Dose-response modeling of life shortening in a retrospective analysis of the combined data from the JANUS program at Argonne National Laboratory

Life shortening was investigated in both sexes of the B6CF1 (C57BL/6 x BALB/c) mouse exposed to fission neutrons and 60Co gamma rays. Three basic exposure patterns for both neutrons and gamma rays were compared: single exposures, 24 equal once-weekly exposures, and 60 equal once-weekly exposures. Ten different dose-response models were fitted to the data for animals exposed to neutrons. The response variable used for all dose-response modeling was mean after-survival. A simple linear model adequately described the response to neutrons for females and males at doses less than or equal to 80 cGy. At higher neutron dose levels a linear-quadratic equation was required to describe the life-shortening response. An effect of exposure pattern was observed prior to the detection of curvature in the dose response for neutrons and emerged as a potentially significant factor at neutron doses in the range of 40-60 cGy. Augmentation of neutron injury with dose protraction was observed in both sexes and began at doses as low as 60 cGy. The life-shortening response for all animals exposed to gamma rays (22-1918 cGy) was linear and inversely dependent upon the protraction period (1 day, 24 weeks, 60 weeks). Depending on the exposure pattern used for the gamma-ray baseline, relative biological effectiveness (RBE) values ranged from 6 to 43. Augmentation, because it occurred only at higher levels of neutron exposure, had no influence on the estimation of RBEm.     

Heritable protein variants induced by exposure to ethylnitrosourea: heritability, subcellular location, and tissue distribution

The heritability, subcellular location, and tissue distribution of liver protein alterations found in the two-dimensional electrophoresis patterns of 4 offspring from male mice treated with N-ethyl-N-nitrosourea (ENU) were studied. Mice homozygous for each of the 4 ENU-induced protein variants were found to be viable and fertile, although the number of homozygous offspring from crosses between heterozygous carriers of one variant (ENU 2) was less than that expected for a nondetrimental trait. Two of the proteins altered by ENU-induced mutations were associated with the crude mitochondrial fraction, another was found predominantly in the microsomal fraction, and the fourth was associated with the mitochondrial, microsomal, and cytosol fractions. All of the ENU-induced mutations affected proteins that were not liver-specific; i.e., the proteins were found in other tissues in addition to the liver.     

Activation by reduction of the resting form of cytochrome c oxidase: tests of different models and evidence for the involvement of CuB

(1) The reaction of the resting form of oxidised cytochrome c oxidase from ox heart with dithionite has been studied in the presence and absence of cyanide. In both cases, cytochrome a reduction in 0.1 M phosphate (pH 7) occurs at a rate of 8.2.10(4) M-1.s-1. In the absence of cyanide, ferrocytochrome a3 appears at a rate (kobs) of 0.016 s-1. Ferricytochrome a3 maintains its 418 nm Soret maximum until reduced. The rate of a3 reduction is independent of dithionite concentration over a range 0.9 mM-131 mM. In the presence or cyanide, visible and EPR spectral changes indicate the formation of a ferric a3/cyanide complex occurs at the same rate as a3 reduction in the absence of cyanide. A g = 3.6 signal appears at the same time as the decay of a g = 6 signal. No EPR signals which could be attributed to copper in any significant amounts could be detected after dithionite addition, either in the presence or absence of cyanide. (2) Addition of dithionite to cytochrome oxidase at various times following induction of turnover with ascorbate/TMPD, results in a biphasic reduction of cytochrome a3 with an increasing proportion of the fast phase of reduction occurring after longer turnover times. At the same time, the predominant steady state species of ferri-cytochrome a3 shifts from high to low spin and the steady-state level of reduction of cytochrome a drops indicating a shift in population of the enzyme molecules to a species with fast turnover. In the final activated form, oxygen is not required for fast internal electron transfer to cytochrome a3. In addition, oxygen does not induce further electron uptake in samples of resting cytochrome oxidase reduced under anaerobic conditions in the presence of cyanide. Both findings are contrary to predictions of certain O-loop types of mechanism for proton translocation. (3) A measurement of electron entry into the resting form of cytochrome oxidase in the presence of cyanide, using TMPD or cytochrome c under anaerobic conditions, shows that three electrons per oxidase enter below a redox potential of around +200 mV. An initial fast entry of two electrons is followed by a slow (kobs approximately 0.02 s) entry of a third electron.(ABSTRACT TRUNCATED AT 400 WORDS)     

Interpretation of cytogenetic damage induced in the germ line of male mice exposed for over 1 year to 239Pu alpha particles, fission neutrons, or 60Co gamma rays

The relative biological effectiveness (RBE) of 239Pu alpha particles, fission neutrons (0.85 MeV), and 60Co gamma rays has been evaluated for the induction of reciprocal chromosome translocations in spermatogonia and of chromosome/chromatid fragments and chromatid rearrangements in the primary spermatocyte of adult male B6CF1 mice. Age concurrency was maintained for both internal and external radiations which were delivered at about 1 rad/week for 239Pu (single intravenous dose of 10 microCi/kg), 0.67, 1.67, and 2.67 rad/week for neutrons, and 6.95, 17.4, and 32 rad/week for gamma rays for at least 60 weeks. In terms of frequency of translocations, the response to the alpha emitter was nonlinear (concave downward) with little dose-response predictability; to cumulative neutron exposures the response was linear, without evidence of a dose-rate effect; and to gamma radiation the responses were linear, and a significant dose-rate effect was seen. RBE estimates are variable. For translocations, the n/gamma ratio is between 10 and 24, depending upon weekly dose level, and the ratio is 1 or less for the alpha particle relative to the neutron. For fragments, the n/gamma ratio is 18 to 22, depending upon age factors, and alpha/n is 1.5. For chromatid rearrangements, n/gamma is 7 and alpha/n is essentially indeterminate, but much below one. The overall response to the alpha emitter is interpreted to be a complex function of (a) microdosimetric heterogeneity, (b) a nearly invariant deposition pattern in the gonad, (c) the high sensitivity of differentiating spermatogonia to cell killing, and (d) the capacity of stem cells in relatively radiation-free areas to progressively assume the major spermatogenic role.     

The comparative tumorigenic effects of fission neutrons and cobalt-60 gamma rays in the B6CF1 mouse.

In the period from 1971 to 1986, both sexes of the B6CF1 (C57BL/6 x BALB/c) mouse were exposed at 110 +/- 7 days of age to single, 24 once-weekly or 60 once-weekly doses of fission neutrons or 60Co gamma rays. A small group of males was also exposed to gamma rays for 22 h/day, 5 days/week, for either 23 or 59 weeks, the elapsed times for the 24 and 60 once-weekly series. All mice were followed for their natural lifetimes. A gross pathology report is available on 32,000 animals, and a histopathology record is available on about 19,000. About 85% died with or from one or more neoplastic diseases. The principal tumors observed at death were of lymphoreticular (45-60%), vascular (20%), or pulmonary (35-50%) origin. From 4 to 10% died with fibrosarcomas, hepatocellular tumors, ovarian tumors, and tumors of the Harderian, adrenal, and pituitary glands. Dose-response equations (linear and linear-quadratic) were fitted to the data for deaths from and occurrences of eight different individual or groups of tumors. Equations were constrained through the control intercepts and fitted separately for the two sexes, the two radiation qualities, and all exposure patterns for the two intervals of 600-799 days and 800-999 days from first exposure. RBE values were derived from the ratios of linear coefficients of dose-response curves. RBE values increased as dose was protracted, largely due to the reduced effectiveness of protracted gamma irradiation; however, about 28% of the increase can be attributed to the increase in neutron-induced injury caused by dose protraction. Highest RBE values were seen for tumors of epithelial tissue origin and the lowest for tumors of connective tissue origin. The range for significant values was from about 2 to over 50. Nonneoplastic diseases accounted for about 5% of all deaths, and 10% were classified as from unknown causes. Neither category responded to differences in radiation quality or exposure patterns.     

Effect of neurotensin on pancreatic function in man

The effect of neurotensin on submaximally-stimulated hepatobiliary and pancreatic secretion was studied in 6 healthy subjects. An intravenous infusion of neurotensin 1.4 ± 0.3 pmol/kg/min, designed to reproduce plasma neurotensin immunoreactivity levels within the physiological range, produced a significant increase in pancreatic bicarbonate output. Plasma concentrations of pancreatic polypeptide rose by 83 ± 16 pmol/l and were associated with a small reduction in trypsin, but no significant change in bilirubin outputs.     

Influence of azacytidine on the induction of tyrosine aminotransferase and the NAD metabolism in rat liver

5-Azacytidine was found to inhibit the induction of tyrosine aminotransferase caused by L-tyrosine and hydrocortisone. The inhibitory effect can be overcome by L-methionine. There was only a slight inhibition of the tryptophan induction by 5-azacytidine in normal animals 4 hr after the administration of tryptophan. At 8 and 12 hr, a superinduction could be observed. The NAD content in adrenalectomized animals increased after application of tryptophan and 5-azacytidine. There was a slight inhibition of ADPR transferase in the rat liver.     

Life shortening in mice exposed to fission neutrons and gamma rays. IV. Further studies with fractionated neutron exposures

When mice were exposed to a total dose of 240 rad of fission neutrons divided into two, four, or six fractions given at 1-week intervals, more life shortening was observed than was seen after a single exposure. Maximum life shortening was observed with four fractions, although the value for six fractions was not significantly lower. Much of the augmentation effect was attributable to an increase in early deaths during the first 200-300 days after exposure, although differences persisted throughout the lifetime of the animals. The changes in life shortening were associated with changes in the distribution of causes of death; however, decrementation of the populations for any given specific cause of death failed to eliminate completely the differences in mean aftersurvival time.