Comparison of Carcinogenic and in vivo Genotoxic Potency Estimates

Abstract

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...

Risk Assessment Approaches for Carcinogenic Food Contaminants

“…This approach is based on information from the IARC Monographs on the evaluation of carcinogenic risks to humans (http://monographs.iarc.fr) which include descriptions of genotoxicity experiments together with the lowest effective dose (LED) giving such responses. Twenty-eight orally administered carcinogens evaluated by IARC were identified to have reported LED values from in vivo genotoxicity studies (Sanner and Dybing, 2005). When these 28 LED values were plotted versus their respective T25 values in a logarithmic plot, the linear regression showed a good correlation between the two sets of values (r 2 = 0.71).…”

“…Another approach identified in scientific literature for risk characterisation of non-threshold compounds which lack carcinogenicity studies is based on the correlation between in vivo genotoxic potency with carcinogenic potency (Sanner and Dybing, 2005). This approach has not been used by BCS.…”

Hazard assessment of nitrosamine and nitramine by-products of amine-based CCS: Alternative approaches

“…No increment in foci could be detected with the lower doses (0.001, 0.01, and 0.1 ppm (c. 0.142, 1.42 and 14.2 lg/kg bw/day, respectively)). Sanner and Dybing (2005) 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 T 25 . The authors used a variety of in vivo genotoxicity assays: micronucleus, sister chromatid exchange, DNA adducts, chromosomal aberrations and Comet.…”

Use of genetic toxicity data in GHS mutagenicity classification and labeling of substances

“…Frameworks have been proposed and used for the risk assessment of mutagens [Favor et al, 1993;EPA, 1986;Dearfield et al, 2002;Sanner and Dybing, 2005;EC, 2008;Soeteman-Hernandez et al, 2016]. In particular, a recent risk assessment by the Scientific Committee on Consumer Products [SCCP, 2005] for glyoxal used an approach presented by Sanner and Dybing [2005]. Glyoxal is an in vivo mutagen but is consistently negative for carcinogenicity in animal studies.…”