PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol.

Introduction: A physiologically based pharmacokinetic (PBPK) model for 3-chloroallyl alcohol (3-CAA) was developed and used to evaluate the design of assays for the in vivo genotoxicity of 3-CAA. Methods: Model development was supported by read across from a published PBPK model for ethanol. Read across was motivated by the expectation that 3-CAA, which like ethanol is a primary alcohol, is metabolized largely by hepatic alcohol dehydrogenases. The PBPK model was used to evaluate how two metrics of tissue dosimetry, maximum blood concentration (Cmax; mg/L) and area under the curve (AUC; mg-hr/L) vary with dose of 3-CAA and with dose route (oral gavage, drinking water). Results: The model predicted that oral gavage results in a 6-fold higher Cmax than the same dose administered in drinking water, but in similar AUCs. Predicted Cmax provided the best correlation with severe toxicity (e.g., lethality) from 3-CAA, consistent with the production of a reactive metabolite. Therefore, drinking water administration can achieve higher sustained concentration without severe toxicity in vivo. Discussion: This evaluation is significant because cytotoxicity is a potential confounder of mutagenicity testing. The PBPK model can be used to ensure that studies meet OECD and USEPA test guidelines and that the highest dose used is not associated with severe toxicity. In addition, PBPK modeling provides assurance of target tissue (e.g., bone marrow) exposure even in the absence of laboratory data, by defining the relationship between applied dose and target tissue dose based on accepted principles of pharmacokinetics, relevant physiology and biochemistry of the dosed animals, and chemical-specific information.

Fossil alpha-recoil analysis of certain variant radioactive halos.

The distribution of alpha-radioactivity in the vicinity of uranium and of certain variant radioactive halos in biotite was investigated by the fossil alpharecoil method. Within the limits of the method I could not confirm a previously proposed hydrothermal mechanism for the origin of certain variant halo types due to polonium isotopes.

Radiohalos in a radiochronological and cosmological perspective.

New photographic evidence, data on halo ring sizes, and x-ray fluorescence analyses provide unambiguous evidence that polonium halos exist as a separate and distinct class apart from uranium halos. Because of the short half-lives of the polonium isotopes involved, it is not clear how polonium halos may be explained on the basis of currently accepted cosmological models of Earth formation.

Giant radioactive halos: indicators of unknown radioactivity?

A new group of giant radioactive halos has been found with radii in excess of anything previously discovered. Since alternate explanations for these giant halos are inconclusive at present, the possibility is considered that they originate with unknown alpha radioactivity, either from isomers of known elements or from superheavy elements.

Hurricane debbie modification experiments, august 1969.

Maximum winds in Hurricane Debbie, August 1969, decreased after modification experiments by Project Stormfury. Clouds surrounding the center of Debbie were seeded with silver iodide particles five times at approximately 2-hour intervals on both 18 and 20 August. Before the first seeding on 18 August, the maximum speed of winds at 3600 meters was 182 kilometers per hour, but, 5 hours after the fifth seeding, these winds decreased to 126 kilometers per hour. On 20 August, the corresponding change was from 183 to 156 kilometers per hour. Analyses of the data suggest that the storm was modified.

Radiohalos: some unique lead isotope ratios and unknown alpha radioactivity.

Previously unreported lead isotope ratios, that is, values for the lead-206/lead-207 ratio ranging from about 20 to 60, primarily radiogenic in origin but unsupported by uranium decay, have been determined in the inclusions of certain polonium halos by means of ion microprobe techniques. Evidence for radiogenic lead-208 unsupported by thorium decay may also be inferred from the existence of a composite polonium halo type with rings from the radioactive precursors of lead-208. Several new dwarf halo sizes, seem to indicate the existence of unknown, very low-energy alpha-emitters. Furthermore, the three-ring "X halo" also provides evidence for an unknown series of genetically related alpha-emitters with energies in the range from 3 to 7 million electron volts.

Underwater vocalization by sea lions: social and mirror stimuli.

Underwater vocal response of three sea lions (Zalophus californianus) increased under conditions of social interaction. When confronted by their mirror images, two animals increased their number of vocalizations, which included "whinny" sounds, barks, buzzing, and varying patterns of click trains. Click vocalizations showed habituation and recovery when the animals were in the presence of the mirror stimulus.

Differential lead retention in zircons: implications for nuclear waste containment.

An innovative ultrasensitive technique was used for lead isotopic analysis of individual zircons extracted from granite core samples at depths of 960, 2170, 2900, 3930, and 4310 meters. The results show that lead, a relatively mobile element compared to the nuclear waste-related actinides uranium and thorium, has been highly retained at elevated temperatures (105 degrees to 313 degrees C) under conditions relevant to the burial of synthetic rock waste containers in deep granite holes.

Radiohalos in coalified wood: new evidence relating to the time of uranium introduction and coalification.

The discovery of embryonic halos around uranium-rich sites that exhibit very high (238)U/(206)Pb ratios suggests that uranium introduction may have occurred far more recently than previously supposed. The discovery of (210)Po halos derived from uranium daughters, some elliptical in shape, further suggests that uranium-daughter infiltration occurred prior to coalification when the radionuclide transport rate was relatively high and the matrix still plastically deformable.

Marine spatial planning makes room for offshore aquaculture in crowded coastal waters.

Marine spatial planning (MSP) seeks to reduce conflicts and environmental impacts, and promote sustainable use of marine ecosystems. Existing MSP approaches have successfully determined how to achieve target levels of ocean area for particular uses while minimizing costs and impacts, but they do not provide a framework that derives analytical solutions in order to co-ordinate siting of multiple uses while balancing the effects of planning on each sector in the system. We develop such a framework for guiding offshore aquaculture (bivalve, finfish, and kelp farming) development in relation to existing sectors and environmental concerns (wild-capture fisheries, viewshed quality, benthic pollution, and disease spread) in California, USA. We identify > 250,000 MSP solutions that generate significant seafood supply and billions of dollars in revenue with minimal impacts (often < 1%) on existing sectors and the environment. We filter solutions to identify candidate locations for high-value, low-impact aquaculture development. Finally, we confirm the expectation of substantial value of our framework over conventional planning focused on maximizing individual objectives.

Evidence of a role for conditioning in the development of liking for flavours in humans in everyday life.

The development of liking for flavours through conditioning has so far been widely demonstrated in the laboratory. The impact of conditioning in the real world however is yet to be reported. This study investigated the development of liking for flavours through conditioning in the real world as part of everyday life. The study investigated the development of liking for four novel flavoured yoghurts paired with energy (high energy/low energy) and energy requirement (high energy requirement/low energy requirement). Liking was assessed before and after conditioning conducted in the laboratory using traditional laboratory procedures and in the real world using new interactive technology. Following conditioning, liking was found to develop for novel flavoured yoghurts when consumed in a state of high energy requirement. Furthermore, effects were comparable in the laboratory and in the real world. These findings suggest that likings for flavours can be conditioned in the real world as part of every day life as well as in the laboratory. This finding suggests that conditioning is a useful and valid explanation for the development of likings for flavours in everyday life.

Energy of proton accelerator necessary for treatment of choroidal melanomas.

We have reviewed 94 patients with choroidal melanoma treated by proton beam therapy at the Harvard Cyclotron Laboratory. A beam penetration of f27 mm would be required to treat 90% of the lesions. We conclude that a machine energy of at least 55 and, preferably, 60 MeV would be necessary for a clinically viable therapy unit for the treatment of choroidal melanomas. An extracted beam current of 10(-9) A would be more than sufficient.

Conservative treatment of uveal melanoma: local recurrence after proton beam therapy.

Twenty-three of 1006 (2.3%) uveal melanoma patients treated with proton beam therapy at the Harvard Cyclotron Laboratory between July 1975 and December 31, 1986 received additional treatment for documented (15 patients) or suspected (eight patients) tumor growth in the irradiated eye. Growth within the initially irradiated volume was documented at Massachusetts Eye and Ear Infirmary in 12 patients. Documented growth occurred in nine of 665 (1.4%) patients with small and intermediate size tumors, at times after treatment ranging from 6 to 48 months (median 16 months), and in three of 341 (.9%) patients with large tumors at 7, 11, and 12 months after treatment. Melanoma growing totally outside the treated volume was also documented in three additional patients at 7, 9, and 45 months; two of these were thought to be "ring melanomas". Eight patients had the treated eye removed elsewhere for suspected tumor growth. The additional treatment in these 23 patients was conservative in nine patients (repeat proton irradiation in five and laser photocoagulation in four). Thirteen underwent immediate enucleation and one had orbital exenteration. Ultimately, 17 of the 23 eyes (74%) were removed. Estimated probability of local control of the melanoma within the irradiated eye at 60 months was 96.3 +/- 1.5%. Dose distributions to the 12 patients with documented local failure within the irradiated volume were analyzed. Ten tumors recurred marginally in an area receiving less than the prescribed dose of 70 CGE (CGE = Cobalt Gray Equivalents = proton Gy X RBE 1.1), whereas only two recurred in the volume receiving full dose. Based on these data, it appears that a dose of 70 CGE in five fractions is associated with very high rates of local control in human uveal melanoma. It is reasonable to consider initiating studies using a lower total dose or a more protracted course, to determine if some of the observed complications are dose-related.

Evaluation of the clinical applicability of proton beams in definitive fractionated radiation therapy.

We report on the treatment of 317 patients treated either wholly or in part with proton beams at the Harvard Cyclotron Laboratory. These include: 130 patients treated for definitive radiation therapy of choroidal melanoma; 17 patients treated for tumors of the base of skull, cervical spine and cranium, which abut structures of the central nervous system (CNS); 23 patients treated for sarcomas of soft tissue and bone; 65 patients treated for carcinoma of the prostate; 14 patients treated for carcinoma of the rectum and anus; and 23 patients treated for squamous carcinoma of the oral cavity and oro-pharynx. Data on causes of failure and morbidity of treatment are presented. Overall the results are judged to be extremely encouraging. In particular, the treatment of the choroidal melanomas and sarcomas abutting CNS structures have clear clinical value, and the treatment of prostatic tumors and tumors of the head and neck are thought to be promising.

Kinetic analysis of bovine factor VIII in the hemophilic dog.

Bovine factor VIII, which did not contain platelet aggregating factor activity, was infused into hemophilic dogs. Factor VIII procoagulant (VIII:C) levels in the dogs increased dramatically, then decreased in a biphasic manner. The half-life of the longest component was 3-7 hrs. The infusions were hemostatically effective and also caused a prolonged shortening of the activated partial thromboplastin time. These studies demonstrate that the platelet aggregating factor activity of bovine factor VIII is not essential for its maintenance in the circulation and that preparations lacking this activity may be clinically useful. When concentrates of partially purified factor VIII: C (essentially free of both platelet aggregating factor and factor VIII-related antigen) were infused, marked increases in VIII: C levels were also observed, but the half-life was significantly shorter (T1/2 of approximately 1 hr.).

Considerations in fractionated proton radiation therapy: clinical potential and results.

Protons have a finite range in tissue and can provide a better concentration of radiation dose in the tumor than conventional X-rays in certain situations. The development of optimized treatment plans for X-rays and protons followed by a comparative evaluation is one method of selecting tumor sites best suited for proton treatment. The preliminary results of comparative treatment planning for base of skull tumors and carcinoma of the prostate are discussed. These comparisons suggest a clinical gain for proton treatment of tumors in these locations. The clinical experience with fractionated proton treatment of several tumor sites is also discussed. The results of high dose proton treatment of chordomas and low grade chondrosarcomas of the base of skull is particularly promising: an actuarial 5-year local control of 78% has been obtained in 50 patients followed for a minimum of 22 months.

A sequence in the 5' flanking region confers progestin responsiveness on the human c-myc gene.

Previous reports have shown that progestins stimulate the proliferation of the human breast cancer cell line T47D in culture. Under different conditions other reports have shown progestin stimulation, inhibition or no effect on growth. It has also been shown that c-myc expression is stimulated at early times by progestins. We are currently testing the hypothesis that the mechanism of growth enhancement by progestins involves the stimulation of expression of c-myc. This hypothesis predicts a progesterone regulatory region in or near the c-myc gene. We have identified a region, from -2327 to -1833, which serves this function. This region includes a 15 bp sequence with homology to the PRE (progesterone response element) consensus sequence. Human progesterone receptor (PR) binds to this sequence in a specific, ligand-enhanced manner in electrophoretic mobility shift assays (EMSA). A 3507 bp HindIII-XbaI fragment of the 5' flanking region of the c-myc gene, -2327 to +1180, containing the progestin regulatory region and the c-myc promoter, confers progestin responsiveness to the CAT (chloramphenicol acetyl transferase) reporter gene in progesterone receptor (PR)-rich T47D human breast cancer cells, but not in PR-negative MDA-MB-231 cells. Removal of the progestin regulatory region abrogates progestin responsiveness. These data demonstrate that the sequence from -2327 to -1833 of the human c-myc gene includes a positive progestin regulatory region.

Central injection in rats of alpha-melanocyte-stimulating hormone analog: effects on food intake and brain Fos.

Lateral cerebroventricular (LCVT) administration of the alpha-MSH agonist analog Nle4DPhe7alpha-MSH (NDP-MSH) inhibited food intake in food-deprived rats, but did not inhibit water intake in water-deprived rats. When NDP-MSH was administered into the fourth ventricle (4CVT), comparable suppressions of food intake were observed. LCVT and 4CVT administration of NDP-MSH also reduced spontaneous 24 h food intake. LCVT injection of NDP-MSH greatly attenuated food intake stimulated in sated rats by acute CVT administration of neuropeptide Y (NPY). These and other data suggest that alpha-MSH is an important endogenous regulator of food intake, possibly acting downstream of NPY. In an attempt to assess further the sites of action of NDP-MSH, a qualitative mapping study of Fos-like immunoreactive (Fos-ir) neurons was performed following LCVT administration of NDP-MSH. LCVT injection of NDP-MSH induced Fos-ir in several forebrain regions including cortex, striatum, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus and arcuate nucleus. The combination of NPY and NDP-MSH did not produce obvious antagonism or cancellation of effects in any region examined. Thus, the site(s) of action of NDP-MSH on food intake remain to be clarified.

Comparison of Fos induced in rat brain by GLP-1 and amylin.

The patterns of Fos-like immunoreactivity (Fos-ir) in rat brain were compared following treatment of rats with two anorectic 'gut' peptides. Central administration of GLP-1 produced dose-related increases in Fos-ir in the area postrema (AP) and caudal nucleus of the solitary tract (cNTS) as well as strong activation in the lateral parabrachial nucleus (LPBE), hypothalamic paraventricular nucleus (PVN), bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). At centrally-active doses, peripheral administration of GLP-1 did not induce Fos-ir in brain. In contrast, peripheral administration of amylin produced strong Fos-ir in the AP and cNTS, as well as the BNST and CeA, but not in the PVN. The common activation of the LPB-BNST-CeA by these and other previously-studied anorectics suggest this is an important circuit involved in satiety.