[en] Due to the low energies of Auger electrons and the correspondingly short distance they travel (of the order of 1 nm to 1 μm), the biological effects of Auger emitters are highly dependent upon their cellular and subcellular distribution. Auger emitters that localise within the cell nucleus and bind to DNA produce effects similar to high LET radiations, in contrast to the low LET type effects seen with emitters present in the cell cytosol or other extranuclear sites. Conventional organ dosimetry will give an estimate of average dose delivered to all cell nuclei in an organ but may strongly underestimate the actual dose, either to all nuclei, in the case of Auger emitters which concentrate in the cell nucleus, or to only some nuclei, in the case of cell-cell heterogeneity in uptake. Where better estimates of the biological risk associated with internal contamination by Auger-emitting radionuclides are required, organ dose should be modified according to the subcellular distribution of the radionuclide or cellular dosimetry methods used. Radionuclides used in diagnostic medical applications present a significant source, in terms of dose to the individual, of exposure to Auger emitters. Under normal circumstances, human exposure to Auger electron-emitting radionuclides in the environment is at very low levels. (author)

[en] The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02)

[en] The effect of systemic administration of the radionuclide ^114mIn on O⁶ -alkylguanine-DNA-alkyltransferase (ATase) activity has been examined in rats. In response to 14.8 MB/1/kg ^114mIn injected intraperitoneally, hepatic ATase was induced maximally approximately fivefold at 7 days after injection, at which time the cumulative radiation dose to the liver was approximately 2 Gy. At 63 days after injection ATase activity was still approximately twofold elevated and remained so at 126 days after injection. By 200 days after injection ATase activity had returned to control values. The ^114mIn content of the liver increased to a maximum of 28.7 kBq/g 48-72 h after injection, after which it began to decrease such that at 126 days only 0.3 kBq/g remained and at 200 days 0.03 kBq/g. In response to 4.44 MBq/kg ^114mIn, hepatic ATase was induced twofold by 7 days after injection, when the liver had received a radiation dose of 0.6 Gy, and was still slightly elevated at 63 days. There was no ATase induction after 0.44 MBq/kg ^114mIn up to 7 days after injection; however, at 42 days after injection activity was approximately twofold higher. These results suggest that induction of hepatic ATase activity by ^114mIn is independent upon cumulative radiation dose and dose rate; both must be above minimum threshold values for induction to occur. The induction of a DNA repair enzyme by radiation exposure from an internal radionuclide may have important consequences for risk assessments of occupational, medical and environmental exposures. 36 refs., 3 figs., 3 tabs

[en] The cytotoxic and mutagenic consequences of systemic administration of ^114mIn have been examined. Adult male rats were dosed intraperitoneally with 14.8 or 3.7 MBq/kg ^114mIn. Approximately 0.25% of the injected radioactivity was localized within the testis by 24 h and was retained with an effective half-life of 49.5 days. Breeding studies were started 3 days after injection, males being housed with two females for seven consecutive mating trials of 19 days, separated by 2 days. Indium-114m caused a reduction in litter size and an increase in the incidence of pre- and postimplantation losses and dominant lethal mutations. These effects became evident from 24 days but were most marked between 87-126 days after treatment and persisted up to 147 days. When animals were mated 200 days after treatment, no significant changes were observed. In a parallel study, administration of 14.8 MBq/kg ^114mIn resulted in decreased testis and epididymal weight and sperm reserves. Maximal reduction occurred between 87-108 days after injection followed by recovery toward control values, but neither organ had reached normal levels at 200 days. A single dose of 3.7 MBq/kg, however, had no effect on reproductive organ weight or sperm content. Male F₁ progeny from the 14.8 MBq/kg group of the second mating period (commencing at 24 days) displayed decreased testis weights and sperm content and provoked a higher incidence of dominant lethal mutations. This effect was not observed in male progeny from any other time or the alternative dose level. 43 refs., 4 figs., 3 tabs

[en] We have investigated the ability of dietary vitamin C (ascorbic acid) to mitigate radiation induced damage to the testis arising from exposure to x-rays or the Auger emitting radionuclide ^114mIn (half-life 50 days). Male mice were maintained on a normal or an ascorbate enriched diet (1% by weight) for 5 days then irradiated with 3 Gy 300 kVp x-rays or injected intraperitoneally with ^114mIn (1.85-14.8 MBq kg^-1). Diets were continued for the duration of the experiment. At 35 days post-irradiation animals were killed and testicular damage was assessed using testis weight and spermhead counts as biological endpoints. Acute irradiation with 3 Gy x-rays resulted in severe damage to the seminiferous epithelium manifested as a 50% reduction in testis weight and more than 80% reduction in spermhead count, no differences were observed between control and ascorbate treated animals. Similarly chronic irradiation by tissue-incorporated ^114mIn caused a dose-dependent reduction in testis weight and spermhead count and no abrogation of this effect was observed with ascorbate. While the enriched diet did result in elevated testicular ascorbate levels this effect was short-lived and appeared to be subject to diurnal variation. These results suggest that vitamin C does not have a role as a radio-protectant in the testis against medical or environmental radiation exposures. (author)

[en] This paper concerns the uptake and dosimetry of Auger electron emitting radionuclides which are used during routine diagnostic nuclear medicine procedures, in human testes and spermatozoa (sperm). A computer model was developed to calculate the doses to sperm heads from cellular localisation of the Auger electron emitting radionuclides ^99mTc, ¹¹¹In, ¹²³I and ²⁰¹Tl. An assumption of ellipsoidal geometry was made to approximate the sperm head. S Factors were determined for differing sub-cellular localisations of radionuclide. The S-Factors determined were then combined with in-vitro data for quantification of radionuclide uptake for ^99mTc pertechnetate, ¹¹¹In chloride and ²⁰¹Tl chloride, to estimate in-vivo doses to sperm heads following intravenous administration of radionuclide in typical diagnostic quantities. The uptake and resulting cellular radiation dose of ¹¹¹In (from the chloride) was significantly larger than the other radionuclides in the chemical forms investigated. Further investigations were carried out to determine localisation of ¹¹¹In on sperm. The results of these experiments indicate that the radiation dose to mature sperm following administration of ¹¹¹In pharmaceuticals for diagnostic purposes might be large enough to result in DNA damage which is not expressed until after fertilisation of an oocyte. Consideration should therefore be given to providing some contraceptive advice following diagnostic administrations of this radionuclide. In order to consider the possible effects of these radionuclides on other spermatogenic cells, further studies were undertaken to obtain in-vivo data for quantification of ¹¹¹In chloride and ²⁰¹Tl chloride uptake into the human testis following intravenous administration. Conventional dosimetry was then used to estimate testicular radiation dose using our values of percentage uptake. The results obtained indicate that the values of testicular radiation doses quoted by ICRP for ¹¹¹In might be too low by a factor of 3, whereas those for ²⁰¹Tl might be too high by a factor of 4. No data was obtained for uptake by differing germ cell types within the testis and therefore no consideration of dosimetry at the cellular level was possible. It was concluded that uptake of diagnostic Auger emitting radionuclides by male germ cells (and especially sperm) is possible following intravenous administration. In the case of ¹¹¹In at least, the resulting cellular radiation dose, calculated to include the contributions of Auger electrons, might be large enough to cause DNA damage with significant biological consequences. (author)