T25: A Simplified Carcinogenic Potency Index: Description of the System and Study of Correlations between Carcinogenic Potency and Species/Site Specificity and Mutagenicity

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.

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“…The determination of T25 is described in more detail by Dybing et al (1997). Any similarities with real chemicals are fortuitous.…”

Section: Methodsmentioning

confidence: 99%

“…The dose descriptor T25 has been presented earlier (Dybing et al 1997). The use of the T25 has advantages in comparison to dose descriptors such as TD50 (Sawyer et al 1984) and LED 10 (US Environmental Protection Agency 1996).…”

mentioning

confidence: 99%

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

Sanner

Dybing²,

Willems

et al. 2001

Pharmacology & Toxicology

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“…For substances where suitable in vivo genotoxic experiments had been identified, available animal experiments were reviewed in the IARC Monographs, and if suitable experiments for quantitative carcinogen hazard characterisation from mouse or rat experiments were available, the lowest T25 dose descriptor (the chronic daily dose in mg/kg b.wt./day which will give 25% of the animals tumours at a specific tissue site, after correction spontaneous incidence within the standard lifespan of that species), was calculated as previously described (Dybing et al 1997;EC. 1999).…”

Section: Methodsmentioning

confidence: 99%

“…In an attempt to develop a procedure that may be helpful in regulation of mutagenic substances when studies on carcinogenicity are unavailable, we have compared the lowest effective dose (LED) giving a response in an in vivo genotoxic test after oral or inhalation exposure with the carcinogenic dose descriptor T25 (Dybing et al 1997). 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.…”

mentioning

confidence: 99%

Comparison of Carcinogenic and in vivo Genotoxic Potency Estimates

Sanner

Dybing

2005

Basic Clin Pharma Tox

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Mutagenic substances classified as carcinogens are primarily regulated on the basis of their carcinogenic effect. Regulation of mutagens that have not been tested for carcinogenicity represents a problem. In cases where a threshold cannot be identified, the substances may be banned or if their uses are deemed to be unavoidable, the exposure may be reduced to as low as technically and economically feasible. In an attempt to develop a procedure that may be helpful in regulation of mutagenic substances when studies on carcinogenicity are lacking, we have compared the lowest effective dose (LED) giving a response in an in vivo genotoxic test after oral or inhalation exposure with the carcinogenic dose descriptor T25 (the chronic daily dose which will give 25% of the animals tumours above background at a specific tissue site). The 34 carcinogens in the present analysis for which genotoxic mechanisms are likely or possible, represent different classes of carcinogens and different genotoxic endpoints, exhibiting carcinogenic and mutagenic potencies both covering a range of 10,000 between the most and least potent substances. A linear correlation was found between the lowest effective dose for in vivo genotoxicity after oral administration or inhalation exposure and the lowest dose descriptor T25 for tumour formation. The finding that the median of the ratio LED/T25 was 1.05 and that the ratio for 90% of the substances studied fell in the range 0.21 to 9.2 shows that the numerical value of LED is similar to the numerical value of T25 within a factor of 5-10. The results suggest that LED may be used as a basis for regulation of mutagens in cases where a threshold cannot be demonstrated or inferred, and where the substance has not been studied in long-term carcinogenicity studies. In such cases LED divided by a specified assessment factor may represent a virtually safe level or a tolerable risk level for a possible carcinogenic effect.Genotoxic effects are assumed to play an important role in tumour induction of a number of chemicals. Since possible carcinogenic effects have been considered to be more critical than germ cell mutagenesis with regard to chemical mutagens, mutagenic substances classified as carcinogens are primarily regulated on the basis of their carcinogenic effect. 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. In cases where a threshold cannot be identified, the substances may be banned or if their uses are deem...

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“…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.…”

Section: Threshold Approaches In Hazard Characterisationmentioning

confidence: 99%