natgillin/translations-raw huggingface dataset:
although the maximum mutant frequency may not manifest itself in slowly proliferating tissues under these conditions.
Proteinskalet som omger en viruspartikel.
If slowly proliferating tissues are of particular importance, then a later sampling time of 28 days following the 28 day administration period may be more appropriate (16) (29).
Ett ämne eller en blandning.
In such cases, the later sampling time would replace the 3 day sampling time, and would require scientific justification.
Klonal expansion
Germ Cells
Produktionen av många celler från en enda (mutant) cell.
TGR assays are well-suited for the study of gene mutation induction in male germ cells (7) (8) (27), in which the timing and kinetics of spermatogenesis have been well-defined (27).
Kolonibildande enhet (CFU)
The low numbers of ova available for analysis, even after super-ovulation, and the fact that there is no DNA synthesis in the oocyte, preclude the determination of mutation in female germ cells using transgenic assays (31).
Ett mått på livskraftigt bakterieantal.
The sampling times for male germ cells should be selected so that the range of exposed cell types throughout germ cell development is sampled, and so that the stage targeted in the sampling has received sufficient exposure.
Konkatamer
The time for the progression of developing germ cells from spermatogonial stem cells to mature sperm reaching the vas deferens/cauda epididymisis ~ 49 days for the mouse (36) and ~70 days for the rat (34) (35).
En lång sammanhängande biomolekyl som består av flera identiska kopior kopplade i serie.
Following a 28-day exposure with a subsequent three day sampling period, accumulated sperm collected from the vas deferens/cauda epididymis (7)(8) will represent a population of cells exposed during approximately the latter half of spermatogenesis, which includes the meiotic and postmeiotic period, but not the spermatogonial or stem cell period.
Cos-ställe
In order to adequately sample cells in the vas deferens/cauda epididymis that were spermatogonial stem cells during the exposure period, an additional sampling time at a minimum of 7 weeks (mice) or 10 weeks (rat), after the end of treatment is required.
Ett 12-nukleotid-segment av enkelsträngat DNA som finns i båda ändarna av den bakteriofaga lambdans dubbelsträngade genom.
Cells extruded from seminiferous tubules after a 28 + 3 day regimen comprise a mixed population enriched for all stages of developing germ cells (7) (8).
En mutation i vilken en eller flera (sekventiella) nukleotider går förlorade genom genomet.
Sampling these cells for gene mutation detection does not provide as precise an assessment of the stages at which germ cell mutations are induced as can be obtained from sampling spermatozoa from the vas deferens/cauda epididymis (since there is a range of germ cell types sampled from the tubules, and there will be some somatic cells contaminating this cell population).
Elektroporering
However, sampling cells from seminiferous tubules in addition to spermatozoa from the vas deferens/cauda epididymis following only a 28 + 3 day sampling regimen would provide some coverage of cells exposed across the majority of phases of germ cell development, and may be useful for detecting some germ cell mutagens.
Tillämpning av elektriska pulser för att öka permeabiliteten hos cellmembran.
General clinical observations should be made at least once a day, preferably at the same time(s) each day and considering the peak period of anticipated effects after dosing.
Endogen gen
If the test chemical is administered via the drinking water, water consumption should be measured at each change of water and at least weekly.
Tillägg av en eller flera nukleotid-baspar i en DNA-sekvens.
Animals exhibiting non-lethal indicators of excess toxicity should be euthanatised prior to completion of the test period (23).
Ett stort antal mutanter som uppstår genom klonal expansion av en enda mutation.
Tissue Collection
Stora deletioner
The rationale for tissue collection should be defined clearly.
Deletioner i DNA av mer än flera kilobaser (som effektivt påvisas med Spi–-selektionsanalys och lacZ-plasmidtester).
Since it is possible to study mutation induction in virtually any tissue, the selection of tissues to be collected should be based upon the reason for conducting the study and any existing mutagenicity, carcinogenicity or toxicity data for the chemical under investigation.
Ligering
Important factors for consideration should include the route of administration (based on likely human exposure route(s)), the predicted tissue distribution, and the possible mechanism of action.
Den kovalenta kopplingen mellan två ändar av DNA-molekyler med hjälp av DNA-ligas.
In the absence of any background information, several somatic tissues as may be of interest should be collected.
En kemikalie som stimulerar en cell att påbörja celldelning och utlöser mitos (dvs. celldelning).
These should represent rapidly proliferating, slowly proliferating and site of contact tissues.
Neutral gen
In addition, spermatozoa from the vas deferens/cauda epididymis and developing germ cells from the seminiferous tubules (as described in paragraphs 32 and 33) should be collected and stored in case future analysis of germ cell mutagenicity is required.
En gen som inte påverkas av positiva eller negativa selektionstryck.
Organ weights should be obtained, and for larger organs, the same area should be collected from all animals.
Packning
Storage of Tissues and DNA
Syntes av infektiösa fagpartiklar från en beredning av fagkapsid- och svansproteiner och en konkatamer av fag-DNA-molekyler.
Tissues (or tissue homogenates) should be stored at or below – 70 °C and be used for DNA isolation within 5 years.
Används vanligen för att packa DNA klonad på en lambdavektor (åtskilda av cos-ställen) i infektiösa lambdapartiklar.
Isolated DNA, stored refrigerated at 4 °C in appropriate buffer, should be used optimally for mutation analysis within 1 year.
Packningseffektivitet
Selection of Tissues for Mutant Analysis
Den effektivitet med vilken packade bakteriofager återvinns i värdbakterier.
The choice of tissues should be based on considerations such as:
Plackbildande enhet (pfu)
the route of administration or site of first contact (e.g. glandular stomach if administration is oral, lung if administration is through inhalation, or skin if topical application has been used);
Ett mått på livskraftigt bakteriofagantal.
and 2) pharmacokinetic parameters observed in general toxicity studies, which indicate tissue disposition, retention or accumulation, or target organs for toxicity.
Punktmutation
If studies are conducted to follow up carcinogenicity studies, target tissues for carcinogenicity should be considered.
En allmän term för en mutation som påverkar endast en liten sekvens av DNA inklusive små insertioner, deletioner och basparssubstitutioner.
The choice of tissues for analysis should maximise the detection of chemicals that are direct-acting in vitro mutagens, rapidly metabolised, highly reactive or poorly absorbed, or those for which the target tissue is determined by route of administration (6).
Positiv selektion
In the absence of background information and taking into consideration the site of contact due to route of administration, the liver and at least one rapidly dividing tissue (e.g. glandular stomach, bone marrow) should be evaluated for mutagenicity.
En metod som endast tillåter mutanter att överleva.
In most cases, the above requirements can be achieved from analyses of two carefully selected tissues, but in some cases, three or more would be needed.
Reportergen
If there are reasons to be specifically concerned about germ cell effects, including positive responses in somatic cells, germ cell tissues should be evaluated for mutations.
En gen vars muterade genprodukt lätt upptäcks.
Methods of Measurement
Provtagningstid
Standard laboratory or published methods for the detection of mutants are available for the recommended transgenic models:
I slutet av den tidsperiod, före avlivningen, under vilken kemikalien inte administreras och under vilka obearbetade DNA-skador fixeras till stabila mutationer.
lacZ lambda bacteriophage and plasmid (30);
Skyttelvektor
lacI mouse (2) (18);
Transgen
gpt delta mouse (22);
Avser en organism vars genom har förändrats genom överföring av en gen eller gener från en annan art.”
gpt delta rat (28);
Beroende på hur känsliga de kognitiva funktionstesterna är, bör en undersökning med ett större antal djur övervägas, t.ex. upp till 1 hane och 1 hona per kull (för djurtilldelning, se tillägg 1) (ytterligare vägledning om urvalsstorlek finns i OECD:s vägledning 43 [se hänvisning 8]).
Modifications should be justified and properly documented.
Denna tabell visar minsta antalet mättillfällen.
Data from multiple packagings can be aggregated and used to reach an adequate number of plaques or colonies.
Beroende på de förväntade effekterna och resultaten av de inledande mätningarna, kan det vara lämpligt att lägga till ytterligare tidpunkter (t.ex. äldre djur) eller utföra mätningarna under andra utvecklingsstadier.
However, the need for a large number of packaging reactions to reach the appropriate number of plaques may be an indication of poor DNA quality.
Det rekommenderas att avkomman inte testas under två dagar efter avvänjningen (se punkt 32).
In such cases, data should be considered cautiously because they may be unreliable.
Rekommenderade åldrar för testning av ungdjur är:
The optimal total number of plaques or colonies per DNA sample is governed by the statistical probability of detecting sufficient numbers of mutants at a given spontaneous mutant frequency.
Rekommenderade åldrar för att testa unga vuxna är PND 60–70.
In general, a minimum of 125000 to 300000 plaques is required if the spontaneous mutant frequency is in the order of 3 × 10–5 (15).
Kroppsvikten bör mätas minst två gånger i veckan vid direktdosering av ungarna för att justera doserna under perioder med snabb viktuppgång.
For the Big Blue® lacI assay, it is important to demonstrate that the whole range of mutant colour phenotypes can be detected by inclusion of appropriate colour controls concurrent with each plating.
Hjärnvikter och neuropatologi kan bedömas vid en tidigare tidpunkt (t.ex.
Tissues and the resulting samples (items) should be processed and analysed using a block design, where items from the vehicle/solvent control group, the positive control group (if used) or positive control DNA (where appropriate), and each treatment group are processed together.
PND 11), vid behov (se punkt 39).
Treatment of Results
Andra utvecklingsmarkörer utöver kroppsvikten (t.ex. öppna ögon) bör registreras vid behov (se punkt 31).
Individual animal data should be presented in tabular form.
Se punkt 35.
The experimental unit is the animal.
Variationskoefficientens tröskelvärde för en given vävnad identifierades från en kurva över variationskoefficientvärden – ordnade från minsta sekventiella till största – för alla medelvärden från alla experiment under valideringsperioden med användning av en specifik modell (agonist eller antagonist).
The report should include the total number of plaque-forming units (pfu) or colony-forming units (cfu), the number of mutants, and the mutant frequency for each tissue from each animal.
Forskning har visat att bröstkörteln, framför allt i bröstkörtelns tidiga utveckling, är en känslig endpoint för östrogen verkan.
If there are multiple packaging/rescue reactions, the number of reactions per DNA sample should be reported.
Det rekommenderas att endpoints som involverar ungarnas mjölkkörtlar hos båda könen bör ingå i denna testmetod, när den har validerats.
While data for each individual reaction should be retained, only the total pfu or cfu need be reported.
Med ny sats avses en ny sats av celler erhållna från ATCC.
Data on toxicity and clinical signs as per paragraph 34 should be reported.
Med fryst sats avses celler som tidigare har odlats och sedan frysts vid ett annat laboratorium än ATCC.
Any sequencing results should be presented for each mutant analysed, and resulting mutation frequency calculations for each animal and tissue should be shown.
Om extraktion krävs, utförs tre upprepade mätningar för varje extrakt.
Statistical Evaluation and Interpretation of Results
Varje prov extraheras endast en gång.
There are several criteria for determining a positive result, such as a dose-related increase in the mutant frequency, or a clear increase in the mutant frequency in a single dose group compared to the solvent/vehicle control group.
Metodens mätgränser baseras på de basala hormonproduktionsvärden som anges i tabell 5, och är prestationsbaserade.
At least three treated dose groups should be analysed in order to provide sufficient data for dose-response analysis.
Om man kan uppnå ökad basal hormonproduktion så kan gränsen vara större.
While biological relevance of the results should be the primary consideration, appropriate statistical methods may be used as an aid in evaluating the test results (4) (14) (15) (25) (26).
Vissa T- och E2-antikroppar kan korsreagera med androstendion och östron, respektive, vid en större procentandel.
Statistical tests used should consider the animal as the experimental unit.
I sådana fall är det inte möjligt att exakt fastställa effekterna på 17β-HSD.
A test chemical for which the results do not meet the above criteria in any tissue is considered non-mutagenic in this assay.
Däremot kan data fortfarande ge användbar information om effekterna på östrogen eller androgen produktion i allmänhet.
For biological relevance of a negative result, tissue exposure should be confirmed.
I sådana fall bör data uttryckas som androgen/östrogen respons snarare än E2 och T.
For DNA sequencing analyses, a number of statistical approaches are available to assist in interpreting the results (1) (5) (9) (19).
Dessa inkluderar:
Consideration of whether the observed values are within or outside of the historical control range can provide guidance when evaluating the biological significance of the response (32).
kolesterol, pregnenolon, progesteron, 11-deoxikortikosteron, kortikosteron, aldosteron, 17α-pregnenolon, 17α-progesteron, deoxikortisol, kortisol, DHEA, androstendion, östron.
identification data and CAS no, if known;
Lösningsmedel (DMSO)-kontroll (0), 1 μl DMSO/hål.
source, lot number if available;
+, positiv
physical nature and purity;
Celler i blankhål får endast medium (dvs. inget lösningsmedel).
physiochemical properties relevant to the conduct of the study;
Metanol (MeOH) tillsätts efter att exponeringen har avslutats och mediet avlägsnas från dessa hål.
stability of the test chemical, if known;
DMSO-lösningsmedelskontroll (1 μl/hål).
Solvent/vehicle:
Bekräfta tidigare omgång med användning av samma experimentella upplägg.
justification for choice of vehicle;
Ny testomgång med 1/2-log koncentrationsindelning (med ett intervall som inkluderar den koncentration som testades signifikant annorlunda i föregående experiment).
solubility and stability of the test chemical in the solvent/vehicle, if known;
X-faldig förändring vid en koncentration är statistiskt signifikant annorlunda jämfört med SC.
preparation of dietary, drinking water or inhalation formulations;
Avser replikata mätningar för samma prov.
analytical determinations on formulations (e.g. stability, homogeneity, nominal concentrations);
Ordförande
species/strain used and justification for the choice;
En studie om utvecklingsneurotoxicitet kan genomföras som en separat studie som ingår i en studie om reproduktionstoxicitet och/eller vuxenneurotoxicitet (t.ex. testmetoderna B.34 [se hänvisning 14], B.35 [se hänvisning 15], B.43 [se hänvisning 16]), eller läggas till i en studie om prenatal utvecklingstoxicitet (t.ex.testmetod B.31 [se hänvisning 17]).
number, age and sex of animals;
När studien om utvecklingsneurotoxicitet införlivas i, eller ansluts till, en annan studie är det viktigt att bevara integriteten för båda studietyperna.
source, housing conditions, diet, etc.;
Alla tester ska följa gällande lagstiftning eller statliga och institutionella riktlinjer för användning av försöksdjur inom forskningen (se t.ex.hänvisning 18).
individual weight of the animals at the start of the test, including body weight range, mean and standard deviation for each group;
Testlaboratoriet bör analysera all tillgänglig information om testkemikalien innan studien genomförs.
positive and negative (vehicle/solvent) control data;
Sådan information innehåller kemikaliens identitet och struktur, dess fysikalisk-kemiska egenskaper, resultaten från andra in vitro- eller in vivo-toxicitetsstudier av kemikalien, toxikologiska data om strukturellt närbesläktade kemikalier samt den förväntade användningen av kemikalien.
data from the range-finding study;
Denna information är nödvändig för att förvissa alla berörda parter om att testet är relevant för skyddet av människors hälsa, och att det är behjälpligt vid valet av en lämplig startdos.
details of test chemical preparation;
effekter på testkemikaliens kemiska egenskaper som kan ändra dess toxiska egenskaper, samt påverkan på foder- eller vattenkonsumtionen eller djurens näringsstatus.
rationale for route of administration;
Administrationsvägen är i allmänhet oral (t.ex.sondmatning, via föda, via dricksvatten) men andra vägar (t.ex.hud eller inandning) kan användas beroende på egenskaper och förväntade eller kända vägar för mänsklig exponering (ytterligare vägledning finns i vägledningsdokument 43 [se hänvisning 8]).
methods for measurement of animal toxicity, including, where available, histopathological or haematological analyses and the frequency with which animal observations and body weights were taken;
Motivering bör ges för valet av administrationsväg.
methods for verifying that the test chemical reached the target tissue, or general circulation, if negative results are obtained;
Testkemikalien bör ges vid ungefär samma tid varje dag.
actual dose (mg/kg body weight/day) calculated from diet/drinking water test chemical concentration (ppm) and consumption, if applicable;
För avkomma som avlivats från PND 22 bör hjärnvävnaden utvärderas, för djur som avlivats vid avslutningen, bör både centrala nervsystemets (CNS) och perifera nervsystemets (PNS) vävnader utvärderas.
details of food and water quality;
OECD (1995).
detailed description of treatment and sampling schedules and justifications for the choices;
Köpenhamn, Danmark, 13–14 juni 1995.
Gorelick (1996), “Mutational Spectra in Transgenic Animal Research: Data Analysis and Study Design Based upon the Mutant or Mutation Frequency”, Environ.
De Cabo, C., Viveros, M.P.
Brooks, B. Burlinson, J. Mirsalis, B. Myhr, L. Recio and V. Thybaud (1999), “Transgenic Mouse Mutation Assay Systems can Play an important Role in Regulatory Mutagenicity Testing in vivo for the Detection of Site-of-contact Mutagens”, Mutagenesis, 14(1):
Teratol., 19:499–509.
Douglas and D. Krewski (1998), “Statistical Analysis of lacZ Mutant Frequency Data from Muta™Mouse Mutagenicity Assays”, Mutagenesis, 13(3):
Krasnegor, N.A., Blass, E.M., Hofer, M.A., Smotherman, W.
Skopek, V. Thybaud, K.R.Tindall and N. Yajima (2000), “In vivo Transgenic Mutation Assays”, Environ.
Zoetis, T., Walls, I. (2003) Principles and Practices for Direct Dosing of Pre-Weaning Mammals in Toxicity Testing and Research.
Muller, B. Paul, S. Adhya and S. Garges (1996), “Analysis of Genetic Instability during Mammary Tumor Progression using a novel Selection-based Assay for in vivo Mutations in a Bacteriophage λ Transgene Target”, Proc.
Int.
Burns (2008), “Comparison of Induced and Cancer-associated Mutational Spectra using Multivariate Data Analysis”, Carcinogenesis, 29(4):
Conolly, R.B., Beck, B.D., Goodman, J.I.
Nohmi, T., M. Katoh, H. Suzuki, M. Matsui, M. Yamada, M. Watanabe, M. Suzuki, N. Horiya, O. Ueda, T. Shibuya, H. Ikeda and T. Sofuni (1996), “A new Transgenic Mouse Mutagenesis Test System using Spi– and 6-thioguanine Selections”, Environ.
ICH (1993) ICH Harmonised Tripartite Guideline:
Nohmi, T., M. Suzuki, K. Masumura, M. Yamada, K. Matsui, O. Ueda, H. Suzuki, M. Katoh, H. Ikeda and T. Sofuni (1999), “Spi– Selection: an Efficient Method to Detect γ-ray-induced Deletions in Transgenic Mice”, Environ.
Lochry, E.A.
Masumura (2000), “Recent Advances in the Protocols of Transgenic Mouse Mutation Assays”, Mutation Res., 455(1–2):
Toxicol., 6:433–439.
OECD (2000), Guidance Document on the Recognition, Assessment and Use of Clinical Signs as Humane Endpoints for Experimental Animals Used in Safety Evaluation, Series on Testing and Assessment, No 19, ENV/JM/MONO(2000)7, OECD, Paris.
Tachibana, T., Narita, H., Ogawa, T., Tanimura, T. (1998) Using postnatal age to determine test dates leads to misinterpretation when treatments alter gestation length, results from a collaborative behavioral teratology study in Japan.
OECD (2009), Detailed Review Paper on Transgenic Rodent Mutation Assays, Series on Testing and Assessment, No 103, ENV/JM/MONO(2009)7, OECD, Paris.
Teratol., 20:449–457.
Tindall (1995), “Study Design and Sample Sizes for a lacI Transgenic Mouse Mutation Assay”, Environ.
Gallavan, R.H.
Gorelick (1997), “Sources of Variability in Data from a Positive Selection lacZ Transgenic Mouse Mutation Assay: an Interlaboratory Study”, Mutation.
Toxicol., 13:383–390.
Yauk (2006), “Detection of Induced Male Germline Mutation: Correlations and Comparisons between Traditional Germline Mutation Assays, Transgenic Rodent Assays and Expanded Simple Tandem Repeat Instability Assays”, Mutation.
Gray, L.E.
Kurata, M. Takamune, M. Yamada, H. Sanada, T. Umemura, A. Nishikawa and T. Nohmi (2010), “Integration of in vivo Genotoxicity and Short-term Carcinogenicity Assays using F344 gpt delta Transgenic Rats: in vivo Mutagenicity of 2,4-diaminotoluene and 2,6-diaminotoluene Structural Isomers”, Toxicol.
Sci., 58:350–365.
Martus, J.C. Mirsalis, T. Suzuki and N. Yajima (2003), “In vivo Transgenic Mutation Assays”, Mutation Res., 540:
Adams, J., Buelke-Sam, J., Kimmel, C.A., Nelson, C.J., Reiter, L.W., Sobotka, T.J., Tilson, H.A., Nelson, B.K.
Douglas (1996), “Bacteriophage λ and Plasmid lacZ Transgenic Mice for studying Mutations in vivo” in:
Teratol., 7:579–586.
Douglas (2005), “A lacZ Transgenic Mouse Assay for the Detection of Mutations in Follicular Granulosa Cells”, Mutation Res., 578(1-2):
Korenbrot, C.C., Huhtaniemi, I.T., Weiner, R.W.
Martus, V. Thybaud (2011), “Compilation and Use of Genetic Toxicity Historical Control Data”, Mutation Res., doi:10.1016/j.mrgentox.2010.09.007.
Reprod., 17:298–303.
OECD (2011), Retrospective Performance Assessment of OECD Test Guideline on Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays, Series on Testing and Assessment, No 145, ENV/JM/MONO(2011)20, OECD, Paris.
Spear, L.P.
, “The Epididymis”, in Neil, J.D., Pfaff, D.W., Chalis, J.R.G., de Kretser, D.M., Richards, J.S., and P. M, Wassarman (eds.), Physiology of Reproduction, Elsevier, the Netherlands, pp. 1071-1148.
Altman, J., Sudarshan, K. (1975) Postnatal development of locomotion in the laboratory rat.
, “Effects of male germ-cell stage on the frequency, nature, and spectrum of induced specific-locus mutations in the mouse”, Genetica, 122:
Behav., 23:896–920.
Administration period
Adams, J. (1986) Methods in Behavioral Teratology.
the total period during which an animal is dosed.
Reiter, L.W., MacPhail, R.C.
Base pair substitution
Toxicol., 1:53–66.
Capsid
A critique of the methods available for the measurement of spontaneous motor activity, Handbook of Psychopharmacology, Vol.
the protein shell that surrounds a virus particle.
7, Iverson, L.L., Iverson, D.S., Snyder, S.H., (eds.)
a substance or a mixture.
Plenum Press, New York, s. 37–82.
the production of many cells from a single (mutant) cell.
Teratol., 15:117–129.
a measure of viable bacterial numbers.
Psychobiol., 18:247–260.
Concatamer
Crofton, K.M., Howard, J.L., Moser, V.C., Gill, M.W., Reiter, L.W., Tilson, H.A., MacPhail, R.C.
a long continuous biomolecule composed of multiple identical copies linked in series.
Teratol., 13:599–609.
Cos site
Ross, J. F., Handley, D. E., Fix, A. S., Lawhorn, G. T., Carr, G. J. (1997) Quantification of the hind-limb extensor thrust response in rats.