Until 1990 biokinetic studies of aluminium metabolism and biokinetics in man and other animals had been substantially inhibited by analytical and practical difficulties. Of these, the most important are the difficulties in differentiating between administered aluminium and endogenous aluminium-especially in body fluids and excreta and the problems associated with the contamination of samples with environmental aluminium. As a consequence of these it was not possible to detect small, residual body burdens of the metal following experimental administrations. Consequently, many believed aluminium to be quantitatively excreted within a short time of uptake in all, but renal-failure patients. Nevertheless, residual aluminium deposits in a number of different organs and tissues had been detected in normal subjects using a variety of techniques, including histochemical staining methods. In order to understand the origins and kinetics of such residual aluminium deposits new approaches were required. One approach taken was to employ the radioisotope (67)Ga as a surrogate, but this approach has been shown to be flawed-a consequence of the different biological behaviours of aluminium and gallium. A second arose from the availability, in about 1990, of both (26)Al-a rare and expensive isotope of aluminium-and accelerator mass spectrometry for the ultra-trace detection of this isotope. Using these techniques the basic features of aluminium biokinetics and bioavailability have been unravelled. It is now clear that some aluminium is retained in the body-most probably within the skeleton, and that some deposits in the brain. However, most aluminium that enters the blood is excreted in urine within a few days or weeks and the gastrointestinal tract provides an effective barrier to aluminium uptake. Aspects of the biokinetics and bioavailability of aluminium are described below.

The hypothesis that single low dose exposures (0.025–0.5 Gy) to low LET radiation, given at either high (about 150 mGy/min) or low (1 mGy/min) dose rate, would promote aortic atherosclerosis was tested in female C57BL/6J mice genetically predisposed to this disease (ApoE−/− ). Mice were exposed either at early stage disease (2 months of age) and examined 3 or 6 months later, or at late stage disease (8 months of age) and examined 2 or 4 months later. Changes in aortic lesion frequency, size and severity, as well as total serum cholesterol levels and the uptake of lesion lipids by lesion associated macrophages were assessed. Statistically significant changes in each of these measures were observed, depending on dose, dose rate and disease stage. In all cases, the results were distinctly non-linear with dose, with maximum effects tending to occur at 25 or 50 mGy. In general, low doses given at low dose rate at either early or late stage disease were protective, slowing the progression of the disease by one or more of these measures. Most effects appeared and persisted for months after the single exposures, but some were ultimately transitory. In contrast to exposure at low dose rate, high dose rate exposure at early stage disease produced both protective and detrimental effects, suggesting that low doses may influence this disease by more than one mechanism, and dose rate is an important parameter. These results contrast with the known, generally detrimental effects of high doses on the progression of this disease in the same mice, and in humans, suggesting that a linear extrapolation of the known increased risk from high doses to low doses is not appropriate.

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Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNFα, INFγ, IL-1β, TGFβ, INFγ, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025–0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025–2.0 Gy. In contrast, an enhancement of MCP-1, TNFα and fibrinogen at 0.05–2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy.

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