Info

translocations, etc.

HPRT, hypoxanthine phosphoribosyl transferase; TK, thymidine kinase.

HPRT, hypoxanthine phosphoribosyl transferase; TK, thymidine kinase.

unscheduled DNA synthesis (UDS) in rat liver or gut is recommended by most regulatory authorities if there is a positive response in any in vitro assay and a negative response in an in vivo cytogenetics assay. Other test methods and end points are under consideration by regulatory authorities as indicators of genotoxic potential including the COMET assay for assessing DNA damage, and aneuploidy, the change in chromosome number resulting from damage to the cellular architecture (spindle) controlling chromosome replication.

The last two decades have seen extensive efforts to determine whether short-term tests are suitable for predicting carcinogenic potential. The early validation studies suggested good predictability, with correct identification of over 90% of carcinogens (high sensitivity) and over 90% of noncarcinogens (high specificity). In later evaluations, a much lower figure (60%) was obtained. However, when carcinogens known to react by nongenotoxic mechanisms (e.g., hormones or peroxisome proliferators) were excluded, the predictability was improved suggesting that short-term tests are suitable for detecting those carcinogens that act by a genotoxic mechanism.

Although many regulatory authorities have guidelines for carcinogenicity evaluation, which include short-term tests, they all still require animal studies as the ultimate test for carcinogenicity. However, the use made of short-term tests varies. In the US, the Food and Drugs Administration (FDA) recommends a battery of short-term tests for all 'additives' for which cumulative dietary intake is expected to exceed 1.5 mg per person per day in order to assist in the interpretation of animal feeding studies. Some expert bodies, such as The International Agency for Research in Cancer, use short-term tests as an adjunct to animal carcino-genicity studies in their evaluation process, giving added weighting in their assessment of likely human hazard to an animal carcinogen that is also positive in short-term tests.

However, until a consensus can be reached as to what a positive or negative result in an animal feeding study means in terms of whether the compound may or may not be a human carcinogen, the further development of better (faster/cheaper) short-term tests may be a futile exercise.

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