natgillin/translations-raw huggingface dataset:
Animals killed at study termination should be fixed by perfusion.
Pregledati je treba, ali so v možganih dokazi za nevropatološke spremembe, povezane s tretiranjem, pri čemer je treba ustrezne vzorce odvzeti iz vseh pomembnih možganskih regij (npr. vohalni bulbus, možganska skorja, hipokamus, bazalni gangliji, talamus, hipotalamus, srednjimi možgani (tektum, tegmentum in možganski pedunkli), most, podaljšana hrbtenjača in mali možgani), da se zagotovi natančen pregled.
All aspects of the preparation of tissue samples, from the perfusion of animals, through the dissection of tissue samples, tissue processing, and staining of slides should employ a counterbalanced design such that each batch contains representative samples from each dose group.
Pomembno je, da so vse rezine odvzete iz iste ravnine.
Additional guidance on neuropathology can be found in OECD Guidance Document No 20(9), see also (103).
Pri odraslih živalih, ki so bile humano usmrčene ob koncu študije, je treba odvzeti reprezentativne rezine hrbtenjače in perifernega živčnega sistema.
Processing of tissue samples
Območja, ki se pregledujejo, morajo vključevati oko z vidnim živcem in mrežnico, hrbtenjačo ob vratnem in ledvenem delu, dorzalna in ventralna vlakna, proksimalni bedrni živec, proksimalni golenični živec (pri kolenu) in veje goleničnega živca v mečni mišici.
All gross abnormalities apparent at the time of necropsy should be noted.
Rezine hrbtenjače in perifernih živcev morajo vključevati prečne ali diagonalne in vzdolžne rezine.
Tissue samples taken should represent all major regions of the nervous system.
V okviru nevropatološkega vrednotenja je treba poleg celičnih sprememb (npr. vakuolacija, degeneracija in nekroza nevronov) in sprememb tkiva (npr. glioza, infiltracija levkocitov in tvorjenje cist) poiskati morebitne znake razvojnih poškodb živčnega sistema (6) (85) (86) (87) (88) (89).
The tissue samples should be retained in an appropriate fixative and processed according to standardised published histological protocols (69)(70)(71)(103).
V zvezi s tem je pomembno, da se učinki, povezani s tretiranjem, ločijo od običajnih razvojnih dogodkov, za katere je znano, da se pojavijo v razvojni fazi, ki ustreza času usmrtitve (90).
Paraffin embedding is acceptable for tissues of the CNS and PNS, but the use of osmium in post-fixation, together with epoxy embedding, may be appropriate when a higher degree of resolution is required (e.g. for peripheral nerves when a peripheral neuropathy is suspected and/or for morphometric analysis of peripheral nerves).
Primeri pomembnih sprememb, ki kažejo na razvojne poškodbe, med drugim vključujejo:
The purposes of the qualitative examination are:
spremembe v množitvi, migraciji in diferenciaciji, kot kažejo območja čezmerne apoptoze ali nekroze, skupin ali razpršenih populacij ektopičnih, dezorientiranih ali deformiranih nevronov, ali spremembe relativne velikosti različnih plasti kortikalnih struktur,
to identify regions within the nervous system exhibiting evidence of neuropathological alterations;
spremembe vzorcev mielinizacije, vključno s splošnim zmanjšanjem mieliniziranih struktur ali njihovim spremenjenim barvanjem,
to identify types of neuropathological alterations resulting from exposure to the test chemical;
dokaz za hidrocefalus, zlasti povečanje prekatov, stenozo možganskega akvedukta in tanjšanje možganskih polobel.
and
Analiza odvisnosti med odmerkom in odzivom pri nevropatoloških spremembah
to determine the range of severity of the neuropathological alterations.
Za kvalitativno in kvantitativno nevropatološko analizo se priporoča naslednji postopek s posameznimi koraki.
Representative histological sections from the tissue samples should be examined microscopically by an appropriately trained pathologist for evidence of neuropathological alterations.
Najprej se rezine iz skupine z velikim odmerkom primerjajo z rezinami iz kontrolne skupine.
All neuropathologic alterations should be assigned a subjective grade indicating severity.
Če pri živalih iz skupine z velikim odmerkom ni dokazov o nevropatoloških spremembah, nadaljnja analiza ni potrebna.
A hematoxylin and eosin stain may be sufficient for evaluating brain sections from animals humanely killed at PND 22, or earlier.
Če v skupini z velikim odmerkom obstajajo dokazi o nevropatoloških spremembah, se pregledajo živali iz skupin s srednjim in nizkim odmerkom.
However, a myelin stain (e.g. luxol fast blue/cresyl violet) and a silver stain (e.g. Bielschowsky's or Bodians stains) are recommended for sections of CNS and PNS tissues from animals killed at study termination.
Če se skupina z velikim odmerkom konča zaradi smrti ali druge zavajajoče strupenosti, se za analizo nevropatoloških sprememb uporabijo skupine z velikim in srednjim odmerkom.
Subject to the professional judgement of the pathologist and the kind of alterations observed, other stains may be considered appropriate to identify and characterise particular types of alterations (e.g. glial fibrillary acidic protein (GFAP) or lectin histochemistry to assess glial and microglial alterations (72), fluoro-jade to detect necrosis (73)(74), or silver stains specific for neural degeneration (75)).
Če obstajajo znaki nevrotoksičnosti v skupinah z manjšim odmerkom, je treba v teh skupinah opraviti nevropatološko analizo.
Morphometric (quantitative) evaluation should be performed as these data may assist in the detection of a treatment-related effect and are valuable in the interpretation of treatment-related differences in brain weight or morphology (76)(77).
Če se pri kvalitativnem ali kvantitativnem pregledu ugotovijo nevropatološke spremembe, povezane s tretiranjem, je treba na podlagi vrednotenja vseh živali iz skupin z vsemi odmerki določiti odvisnost pojavnosti od odmerka, pogostost in stopnjo resnosti poškodb ali morfometričnih sprememb.
Nervous tissue should be sampled and prepared to enable morphometric evaluation.
V to vrednotenje je treba vključiti vse regije možganov, v katerih so vidni dokazi nevropatoloških sprememb.
Morphometric evaluations may include e.g. linear or areal measurements of specific brain regions (78).
Za vsako vrsto poškodbe je treba opisati značilnosti, ki so uporabljene za opredelitev posamezne stopnje resnosti in kažejo lastnosti, na podlagi katerih se stopnje razlikujejo med sabo.
Linear or areal measurements require the use of homologous sections carefully selected based on reliable microscopic landmarks (6).
Zabeležiti je treba pogostost posamezne vrste poškodb in njihovo stopnjo resnosti ter opraviti statistično analizo, da se ovrednoti vrsta odvisnosti med odmerkom in odzivom.
Stereology may be used to identify treatment-related effects on parameters such as volume or cell number for specific neuroanatomic regions (79)(80)(81)(82)(83)(84).
Priporočena je uporaba kodiranih mikroskopskih preparatov (91).
The brains should be examined for any evidence of treatment-related neuropathological alterations and adequate samples should be taken from all major brain regions (e.g. olfactory bulbs, cerebral cortex, hippocampus, basal ganglia, thalamus, hypothalamus, midbrain (tectum, tegmentum, and cerebral peduncles), pons, medulla oblongata, cerebellum) to ensure a thorough examination.
PODATKI IN POROČANJE
It is important that sections for all animals are taken in the same plane.
Podatki
In adults humanely killed at study termination, representative sections of the spinal cord and the PNS should be sampled.
Podatke je treba sporočati ločeno in jih povzeti v obliki tabele, kjer so za vsako preskusno skupino prikazane vrste sprememb ter število mater in potomcev po spolu in zarodu, ki prikazuje posamezno vrsto spremembe.
The areas examined should include the eye with optic nerve and retina, the spinal cord at the cervical and lumbar swellings, the dorsal and ventral root fibres, the proximal sciatic nerve, the proximal tibial nerve (at the knee), and the tibial nerve calf muscle branches.
Če je bila izvedena neposredna izpostavljenost potomca po rojstvu, je treba sporočiti način, trajanje in obdobje izpostavljenosti.
The spinal cord and peripheral nerve sections should include both cross or transverse and longitudinal sections.
Vrednotenje in razlaga rezultatov
Neuropathological evaluation should include an examination for indications of developmental damage to the nervous system (6)(85)(86)(87)(88)(89), in addition to the cellular alterations (e.g. neuronal vacuolation, degeneration, necrosis) and tissue changes (e.g. gliosis, leukocytic infiltration, cystic formation).
Študija razvojne nevrtoksičnosti bo zagotovila informacije o učinkih ponavljajoče se izpostavljenosti kemikaliji in utero in v zgodnjem razvoju po rojstvu.
In this regard, it is important that treatment-related effects be distinguished from normal developmental events known to occur at a developmental stage corresponding to the time of sacrifice (90).
Ker je poudarek tako na splošni strupenosti kot na razvojni nevrotoksičnosti končnih točk, rezultati študije omogočajo razlikovanje med učinki na razvoj živčevja, ki se pojavijo v odsotnosti splošne strupenosti pri materi, in učinki, ki so izraženi samo na stopnjah, ki so strupene tudi za mater.
Examples of significant alterations indicative of developmental insult include, but are not restricted to:
Zaradi zapletenih medsebojnih odvisnosti med zasnovo študije, statistično analizo in biološko pomembnostjo podatkov bo ustrezna interpretacija podatkov o razvojni nevrotoksičnosti vključevala strokovno presojo (107) (109).
alterations in the gross size or shape of the olfactory bulbs, cerebrum or cerebellum;
Razlaga rezultatov preskusa mora temeljiti na pristopu tehtnosti dokazov (20) (92) (93) (94).
alterations in the relative size of various brain regions, including decreases or increases in the size of regions resulting from the loss or persistence of normally transient populations of cells or axonal projections (e.g. external germinal layer of cerebellum, corpus callosum);
Potrebna je razprava o vzorcih vedenjskih ali morfoloških ugotovitev, če so prisotni, in dokazih odziva na odmerek.
alterations in proliferation, migration, and differentiation, as indicated by areas of excessive apoptosis or necrosis, clusters or dispersed populations of ectopic, disoriented or malformed neurons or alterations in the relative size of various layers of cortical structures;
V to opredelitev je treba vključiti podatke iz vseh študij, ki zadevajo vrednotenje razvojne nevrotoksičnosti, vključno z epidemiološkimi študijami na ljudeh ali poročili o primerih in eksperimentalnimi študijami na živalih (npr. podatki o toksikonetiki, informacije o aktivnosti strukture in podatke iz drugih študij strupenosti).
alterations in patterns of myelination, including an overall size reduction or altered staining of myelinated structures;
To vključuje odvisnost med odmerki preskusne kemikalije in prisotnostjo ali odsotnostjo, pojavnostjo in obsegom katerega koli nevrotoksičnega učinka za posamezni spol (20) (95).
evidence of hydrocephalus, in particular enlargement of the ventricles, stenosis of the cerebral aqueduct and thinning of the cerebral hemispheres.
V vrednotenje podatkov je treba vključiti razpravo o biološki in statistični značilnosti.
Analysis of the dose-response relationship of neuropathological alterations
Statistične analize je treba obravnavati kot orodje, ki usmerja razlago podatkov, vendar je ne določa.
The following stepwise procedure is recommended for the qualitative and quantitative neuropathological analyses.
Odsotnost statistične značilnosti ne sme biti edini razlog za sklep o odsotnosti učinkov, povezanih s tretiranjem, tako kot statistična značilnost ne sme biti edina utemeljitev za sklepno ugotovitev o učinku, povezanem s tretiranjem.
First, sections from the high dose group are compared with those of the control group.
Da bi preprečili morebitne lažno negativne ugotovitve in neločljive težave pri ‚dokazovanju negativnega rezultata‘, je treba obravnavati razpoložljive pozitivne podatke in pretekle kontrolne podatke, zlasti če ni učinkov, povezanih s tretiranjem (102) (106).
If no evidence of neuropathological alterations is found in animals of the high dose group, no further analysis is required.
Verjetnost lažno pozitivnih rezultatov je treba obravnavati ob upoštevanju statističnega vrednotenja vseh podatkov (96).
If evidence of neuropathological alterations is found in the high dose group, then animals from the intermediate and low dose groups are examined.
Vrednotenje naj vključuje odnos med ugotovljenimi nevropatološkimi in vedenjskimi spremembami, če obstaja.
If the high dose group is terminated due to death or other confounding toxicity, the high and intermediate dose groups should be analysed for neuropathological alterations.
Vse rezultate je treba analizirati z uporabo statističnih modelov, ki ustrezajo zasnovi preskusa (108).
If there is any indication of neurotoxicity in lower dose groups, neuropathological analysis should be performed in those groups.
Izbiro parametrske ali neparametrske analize je treba utemeljiti z upoštevanjem dejavnikov, kot so vrsta podatkov (pretvorjeni ali ne) in njihova porazdelitev ter relativna zanesljivost izbrane statistične analize.
If any treatment-related neuropathological alterations are found in the qualitative or quantitative examination, the dose-dependence of the incidence, frequency and severity grade of the lesions or of the morphometric alterations should be determined, based on an evaluation of all animals from all dose groups.
Statistične analize morajo biti izbrane ob upoštevanju namena in zasnove študije, da se čim bolj zmanjšajo napake tipa I (lažno pozitivni rezultati) in tipa II (lažno negativni rezultati) (96) (97) (104) (105).
All regions of the brain that exhibit any evidence of neuropathologic alteration should be included in this evaluation.
Razvojne študije, v katerih se uporabljajo multiparne vrste in preskuša več mladičev na zarod, morajo v statistični model vključiti zarod, da se preprečijo povečane stopnje napak tipa I (98) (99) (100) (101).
For each type of lesion, the characteristics used to define each severity grade should be described, indicating the features used to differentiate each grade.
Statistična enota meritve mora biti zarod in ne mladič.
The frequency of each type of lesion and its severity grade should be recorded and a statistical analysis should be performed to evaluate the nature of a dose-response relationships.
Preskuse je treba zasnovati tako, da se živali iz istega zaroda ne obravnavajo kot neodvisna opazovanja.
The use of coded slides is recommended (91).
Vse končne točke, ki se vedno znova izmerijo pri istem subjektu, je treba analizirati z uporabo statističnih modelov, ki upoštevajo odvisnost navedenih meritev.
DATA AND REPORTING
Poročilo o preskusu
Data
Poročilo o preskusu mora vključevati naslednje podatke:
Data should be reported individually and summarised in tabular form, showing for each test group the types of change and the number of dams, offspring by sex, and litters displaying each type of change.
Preskusna kemikalija:
If direct postnatal exposure of the offspring has been performed, the route, duration and period of exposure should be reported.
agregatno stanje in, če je to ustrezno, fizikalno-kemijske lastnosti,
Evaluation and interpretation of results
identifikacijske podatke, vključno z virom,
A developmental neurotoxicity study will provide information on the effects of repeated exposure to a chemical during in utero and early postnatal development.
čistost pripravka ter znane in/ali pričakovane nečistote.
Since emphasis is placed on both general toxicity and developmental neurotoxicity endpoints, the results of the study will allow for the discrimination between neurodevelopmental effects occurring in the absence of general maternal toxicity, and those which are only expressed at levels that are also toxic to the maternal animal.
Nosilec (po potrebi):
Due to the complex interrelationships among study design, statistical analysis, and biological significance of the data, adequate interpretation of developmental neurotoxicity data will involve expert judgment (107)(109).
utemeljitev izbire nosilca, če to ni voda ali fiziološka raztopina.
The interpretation of test results should use a weight-of-evidence-approach (20)(92)(93)(94).
Preskusne živali:
Patterns of behavioural or morphological findings, if present, as well as evidence of dose-response should be discussed.
uporabljene vrste in seve ter utemeljitev, če to ni podgana,
Data from all studies relevant to the evaluation of developmental neurotoxicity, including human epidemiological studies or case reports, and experimental animal studies (e.g. toxicokinetic data, structure-activity information, data from other toxicity studies) should be included in this characterisation.
dobavitelja preskusnih živali,
This includes the relationship between the doses of the test chemical and the presence or absence, incidence, and extent of any neurotoxic effect for each sex (20)(95).
število, začetno starost in spol živali,
Evaluation of data should include a discussion of both the biological and statistical significance.
izvor, nastanitvene pogoje, hrano, vodo itd.,
Statistical analysis should be viewed as a tool that guides rather than determines the interpretation of data.
težo posamezne živali na začetku preskusa.
Lack of statistical significance should not be the sole rationale for concluding a lack of treatment related effect, just as statistical significance should not be the sole justification for concluding a treatment-related effect.
Preskusni pogoji:
To guard against possible false-negative findings and the inherent difficulties in “proving a negative,” available positive and historical control data should be discussed, especially when there are no treatment-related effects (102)(106).
utemeljitev izbire velikosti odmerka,
The probability of false positives should be discussed in light of the total statistical evaluation of the data (96).
utemeljitev načina in trajanja odmerjanja,
The evaluation should include the relationship, if any, between observed neuropathological and behavioural alterations.
specifikacije uporabljenih odmerkov, vključno s podatki o nosilcu, količini in fizični obliki danega materiala,
All results should be analysed using statistical models appropriate to the experimental design (108).
podrobne podatke o formulaciji preskusne kemikalije in pripravi hrane, doseženi koncentraciji, stabilnosti in homogenosti pripravka,
The choice of a parametric or a nonparametric analysis should be justified by considering factors such as the nature of the data (transformed or not) and their distribution, as well as the relative robustness of the statistical analysis selected.
metodo, uporabljeno za edinstveno identifikacijo mater in potomcev,
The purpose and design of the study should guide the choice of statistical analyses to minimise Type I (false positive) and Type II (false negative) errors (96)(97)(104)(105).
podroben opis postopkov randomizacije, uporabljenih za razdelitev mater v tretirane skupine, izbiro mladičev za izločitev in razdelitev mladičev v preskusne skupine,
Developmental studies using multiparous species where multiple pups per litter are tested should include the litter in the statistical model to guard against an inflated Type I error rates (98)(99)(100)(101).
podrobne podatke o dajanju preskusne kemikalije,
The statistical unit of measure should be the litter and not the pup.
če je primerno, pretvorbo koncentracije preskusne kemikalije, vnesene s hrano ali vodo ali vdihavanjem (ppm), v dejanski odmerek (mg/kg telesne teže/dan),
Experiments should be designed such that littermates are not treated as independent observations.
okoljske pogoje,
Any endpoint repeatedly measured in the same subject should be analysed using statistical models that account for the non-independence of those measures.
podrobne podatke o kakovosti hrane in vode (npr. voda iz pipe, destilirana voda),
Test report
datum začetka študije in datum konca študije.
The test report should include the following information:
Opazovanje in preskusni postopki:
Test chemical:
podroben opis postopkov, uporabljenih za standardizacijo opazovanj in postopkov ter operativne opredelitve za vrednotenje opazovanj,
physical nature and, where relevant, physiochemical properties;
seznam vseh uporabljenih preskusnih postopkov in utemeljitev njihove uporabe,
identification data, including source;
podrobnosti o uporabljenih vedenjskih/funkcionalnih, patoloških, nevrokemijskih in elektrofizioloških postopkih, vključno z informacijami in podrobnostmi o avtomatiziranih napravah,
purity of the preparation, and known and/or anticipated impurities.
postopke za umerjanje in zagotavljanje enakovrednosti naprav ter uravnoteženje tretiranih skupin v preskusnih postopkih,
Vehicle (if appropriate):
kratko utemeljitev, s katero se pojasnijo odločitve na podlagi strokovne presoje.
justification for choice of vehicle, if other than water or physiological saline solution.
Rezultati (posamezni rezultati in povzetek, vključno s srednjo vrednostjo in varianco, če je ustrezno):
Test animals:
število živali na začetku študije in število na koncu študije,
species and strain used, and a justification if other than the rat;
število živali in zarodov, uporabljenih za posamezno preskusno metodo,
supplier of test animals;
identifikacijsko številko posamezne živali in zarod, iz katerega prihaja,
number, age at start, and sex of animals;
velikost zaroda in povprečno težo pri rojstvu po spolu,
source, housing conditions, diet, water, etc.;
telesno težo in podatke o spremembi telesne teže, vključno s terminalno telesno težo matere in potomcev,
individual weights of animals at the start of the test.
podatke o porabi hrane in, če je ustrezno, podatke o porabi vode (npr. če se preskusna kemikalija daje prek vode),
Test conditions:
podatke o odzivu na strupenost po spolu in velikost odmerka, vključno z znaki strupenost ali smrtnosti, vključno s časom in vzrokom smrti, če je ustrezno,
rationale for dose level selection;
vrsto, resnost, trajanje, dan nastopa, čas dneva in nadaljnji potek podrobnih kliničnih opazovanj,
rationale for dosing route and time period;
vrednotenje posameznih razvojnih znakov (teža, spolna zrelost in vedenjska ontogenija) pri posamezni časovni točki opazovanja,
specifications of the doses administered, including details of the vehicle, volume and physical form of the material administered;
podroben opis vseh vedenjskih, funkcionalnih, nevropatoloških, nevrokemijskih in elektrofizioloških ugotovitev po spolu, vključno s povečanjem in zmanjšanjem iz kontrolnih skupin,
details of test chemical formulation/diet preparation, achieved concentration, stability and homogeneity of the preparation;
izsledke obdukcije,
method used for unique identification of dams and offspring;
teže možganov,
a detailed description of the randomisation procedure(s) used to assign dams to treatment groups, to select pups for culling, and to assign pups to test groups;
diagnoze, ki izhajajo iz nevroloških znakov in poškodb, vključno z naravno nastalimi boleznimi ali stanji,
details of the administration of the test chemical;
slike vzorčnih ugotovitev,
conversion from diet/drinking water or inhalation test chemical concentration (ppm) to the actual dose (mg/kg body weight/day), if applicable;
slike majhne povečave za oceno homologije rezin, uporabljenih za morfometrijo,
environmental conditions;
podatke o absorpciji in presnovi, vključno z dopolnilnimi podatki iz ločene študije toksikokinetike, če so na voljo,
details of food and water (e.g. tap, distilled) quality;
statistično obdelavo rezultatov, vključno s statističnimi modeli, uporabljenimi za analizo podatkov, in rezultate, ne glede na to, ali so bili značilni ali ne,
dates of study start and end.
seznam osebja, ki je sodelovalo pri študiji, vključno s strokovno usposobljenostjo.
Observations and test procedures:
Razprava o rezultatih:
a detailed description of the procedures used to standardise observations and procedures as well as operational definitions for scoring observations;
informacije o odzivu na odmerek po spolu in skupini,