Threshold of concern

Munro, l.C., R.A. Ford, E. Kennepohl, and J.G. Sprenger. 1996. Correlation of structural class with no-observed-effect levels A proposal for estabhshing a threshold of concern. Food Chem. Toxicol. 34 829-867. 

Rulis, A.M. 1989. Establishing a threshold of concern. In Bonin, J.J. and Donald, E.S., eds. Risk Assessment in Setting National Priorities, Vol. 7., 271-278. New York Plenum Press. 

Aggregate exposure assessment is naturally more complex than the methods used for dietary risk assessment. In the simplest analysis a worst case can be established for each source and exposure route and then summed to give a total exposure. If this were below any threshold of concern such as the PTWI then no further action would be required. However, if the total worst case exposure was above a PTWI then it is unlikely to reflect the real situation since the probability that any individual would be exposed to each source by each route at the maximum level is very remote. 

Alternatively, a threshold of concern could be assumed for the risk of serious effects, such as cancer and hereditary disease or serious impairment of the intellectual ability (loss of more than 10 IQ points). One option might be that lifetime exposure entails a lifetime risk of 10 in one million of suffering such a serious effect. This is the level of cancer risk associated with the WHO guidelines for drinking water for the sake of comparison, it is about 400 times stricter than the risk for cancer and hereditary disease associated with radiation exposures at the dose limit for the public (ICRP 2008). 

Munro I.C., Ford R.A., Kennepohl E., Sprenger J.G., (1996), Correlation of a structural class with no-observed-effect levels a proposal for establishing a threshold of concern. Food and Chemical Toxicology 34, pp 829-867. 

Health concern levels are those exposure levels that are the threshold of concern for exposure for a few hours. Injury levels are much higher. 

Step A3. The estimated daily per capita intakes for the 13 flavouring agents in structural class I are below the threshold of concern (i.e. 1800 pg/ person per day for class I). The estimated daily per capita intakes for the 2 flavouring agents in structural class II are below the threshold of concern (540 pg/person per day for class II). According to the Procedure, the safety of these 15 flavouring agents raises no concern when they are used at their current estimated levels of intake. 

Step B3. The estimated daily per capita intakes of the 40 flavouring agents in this group in structural class I are below the threshold of concern (i.e. 1800 pg/person per day for class I). The estimated daily per capita... 

Even if a child is never exposed to a single large dose of lead, all of the tiny amounts a child is exposed to can add up to trouble. For instance, the average child living in a town near a smelter may have a blood-lead level of 8 micrograms per deciliter from exposure to emissions. A relatively small exposure to lead paint, therefore, will bring his or her blood lead level over the threshold of concern of 10 micrograms per deciliter. Likewise, a child who drinks lead-contaminated water will be much more likely to suffer toxic effects if exposed later to lead-contaminated soil or dust. 

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. 

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