The Food and Drug Administration and atrial defibrillation devices.

CONTEXT: Atrial fibrillation is a common arrhythmia. It leads to significant morbidity and mortality, primarily from the increased incidence of stroke. The implantable atrial defibrillator, a new therapeutic option for the management of atrial fibrillation, is currently undergoing Food and Drug Administration (FDA) scrutiny for approval to market in the United States. DATA SOURCES: A review of the basic epidemiology of atrial fibrillation, as well as the current status of accepted treatment options in light of the development of the implantable atrial defibrillator, was conducted. A literature search using the terms atrial fibrillation, implantable defibrillator, Food and Drug Administration, medical devices, and medical device regulatory law was conducted using the MEDLINE and Current Contents databases. RESULTS: Currently, there is no consensus on the optimal treatment of atrial fibrillation. Despite the lack of definitive studies showing overall benefit associated with maintaining sinus rhythm in patients in atrial fibrillation, the implantable atrial defibrillator may soon reach the general market. We examine the FDA process for the evaluation of this new medical device and discuss implications for the patient, physician, industry, and health insurers. CONCLUSIONS: Current FDA approval processes for new devices are a compromise between (a) the needs for expediency and encouraging innovation by the medical device industry and (b) the need to ensure that new devices will contribute to improved patient outcomes. We suggest alternative FDA-approval processes that address these issues.

Postmenopausal loss of Ra acquired in adolescence or young adulthood: quantitative relationship to radiation-induced skeletal damage and dosimetric implications.

From the results of serial measurements of body 226Ra activity in 13 former luminous dial workers 30-60 y after relatively brief periods of intake of luminous compounds in adolescence or young adulthood, we determined the postmenopausal rate of elimination of Ra in percent of contemporary body Ra content per year. This rate was negatively correlated with the "reduced x-ray score," a measure of radiation osteonecrosis observed radiographically in the 13 subjects (r = -0.85, P less than 0.001). The clearance rates of subjects retaining low Ra activity were greater than predicted by retention models. We conclude that for those members of the Ra-exposed population under study for health effects at our institution who sustained the lesser degrees of macroscopic skeletal damage, present estimates of skeletal absorbed dose are systematically low, by at most a factor of 2.

The estimation and potential radiobiological significance of the intake of 228Ra by early Ra dial workers in Illinois.

We made radiochemical determinations of 226Ra and the 228Ra-decay product, 228Th, in samples of bone from former Ra dial workers who belonged to a major cohort of Ra-exposed persons under study for health effects at our institution. Most of the former workers were long-term residents of two communities supplied with drinking water containing elevated natural levels of 228Ra and 226Ra, so determinations also were made of radioactivity in samples of bone from long-term residents not occupationally exposed to Ra. The 228Th activity of the bones of the former workers, after correction for the presence of natural radioactivity, showed that some had significant occupational intakes of 228Ra, contrary to published reports that 228Ra was never used by the Illinois company that had employed the cohort of early workers. For 14 workers hired in the years 1920-23, the calculated ratio of the occupational intake of 228Ra to 226Ra activity averaged 0.15 (coefficient of variation 0.65), whereas for three workers hired in 1924, it was not significantly different from zero (mean 0.05, coefficient of variation 1.5). The risk of radiogenic cancer for the typical worker hired before 1924 may have been nearly twice that incurred in the absence of the 228Ra component of the Ra intakes.

Consideration of age-dependent radium retention in people on the basis of the beagle model.

This paper examines in humans the proposition emanating from studies in beagles that initial retention of radium varies in proportion to the calcium addition rate at the time of intake. Human calcium addition rates were scaled from those in beagles, the relative calcium accretion rates in the two species at equivalent stages of skeletal growth providing the scaling factor. The variation of radium retention with age was determined by fitting a modified power function to data on the retention of radium from about 30 to 15000 days following a series of therapeutic injections of 226Ra in humans ranging in age from 18 to 63 yr. The fractional retention R at t days following a single injection of 226Ra was described by R = (1 + t/d)-0.44. The age-dependent parameter d in the retention function was found to be proportional to the calcium addition rate at the time of injection in subjects receiving less than 200 micrograms 226Ra.

Retention of uranium in the chest: implications of findings in vivo and postmortem.

An unusually protracted retention of uranium in the chests of certain workers at a uranium processing plant has been reported in the literature. This finding has implications for the protection of current uranium workers and for health-effects studies of early workers. It is shown that the limited data obtained postmortem that have been reported do not reveal a significant unusually protracted retention of uranium in the pulmonary region or in the tracheobronchial lymph nodes. Probable explanations of the disparate findings are discussed. Data are presented on mortality from cancers of lymphatic tissues among males who worked in the period from 1943 to 1947 at the Y-12 Plant, Tennessee-Eastman Corp., Oak Ridge. No significantly increased mortality from these cancers was evident.

Soft tissue dosimetry of radium in humans--I. Alpha-particle doses from the decay of 226Ra and 228Ra in soft tissues.

Estimates are presented of the alpha particle doses accumulated by individual organs and soft tissues of Reference Man in a 50-yr period following single intakes of 226Ra and 228Ra. With no decay of 226 Ra daughter products in soft tissue, the median dose is 67 mrad per muCi 226Ra intake. With no translocation of 228Ra daughter products, the dose per muCi 228Ra intake is 5.77 times the corresponding value for 226Ra. Biological variability introduces substantial uncertainty when applying these estimates to a particular individual.

Measurement techniques for radium and the actinides in man at the Center for Human Radiobiology.

Various techniques are employed to determine the amounts, retention, and distribution of radioactivity in human subjects in vivo. The principal method is gamma-ray spectrometry with large NaI(Tl) scintillation crystals ("whole-body counting"). The geometries used include an arc of 1.5-m radius in which all parts of the body are roughly equidistant from the detector, a reclining chair and a flat bed with detectors placed above and below the subject. When a sufficient amount of radioactivity is present in a subject, scanning techniques assist in determining its distribution in the body. Specialized instruments such as a xenon-filled proportional counter and a dual-crystal (phoswich) detector are used to measure low-energy photon emitters, primarily plutonium and americium. americium. There are three primary methods of calibrating the detectors. The first is analytical, in which a rigorous mathematical treatment is employed; the second involves the administration of tracer amounts of radioactivity to human volunteers; the third consists of determining detector response to known amounts of radioactivity in a phantom. All three methods can be intercompared, and further evaluated by comparing the results of measurements in vivo with those of postmortem analyses. For both radium and thorium cases measured in vivo, the interpretation of the results is complicated by the fact that neither radium nor thorium emit gamma rays of any consequence. Instead, the observed gamma rays result from the decay of 214Bi (RaC) and 208Tl (ThC"), respectively. Since each of these nuclides is preceded in the decay chain by an isotope of the noble gas radon, some of which is exhaled, its activity is not equal to that of the parent radium or thorium. Therefore, breath samples are collected to determine the exhalation rate of the precursor isotope, 222Rn (radon) or 220Rn (thoron). The total body content is then the sum of the gamma activity and the exhaled radioactivity, referred to as the retained and emanating fractions, respectively.

Radium-induced malignant tumors of the mastoid and paranasal sinuses.

In the records of 5,058 persons with therapeutic or occupational exposure to radium, 21 patients with carcinoma of the mastoid and 11 with malignant tumors of the paranasal sinuses were identified. Tumor induction times were 21-50 years for mastoid tumors (median, 33) and 19-52 years for paranasal sinus tumors (median, 34). Dosimetric data are given for the patients whose body burdens of radium have been measured. We found a high proportion of mucoepidermoid carcinoma, comprising 38% of the mastoid and 36% of the paranasal sinus tumors. Three patients had antecedent bone sarcoma at 20, 11, and 5 years, respectively, and a bone sarcoma was discovered at autopsy in a fourth patient. Radiographic changes in the mastoid and paranasal sinuses were similar to those seen in nonradium malignant tumors. More than 800 known persons exposed to radium before 1930 and another group of unknown size who received radium water or injections of radium from physicians are still alive and at risk of developing malignant tumors of the mastoid and paranasal sinuses.

Radium isotope accumulation in animal thyroids.

Uranium and thorium daughters are ten times more concentrated in thyroids from some bovine animals than in the teeth of the same animals. These radioactive isotopes are believed to be from natural sources, but their resulting annual dosage of thyroid radiation has exceeded that from iodine-131 fallout.