Precision Constraints for Three-Flavor Neutrino Oscillations from the Full MINOS+ and MINOS Dataset.

We report the final measurement of the neutrino oscillation parameters Δm_{32}^{2} and sin^{2}θ_{23} using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of 23.76×10^{20} protons on target producing ν_{µ} and ν[over ¯]_{µ} beams and 60.75 kt yr exposure to atmospheric neutrinos. The measurement of the disappearance of ν_{µ} and the appearance of ν_{e} events between the Near and Far detectors yields |Δm_{32}^{2}|=2.40_{-0.09}^{+0.08}(2.45_{-0.08}^{+0.07})×10^{-3} eV^{2} and sin^{2}θ_{23}=0.43_{-0.04}^{+0.20}(0.42_{-0.03}^{+0.07}) at 68% C.L. for normal (inverted) hierarchy.

Intraoperative gamma detection of 125I-lanreotide in women with primary breast cancer.

BACKGROUND: Somatostatin receptors are present in most human breast cancers. We performed a pilot trial of intraoperative tumor-gamma detection using the radiolabeled somatostatin analog 125I-lanreotide in 13 women with 14 primary breast carcinomas. METHODS: All patients were given 125I-lanreotide intravenously before surgery. Patients underwent lumpectomy, and postresection margins were evaluated with the gamma probe. Axillary dissection specimens were evaluated ex vivo. RESULTS: Seven of 13 women had gamma probe-positive or clinically suspicious margins re-excised at the time of lumpectomy. Four of six probe-positive margins were histologically positive, and two of six probe-positive margins were histologically negative; a single clinically suspicious margin was histologically positive. A total of 270 axillary lymph nodes were evaluated ex vivo by gamma probe and histology. McNemar's contingency tests demonstrated a highly statistical correlation between histology and gamma probe counts (P < .0001). CONCLUSIONS: The overall accuracy of nodal evaluation with 125I-lanreotide/intraoperative gamma detection was 77%; the negative predictive value of this technique was 97%, however. This technique predicted the presence of tumor in 20% of axillary lymph nodes that were negative by routine histology. This technique appears safe and is able to detect positive tumor resection margins and accurately predict axillary lymph node negativity. Further trials of this technique are required to validate its utility.

Feasibility of micronucleus methods for monitoring genetic damage in two feral species of small mammals.

Peromyscus leucopus (white-footed mouse) and Cryptotis parva (least shrew) possess desirable attributes for biomonitoring contamination of terrestrial ecosystems, but few studies have examined the potential use of these species for monitoring exposure to genotoxic contaminants. The susceptibility of laboratory-reared C. parva, P. leucopus, and Mus musculus (house mouse, strain CD-1) to micronucleus (MN) induction by known clastogens was evaluated. Animals were exposed for 24 hr to methyl methanesulfonate (MMS; 12.5, 25, and 50 mg/kg), 4-nitroquinoline 1-oxide (4-NQO; 7.5, 15, and 30 mg/kg), or mercuric chloride (HgCl2; 6, 12, and 24 mg/kg). Both MMS and 4-NQO induced dose-related increases in micronucleated polychromatic erythrocytes (MNPCE) in all three species, whereas HgCl2 induced a weak response only in P. leucopus. P. leucopus and C. parva were more sensitive than M. musculus to MMS. Similar micronucleus responses to 4-NQO were seen in each of the species. The feasibility of using blood for MN assessment was evaluated by comparing MN frequencies in bone marrow (BM) PCE, and blood PCE and normochromatic erythrocytes (NCE) in untreated animals, and following daily treatment for 1, 2, 3, and 10 days with 0.4 mg/kg triethylenemelamine (TEM). The results indicated that micronucleated erythrocytes were removed from the circulating blood in P. leucopus, but not in C. parva. Measurement of BM and blood MN levels appears feasible for monitoring exposure to genotoxic agents in C. parva and P. leucopus, and for distinguishing between acute and chronic exposure in C. parva.

Application of plant and earthworm bioassays to evaluate remediation of a lead-contaminated soil.

Earthworm acute toxicity, plant seed germination/rootelongation (SG/RE) and plant genotoxicity bioassays were employed to evaluatethe remediation of a lead-contaminated soil. The remediation involved removalof heavy metals by a soil washing/soil leaching treatment process. A portionof the soil after remediation was rinsed with water in order to simulateexposure to rainfall. The bioassay results showed that the soils beforetreatment (BT) and after treatment plus water rinsing (RT) were not toxic toearthworms in a 14-day exposure, while after treatment (AT) showedsignificant toxicity. The LC50 values for Eisenia fetida andLumbricus terrestris were 44.04 and 28.83 (as % AT soilsupplemented in artificial soil), respectively. The phytotoxicity dataindicated that all three test soils significantly inhibited lettuce SG/RE ina dose-related manner, with AT being the most phytotoxic. In oats, RT had noeffect on SG/RE and AT was more toxic than BT. For the two local site grassseeds tested (blue grama and sideoat grama), the AT soil was the mostphytotoxic followed by BT and RT. In Allium cepa (common onion), BTand AT induced similar levels of genetic damage to root tip cells, whereas RTwas not genotoxic. High salt levels generated during the remediation processappeared to be responsible for the increased toxicity of AT soil for bothplants and earthworms. The rinsing of the AT soil with water effectivelyremoved both acutely toxic and genotoxic components of the soil.

Urine mutagenicity and biochemical effects of the drinking water mutagen, 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), following repeated oral administration to mice and rats.

Mutagenicity analysis of urine from rats treated by oral gavage with MX at a dose of 64 mg/kg for 14 days revealed that only 0.3% of the administered compound was excreted in a genotoxically active form. At lower doses, mutagenicity was not detectable. No evidence of micronucleus induction in peripheral blood erythrocytes was observed in mice treated similarly. These findings indicate that MX is extensively detoxified in vivo and is unlikely to cause genetic damage in systemic tissues except at relatively high doses where detoxification pathways become saturated. In a separate experiment, significant depressions were observed in D-glucaric acid and thioether excretion and in levels of several liver enzymes involved in xenobiotic metabolism. The mechanism for these metabolic alterations and their relevance to the in vivo metabolism of the compound require further investigation.

Venous velocity increase with a pneumatic foot compression garment.

Intermittent compression garments have been widely accepted for prophylaxis of deep venous thrombosis. They have broad applicability in both elective and emergent situations. Development of a new type of garment that acts to compress the plantar plexus of the foot provides a potential method of prophylaxis for patients with contraindications to the traditional calf- or thigh-high garments. Evaluation of the ability of the foot compression garment demonstrates a statistically significant increase in peak femoral venous velocity (40.6 cm/sec) as compared with the resting state (25.9 cm/sec). This increase in femoral venous velocity is comparable to that seen with single-cell compression socks. The authors conclude that the recently introduced foot garment produces increases in peak femoral venous velocity similar to those produced by existing garments and that use of the foot compression garment may provide deep venous thrombosis prophylaxis in patients who previously have not been candidates for a compression garment.

Comparison of blood protein and target organ DNA and protein binding following topical application of benzo[a]pyrene and 7H-dibenzo[c,g]carbazole to mice.

7H-Dibenzo[c,g]carbazole (DBC) induces skin and liver tumors in mice following topical application, whereas benzo[a]pyrene (BP) induces only skin tumors. DBC also binds to liver DNA to a much greater extent than does BP. The present study examined factors that might account for the difference in DNA binding activity. [3H]DBC was applied topically to CD-1 mice at doses of 15, 100 and 1000 nmol/mouse and tissues and blood samples were taken 24 h later. Absorption of DBC from skin into blood and binding to blood proteins occurred linearly with dose. DBC bound to albumin at a 50-fold higher level than to globin and levels of albumin adducts showed good correlation with levels of DNA adducts in liver. Hepatic preference over skin in DNA binding was found to be dose-dependent. For comparison of [3H]BP and [3H]DBC binding, doses of 1000 nmol/mouse were used and the mice were sacrificed at 12, 24 and 48 h. The rate of DBC uptake from skin was 70% higher than for BP over the first 24 h, which was reflected in 40-50% higher plasma levels of DBC radiolabel. Skin protein and DNA binding were 2- to 5-fold higher for BP than DBC. Conversely, total 3H radioactivity levels in liver were 2- to 3-fold higher and liver DNA and protein binding were 15- to 20-fold and 3- to 5-fold higher respectively for DBC. Blood protein adduct levels were similar for both chemicals, suggesting that DBC metabolites formed in the liver were too reactive to re-enter the systemic circulation. Only minor amounts of the radiolabel in the liver were present as the parent compounds by 12 h after dosing. These results indicate that more rapid absorption from skin and selective accumulation in the liver contribute to the greater liver DNA binding seen with DBC, but the types of liver metabolites appear to be the major factor accounting for the binding difference.

Reduction of genotoxicity of a creosote-contaminated soil after fungal treatment determined by the Tradescantia-micronucleus test.

The fungal degradation of polyaromatic hydrocarbons (PAH) in a contaminated soil from a hazardous waste site was evaluated in a pilot-scale study. As some PAH are known to be mutagens, the Tradescantia-micronucleus test (TRAD-MCN) was selected to evaluate the genotoxicity of the soil before and after fungal treatment. The genotoxicity test was conducted with Tradescantia clone 4430. Cuttings were exposed for 30 h to different dilutions of soil extracts from the PAH-contaminated soil before and after fungal treatment. Soil extracts before fungal treatment exhibited a relatively strong genotoxic effect in the meiotic pollen mother cells even at a 1% concentration, and the highest concentration without significant effect was 0.25%. After fungal treatment, the depletion of selected PAH was associated with a reduction of the soil genotoxicity. The 2% concentration of the extract from the fungal-treated soil showed genotoxic effects comparable to the 1% soil extract without fungal treatment. These results indicate that the Trad-MCN test has a potential utility for evaluating the efficiency of bioremediation of genotoxic soil contaminants.

Advances in research on carcinogenic and genotoxic by-products of chlorine disinfection: chlorinated hydroxyfuranones and chlorinated acetic acids.

The introduction of chlorination of public drinking water in the early 1900's was a major factor in the fight against waterborne disease. In the 1970's it was discovered that chlorine reacted with naturally occurring organic constituents, particularly in surface water, to yield small quantities of chlorinated by-products such as chloroform for which regulations were subsequently developed. Since then there has been shown to be a substantial number of other by-products some in concentrations of a few nanograms/l and others similar concentrations to the THM. Of particular note are the potent bacterial mutagen MX and the chlorinated acetic acids. Current research into the significance of these for man is described and the key issues for risk assessment are identified.

[Silo filler's syndrome]. / Siloentladersyndrom.

In 1975 an acute febrile bronchopulmonary illness after massive inhalation of fungal spores in silos was described as "pulmonary mycotoxicosis". Subsequently the disorder was referred to as "silo unloader's syndrome" or as a special form of "organic dust toxic syndrome" (ODTS). In this article the three cases of silo unloader's syndrome recognized by the Swiss National Accident Insurance Company (SUVA) between 1978 and 1989 as being an occupational disease are described. Two of the three patients with ODTS were wrongly diagnosed as suffering from allergic alveolitis and a change of occupation was proposed. Therefore, it is important to recognize ODTS in order to avoid unnecessary treatment and a change of occupation. ODTS can be prevented by technical measures such as prevention of mould formation and, in the case of exposure to fungal spores, use of an adequate breathing mask or a powered dust respirator helmet.

Human papillomavirus type 18 in conjunctival intraepithelial neoplasia.

Human papillomaviruses are oncogenic viruses that have been found in a variety of epithelial neoplasias. We sought to confirm their presence in conjunctival intraepithelial neoplasia. Five tumors were studied with a polymerase chain-reaction assay designed to detect the E6 region of human papillomavirus types 16 and 18. Human papillomavirus type-16 DNA was found in four of the five tumors, including two tumors that contained both type-16 and type-18 DNA. Viral DNA was not present in the fifth tumor.

Activity of 1,1,1- and 1,1,3-trichloroacetones in a chromosomal aberration assay in CHO cells and the micronucleus and spermhead abnormality assays in mice.

1,1,1- and 1,1,3-trichloroacetones (TCA) result from the disinfection of municipal water supplies with chlorine, and are direct-acting mutagens in the Ames/Salmonella assay. The objective of this study was to further investigate the genotoxicity of these compounds in mammalian cells using an in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells and the micronucleus and spermhead abnormality assays in mice. Both compounds induced significant increases in structural chromosomal aberrations in CHO cells in the presence and in the absence of rat S9 metabolic activation (MA). 1,1,3-TCA was more cytotoxic to CHO cells but 1,1,1-TCA resulted in a higher proportion of cells with aberrations. The clastogenic activities of both compounds were reduced in assays conducted with MA. Neither compound resulted in the induction of a significant increase in micronucleated polychromatic erythrocytes from bone marrow of Swiss-Webster mice when administered by oral gavage; nor were effects seen on the incidence of sperm with head-shape abnormalities, testis weight, or epididymal sperm concentration in B6C3F1 mice 21 or 35 days after treatment. These data indicate that the drinking water contaminants 1,1,1- and 1,1,3-TCA are clastogenic in vitro, but are not clastogenic to bone marrow cells in vivo, and do not adversely affect several indicators of testicular function in mice.

Genotoxic activity of organic chemicals in drinking water.

The information summarized in this review provides substantial evidence for the widespread presence of genotoxins in drinking water. In many, if not most cases, the genotoxic activity can be directly attributed to the chlorination stage of drinking water treatment. The genotoxic activity appears to originate primarily from reactions of chlorine with humic substances in the source waters. Genotoxic activity in drinking water concentrates has been most frequently demonstrated using bacterial mutagenicity tests but results with mammalian cell assay systems are generally consistent with the findings from the bacterial assays. There is currently no evidence for genotoxic damage following in vivo exposures to animals. In some locations genotoxic contaminants of probable industrial and/or agricultural origin occur in the source waters and contribute substantially to the genotoxic activity of finished drinking waters. The method used for sample concentration can have an important bearing on study results. In particular, organic acids account for most of the mutagenicity of chlorinated drinking water, and their recovery from water requires a sample acidification step prior to extraction or XAD resin adsorption. Considerable work has been done to determine the identity of the compounds responsible for the mutagenicity of organic concentrates of drinking water. Recently, one class of acidic compounds, the chlorinated hydroxyfuranones, has been shown to be responsible for a major part of the mutagenic activity. Strategies for drinking water treatment that have been evaluated with respect to reduction of genotoxins in drinking water include granular activated carbon (GAC) filtration, chemical destruction, and the use of alternative means of treatment (i.e., ozone, chlorine dioxide, and monochloramine). GAC treatment has been found to be effective for removal of mutagens from drinking water even after the GAC is beyond its normal use for organic carbon removal. All disinfectant chemicals appear to have the capacity of forming mutagenic chemicals during water treatment. However, the levels of mutagenicity formed with the alternative disinfectants have been generally less than those seen with chlorine and, especially in the case of ozone, highly dependent on the source water.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies on the potent bacterial mutagen, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone: aqueous stability, XAD recovery and analytical determination in drinking water and in chlorinated humic acid solutions.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was detected by gas chromatography/mass spectrometry in drinking water samples from 3 locations in the U.S.A., and also in a chlorinated humic acid solution. MX appears to account for a significant proportion of the mutagenicity of these samples, as measured in the Ames test using strain TA100 without metabolic activation. Studies on recovery of MX from spiked water samples by XAD-2/8 resin adsorption/acetone elution indicated that sample acidification prior to resin adsorption was essential to the effective recovery of MX. The stability of MX in aqueous solution was pH and temperature dependent. At 23 degrees C the order of stability, based on persistence of mutagenic activity was found to be: pH 2 greater than pH 4 greater than pH 8 greater than pH 6. The half-life at pH 8 and 23 degrees C was 4.6 days. One of the degradation products has been tentatively identified as 2-chloro-3-(dichloromethyl)-4-oxo-2-butenoic acid, an open form of MX which appears to be in the "E" configuration. Overall, these results suggest that MX is formed during water chlorination as a result of reaction of chlorine with humic substances, and that a substantial fraction of the MX formed is likely to persist throughout the distribution system.

Chemical reactivity, cytotoxicity, and mutagenicity of chloropropanones.

Studies were conducted to assess the in vitro toxicity of three chloropropanones: monochloropropanone (MCP), 1,1-dichloropropanone (1,1-DCP), and 1,3-dichloropropanone (1,3-DCP). Chloropropanones reacted directly with reduced glutathione (GSH) in sodium phosphate buffer at pH 7.4. All chloropropanones were cytotoxic to suspensions of male rat hepatocytes in a concentration range of 0.5-10 mM. Cytotoxicity was preceded by rapid decline in cellular GSH levels. Mutagenic potencies among the chloropropanones in Salmonella typhimurium bacteria differed greatly. 1,3-DCP was mutagenic in the nanomole range, 1,1-DCP was weakly mutagenic in the micromole range, and MCP was not mutagenic. Mutagenicity of the dichloropropanones was evident without metabolic activation. These results suggest that the three chloropropanones may, in part, be directly cytotoxic but only 1,3-DCP and 1,1-DCP are directly mutagenic.

Mutagenic and clastogenic properties of 3-chloro-4-(dichloromethyl)-5-hydroxy-2 (5H)-furanone: a potent bacterial mutagen in drinking water.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was found to be a direct-acting mutagen in the Ames test for strains TA1535, TA1538, TA92, TA97, TA98, TA100 and TA102. The highest mutagenic response (approximately 13,000 revertants/nmol) was seen in strain TA100. The TA100 response was six- to tenfold higher than in TA98, TA97, and TA102, and 100- to 500-fold higher than in TA1535, TA92, and TA1538. The addition of a 9,000 x g supernatant fraction (S-9) from livers of polychlorinated biphenyl-treated rats, along with cofactors for NADPH generation, resulted in a 90% reduction in the TA100 mutagenicity. MX induced chromosomal aberrations in Chinese hamster ovary cells after 6-8 hr exposure without S-9 at a dose as low as 4 micrograms/ml, and after 2 hr exposure with S-9 at a dose of 75 micrograms/ml. The oral dose of MX lethal to 50% (LD50) in Swiss-Webster mice was determined to be 128 mg/kg. MX did not induce micronuclei in mouse bone marrow when administered by oral gavage at doses up to 70% of the LD50.

Mutagenic by-products from chlorination of humic acid.

Chlorination of humic and fulvic acid results in the formation of direct-acting mutagenicity, detectable in the Salmonella/microsome assay (Ames test). This mutagenicity is being characterized as part of an overall effort aimed at evaluating potential health risks associated with the presence of mutagenic chemicals in drinking water. A number of chlorinated organic compounds, including several known mutagens, have been identified and quantified in diethyl ether extracts of chlorinated humic acid solutions. However, the total mutagenicity of these compounds accounts for only about 7% of the original mutagenicity. Synergistic or antagonistic interactions among the identified components have been ruled out as possible explanations for the failure to account for a higher percentage of the activity. Recent progress has been made to separate the activity into neutral and strong acid fractions. Further isolation of the strong acids by high-pressure liquid chromatography (HPLC) has resulted in the purification of the mutagenicity into a major peak of activity with a specific mutagenicity of about 20,000 TA100 revertants per milligram. Several trichlorohydroxyfuranone isomers have been tentatively identified in this fraction. The contribution of these types of compounds to the mutagenicity of chlorinated humic acid is under investigation.