Molecular biology, epidemiology, and the demise of the linear no-threshold (LNT) hypothesis.

The prime concern of radiation protection policy since 1959 has been protecting DNA from damage. The 1995 NCRP Report 121 on collective dose states that since no human data provides direct support for the linear no threshold hypothesis (LNT), and some studies provide quantitative data that, with statistical significance, contradict LNT, ultimately, confidence in LNT is based on the biophysical concept that the passage of a single charged particle could cause damage to DNA that would result in cancer. Current understanding of the basic molecular biologic mechanisms involved and recent data are examined before presenting several statistically significant epidemiologic studies that contradict the LNT hypothesis. Over eons of time a complex biosystem evolved to control the DNA alterations (oxidative adducts) produced by about 10(10) free radicals/cell/d derived from 2-3% of all metabolized oxygen. Antioxidant prevention, enzymatic repair of DNA damage, and removal of persistent DNA alterations by apoptosis, differentiation, necrosis, and the immune system, sequentially reduce DNA damage from about 10(6) DNA alterations/cell/d to about 1 mutation/cell/d. These mutations accumulate in stem cells during a lifetime with progressive DNA damage-control impairment associated with aging and malignant growth. A comparatively negligible number of mutations, an average of about 10(-7) mutations/cell/d, is produced by low LET radiation background of 0.1 cGy/y. The remarkable efficiency of this biosystem is increased by the adaptive responses to low-dose ionizing radiation. Each of the sequential functions that prevent, repair, and remove DNA damage are adaptively stimulated by low-dose ionizing radiation in contrast to their impairment by high-dose radiation. The biologic effect of radiation is not determined by the number of mutations it creates, but by its effect on the biosystem that controls the relentless enormous burden of oxidative DNA damage. At low doses, radiation stimulates this biosystem with consequent significant decrease of metabolic mutations. Low-dose stimulation of the immune system may not only prevent cancer by increasing removal of premalignant or malignant cells with persistent DNA damage, but used in human radioimmunotherapy may also completely remove malignant tumors with metastases. The reduction of gene mutations in response to low-dose radiation provides a biological explanation of the statistically significant observations of mortality and cancer mortality risk decrements, and contradicts the biophysical concept of the basic mechanisms upon which, ultimately, the NCRPs confidence in the LNT hypothesis is based.

Nonlinearity of radiation health effects.

The prime concern of radiation protection policy since 1959 has been to protect DNA from damage. In 1994 the United Nations Scientific Community on the Effects of Atomic Radiation focused on biosystem response to radiation with its report Adaptive Responses to Radiation of Cells and Organisms. The 1995 National Council on Radiation Protection and Measurements report Principles and Application of Collective Dose in Radiation Protection states that because no human data provides direct support for the linear nonthreshold hypothesis (LNT), confidence in LNT is based on the biophysical concept that the passage of a single charged particle could cause damage to DNA that would result in cancer. Several statistically significant epidemiologic studies contradict the validity of this concept by showing risk decrements, i.e., hormesis, of cancer mortality and mortality from all causes in populations exposed to low-dose radiation. Unrepaired low-dose radiation damage to DNA is negligible compared to metabolic damage. The DNA damage-control biosystem is physiologically operative on both metabolic and radiation damage and effected predominantly by free radicals. The DNA damage-control biosystem is suppressed by high dose and stimulated by low-dose radiation. The hormetic effect of low-dose radiation may be explained by its increase of biosystem efficiency. Improved DNA damage control reduces persistent mis- or unrepaired DNA damage i.e., the number of mutations that accumulate during a lifetime. This progressive accumulation of gene mutations in stem cells is associated with decreasing DNA damage control, aging, and malignancy. Recognition of the positive health effects produced by adaptive responses to low-dose radiation would result in a realistic assessment of the environmental risk of radiation.

Cellular and vascular responses in acute experimental ocular inflammation.

PURPOSE: To measure simultaneously blood volume, altered vascular permeability, and leukocyte extravasation in ocular inflammation in rabbits at various times and in different anatomic locations after intravitreal endotoxin (lipopolysaccharide [LPS]). METHODS: Nuclides of different emission and decay were used for labeling and then injected intravenously. Ocular blood volumes were measured with technetium 99m, altered vascular permeability with I-125 albumin, and polymorphonuclear leukocyte or mononuclear cell extravasation after labeling with Indium 111. Eyes were divided into anterior eye section, iris-ciliary body, aqueous, and vitreous and posterior eye sections, and measurements were made at 3, 6, 9, 18, and 24 hours after intravitreal LPS injection. Blood volume measurements made it possible to estimate the amount of extravascular protein and the number of extravascular leukocytes. RESULTS: Blood volumes were consistently elevated at all times, usually by approximately 50% and predominantly in the anterior segment. Altered vascular permeability was present at 3 hours, increased at 6 hours, decreased at 9 hours, and was elevated at 18 to 24 hours, predominantly in the anterior eye. Leukocytes in iris-ciliary body appeared in small numbers at 6 hours, increased at 9 hours, and continued to extravasate at 18 and 24 hours. Mononuclear cells were as numerous as polymorphonuclear leukocytes at each time measured. CONCLUSIONS: The quantitation of multiple parameters of ocular inflammation in this experimental model has been helpful in defining when and in what tissue changes occur. Leukocytes are primarily within tissues, particularly in the iris-ciliary body region. Mononuclear leukocytes are a prominent feature at all times and add further support to the concept that the mononuclear phagocyte plays a pivotal role in reactions to LPS.

Independence of intrapericardial right and left ventricular performance in septic pulmonary hypertension.

To study the effect of septic pulmonary hypertension on right/left ventricular intrapericardial interactions thirteen trauma patients, seven septic and six non-septic controls, were compared. Ventricular volumes were derived from first-pass or gated equilibrium radionuclide angiocardiography, and related to body surface area. Systemic and pulmonary pressures were measured invasively. Pulmonary arterial pressure was significantly increased in the sepsis group. Although right ventricular end-diastolic volumes were higher in sepsis, left ventricular end-diastolic volumes were not decreased. In terms of intrapericardial right/left ventricular interactions these results indicate that the right and left ventricles operate independently in septic pulmonary hypertension.

Portasystemic shunt fraction quantification using transrectal administration of iodine-123 iodoamphetamine in dogs with chronic bile duct ligation and after propranolol administration.

Following transrectal administration, 123I iodoamphetamine (IMP) has been shown in both animal and patient studies to be capable of detecting the presence of portasystemic shunting (PSS). However, the ability of this method to actually quantitate PSS in the presence of cirrhosis and propranolol has not been demonstrated. We studied nine dogs with hitologically proven cirrhosis induced by chronic bile duct ligation. After intravenous injection of propranolol, PSS were measured with both the IMP method and the standard of portal vein infusion of 99mTc macroaggregated albumin (MAA) given through a mesenteric vein catheter. Based on linear regression, a close relationship was seen, given by the equation: MAA = IMP 0.9 + 0.035, with correlation coefficient of 0.99. Thus, in dogs with cirrhosis secondary to chronic bile duct ligation and after propranolol administration, PSS can be quantitated with the transrectal IMP method.

Quantitation of acute experimental ocular inflammation with 111indium-leukocytes.

The cellular component of an acute ocular inflammation in rabbits was measured with autologous leukocytes exogenously labeled with 111Indium tropolonate. Inflammation was induced by intravitreal bacterial lipopolysaccharide (LPS). After 16 hr blood was removed, leukocytes separated, labeled with 111Indium tropolonate and reinjected. Three cell fractions were examined: a leukocyte rich fraction which had been prepared with Dextran; and polymorphonuclear and mononuclear leukocyte fractions which had been prepared using a discontinuous Percoll gradient. Two hours after labeled leukocytes were injected, measurements of 111Indium were made in blood, plasma, the whole eye and in ocular compartments. From these data the numbers of each leukocyte population present were estimated and compared directly to histopathologic changes. Both polymorphonuclear and mononuclear leukocytes entered ocular tissues during the 2 hr period beginning 20 hr after LPS injection. Altered ocular vascular permeability was successfully measured with 125Iodine-albumin in some of these same rabbits. Both the number and type of inflammatory cell entering ocular tissues during a set period of time of the inflammatory response could thus be measured. This technique provides an opportunity to define the relationship of leukocyte infiltration and altered ocular vascular permeability in ocular tissues during the inflammatory response.

Portasystemic shunt fraction quantification with colonic iodine-123 iodoamphetamine.

Portasystemic shunting was quantified in dogs with [123I]iodoamphetamine (IMP) administered transrectally into the colon and monitored externally with a gamma camera. IMP was absorbed rapidly and unchanged from the colon. After direct injection into the portal vein, IMP was almost completely extracted by the liver on the first pass, and the washout half-life was approximately 60 min. Based on these kinetic data, computer simulation of this biologic system was carried out. Errors associated with simplified models are calculated. The simplest model with insignificant error, which assumed that the tracer behaved like microspheres, was used to quantitate portasystemic shunt fraction in animals with surgically created shunts. Results were compared with the standard of 99mTc-labeled macroaggregated albumin infused into a branch of inferior mesenteric vein. For shunt fractions ranging from 0 to 100%, an excellent correlation was seen, indicating that this approach is potentially a simple, noninvasive method of portasystemic shunt fraction quantification.

Iron overload syndromes.

Iron overload is relatively common and is now detected more frequently because of inclusion of serum iron measurement in automated clinical chemistry panels. Secondary hemosiderosis and hemochromatosis result from increased iron absorption associated with increased erythropoiesis compensating for hemolysis, increased dietary iron, inappropriate prolonged oral iron therapy or chronic multiple transfusions. Primary hemochromatosis is a genetic metabolic disorder associated with the HLA locus on chromosome 6 resulting in increased iron absorption, though erythropoiesis and dietary iron are normal, and abnormal diversion of iron from reticuloendothelial (RE) to parenchymal cells. A genetic increase of intracellular iron carrier is a proposed basic mechanism. Only in the cirrhotic stage of primary hemochromatosis do RE iron and serum ferritin increase. Since both serum iron and serum ferritin may remain normal in the precirrhotic stage and may be falsely positive in the absence of iron overload, direct measurement of body iron stores is often useful. Measurement of tissue iron in liver biopsy specimens is widely used. However, quantitation of total mobilizable body iron by measurement of a 6-hour urine collection after intravenous injection of 59Fe-DTPA is noninvasive, sensitive, relatively accurate, and together with other laboratory and clinical data provides a practical means of establishing the correct diagnosis and therapy early enough to minimize organ damage.

Radiation absorbed doses from iron-52, iron-55, and iron-59 used to study ferrokinetics.

Biological data obtained principally with Fe-59 citrate are used with physical data to calculate radiation absorbed doses for ionic or weak chelate forms of Fe-52, Fe-55, and Fe-59, administered by intravenous injection. Doses are calculated for normal subjects, primary hemochromatosis (also called idiopathic or hereditary hemochromatosis), pernicious anemia in relapse, iron-deficiency anemia, and polycythemia vera. The Fe-52 doses include the dose from the Mn-52m daughter generated after injection of Fe-52. Special attention has been given to the dose to the spleen, which has a relatively high concentration of RBCs and therefore of radioiron, and which varies significantly in size in both health and disease.

Rupture of a spontaneous aortoduodenal fistula visualized with Tc-RBC scintigraphy.

We present what we believe is the first reported case of a spontaneous aortoduodenal fistula, with massive rupture into the duodenum during the performance of a radionuclide study of gastrointestinal bleeding. Our experience suggests that nuclear scintigraphy with labeled red blood cells can help in the diagnosis of this disorder by demonstrating both the presence of an abdominal aortic aneurysm and bleeding in the gut.

Altered metabolism of the methionine methyl group in the leukocytes of patients with schizophrenia.

Previous work has indicated that abnormal methylation processes may be associated with schizophrenia. In this study, leukocytes from patients with schizophrenia were incubated with methyl-14C-L-methionine and the evolved 14CO2 measured. With increasing concentration of methionine, the evolved 14CO2 was lower in the patients than in normal control subjects. The incorporation of 14C into protein was the same in both groups, and when carboxyl-14C-L-methionine was used the evolved 14CO2 was the same in both groups, thus excluding the possibility that altered incorporation into protein or oxidation of the methionine molecule as a whole were responsible. The observed differences in methionine-methyl metabolism suggest that an abnormality in transmethylation processes or in oxidation of the methyl group to CO2 is associated with schizophrenia. That this occurs in a peripheral tissue indicates that the abnormality is not restricted to the central nervous system.

Studies of the erythron.

Radionuclide studies of the erythron are valuable to the physician in evaluating the clinical situation in a wide variety of hematologic disorders. A complete and accurate analysis of the life cycle of the red cell can be obtained with a full iron kinetic study, in conjunction with a DF32P red-cell survival study. However, a complete iron kinetic study is not always necessary. It may be abbreviated by deleting the in vitro phase of the iron kinetic procedure. The abbreviated iron kinetic study is also done in conjunction with a DF32P red-cell survival study. It can easily be performed by injecting 59Fe-labeled plasma and monitoring externally over the spleen, liver, and sacrum. Measurements of red-cell survival may be obtained with either 51Cr or DF32P. Although 51Cr provides a relatively uniform label of circulating red cells and is convenient to count in vitro, its highly variable elution rate precludes an accurate measurement of erythrocyte survival. The 51Cr method provides only a rough index of circulating red-cell half-times as a measure of red-cell survival. DF32P, HOWEVER, IS A PERMANENT LABEL OF CIRCULATING RED CELLS. It provides a direct measurement of erythrocyte survival and permits in vivo labeling of red cells simply by means of direct intravenous injection. Because it has an elution rate that is virtually zero after minimal elution on the day of injection, and because it is not reutilized, DF32P is unquestionably the best agent known for the determination of red-cell survival. In addition to these diagnostic data, the complete iron kinetic study can provide data on the deposition of iron in storage and the rate of iron storage exchange. It can also determine if erythropoiesis is quantitatively abnormal and if the abnormality is located in the bone marrow or in other organs such as the liver or spleen. Although the study of hematologic disorders is one of the most rapidly developing areas of medical research, techniques that are currently available can provide an understanding of the life cycle of the red cell and valuable data that can be applied directly to the clinical situation. When performed accurately, these studies provide a thorough analysis of the pathophysiology of the erythron and are valuable clinical tools that can be used successfully in the diagnosis and evaluation of a broad spectrum of hematological disorders.