highest dose to be used it will be somewhere below the minimum lethal dose. There is usually little basis for deciding the lowest dose it is often set at some small fraction of the high dose. Whether it turns out to be a NOAEL will not be known until the experiment is completed. Sometimes bioassays have to be repeated to identify the NOAEL. 

There are many circumstances in which the only information we can develop on toxic hazards and dose-response relationships derives from experiments on laboratory animals. The example of the food additive, presented in the opening pages, is just one of many circumstances in which condition A involves animal toxicology data, and condition B involves a human population, almost always exposed at small fractions of the dose used in animals, and sometimes exposed for much larger fractions of their lifetime than the animals, and even by different routes. Extrapolations under these circumstances should cause individuals trained in the rigors of the scientific method to seek some form of psychological counsel, or, better yet, to return to the laboratory. 

Fig. 1.4 Hemagglutination assay results from the active fraction of the red alga Gigartina skottsbergii. a Red blood cells (RBCs) hemagglutinate in the presence of influenza virus top row) and with extract A4 -t- virus or extract A4 alone. The bottom two rows present the back titration of the virus used in this experiment, b In contrast to the other anti-influenza drugs (ribavirin, amantadine, rimantadine, and zanamivir) that do not induce hemagglutination of human as well as chicken RBCs, extract A4 does it in a dose-dependent manner...

Figure 12 Top Maximum wavelength of the plasmon band of alloyed gold-silver clusters as a function of the mole fraction x of gold in alloyed gold-silver clusters, produced at the dose rate 7.9 MGy hr and the dose 20 kGy. Experiments, calculated values by Mie model. Bottom Extinction coefficient at the maximum of the plasmon band as a function of the mole fraction x of gold in alloyed gold-silver clusters. Experiments, calculated values from Kreibig equation [74] with r = 5 nm A with r = 3 nm. (From Ref 102.)...

A dose of 1 at 30 mg/kg increased the effects of intravenous doses of epinephrine at 5 g/kg and of dl-noreplnephrine at 10 ug/kg on both blood flow and blood pressure. Intravenous phenoxybenzamine at 15 mg/kg plus tolazollne at 2 mg/kg prevented almost completely the actions of I on blood pressure and blood flow Intravenous reserpine at 2 mg/kg increased markedly the effects of I at 30 mg/kg on blood pressure and peripheral resistance, but converted the usual immediate, small, temporary increase in blood flow into an immediate, small, temporary decrease. These various responses would be expected from either a mild sympathomimetic amine or an inhibitor of the breakdown of endogenous catecholamines Indeed, I at 10 M, was found to inhibit the monoamlneoxldase of the rat s liver. If the dose of I used in these experiments were distributed into the same fraction of the body water as that estimated for the human body,the concentration in the plasma would be about 9 times that stated above as the effective concentration for inhibiting the mono amine oxIdase. It is possible that inhibition of monoamlneoxldase by I plays a part in inducing the effects of the oxime on blood vessels and blood pressure. It is possible also that I interferes with reuptake of catecholamines by nerve endings this possibility seems not to have been explored. 

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