Threshold of Regulatory Concern

EPA (2000), Choosing a Percentile of Acute Dietary Exposure as a Threshold of Regulatory Concern, EPA Office of Pesticide Programs, Washington DC. 

In general, it is difficult to determine whether there is an effect on the mean QT/QTc interval that is so small as to be of no clinical consequence. However, drugs that prolong the mean QT/QTc interval by around 5 ms or less do not appear to cause TdP. On that basis, the threshold level of regulatory concern is 5 ms. 

Delaney, F.J. (2007) An impact analysis of the application of the threshold of toxicological concern concept to pharmaceuticals. Regulatory Toxicology and Pharmacology, 49, 107-124. 

On the basis of the results of these analyses, FDA concluded that the noncarcino-genic toxic effects caused by the majority of unstudied compounds would be unlikely to occur below dietary concentration of 1 mg/kg. To provide an adequate safety margin, however, the dietary concentration chosen as a level that presents no regulatory concern should be well below 1 mg/kg. Therefore, FDA established a dietary concentration of 0.5 pg/kg (0.5 ppb) as the threshold of regulation for substances used in food contact articles. A 0.5 pg/kg (0.5 ppb) threshold is 2000 times lower than the dietary concentration at which the vast majority of studied compounds are likely to cause noncarcinogenic toxic effects and 200 times lower than the chronic exposure level at which potent pesticides induce toxic effects. FDA believes that these safety margins,... 

Simulations using the concentration-effect model established for QTcF vs. losmapimod concentration at concentrations 4x the maximum concentration of the therapeutic dose did not exceed the regulatory thresholds of concern of 5 milliseconds for the mean (4.57 milliseconds) and 10 milliseconds for the upper bound of the 90% Cl (90%CI 2.88, 6.10). Modeling demonstrated that the discrepant results may have been due to a baseline shift after repeat dosing and basehne differences between the treatments. Considering the results of the concentration-effect modeling, previous losmapimod data, and the high false-positive rate associated with the ICH E14 statistical analysis, the statistical analysis was likely a false-positive. 

The issue that must be managed is the appropriate threshold to communicate the change and initiate appropriate approval processes. Tolls subject to regulatory requirements may use the regulatory guidance as the threshold for management of change processes other tolls must establish the threshold appropriate to process risks, quality systems, and business concerns. 

Step 9 Obtain action level (regulatory threshold) Ca for the contaminant of concern Ca Ca =... 

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