Tr-106 pdf

Equivocal Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing a marginal increase of neoplasms that may be chemically related. No Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing no chemical-related increases in malignant or benign neoplasms. Inadequate Study of Carcinogenic Activity is demonstrated by studies that because of major qualitative or quantitative limitations cannot be interpreted as valid for showing either the presence or absence of carcinogenic activity.

For studies showing multiple chemical-related neoplastic effects that if considered individually would be assigned to different levels of evidence categories, the following convention has been adopted to convey completely the study results.

In a study with clear evidence of carcinogenic activity at some tissue sites, other responses that alone might be deemed some evidence are indicated as "were also related" to chemical exposure.

In studies with clear or some evidence of carcinogenic activity, other responses that alone might be termed equivocal evidence are indicated as "may have been" related to chemical exposure. When a conclusion statement for a particular experiment is selected, consideration must be given to key factors that would extend the actual boundary of an individual category of evidence.

Such consideration should allow for incorporation of scientific experience and current understanding of long-term carcinogenesis studies in laboratory animals, especially for those evaluations that may be on the borderline between two adjacent levels.

These considerations should include:. Note on Accessibility : Persons with disabilities or using assistive technology may find some documents are not fully accessible. We will assist you in accessing the content of these files. NIEHS has helpful information on accessibility.

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If only one arrow is displayed, that column is sorted in the direction of the arrow. Only one column can be sorted at a time. The testing protocol contains more information. Detailed explanations of the micronucleus assay methods and cell scoring are also available. The erythrocyte micronucleus test examines the ability of substances to cause chromosome damage in developing red blood cells inside bone marrow.

A micronucleus literally, "little nucleus" is a biomarker of structural chromosome damage e. If a chromosome is broken or fails to migrate properly with other chromosomes during cell division, the broken piece or lost chromosome will form a small micro nucleus of its own in one of the two daughter cells produced. Detection of chromosomal damage is important because it has been linked to birth defects, infertility, and certain diseases, including cancer.

The micronucleus test is performed in rapidly dividing cell populations, and bone marrow is a site of rapid blood cell division. Both bone marrow and peripheral blood samples can be examined for the presence of micronuclei in red blood cells.

Animals are treated with a test substance once or daily over a period of time, and the frequency of micronucleated cells is determined 24—48 hours after the final treatment, depending on the source of the cells bone marrow or blood that are examined and the treatment regimen. If treated animals show significantly higher frequencies of micronucleated red blood cells than untreated animals, the test substance is considered capable of causing chromosomal damage. The test subjects are rodents rats or mice that are exposed to the test substance, usually by oral gavage or injection.

Typically, one to three daily treatments of the test substance are administered over a range of doses; the highest dose tested is near the maximum tolerated dose. Groups of negative and positive control animals are included for each test. Bone marrow samples are obtained from all animals 24 hours after the last treatment, and red blood cells are examined for the presence of micronuclei.

Micronucleus tests are performed on male and female rodents that are exposed to the test substance orally, dermally, or by inhalation in subchronic e. Samples may be examined using standard slide scoring procedures or automated flow cytometric approaches.

Since , NTP has routinely relied on flow cytometry to evaluate the frequency of micronucleated cells in peripheral blood. Peripheral blood micronucleus assays are typically integrated into all NTP toxicity studies, and they also lend themselves to serial monitoring of micronucleus frequencies over time, since blood samples can be obtained without the need to sacrifice the animals.

Blood or bone marrow samples from treated animals are compared to samples from untreated animals. With the slide-based approach for data acquisition, — cells were scored per animal. Using flow cytometric procedures to evaluate blood samples, 20, immature red blood cells and around one million mature red blood cells are examined per animal, resulting in a marked increase in the ability to detect small changes in the frequency of micronucleated red blood cells.

The data is analyzed using statistical methods to determine if there is a significant increase in the frequency of cells containing micronuclei. Both dose-related responses and the magnitude of response for each independent dose group are considered during the evaluation of the data. For a positive test, both a significant dose response trend and at least one significant dose group are required.

If only one of these measures is present, the test is determined to be questionable. The absence of either condition results in a negative test. The final conclusions for micronucleus tests are determined by considering the results of statistical analyses, reproducibility of any observed effects, and the magnitude of the effects.

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