A Simple Method for Quantitative Risk Assessment of Non‐Threshold Carcinogens Based on the Dose Descriptor T25

Abstract

This report provides guidance for using the dose-descriptor T25 from animal studies as a basis for quantitative risk characterisation of non-threshold carcinogens. T25 is presently used within the European Union for setting specific concentration limits for carcinogens in relation to labelling of preparations (formulations). The T25 is defined as the chronic dose rate which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard life-time of that species. The T25 is converted to the corresponding human dose descriptor, HT25, by dividing it with the appropriate scaling factor for interspecies dose scaling based on comparative metabolic rates. Subsequently, the human dose (expressed in mg per kg body-weight per day) is calculated from the available exposure data. The corresponding human life-time cancer risk is then obtained by using linear extrapolation by dividing the exposure dose with the coefficient (HT25/0.25). The results with this new method, which can easily be calculated without computer programmes, are in excellent agreement with results from computer-based extrapolation methods such as the linearised multistage model and the benchmark method using LED 10 , even though the present method only takes into consideration one single dose-response point. To overcome possible shortcomings of the present method, the estimated life-time risks are proposed to be accompanied by a commentary statement giving an overall evaluation of data that may have bearing on the carcinogenic risk and that may indicate whether the real human risk is likely to be higher or lower than the calculated life-time risk. By using the present guidance and a harmonized set of criteria and default values, the calculation of life-time cancer risk should be transparent and easy to comprehend.

Comparison of Carcinogenic and in vivo Genotoxic Potency Estimates

“…Previously, it has been observed that the dose descriptor T25 gives very similar results as the dose descriptor TD50. Moreover, hazard characterization based on T25 gives results that are in good agreement with results based on the linearised multistage model and the benchmark method using LED 10 (Sanner et al 2001). Recently, a good agreement has been observed between hazard characterization based on animal studies using the T25 method and epidemiological studies (Sanner & Dybing 2005).…”

“…The T25 method is used within EU in setting specific concentration limits for carcinogens in preparations (EC 1999) and this method for quantitative hazard assessment of non-threshold carcinogens (Sanner et al 2001) is presently used in several regulatory areas within EU (e.g. SCCNFP 2003).…”

“…Several methods for quantitative hazard and risk characterisation (e.g. the linearised multistage (LMS) model (US EPA 1986), the LED10 method (US EPA 1996), and the T25 method (Sanner et al 2001) have been used in the regulation of carcinogens.Regulation of mutagens that have not been tested for carcinogenicity, represents a problem. In cases where the genotoxic effect is presumed to exhibit a dose threshold, and the description of the threshold is considered to be robust both from a mode of action point of view and from the available experimental results, a margin of safety approach may be recognised as appropriate for regulation.…”

“…Several methods for quantitative hazard and risk characterisation (e.g. the linearised multistage (LMS) model (US EPA 1986), the LED10 method (US EPA 1996), and the T25 method (Sanner et al 2001) have been used in the regulation of carcinogens.…”

Risk characterisation of chemicals in food and diet

“…a certain percentage tumour incidence) within but towards the lower end of the doseresponse curve, that is derived by fitting a mathematical model to the data (Lovell and Thomas, 1996;Dybing et al, 1997;Sanner et al, 2001;Van Landingham et al, 2001). The fixed response can be used directly to produce advice that allows comparisons to be made between different compounds producing the same response in the same species and strain of animals.…”