natgillin/translations-raw huggingface dataset:
In this case, it may be appropriate to perform a study in both sexes, e.g. as part of a repeated dose toxicity study.
merila za izbor najvišjega odmerka so skladna z merili, opisanimi v odstavkih 25 do 28.
It might be appropriate to use the factorial design in case both sexes are used.
Vrednotenje in razlaga rezultatov
Details on how to analyse the data using this design are given in Appendix 2.
Pod pogojem, da so izpolnjena vsa merila za sprejemljivost, se preskusna kemikalija šteje za jasno pozitivno, če:
Group sizes at study initiation should be established with the aim of providing a minimum of 5 analysable animals of one sex, or of each sex if both are used, per group.
se vsaj pri eni od tretiranih skupin pokaže statistično značilno povečanje pogostosti celic s strukturnimi kromosomskimi aberacijami (razen vrzeli) v primerjavi s sočasno negativno kontrolo;
Where human exposure to chemicals may be sex-specific, as for example with some pharmaceuticals, the test should be performed with the appropriate sex.
b. je to povečanje povezano z odmerkom pri vsaj enem času vzorčenja, kadar se ocenjuje z ustreznim trendnostnim testom;
As a guide to maximum typical animal requirements, a study in bone marrow at two sampling times with three dose groups and a concurrent negative control group, plus a positive control group (each group composed of five animals of a single sex), would require 45 animals.
c. je kateri koli od teh rezultatov zunaj porazdelitve podatkov o negativnih kontrolah iz preteklih preskusov (npr. 95-odstotna kontrolna meja, ki temelji na Poissonovi porazdelitvi).
Dose levels
Če se pri določenem času vzorčenja prouči le najvišji odmerek, se preskusna kemikalija šteje kot jasno pozitivna, če obstaja statistično značilno povečanje v primerjavi s sočasno negativno kontrolo in so rezultati zunaj porazdelitve podatkov o negativnih kontrolah iz preteklih preskusov (npr. 95-odstotna kontrolna meja, ki temelji na Poissonovi porazdelitvi).
If a preliminary range-finding study is performed because there are no suitable data already available to aid in dose selection, it should be performed in the same laboratory, using the same species, strain, sex, and treatment regimen to be used in the main study (10).
Priporočila glede najustreznejših statističnih metod so navedena v virih (13).
The study should aim to identify the maximum tolerated dose (MTD), defined as the highest dose that will be tolerated without evidence of study-limiting toxicity, relative to the duration of the study period (for example, by inducing body weight depression or hematopoietic system cytotoxicity), but not death or evidence of pain, suffering or distress necessitating humane euthanasia (11).
Pri analizi razmerja med odmerkom in odzivom je treba analizirati vsaj tri tretirane skupine, ki prejemajo odmerke.
The highest dose may also be defined as a dose that produces some indication of toxicity to the bone marrow.
V statističnih preskusih se kot poskusna enota uporabi žival.
Chemicals that exhibit saturation of toxicokinetic properties, or induce detoxification processes that may lead to a decrease in exposure after long-term treatment may be exceptions to the dose-setting criteria and should be evaluated on a case-by-case basis.
Pozitivni rezultati preskusa kromosomskih aberacij kažejo, da preskusna kemikalija povzroči nastanek strukturnih kromosomskih aberacij v kostnem mozgu preskušane vrste.
In order to obtain dose response information, a complete study should include a negative control group and a minimum of three dose levels generally separated by a factor of 2, but not greater than 4.
Pod pogojem, da so izpolnjena vsa merila za sprejemljivost, se preskusna kemikalija šteje za jasno negativno, če se v katerem koli od proučevanih preskusnih pogojev:
If the test chemical does not produce toxicity in a range-finding study or based on existing data, the highest dose for a single administration should be 2000 mg/kg body weight.
pri nobeni tretirani skupini ne pokaže statistično značilno povečanje pogostosti celic s strukturnimi kromosomskimi aberacijami (razen vrzeli) v primerjavi s sočasno negativno kontrolo;
However, if the test chemical does cause toxicity, the MTD should be the highest dose administered and the dose levels used should preferably cover a range from the maximum to a dose producing little or no toxicity.
b. pri katerem koli času vzorčenja ne pojavi z odmerkom povezano povečanje, če se ocenjuje z ustreznim trendnostnim testom;
When target tissue (bone marrow) toxicity is observed at all dose levels tested, further study at non-toxic doses is advisable.
c. so vsi rezultati znotraj porazdelitve podatkov o negativnih kontrolah iz preteklih preskusov (npr. 95-odstotna kontrolna meja, ki temelji na Poissonovi porazdelitvi) ter
Studies intending to more fully characterise the quantitative dose-response information may require additional dose groups.
d. se je pojavila izpostavljenost kostnega mozga preskusnim kemikalijam.
For certain types of test chemicals (e.g. human pharmaceuticals) covered by specific requirements, these limits may vary.
Priporočila glede najustreznejših statističnih metod so navedena v virih (13).
Limit test
Dokazi o izpostavljenosti kostnega mozga preskusni kemikaliji lahko vključujejo zmanjšanje mitotičnega indeksa ali meritve ravni preskusnih kemikalij v plazmi ali krvi.
If dose range-finding experiments, or existing data from related animal strains, indicate that a treatment regime of at least the limit dose (described below) produces no observable toxic effects, (including no depression of bone marrow proliferation or other evidence of target tissue cytotoxicity), and if genotoxicity would not be expected based upon in vitro genotoxicity studies or data from structurally related chemicals, then a full study using three dose levels may not be considered necessary, provided it has been demonstrated that the test chemical(s) reach(es) the target tissue (bone marrow).
Pri intravenoznem dajanju dokaz o izpostavljenosti ni potreben.
In such cases, a single dose level, at the limit dose, may be sufficient.
Negativni rezultati pomenijo, da preskusna kemikalija pri preskusnih pogojih ne povzroča nastanka mikronukleusov v nezrelih eritrocitih preskušane vrste.
For an administration period of > 14 days, the limit dose is 1000 mg/kg body weight/day.
Preverjanje jasno pozitivnega ali jasno negativnega odziva ni potrebno.
For administration periods of 14 days or less, the limit dose is 2000 mg/kg/body weight/day.
V primerih, ko odziv ni jasno negativen ali pozitiven, in za pomoč pri opredelitvi biološke pomembnosti rezultatov (npr. šibko ali mejno povečanje), je treba podatke oceniti s strokovno presojo in/ali nadaljnjimi preiskavami zaključenih obstoječih poskusov.
Administration of doses
V nekaterih primerih je koristno, če se analizira več celic ali poskus ponovi s spremenjenimi preskusnimi pogoji.
The anticipated route of human exposure should be considered when designing an assay.
Podatki v redkih primerih celo po izvedbi nadaljnjih preiskav ne omogočajo sklepa o tem, ali preskusna kemikalija povzroča pozitivne ali negativne rezultate, zato se zaključi, da je odziv dvoumen.
Therefore, routes of exposure such as dietary, drinking water, topical, subcutaneous, intravenous, oral (by gavage), inhalation, intratracheal, or implantation may be chosen as justified.
Pogostost poliploidnih in endoredupliciranih metafaz med skupnim številom metafaz je treba zabeležiti posebej.
In any case, the route should be chosen to ensure adequate exposure of the target tissue(s).
Povečanje števila poliploidnih/endoredupliciranih celic kaže na to, da ima preskusna kemikalija potencial za zaviranje mitotičnih procesov ali poteka celičnega cikla (glej odstavek 3).
Intraperitoneal injection is generally not recommended since it is not an intended route of human exposure, and should only be used with specific scientific justification.
Poročilo o preskusu
If the test chemical is admixed in diet or drinking water, especially in case of single dosing, care should be taken that the delay between food and water consumption and sampling should be sufficient to allow detection of the effects (see paragraphs 33-34).
Povzetek
The maximum volume of liquid that can be administered by gavage or injection at one time depends on the size of the test animal.
vir, številka serije, rok uporabe, če je na voljo;
The volume should not normally exceed 1 ml/100 g body weight except in the case of aqueous solutions where a maximum of 2 ml/100 g may be used.
stabilnost preskusne kemikalije, če je znana.
The use of volumes greater than this should be justified.
Priprava preskusne kemikalije:
Except for irritating or corrosive test chemicals, which will normally produce exacerbated effects at higher concentrations, variability in test volume should be minimised by adjusting the concentration to ensure administration of a constant volume in relation to body weight at all dose levels.
utemeljitev izbire vehikla;
Treatment schedule
topnost in stabilnost preskusne kemikalije v topilu/vehiklu, če je znana;
Test chemicals are normally administered as a single treatment, but may be administered as a split dose (i.e. two or more treatments on the same day separated by no more than 2-3 hours) to facilitate administering a large volume.
priprava pripravkov hrane in pitne vode ali pripravkov za vdihavanje;
Under these circumstances, or when administering the test chemical by inhalation, the sampling time should be scheduled based on the time of the last dosing or the end of exposure.
analitsko določanje sestave (npr. stabilnost, homogenost, nominalne koncentracije), če je na voljo.
There are little data available on the suitability of a repeated-dose protocol for this test.
uporabljena vrsta/sev in utemeljitev izbire;
However, in circumstances where it is desirable to integrate this test with a repeated-dose toxicity test, care should be taken to avoid loss of chromosomally damaged mitotic cells as may occur with toxic doses.
število, starost in spol živali;
Such integration is acceptable when the highest dose is greater or equal to the limit dose (see paragraph 29) and a dose group is administered the limit dose for the duration of the treatment period.
izvor, nastanitvene razmere, prehrana itd.;
The micronucleus test (test method B.12) should be viewed as the in vivo test of choice for chromosomal aberrations when integration with other studies is desired.
metoda edinstvene identifikacije živali;
Bone marrow samples should be taken at two separate times following single treatments.
pozitivne in negativne kontrole (z vehiklom/topilom);
For rodents, the first sampling interval should be the time necessary to complete 1,5 normal cell cycle lengths (the latter being normally 12-18 hours following the treatment period).
podatki iz študije za ugotavljanje območja, če je bila izvedena;
Since the time required for uptake and metabolism of the test chemical(s) as well as its effect on cell cycle kinetics can affect the optimum time for chromosomal aberration detection, a later sample collection 24 hours after the first sampling time is recommended.
utemeljitev izbire velikosti odmerkov;
At the first sampling time, all dose groups should be treated and samples collected for analysis; however, at the later sampling time(s), only the highest dose needs to be administered.
podrobnosti o pripravi preskusne kemikalije;
If dose regimens of more than one day are used based on scientific justification, one sampling time at up to approximately 1,5 normal cell cycle lengths after the final treatment should generally be used.
podrobnosti o dajanju preskusne kemikalije;
Following treatment and prior to sample collection, animals are injected intraperitoneally with an appropriate dose of a metaphase-arresting agent (e.g. colcemid or colchicine), and samples are collected at an appropriate interval thereafter.
utemeljitev načina in trajanja dajanja kemikalije;
For mice this interval is approximately 3-5 hours prior to collection and for rats it is 2-5 hours.
metode za preverjanje, ali je preskusna kemikalija dosegla krvni obtok ali kostni mozeg;
Cells are harvested from the bone marrow, swollen, fixed and stained, and analysed for chromosomal aberrations (12).
dejanski odmerek (v mg/kg telesne teže/dan), izračunan glede na koncentracijo preskusne kemikalije (v ppm) v hrani/pitni vodi in porabo hrane/pitne vode, če je ustrezno;
Observations
podrobnosti o kakovosti hrane in vode;
General clinical observations of the test animals should be made and clinical signs recorded at least once a day, preferably at the same time(s) each day and considering the peak period of anticipated effects after dosing.
metoda za evtanazijo;
At least twice daily during the dosing period, all animals should be observed for morbidity and mortality.
metoda za analgezijo (če se uporablja);
All animals should be weighed at study initiation, at least once a week during repeated-dose studies, and at euthanasia.
podroben opis časovnega razporeda tretiranj in vzorčenj ter utemeljitev izbir;
In studies of at least one-week duration, measurements of food consumption should be made at least weekly.
metode za pripravo preparatov;
If the test chemical is administered via the drinking water, water consumption should be measured at each change of water and at least weekly.
metode za merjenje toksičnosti;
Animals exhibiting non-lethal indicators of excessive toxicity should be humanely euthanised prior to completion of the test period (11).
identiteta kemikalije, ki zavira metafazo, njena koncentracija, odmerek in čas dajanja pred vzorčenjem;
Target tissue exposure
postopki za izolacijo in hrambo vzorcev;
A blood sample should be taken at appropriate time(s) in order to permit investigation of the plasma levels of the test chemicals for the purposes of demonstrating that exposure of the bone marrow occurred, where warranted and where other exposure data do not exist (see paragraph 44).
število analiziranih celic v metafazi na žival in število analiziranih celic za določitev mitotičnega indeksa;
Bone marrow and chromosome preparations
merila za sprejemljivost študije;
Immediately after humane euthanasia, bone marrow cells are obtained from the femurs or tibias of the animals, exposed to hypotonic solution and fixed.
merila za obravnavanje študij kot pozitivnih, negativnih ali nedokončnih.
The metaphase cells are then spread on slides and stained using established methods (see (3) (12)).
stanje živali pred preskusnim obdobjem in med njim, vključno z znaki toksičnosti;
All slides, including those of positive and negative controls, should be independently coded before analysis and should be randomised so the scorer is unaware of the treatment condition.
mitotični indeks, naveden za vsako žival posebej;
The mitotic index should be determined as a measure of cytotoxicity in at least 1000 cells per animal for all treated animals (including positive controls), untreated or vehicle/solvent negative control animals.
vrsta in število aberacij ter celic z aberacijami, navedene za vsako žival posebej;
At least 200 metaphases should be analysed for each animal for structural chromosomal aberrations including and excluding gaps (6).
skupno število aberacij na skupino s srednjimi vrednostmi in standardnimi odkloni;
However, if the historical negative control database indicates the mean background structural chromosomal aberration frequency is < 1 % in the testing laboratory, consideration should be given to scoring additional cells.
število celic z aberacijami na skupino s srednjimi vrednostmi in standardnimi odkloni;
Chromatid and chromosome-type aberrations should be recorded separately and classified by sub-types (breaks, exchanges).
spremembe v ploidnosti, če so opažene, vključno s pogostostjo poliploidnih in/ali endoredupliciranih celic;
Recognising that slide preparation procedures often result in the breakage of a proportion of metaphases with a resulting loss of chromosomes, the cells scored should, therefore, contain a number of centromeres not less than 2n ± 2, where n is the haploid number of chromosomes for that species.
razmerje med odmerkom in odzivom, če je mogoče;
Treatment of Results
uporabljena statistična analiza in metoda;
Individual animal data should be presented in tabular form.
podatki, ki dokazujejo, da je prišlo do izpostavljenosti kostnega mozga;
The mitotic index, the number of metaphase cells scored, the number of aberrations per metaphase cell and the percentage of cells with structural chromosomal aberration(s) should be evaluated for each animal.
podatki o sočasnih negativnih kontrolah in pozitivnih kontrolah z območji, srednjimi vrednostmi in standardnimi odkloni;
Different types of structural chromosomal aberrations should be listed with their numbers and frequencies for treated and control groups.
podatki o negativnih in pozitivnih kontrolah iz preteklih preskusov z območji, srednjimi vrednostmi in standardnimi odkloni in 95-odstotne kontrolne meje za porazdelitev ter obravnavano časovno obdobje in število opazovanj;
Gaps, as well as polyploid cells and cells with endoreduplicated chromosomes are recorded separately.
izpolnjena merila za pozitivni ali negativni odziv.
The frequency of gaps is reported but generally not included in the analysis of the total structural aberration frequency.
Sklepna ugotovitev
If there is no evidence for a difference in response between the sexes, the data may be combined for statistical analysis.
Viri
Data on animal toxicity and clinical signs should also be reported.
Cytogenetic Tests in Mammals, in Mutagenicity Testing: A Practical Approach.
The following criteria determine the acceptability of the test:
Venittand, S. in Parry, J. M. (eds.), IRL Press, Washington, DC, str. 275–306.
The concurrent negative control data are considered acceptable for addition to the laboratory historical control database (see paragraphs 11-14);
In Vivo Cytogenetics Assays, v Basic Mutagenicity Tests, UKEMS Recommended Procedures.
The concurrent positive controls or scoring controls should induce responses that are compatible with those generated in the historical positive control database and produce a statistically significant increase compared with the negative control (see paragraphs 20-21);
Part I revised.
The appropriate number of doses and cells has been analysed;
Kirkland, D. J. (ed.), Cambridge University Press, Cambridge, str. 115–141.
The criteria for the selection of highest dose are consistent with those described in paragraphs 25-28.
OECD (2000), Guidance Document on the Recognition, Assessment and Use of Clinical Signs as Humane Endpoints for Experimental Animals Used in Safety Evaluation, OECD Environment, Health and Safety Publications (EHS), Series on Testing and Assessment, št.°19, OECD Publishing, Pariz.
Evaluation and Interpretation of Results
Statistical Analysis of in vivo Cytogenetic Assays, in Statistical Evaluation of Mutagenicity Test Data.
Providing that all acceptability criteria are fulfilled, a test chemical is considered clearly positive if:
(ed.), Cambridge University Press, Cambridge, str. 184–232.
At least one of the treatment groups exhibits a statistically significant increase in the frequency of cells with structural chromosomal aberrations (excluding gaps) compared with the concurrent negative control,
je vsako odstopanje od normalnega diploidnega (ali haploidnega) števila kromosomov za en ali več kot en kromosom, vendar ne za večkratnik celotnega števila kromosomov (prim.: poliploidija).
If only the highest dose is examined at a particular sampling time, a test chemical is considered clearly positive if there is a statistically significant increase compared with the concurrent negative control and the results are outside the distribution of the historical negative control data (e.g. Poisson-based 95 % control limits).
Aberacija kromosomskega tipa
Recommendations for appropriate statistical methods can be found in the literature (13).
Endoreduplikacija
When conducting a dose-response analysis, at least three treated dose groups should be analysed.
proces, pri katerem v jedru po podvajanju DNK v fazi S ne začne potekati mitoza, temveč takoj nastopi druga faza S. Rezultat tega so kromosomi s 4, 8, 16 … kromatidami.
Statistical tests should use the animal as the experimental unit.
Vrzel
Positive results in the chromosomal aberration test indicate that a test chemical induces structural chromosomal aberrations in the bone marrow of the species tested.
akromatska lezija, ki je manjša od širine ene kromatide, z zelo majhno neporavnanostjo kromatid.
Providing that all acceptability criteria are fulfilled, a test chemical is considered clearly negative if in all experimental conditions examined:
Mitotični indeks
None of the treatment groups exhibits a statistically significant increase in the frequency of cells with structural chromosomal aberrations (excluding gaps) compared with the concurrent negative control,
razmerje med številom celic v mitozi in skupnim številom celic v populaciji, ki je merilo statusa proliferacije navedene celične populacije.
There is no dose-related increase at any sampling time when evaluated by an appropriate trend test,
sprememba števila kromosomov, ki se razlikuje od normalnega števila, ki je značilno za uporabljene živali (anevploidija).
All results are inside the distribution of the historical negative control data (e.g. Poisson-based 95 % control limits), and
numerična kromosomska aberacija, ki vključuje spremembo števila celotnega seta kromosomov v primerjavi s spremembo števila v delu seta kromosomov (prim.: anevploidija).
Bone marrow exposure to the test chemical(s) occurred.
Strukturna kromosomska aberacija
Recommendations for the most appropriate statistical methods can be found in the literature (13).
sprememba v strukturi kromosoma, ki se lahko odkrije pri mikroskopskem pregledu metafaze celične delitve in je vidna v obliki delecij in fragmentov, transpozicij ali interkromosomskih translokacij.
Evidence of exposure of the bone marrow to a test chemical may include a depression of the mitotic index or measurement of the plasma or blood levels of the test chemical(s).
ZASNOVA PRESKUSA Z VEČ DEJAVNIKI ZA OPREDELITEV RAZLIK MED SPOLOMA PRI PRESKUSU KROMOSOMSKIH ABERACIJ IN VIVO
In the case of intravenous administration, evidence of exposure is not needed.
Zasnova preskusa z več dejavniki in analiza v njenem okviru
Alternatively, ADME data, obtained in an independent study using the same route and same species can be used to demonstrate bone marrow exposure.
Pri tej zasnovi se preskusi vsaj 5 živali moškega in vsaj 5 živali ženskega spola pri vsaki koncentraciji, tako da se uporabi vsaj 40 živali (20 moškega in 20 ženskega spola ter ustrezne pozitivne kontrole).
Negative results indicate that, under the test conditions, the test chemical does not induce structural chromosomal aberrations in the bone marrow of the species tested.
Ta zasnova, ki je ena enostavnejših zasnov preskusa z več dejavniki, je enakovredna dvosmerni analizi variance, pri čemer sta glavna učinka spol in koncentracija.
There is no requirement for verification of a clear positive or clear negative response.
Podatki se lahko analizirajo z različnimi standardnimi statističnimi programskimi paketi, kot so SPSS, SAS, STATA, Genstat, ter z uporabo programskega jezika R.
In cases where the response is not clearly negative or positive and in order to assist in establishing the biological relevance of a result (e.g. a weak or borderline increase), the data should be evaluated by expert judgement and/or further investigations of the existing experiments completed.
Z analizo se variabilnost v naboru podatkov popolnoma razvrsti v variabilnost med spoloma, variabilnost med koncentracijami in variabilnost, povezano z medsebojnim vplivom med spoloma in koncentracijami.
In some cases, analysing more cells or performing a repeat experiment using modified experimental conditions could be useful.
Vsak pogoj se preskusi glede na oceno variabilnosti med živalmi iz ponovljenih preskusov v skupinah živali istega spola pri isti koncentraciji.