Toxic Hazards Research Unit

The activities of the Toxic Hazards Research Unit (THRU) for the period of June 1970 through May 1971 reviewed. Modification of the animal exposure facilities primarily for improved human safety but also for experimental integrity and continuity are discussed. Acute toxicity experiments were conducted on hydrogen fluoride (HF), hydrogen chloride (HCl), nitrogen dioxide (NO2), and hydrogen cyanide (HCN) both singly and in combination with carbon dioxide (CO). Additional acute toxicity experiments were conducted on oxygen difluoride (OF2) and chlorine pentafluoride (ClF5). Subacute toxicity studies were conducted on methylisobutylketone and dichloromethane (methylene dichloride). The interim results of further chronic toxicity experiments on monomethylhydrazine (MMH) are also described

Toxic Hazards Research Unit annual technical report, 1969 Final report, Jun. 1968 - May 1969

Apollo materials toxicity screening tests and effects of ethylene glycol, monomethylhydrazine, NF3, OF2, and ClF

Continuous animal exposure to dichloromethane

Continuous exposures of dogs, monkeys, rats and mice to 5000 ppm and 1000 ppm of dichloromethane vapor (CH2Cl2) produced severe toxic effects on dogs, rats and mice. Dogs died after 3 weeks exposure to 1000 ppm and after 6 weeks exposure to 5000 ppm. Thirty percent of the mice also succumbed during four weeks exposure to 5000 ppm CH2Cl2. Although rats survived 14 weeks exposure to 5000 ppm, they experienced subnormal weight gains. Significant gross and histopathological hepatic lesions were noted in all 3 species at death or experimental termination in 14 weeks. In addition, rats showed abnormal kidney histopathology. Fat stains disclosed mild fatty increase in monkey livers after 14 weeks exposure to 1000 ppm CH2Cl2

Effect of 90-day continuous exposure to methylisobutylketone on dogs, monkeys and rats

Continuous exposure of rats, dogs and monkeys to 410 mg/cu M methylisobutylketone vapor (MIBK) was conducted to evaluate the provisional spacecraft exposure limit of 20 ppm established by the Space Science Board in 1968. The exposure, conducted in a simulated space cabin environment, did not produce any measurable changes in dogs or monkeys. Rats developed hyaline droplet nephrosis within 2 weeks of exposure which was reversible upon removal from the MIBK even after 90 days. The data obtained indicated that the 60-minute emergency exposure limit of 100 ppm and the 90- and 1000-day provisional limits as established by the Space Science Board contain a wide margin of safety

Acute inhalation toxicology and proposed emergency exposure limits of nitrogen trifluoride,

Acute exposures of rats, mice, dogs and monkeys to nitrogen trifluoride have been carried out and median lethal concentrations were determined for rats and mice. Confirmative evidence was obtained that the immediate effects of acute exposure are caused by extensive methemoglobin formation and resulting anoxia. Dogs surviving exposure to 9600 ppm for 60 min exhibit a Heinz body anemia with red blood cell count, hemoglobin and hematocrit decreasing 33% to minimum values by the end of the second week postexposure. Recovery of hematologic values to preexposure levels is attained in 40 days. In dogs, the anemia caused by a dose level of 120,000 ppm-min is severe enough to invalidate that dose as an emergency exposure limit (EEL). At 30,000 ppm-min, however, no detectable anemia occurs, and no other toxic effects are discernible. The results of experiments conducted at subacute levels justify recommending an upward revision of the EEL to 30,000 ppm-min from the proposed National Academy of Science, National Research Council value of 3000 ppm-min.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33816/1/0000072.pd

Genome sequence of the button mushroom Agaricus bisporus reveals mechanisms governing adaptation to a humic-rich ecological niche

Agaricus bisporus is the model fungus for the adaptation, persistence, and growth in the humic-rich leaf-litter environment. Aside from its ecological role, A. bisporus has been an important component of the human diet for over 200 y and worldwide cultivation of the "button mushroom" forms a multibillion dollar industry. We present two A. bisporus genomes, their gene repertoires and transcript profiles on compost andduringmushroomformation.The genomes encode a full repertoire of polysaccharide-degrading enzymes similar to that of wood-decayers. Comparative transcriptomics of mycelium grown on defined medium, casing-soil, and compost revealed genes encoding enzymes involved in xylan, cellulose, pectin, and protein degradation aremore highly expressed in compost. The striking expansion of heme-thiolate peroxidases and β-etherases is distinctive from Agaricomycotina wood-decayers and suggests a broad attack on decaying lignin and related metabolites found in humic acid-rich environment. Similarly, up-regulation of these genes together with a lignolytic manganese peroxidase, multiple copper radical oxidases, and cytochrome P450s is consistent with challenges posed by complex humic-rich substrates. The gene repertoire and expression of hydrolytic enzymes in A. bisporus is substantially different from the taxonomically related ectomycorrhizal symbiont Laccaria bicolor. A common promoter motif was also identified in genes very highly expressed in humic-rich substrates. These observations reveal genetic and enzymatic mechanisms governing adaptation to the humic-rich ecological niche formed during plant degradation, further defining the critical role such fungi contribute to soil structure and carbon sequestration in terrestrial ecosystems. Genome sequence will expedite mushroom breeding for improved agronomic characteristics

Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry

Modern humans appeared in Europe by at least 45,000 years ago1–5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common

Zaštitno djelovanje selenija protiv prekomjerne ekspresije apoptotskih gena povezanih s karcinomom u štakora izloženih o-krezolu

Cresols are monomethyl derivatives of phenol frequently used as solvents and intermediates in the production of disinfectants, fragrances, pesticides, dyes, and explosives, which is probably why they are widely distributed in the environment. General population may be exposed to cresols mainly through inhalation of contaminated air. In this study we evaluated the toxicological effects of o-cresol on differential gene expression profile of rat liver and prostate. Experiments were conducted on 80 male rats, 60 of which were exposed to o-cresol (1.5 g kg-1, 5 g kg-1, or 15 g kg-1) through feed for 8 weeks. Three groups of rats were supplemented with 0.1 mg kg-1 selenium (Se, in the form of, sodium selenite) in addition to o-cresol to evaluate its effectiveness against o-cresol toxicity. Control group received neither o-cresol nor Se, while one group received Se alone. Survival was similar between the exposed and control animals. Rats exposed to 15 g kg-1 of o-cresol showed a 16 % loss in body weight by the end of the study, which may have been related to o-cresol making feed unpalatable at this concentration. Liver and prostate tissue samples were collected at the end of the treatment. mRNA analysis revealed that apoptotic genes (CYP3A, COX-2, PPARγ, BAX, BCL2, AKT-1, and PKCα) related to cancer were up-regulated in liver and prostate tissues isolated from groups exposed to 5 g kg-1 and 15 g kg-1 o-cresol in comparison to control. Changes in gene expression profile were prevented when rats were supplemented with Se. The exact mechanisms underlying its protective effect remain to be clarified by future studies.Krezoli su monometilni derivati fenola koji se često rabe kao otapala te kao posrednici u proizvodnji dezinfekcijskih sredstava, mirisa, pesticida, boja i eksploziva. Otuda i njihova rasprostranjenost u okolišu. Opća je populacija izložena krezolima uglavnom putem zraka. U ovome se toksikološkom istraživanju ocijenilo djelovanje o-krezola, jednoga od tri krezolova izomera, na ekspresiju gena u tkivima jetre i prostate mužjaka štakora. Istraživanje je provedeno na 80 mužjaka, od kojih je 60 tijekom osam tjedana bilo izloženo o-krezolu (1,5 g kg-1, 5 g kg-1, odnosno 15 g kg-1) preko krmiva. Tri skupine štakora primale su uz o-krezol nadomjestak selenija u dozi od 0.1 mg kg-1 (Se, u obliku natrijeva selenita) radi ocjene njegove djelotvornosti protiv toksičnosti o-krezola. Kontrolna skupina nije primala ni o-krezol ni Se, dok je jedna skupina primala samo Se. Preživljenje je bilo podjednako u svih skupina životinja. Štakori izloženi najvišoj dozi o-krezola (15 g kg-1) imali su 16 % manju tjelesnu masu od kontrolne skupine na kraju ispitivanja, što može biti povezano s lošim okusom krmiva zbog primjese visoke doze o-krezola. S istekom osmotjednoga izlaganja o-krezolu životinje su eutanazirane te su prikupljeni uzorci tkiva jetre i prostate. Analiza m-RNA pokazala je značajno povišenu ekspresiju apoptotskih gena CYP3A, COX-2, PPARγ, BAX, BCL2, AKT-1 i PKCα, koji su povezani s nastankom karcinoma u skupinama štakora izloženim o-krezolu (5 g kg-1 i 15 g kg-1 u odnosu na kontrolu. Ova je prekomjerna ekspresija poništena u štakora koji su primali selenij. Još nisu jasni mehanizmi iza ovoga zaštitnog djelovanja, na što će odgovoriti buduća istraživanja

The evolution and appearance of c3 duplications in fish originate an exclusive teleost c3 gene form with anti- inflammatory activity

12 páginas, 6 figuras, 3 tablas.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThe complement system acts as a first line of defense and promotes organism homeostasis by modulating the fates of diverse physiological processes. Multiple copies of component genes have been previously identified in fish, suggesting a key role for this system in aquatic organisms. Herein, we confirm the presence of three different previously reported complement c3 genes (c3.1, c3.2, c3.3) and identify five additional c3 genes (c3.4, c3.5, c3.6, c3.7, c3.8) in the zebrafish genome. Additionally, we evaluate the mRNA expression levels of the different c3 genes during ontogeny and in different tissues under steady-state and inflammatory conditions. Furthermore, while reconciling the phylogenetic tree with the fish species tree, we uncovered an event of c3 duplication common to all teleost fishes that gave rise to an exclusive c3 paralog (c3.7 and c3.8). These paralogs showed a distinct ability to regulate neutrophil migration in response to injury compared with the other c3 genes and may play a role in maintaining the balance between inflammatory and homeostatic processes in zebrafishThis work has been funded by the project CSD2007-00002 “Aquagenomics” from the Spanish Ministerio de Ciencia e Innovación, the ITN 289209 “FISHFORPHARMA” (EU) and project 201230E057 from the Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC).Peer reviewe