Identification, characterization, and control of potential human carcinogens: a framework for Federal decision-making.

A two-stage process is proposed for a uniform framework for Federal agency decisions regarding the identification, characterization, and control of potential human carcinogens. Stage I would include the identification, through epidemiologic and/or laboratory studies, of chemicals that represent a potential carcinogenic risk and the characterization of that risk. Stage II would encompass the actual regulatory decision-making process regarding control of potential carcinogens. Stage I relies predominantly on scientific activity and judgment. Centralized management could enhance the efficiency and effectiveness of this process. The new National Toxicology Program may be able to perform this function. Stage II judgments are social and political. Centralization of stage II decision-making is not possible under current law.

Radiation protection standards: their evolution from science to philosophy.

The concept of applying constraints on individual sources to a small fraction of the public dose limit has been deemed inappropriate when shielding the medical X-ray sources. This represents a broad-based consensus of medical physics and radiological societies in the United States, and the report series on the shielding design for medical X-ray sources (including dental, X-ray imaging and therapeutic X ray) from the National Council on Radiation Protection and Measurements (NCRP) utilises 1 mSv y(-1) as a source control limit. In the present study, the rationale for such a conclusion is discussed, and a somewhat critical look at the current model of radiation protection of the public is made.

Problems in extrapolating toxicity data for laboratory animals to man.

Some of the problems in extrapolating laboratory animal toxicity data to man are considered. The quantitative predictiveness of preclinical studies of anticancer drugs using dogs and monkeys for man has also been examined. The relationship between the maximum tolerated dose (MTD) in the dog, monkey, and the more sensitive of the two species and clinical observations are discussed. The effectiveness of using doses expressed on the basis of body weight (mg/kg) and body surface area (mg/m2) are compared. A method is introduced to assess the "statistical risk" associated with the extrapolation of the initial clinical (phase I) dose from experimental animal data. The best clinical prediction is obtained when one uses the experimental MTD expressed in mg/kg for the more sensitive of the large animal species (dogs or monkeys). The clinical introduction of a new anticancer agent at a dose 1/10 the MTD in the more sensitive species carries a statistical risk of about 3%; that is, the initial doses of about 3 of every 100 new drugs introduced into the clinic will produce some toxic effects in man. These same data have been extended theoretically to the total population and toxic chemicals in general. Reliable extrapolation from laboratory test models to man requires a much more complete understanding of structure--activity relationships, pharmacokinetic factors, and mechanisms of toxicity.

Factors influencing reproduction and genetic toxic effects on male gonads.

The objective of toxicological study of a target organ, such as the testis, is to elucidate the qualitative and quantitative toxic effects of a chemical on that organ. The ultimate objective is to assess the toxic effects of a chemical in laboratory animals and extrapolate the pertinent experimental data to man. To accomplish these objectives, one must consider the main factors which may influence and modulate the toxic effects of chemicals in the organ. In the male gonads, such modifying factors are the pharmacokinetic parameters governing the absorption, distribution, activation and detoxification of indirect carcinogens, covalent bindings to macromolecules, and DNA damage as well as DNA repair of damaged germ cells. All of these factors have been presently studied in our laboratory and are discussed in this paper with the exception of covalent bindings to macromolecules.The pharmacokinetic studies demonstrated that the functional blood-testis barrier (BTB) closely resembles the blood-brain barrier in transport characteristics: the permeability of nonelectrolytes and the acidic drugs with pK(a) values depend upon their molecular size and their partition coefficients, respectively. Thus, the functional BTB, restricts the permeability of many foreign compounds to male germ cells. Studies of mixed function oxidases and cytochrome P-450 system in male gonads demonstrated that the presence of AHH, EH, and GSH-ST implicate activation and detoxification of polycyclic hydrocarbons. Thus, active electrophiles may exert significant toxic effects locally within both interstitial and germ cell compartments. The presence of an efficient DNA repair system in premeiotic spermatogenic cells (and not in spermiogenic cells) can further modify both toxic and mutagenic events in the subsequent differentiation of germ cells to mature spermatozoa.

Assessment of environmental factors affecting male fertility.

Exposure to drinking water containing as much as 500 ppm aluminum chloride for periods of 30, 60, and 90 days had no apparent effect on male reproductive processes. In an attempt to correlate enzyme activity with particular spermatogenic cell types, postnatal development of testicular enzymes was studied. Eight enzymes were selected: hyaluronidase (H), lactate dehydrogenase isoenzyme-X (LDH-X), dehydrogenases of sorbitol (SDH), alpha-glycerophosphate (GPDH), glucose-6-phosphate (G6PDH), malate (MDH), glyceraldehyde-3-phosphate (G3PDH), and isocitrate (ICDH). Enzyme specific activities in testicular homogenates were determined. Two types of enzyme developmental patterns were observed. One was represented by H, LDH-X, SDH, and GPDH; and the other by G6PDH, MDH, G3PDH, and ICDH. The former was characterized by a change in enzyme activities from low in newborn to high in adult while in the latter this pattern was reversed. The two complementary enzyme systems crossed each other at puberty. Prior to puberty, only spermatogonial cells are present; sperm differentiation initiated at puberty adds spermatocytes and spermatids to the testicular cell population. Male rats were exposed to borax in their diet for periods of 30 and 60 days. Concentrations of boron were 0, 500, 1000, and 2000 ppm. At the end of each experimental period, the specific activities of the selected enzymes were determined in the testis and prostate. Correlations of enzyme activity with testicular histology and androgen activities of the male accessory organs were sought. In addition, plasma FSH, LH, and testosterone levels were measured to assess pituitary-testicular interaction. Plasma and testicular boron concentrations were determined and a minimum boron concentration which induced germinal aplasia and male infertility was estimated. In both 30 and 60 day feeding studies, male rats receiving 500 ppm failed to demonstrate any significant adverse effects. In contrast, male rats receiving 100 and 2000 ppm boron displayed a significant loss of germinal elements, although most of the Leydig and Sertoli cells appeared normal. Testicular atrophy was associated with a decrease in seminiferous tubular diameter and a marked reduction of spermatocytes and spermatogenic cells. These morphologic alterations were associated with a concomitant reduction of H, SDH, and LDH-X specific activities. In contrast, the specific activities of G3PDH and MDH were significantly elevated above control. The increase in these enzyme activities can be attributed to the relative enrichment of spermatogonial cells during the loss of spermatocytes and spermiogenic cells. Boron-induced male germinal aplasia was also associated with significantly elevated plasma FSH while plasma LH and testosterone levels were not significantly altered. Plasma testosterone levels were unaltered. Male fertility studies demonstrated that at the 500 ppm boron level, fertility was unaffected. However, at 1000 and 2000 ppm boron, male fertility was significantly reduced. Most effects were reversible within 5 weeks. However, the male group receiving 2000 ppm boron for 60 days remained sterile. There was no dose-related decrease in litter size or fetal death in utero. Therefore, the boron-induced infertility was apparently not due to a dominant lethal effect but rather to germinal aplasia. Boron appears toxic to spermatogenic cells at testicular concentrations of 6-8 ppm.

Methods to assess reproductive effects of environmental chemicals: studies of cadmium and boron administered orally.

Results of a U.S.S.R.--U.S. cooperative laboratory effort to improve and validate experimental techniques used to assess subtle reproductive effects in male laboratory animals are reported. The present studies attempted to evaluate the reproductive toxicity of cadmium as cadmium chloride and boron as borax (Na2B4O7) and to investigate the mechanism of toxicity in the rat following acute and subchronic oral exposure. In vitro cell separation techniques, in vivo serial mating tests, and plasma assays for hormones were utilized. Effects on the seminal vesicle and prostate were evaluated with chemical and enzyme assays. Clinical chemistry was monitored routinely. Acute oral doses, expressed as boron were 45, 150, and 450 mg/kg while doses for cadmium equivalent were 6.25, 12.5, and 25 mg/kg. Rats were also allowed free access to drinking water containing either boron (0.3, 1.0, and 6.0 mg/l.) or cadmium (0.001, and 0.l mg/l.) for 90 days. Randomly selected animals were studied following 30, 60, and 90 days of treatment. These initial studies, utilizing a variety of methods to assess the reproductive toxicity of environmental substances in male animals, suggest that cadmium and boron at the concentrations and dose regimens tested are without significant reproductive toxicity.

Inhalation toxicity of vinyl chloride and vinylidene chloride.

Exposure of mice to 1000 ppm of vinyl chloride (VC), 6 hr/day, 5 days/week, caused some acute deaths with toxic hepatitis and marked tubular necrosis of the renal cortex. Starting the sixth month, mice exposed to 1000, 250, or 50 ppm of VC became lethargic, lost weight quickly, and died. Only a few mice exposed to 50 ppm survived for 12 months. Pulmonary macrophage count was elevated in some mice. There was a high incidence of bronchiolo-alveolar adenoma, mammary gland tumors including ductular adenocarcinoma, squamous and anaplastic cell carcinomas with metastasis to the lung, and hemangiosarcoma in the liver, and, to a lesser extent, in some other organs. The incidence of these tumors quickly increased, and the severity was in direct proportion to the levels of VC and the length of exposure. Malignant lymphoma involving various organs was observed in a few mice. Rats were more resistant to the toxic effects of VC. Exposure to 1000 ppm slightly depressed the body weight of the females. Exposures of 250 or 1000 ppm caused a number of deaths and hemangiosarcoma in the liver starting the ninth month. Most rats with hepatic hemangiosarcoma also developed hemangiosarcoma in the lung. Hemangiosarcoma occasionally occurred in other tissues of one or two rats exposed to 50 ppm or higher level of VC. Exposure of mice to 55 ppm of vinylidene chloride (VDC) also caused a few acute deaths and a few hepatic hemangiosarcomas. Inflammatory, degenerative, and mitotic changes occurred in the liver. No mouse exposed to VDC developed any mammary gland tumors. Several mice had bronchioloalveolar adenoma. Exposure of rats to 55 ppm of VDC slightly depressed the body weight. Hemangiosarcoma occurred in the mesenteric lymph node or subcutaneous tissue in two rats.

Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES).

Prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, has been associated with a low incidence of vaginal adenocarcinoma as well as a variety of more numerous benign abnormalities in the reproductive tract of human beings and experimental animals. For the purpose of assessing the effects of prenatal exposure to DES on postnatal reproduction tract function, timed pregnant CD-1 mice were treated subcutaneously with doses of DES ranging from 0.01 to 100 microgram/kg/day on days 9 through 16 gestation. The fertility of the female offspring was determined postnatally by a repetitive forced breeding technique. The most striking effect observed was a dose-related decrease in reproductive capacity ranging from minimal subfertility at the lower DES doses to a high frequency of total sterility at the highest DES doses. Reduced reproductive capacity appeared to be a reflection of both a decrease in the total number of litters and smaller litter sizes. A major component of the sterility seen in those females given higher doses of DES was oviductal/ovarian, since the number of ova recovered from the oviductal ampullae after induced ovulation was less than 30% that of controls. In addition, structural abnormalities of the oviduct, uterus, cervix, and vagina were observed, and contributed to infertility. These data suggest that in utero exposure to DES results in permanent impairment of female mouse reproductive capacity. Recent reports of altered pregnancy outcomes in young women who were exposed in utero to DES demonstrate the clinical importance of the findings obtained in mice.

On the primary barrier in diagnostic x-ray shielding.

The traditional approach to shielding design for diagnostic x-ray facilities has been to designate as primary barriers the floor and those walls on which the useful beam may impinge, and to ignore the attenuation provided by the patient, grid, cassette, cassette holder, and x-ray table in computing the required thickness of these barriers. The degree of attenuation provided by the aforementioned materials has been measured on three-phase x-ray equipment including a variety of modern x-ray tables, grids, and cassettes. The primary beam is shown to be attenuated by more than two orders of magnitude at 100 kVp by the x-ray tables tested prior to impinging on the floor (ignoring patient attenuation). If patient attenuation is included, the attenuation is more than three orders of magnitude. Transmission factors as well as lead and concrete equivalencies for the various attenuating materials have been determined and included in tabular form. Example calculations for a heavy work load show that only a modest amount of concrete is required in the floor as a primary barrier if attenuation by these materials is taken into consideration (less than 2.5 cm at 80 kVp and less than 4 cm at 100 kVp) and the required secondary barrier may be thicker than the primary barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Linear accelerator calibration monitor with a memory.

A calibration monitor has been designed for measuring the constancy of linear accelerator or cobalt unit output between full calibrations. This monitor is battery operated, light-weight and slides into the shadow tray attachment on a linear accelerator or cobalt unit for easy setup. It provides a digital readout of the dose delivered, and a consistency check can be made in less than two minutes. The precision of the monitor, determined by cobalt-60 irradiations over a 2 1/2 period, is +/- 0.6% (standard deviation). The monitor also retains the dose reading in a CMOS digital counter indefinitely, hence it can be used in the same fashion as mailed thermoluminescent dosimeters (TLD) for calibration checks at remote facilities without the complicated readout procedures associated with TLD. The monitor can be mailed to a remote facility, positioned without ambiguity, and irradiated; and the reading can be verified on return to the originating center simply by pressing a switch. The monitor can easily be set up to carry out a "blind" check in which the reading obtained is not known to the remote facility.

Heuristic model for understanding x-ray film characteristics.

A simple, heuristic model of a photographic emulsion is described for the purpose of illustrating the fundamental physical processes and emulsion properties which determine the characteristics of an x-ray film (viz., the shape of the H - D curve, film gamma, and film speed). By means of this model, it is shown that the contrast multiplication afforded by an x-ray film (i.e., a film gamma greater than unity) is a direct result of the exponential attenuation of the viewing light by the developed film, and that film gamma is proportional to grain size, grain density, and emulsion thickness. The difference in the H - D curve that is observed when the same film is exposed to light from an intensifying screen or directly to x rays is also predicted by the model.

Series of high-sensitivity TL phosphors made from divalent-metal sulfates.

A systematic survey of the thermoluminescence (TL) of rare earth activated sulfates of the form MeSO4:RE was made, where Me denotes a divalent metal and RE the rare earth. SrSO4:Tb(3+) and BaSO4:Eu(2+) exhibit very high TL efficiency following gamma irradiation, comparable to that of the most sensitive phosphors currently available for TL dosimetry. Due to their relatively high Z, these phosphors could prove useful as quality indicators for personnel dosimetry or for detecting very small exposures of low-energy X rays of a known quality.

The problem of obliquely incident beams in electron-beam treatment planning.

Oblique incidence of an electron beam can alter the central axis depth dose. The incident beam can be considered to be an integration of many pencil beams or slit beams. Depending on the depth in the phantom, neighboring pencil beams may have a greater or lesser contribution to the dose at a point on the central axis compared to the contribution under normal incidence. The effect has been studied experimentally and theoretically. For 6- and 9-MeV electron beans, oblique incidence is found to produce an increased dose at shallow depths and a decreased dose at normal treatment depths.

The physics of proton NMR.

The physics of pulse NMR which is pertinent to an understanding of proton NMR imaging has been condensed and directed toward the medical physicist. The basic physical principals of spin manipulations using rf pulses are presented, and the relation between the quantum mechanical and the classical descriptions is covered in a rigorous fashion. The physics of relaxation is described and the relaxation times T1 and T2 are explained in some detail. Application of these spin manipulation techniques is illustrated by showing how they may be used in creating an image.

Performance evaluation of a new quality control dose monitor for radiation therapy.

The performance of a new quality control dose monitor for radiation therapy with respect to precision, stability, temperature coefficient, and radiation damage has been extensively evaluated. The results of routine use at several centers are reported.

The relationship between NMR spin-lattice relaxation times for human tumor tissue at 24 and 6.25 MHz.

The nuclear magnetic resonance (NMR) spin-lattice relaxation time (T1) of samples taken from human tumors was measured in vitro at Larmor frequencies of 24 and 6.25 MHz. It was found that on the average T1 at 6.25 MHz was linearly related to T1 at 24 MHz. An analogous set of measurements was performed on pieces of normal rat tissue. In this case, the relationship between T1 at the two frequencies was similar to that found for the human tumor tissue.

Proton NMR relaxation times in the peripheral blood of cancer patients.

The proton spin lattice relaxation time (T1) of serum and leucocytes of cancer patients and normal volunteers was measured using pulsed NMR techniques. There was no statistically significant difference in the serum T1 values of cancer patients relative to normal. An increase in T1 relative to normal values was detected in the white blood cells of patients with active leukaemia. In these patients T1 fell to normal levels after the initiation of treatment. The variation of leucocyte T1 with the course of the disease for five patients having leukaemia is presented.

Sister-chromatid exchange analyses in rodent maternal, embryonic and extra-embryonic tissues: transplacental and direct mutagen exposures.

Sister-chromatid exchange (SCE) analyses were conducted in maternal, embryonic and extraembryonic tissues of pregnant rats and mice. The various tissues were substituted in vivo with 5-bromodeoxyuridine (BrdU) by implantation of a BrdU tablet in pregnant animals at mid-gestation. Following maternal exposure to 5-20 mg/kg cyclophosphamide, embryonic liver cells demonstrated dose-dependent SCE increases up to 10-fold that of control. Rat embryos revealed little intralitter variability for this transplacental effect. Maternal marrow and yolk sac cells examined in the rat also underwent significant increases in SCE, although to different extents. While marrow SCE frequencies were similar to those of embryo liver, yolk sac SCE frequencies were generally much lower. SCE analyses were also conducted in rat yolk sac cells substituted in vivo with BrdU and subsequently explanted to whole-embryo culture. In vitro exposure to cyclophosphamide at concentrations up to 100 microgram/ml had no SCE-inducing effect. However, similar exposures to phosphoramide mustard, a presumed metabolite of cyclophosphamide, caused dose-dependent increases in SCE up to 8-fold higher than control at 2 microgram/ml. Thus, cyclophosphamide appears to require maternal metabolic activation in order to cause an increased SCE frequency in yolk sac cells. The system described permits versatile SCE analyses which can help to define relative maternal and embryo tissue-specific sensitivities to chemical-induced genetic damage.

Nuclear magnetic resonance imaging.

Nuclear magnetic resonance imaging has reached the point at which it is clear that such images will have a definite role in clinical practice. This article reviews the basic physical principles of nuclear magnetic resonance imaging, its current uses in disorders of the central nervous system, and its potential future applications in this field. The technique is also compared with computed tomography and positron emission tomography. Because nuclear magnetic resonance imaging is still in its infancy and its potential is great, definitive statements on present clinical use are difficult. Continual change and expansion of the role of nuclear magnetic resonance imaging in clinical practice in the next few years should be the rule.

CT diagnosis of acute flank pain from urolithiasis.

The use of noncontrast helical CT (NHCT) to assess patients with acute flank pain and hematuria for potential urinary tract stone disease was first reported in 1995. After several years of experience with the technique, sensitivity and specificity of NHCT has proven to be better than intravenous urography for evaluating ureteral stones. NHCT imaging findings for urinary calculi and the differential diagnosis are discussed in this article. Various extraurinary diseases found while using NHCT in searching for stone disease are addressed and illustrated. As experience with the use of NHCT has increased, clinicians have broadened the indications for this technique, which has a lower charge than standard CT, beyond the specific evaluation of urinary colic. This indication creep has increased the number of NHCT examinations ordered. It has also reduced the rate of stone positivity and increased the diagnostic yield for extraurinary disease.