The MIRD Schema: from organ to cellular dimensions.
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Humans↗
Biomedical subjects
R W Howell
Publications and source records attributed to R W Howell.
Relative biological effectiveness of alpha-particle emitters in vivo at low doses.
The therapeutic potential of radionuclides that emit alpha particles, as well as their associated health hazards, have attracted considerable attention. The 224Ra daughters 212Pb and 212Bi, by virtue of their radiation properties which involve emission of alpha and beta particles in their decay to stable 208Pb, have been proposed as candidates for radioimmunotherapy. Using mouse testes as the experimental model and testicular spermhead survival as the biological end point, the present work examines the radiotoxicity of 212Pb and its daughters. When 212Pb, in equilibrium with its daughters 212Bi, 212Po and 208Tl, was administered directly into the testis, the dose required to achieve 37% survival (D37) was 0.143 +/- 0.014 Gy and the corresponding RBE of the mixed radiation field was 4.7 when compared to the D37 for acute external 120 kVp X rays. This datum, in conjunction with our earlier results for 210Po, was used to obtain an RBE-LET relationship for alpha particles emitted by tissue-incorporated radionuclides: RBE alpha = 4.8 - 6.1 x 10(-2) LET + 1.0 x 10(-3) LET2. Similarly, the dependence of RBE on alpha-particle energy E alpha was given by RBE alpha = 22 E(-0.73) alpha. These relationships, based on in vivo experimental data, may be valuable in predicting biological effects of alpha-particle emitters.
Alpha Particles↗
Vitamins as radioprotectors in vivo. I. Protection by vitamin C against internal radionuclides in mouse testes: implications to the mechanism of damage caused by the Auger effect.
The potential of vitamin C, an antioxidant, to protect the radiosensitive spermatogonial cells in mouse testes against the effects of chronic irradiation by radionuclides incorporated into tissue was investigated. Interestingly, when injected intratesticularly, a small and nontoxic amount of vitamin C (1.5 microgram in 3 microliters saline) protected the spermatogonia against the damage associated with high-LET radiation caused by Auger electrons from similarly administered 5-(125I)-iodo-2'-deoxyuridine (125IdU). A dose modification factor (DMF) of 2.3 was obtained. In contrast, no protection was observed when 210Po, an alpha-particle emitter, was administered similarly. These findings suggest that the mechanism of action of the Auger effect is of an indirect nature, which is in contrast to the direct action generally believed to be responsible for biological damage caused by high-LET radiations.
Alpha Particles↗
Cellular dosimetry: absorbed fractions for monoenergetic electron and alpha particle sources and S-values for radionuclides uniformly distributed in different cell compartments.
UNLABELLED: The importance of cellular dosimetry in both diagnostic and therapeutic nuclear medicine is becoming increasingly recognized. METHODS: Experimental range-energy relations for electrons and alpha particles, along with derived geometric reduction factors, are used to calculate cellular absorbed fractions for these radiations. The resulting absorbed fractions are employed to calculate cellular S-values for several radionuclides. RESULTS: Cellular absorbed fractions for monoenergetic electron sources with energies ranging from 0.1 keV to 1 MeV, distributed uniformly in the source region, are calculated for several target<--source combinations including cell<--cell, cell<--cell surface, nucleus<--nucleus, nucleus<--cytoplasm and nucleus<--cell surface. Similar data are also provided for monoenergetic alpha particle sources with energies ranging from 3 to 10 MeV. S-values are also conveniently tabulated for 32P, 35S, 86Rb, 89Sr, 90Y, 91Y, 114mIn, 131I. Auger-electron-emitters 51Cr, 67Ga, 99mTc, 111In, 123I, 125I, 201TI, 203Pb and the alpha emitter 210Po. In addition, S-values are given for radionuclides in the 212Pb decay series, including 212Pb, 212Bi and 212Po. Both absorbed fractions and S-values are supplied for a number of different size cells and cell nuclei. CONCLUSIONS: With the absorbed fractions and S-values in hand, along with experimentally determined information on the biokinetics and subcellular distribution of the radionuclides, the cellular self-absorbed dose can be conveniently calculated.
Alpha Particles↗
Testicular and plasma ascorbic acid levels in mice following dietary intake: a high-performance liquid chromatographic analysis.
A modified buffer system is reported for the analysis of vitamin C in mouse plasma and testes, on a reversed-phase high-performance liquid chromatographic column with ultraviolet detection. The buffer, consisting of 0.1 M NaH2PO4 and 0.2 mM Na2EDTA adjusted to pH 3.1 with orthophosphoric acid, resolved the ascorbic acid (AA) peak allowing clear quantitation of the chemical. The method is also applicable to the assay of dehydroascorbic acid after its reduction to ascorbic acid, and overcomes problems of AA stability encountered in previously reported procedures. Using the present technique, variations in the vitamin levels of plasma and testes are studied from 3 to 29 days after the commencement of feeding a vitamin C-rich diet (1%, w/w) in mice. The plasma AA levels were elevated above the controls by a factor of 2.5 by day 8. Contrary to this, testicular AA levels increased marginally (1.2-fold) by day 12 and were maintained at levels close to the control values thereafter. It appears that the feedback inhibition mechanism which is effective in plasma is not operational in the testes. The findings are of clinical significance in that testicular AA levels do not change significantly as a result of dietary intake of vitamin C, whereas plasma AA levels do show an increase.
Animals↗
[35S]cysteamine: facile synthesis, in vivo biokinetics, and subcellular distribution.
Whereas chemical radioprotection against external beams of ionizing radiation is well studied in radiobiology, the aspects relating to tissue incorporated radionuclides have received little attention. The increased use of radionuclides in diagnostic and therapeutic nuclear medicine, as well as the presence of both manmade and natural radioactivity in the environment, indeed call for such investigations. Our ongoing work on a variety of radioprotectors has revealed that cysteamine (MEA), S-2-aminoethylisothio uroniumbromide hydrobromide (AET), and others (e.g. ascorbic acid), protect spermatogonial cells in mouse testis from the effects of chronic irradiation with intratesticularly localized radionuclides. In these experiments, dose modification factors ranging from 2 to 4 and 10 to 14 were obtained using spermhead survival and induction of spermhead abnormalities, respectively, as the biological end points. Similar experiments were carried out by changing the mode of administration of cysteamine to oral intubation. In these studies a dose modification factor of approximately 3 was observed in the spermhead survival assay. In an effort to understand the protection offered by MEA, the present work describes a one-pot synthesis of high specific activity [35S]cysteamine from elemental [35S]sulphur and its use in determining the biokinetics and biodistribution of MEA following intratesticular (i.t.) or oral administration in mice.
Administration, Oral↗
Time-dose-fractionation in radioimmunotherapy: implications for selecting radionuclides.
As currently practiced, the doses delivered to tumors in radioimmunotherapy are less than desirable primarily because of dose-limiting bone marrow toxicity, thus reducing the therapeutic efficacy of this modality. The biological effectiveness of internal radionuclide therapy depends on the total dose, the rate at which it is delivered, and the fractionation schedule of the radiolabeled antibodies administered. A new approach, based on time-dose-fractionation (TDF), which has been used in conventional radiotherapy, is advanced. This approach incorporates differences in dose rates, biological half-lives of the antibodies, physical half-lives of the radionuclides employed and the total doses needed for a given biological effect. The TDF concept is illustrated with several relevant examples for radioimmunotherapy. Based on the TDF approach, it is proposed that under certain biological conditions radionuclides with physical half-lives that are 1-3 times the biological half-life of the radiolabeled antibodies in the tumor are more likely to deliver sterilization doses to tumors than the shorter-lived nuclides presently in use unless precluded by specific activity considerations. Several radionuclides that meet this criteria are suggested with 32P being the most promising among them. Finally, a practical method for treatment planning in radioimmunotherapy using TDF factors is recommended.
Dose-Response Relationship, Radiation↗
Vitamin C as a radioprotector against iodine-131 in vivo.
The capacity of vitamin C (ascorbic acid) to mitigate radiation damage resulting from the tissue-incorporated radionuclide 131I is examined. Spermatogenesis in mice is the experimental model and spermhead survival is the biological endpoint. When a small nontoxic amount of vitamin C was injected, followed by a similar injection of 131I, the 37% spermhead survival dose (D37) increased by a factor of 2.2 compared with the D37 in animals receiving only the radionuclide. Similar radioprotection was also observed when the animals were maintained on a diet enriched with 1% vitamin C (by weight). These results suggest that vitamin C may play an important role as a radioprotector against accidental or medical radiation exposures, especially when radionuclides are incorporated in the body and deliver the dose in a chronic fashion.
Animals↗
On the equivalent dose for Auger electron emitters.
Radionuclides that emit Auger electrons are widely used in nuclear medicine (e.g., 99mTc, 123I, 201Tl) and biomedical research (e.g., 51Cr, 125I), and they are present in the environment (e.g., 40K, 55Fe). Depending on the subcellular distribution of the radionuclide, the biological effects caused by tissue-incorporated Auger emitters can be as severe as those from high-LET alpha particles. However, the recently adopted recommendations of the International Commission on Radiological Protection (ICRP) provide no guidance with regard to calculating the equivalent dose for these radionuclides. The present work, using spermatogenesis in mouse testis as the experimental model, shows that the lethality of the prolific Auger emitter 125I is linearly dependent on the fraction of the radioactivity in the organ that is bound to DNA. This suggests that the equivalent dose for Auger emitters may have a similar linear dependence. Accordingly, a formalism for calculating the equivalent dose for Auger emitters is advanced within the ICRP framework.
Animals↗
Radiotoxicity of some iodine-123, iodine-125 and iodine-131-labeled compounds in mouse testes: implications for radiopharmaceutical design.
In this work, spermhead survival in mouse testis was used to investigate the radiotoxicity of several intratesticularly localized radioiodinated pharmaceuticals. Radioiodines that decay by electron capture and/or internal conversion (123I, 125I) as well as by beta- decay (131I) were coupled to pharmaceuticals that selectively localize in different cell compartments. Dose response curves yield D37 values of 62 cGy, 75 cGy, 61 cGy and 7.7 cGy for 123IMP (N-isopropyl-p-iodoamphetamine), 131IdU (iododeoxyuridine), H131IPDM (N,N,N'-trimethyl-N'-(2-hydroxyl-3-methyl-5-iodobenzyl)-1,3-propanediami ne) and 125IdC (iododeoxycytidine), respectively. At 37% survival, the relative biological effectiveness (RBE) of these radiochemicals, when compared to the pure gamma-emitting radiochemical 7Be-chloride (D37 = 65 cGy), are 1.0, 0.89, 1.1 and 8.4, respectively. Intratesticular 7Be, with an effective half-life of 430 hr in the organ, was used as the source of reference radiation to determine the RBE values because it solely emits 477 keV gamma rays, and the dose to the testis is delivered chronically, as in the case of the other radiocompounds. Subcellular distribution studies show that all of the cellular activity is localized in the cytoplasm in the cases of 123IMP and H131IPDM, while virtually all of 131IdU and 125IdC were bound to DNA in the cell nucleus. In agreement with our earlier in vivo studies, these data show that subcellular distribution plays a key role in the radiotoxicity of Auger electron emitters such as 123I and 125I, and has no role for beta emitters such as 131I. These findings may have implications in the design of radiopharmaceuticals for both diagnosis (localize Auger emitter in cytoplasm of cell) and therapy (localize Auger emitter in cell nucleus).
Amphetamines↗
Absorbed dose calculations for rapidly growing tumors.
One of the most promising areas for cancer therapy with administered radiopharmaceuticals is the treatment of very small tumors and micrometastases. Small tumors and micrometastases, however, may be rapidly growing at the time of treatment, resulting in a substantial change in mass during the period of irradiation. In this work, the formalism required to calculate the average absorbed dose to rapidly growing tumors is developed and applied to an in vitro tumor model. Further application to in vivo human myeloma tumors reveals that tumor growth may have a significant effect on the average dose delivered to the tumor from incorporated radionuclides. These considerations may assist in establishing dose-response relationships necessary for radiopharmaceutical cancer therapy.
Cell Division↗
Radiotoxicity of 125I-iododeoxyuridine in pre-implantation mouse embryos.
The radiotoxicity of DNA incorporated 125I in cultured pre-implantation two-cell mouse embryos was investigated and compared with external gamma-irradiation. The uptake of 125IdU in the two-cell stage embryos was determined as a function of incubation time and concentration of radioactivity (MBq/ml) in the medium. The absorbed dose to the embryos was calculated using conventional procedures. The embryo survival curves show that the dose at 37% survival is only about 15 cGy for 125IdU, whereas for 137Cs-photons it is 175 cGy. The extreme toxicity observed is thought to be due to the localized energy deposition of the numerous low energy Auger electrons emitted in the decay of 125I. These results are consistent with earlier observations in mouse testis and cultured cells and point to the need for assessing the radiation risk from incorporated Auger electron emitting radionuclides based on their subcellular distribution.
Animals↗
The question of relative biological effectiveness and quality factor for auger emitters incorporated into proliferating mammalian cells.
The problem of determining RBE values for Auger emitters incorporated into proliferating mammalian cells is examined. In general, the reference radiation plays a key role in obtaining experimental RBE values. Using survival of cultured Chinese hamster V79 cells as the experimental model, new data are provided regarding selection of a reference radiation for internal Auger emitters. These data show that gamma rays delivered acutely (137Cs) are more than twice as lethal as gamma rays delivered chronically with an exponentially decreasing dose rate (99mTc). The results confirm that the reference radiation should be delivered chronically in a manner consistent with the extended exposure received by the cells in the case of incorporated radionuclides. Through a direct comparison of the radiotoxicity of Auger emitters and alpha emitters, the high RBE values reported for DNA-bound Auger emitters are confirmed. These studies reveal that the DNA binding compound [125I]iododeoxyuridine (125IdU) is about 1.6 times more effective in killing V79 cells than 5.3 MeV alpha particles from intracellularly localized 210Po-citrate. In addition, toxicity studies with the radiochemicals 125IdU and [125]-iododeoxycytidine (125IdC) establish the equivalence of the radiosensitivity of thymine and cytosine base sites in the DNA. In view of these results, and information already available, the question of establishing quality factors for Auger emitters is considered. Finally, a method for calculation of the dose equivalent for internal Auger emitters is advanced.
Animals↗
Induction of sperm head abnormalities by incorporated radionuclides: dependence on subcellular distribution, type of radiation, dose rate, and presence of radioprotectors.
In contrast to the biological effects caused by exposure to external beams of radiation, the effects of tissue-incorporated radionuclides are highly dependent on the type of radiation emitted and on their distribution at the macroscopic, microscopic, and subcellular levels, which are in turn determined by the chemical nature of the radionuclides administered. Induction of abnormalities of sperm heads in mice is investigated in this work after the injection of a variety of radiochemicals including alpha emitters. When the initial slopes of the dose-response curves are used to compare the relative biological effectiveness (RBE) of different radiocompounds, the alpha particles emitted in the decay of 210Po are more effective than Auger electrons emitted by 125I incorporated in the DNA of the spermatogonial cells, and both emissions are more effective than X rays. It is also shown that the Auger emitters (125I, 111In) distributed in the cell nucleus are more efficient in producing abnormalities than the same radionuclides localized in the cytoplasm. These findings are consistent with our earlier observations, where spermatogonial cell survival is assayed as a function of the testicular absorbed dose. Further, chronic irradiation of testis with gamma rays from intratesticularly administered 7Be is about three times more effective in causing abnormalities than a single acute exposure to 120-kVp X rays. The resulting RBE values correlate well with our data on sperm head survival with the same radiocompounds. Finally, the radioprotector cysteamine, when administered in small, nontoxic amounts, significantly reduces the incidence of sperm abnormalities from alpha-particle radiation as well as emissions from 125I incorporated into DNA, the dose reduction factors being 10 and 14, respectively.
Alpha Particles↗
Biological consequence of nuclear versus cytoplasmic decays of 125I: cysteamine as a radioprotector against Auger cascades in vivo.
When the radionuclide 125I is localized in mouse testis as 125I-iododeoxyuridine (an analogue of thymidine) and incorporated into the DNA of spermatogonial cells, the cytocidal effects are as severe as those due to densely ionizing alpha particles. In contrast, 125I confined to the cytoplasm of these cells is much less radiotoxic, the efficacy being the same as for selective irradiation of the testis with sparsely ionizing external X rays. The biological effects, in both cases, are strongly mitigated upon pretreatment of the testes with very small amounts (0.75 microgram) of cysteamine, a radioprotector. These findings suggest an important role for such chemical agents in radiation protection and in understanding the mechanisms of radiation damage involving radionuclides incorporated in tissue.
Animals↗
In-vivo radiotoxicity of DNA-incorporated 125I compared with that of densely ionising alpha-particles.
When the atomic nucleus of 125I decays by orbital electron capture followed by internal conversion, numerous very-low-energy electrons (Auger electrons) are emitted, so that the energy density in the immediate vicinity of the decay site is extremely high. 125I incorporated into DNA was as effective as densely ionising 5.3 MeV alpha-particles from 210Po in reducing the sperm-head population in mice. Hence the biological risks of Auger-electron emitting radionuclides widely used in biology and medicine ought to be reassessed.
Animals↗
Cytotoxicity of some indium radiopharmaceuticals in mouse testes.
The biological effects of [111In]oxine, [111In]citrate, and [114mIn]citrate localized in mouse testes as well as the effects of external x-rays are investigated. The in vivo radiotoxicity of [111In] oxine is far greater than the chemotoxicity of oxine. Of these radiolabeled compounds, [111In] oxine is the most effective in reducing the sperm-head population, the mean lethal dose (D37) to the organ being about 0.16 Gy at 37% survival of the sperm heads. The corresponding values of D37 for [111In]citrate, [114mIn]citrate and x-rays are approximately 0.34, 0.57, and 0.67 Gy, respectively. The present results affirm our earlier finding of the inadequacy of conventional dosimetry in estimating the biologic consequences of Auger-electron emitters in vivo. The very different radiotoxicities of [111In]oxine and [111In]citrate draw attention to the role of the chemical nature of the radiolabeled compounds in the expression of biologic effects in vivo, an aspect that is not considered explicitly in the formulation of conventional dosimetry.
Animals↗
Lantigen oral bacterial antigen in an industrial population.
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Administration, Oral↗