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In regulatory toxicology, it is assumed that genotoxic carcinogens, which induce cancer through genotoxic mechanisms, have no threshold for their action. However, humans possess a number of defense mechanisms against DNA damaging agents, which may reduce the genotoxic and cancer risk at low doses to the spontaneous levels. The defense mechanisms ma...
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... enzymes such as glutathione S-transferase mediate conjugation reac- tions, which enhance hydrophilicity of toxic chemicals and promote the excretion. DNA repairˆxesrepairˆxes damaged DNA by a multiple mechanisms such as removal of damaged or mismatched bases in DNA or rejoining broken DNA strands. TLS is a short DNA synthesis across DNA lesion (Fig. 1) (20). If error-free TLS oc- curs, the mechanism will contribute to tolerance against mutagenic and carcinogenic eŠects of chemicals. However, if error-prone TLS occurs, it will enhance mutation frequency and initiate ...
Citations
... The characteristics of the DNA adducts and of repair processes often also provide insights into the mechanism of cellular pathology. It is important to note that various types of DNA repair are error-prone, and so not only the potential fixation of a mutation via misreading the adducted base but also the potential for errors arising from removal of the adduct or by translesion synthesis may be determinants of the mutational risk [53]. Thus, adduct data can be used to quantify exposures, can contribute to elucidating the biological mechanism of mutagenic and clastogenic events, and/or can be used to quantitatively evaluate dose response relationships. ...
This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose-response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species. Recommendations include the selection of appropriate genetic endpoints and target tissues, uncertainty factors and extrapolation methods to be considered, the importance and use of information on mode of action, toxicokinetics, metabolism, and exposure biomarkers when using quantitative exposure-response data to determine acceptable exposure levels in human populations or to assess the risk associated with known or anticipated exposures. The empirical relationship between genetic damage (mutation and chromosomal aberration) and cancer in animal models was also examined. It was concluded that there is a general correlation between cancer induction and mutagenic and/or clastogenic damage for agents thought to act via a genotoxic mechanism, but that the correlation is limited due to an inadequate number of cases in which mutation and cancer can be compared at a sufficient number of doses in the same target tissues of the same species and strain exposed under directly comparable routes and experimental protocols.
Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
... Therefore, the marketing authorisation holder of Viracept, F. HoŠmann-La Roche, conducted a series of non-clinical investigations (2,6,7,9) to better quantify the risk for adverse eŠects in the exposed individuals. For direct acting, DNA-damaging genotoxins, such as EMS, it has been generally assumed that dose-response relations are linear-or at least non-thresholded-due to their stochastic, all-ornothing, mode of action (10). By default, the formation of tumours, heritable birth defects, and teratogenic eŠects are also accepted to follow a linear dose relation for these genotoxins. ...
The dose response relationships for induction of micronuclei in bone marrow and for induction of lacZ mutations in liver, large intestine, and bone marrow were assessed in mice after treatment with ethyl methanesulfonate (EMS). The animals were treated orally at doses between 1.25 to 260 mg/kg for up to 28 days. Statistical analysis indicated that the dose response curves were well compatible with a thresholded relationship with apparent thresholds ≥ 25 mg/kg/day. In contrast, no threshold was apparent for the induction of alkylation-adducts in proteins and DNA. An approximately linear dose dependency was observed, indicating that the macromolecular targets were alkylated proportionally to the given dose. It is concluded that the cells have the capacity to repair large amounts of EMS-induced alkylations, up to the threshold dose, virtually error free (i.e., without adding to the background burden of clastogenic/mutagenic events). Since the statistical power to define the 'true' shape of the dose response curve is much more limited for in vivo studies compared to in vitro experiments with e.g., a bacterial reverse mutation system we assessed the dose response relationship for EMS induced mutations at the his G46 locus in alkylation repair proficient (TA1535, ogt+) and deficient (YG7104, Δogt) bacteria using as many as 23 dose levels. Clear sublinearity was apparent for TA1535 while linearity was obvious for YG7104. Applying curve fitting with a 'hockeystick' model a threshold dose of about 750 μg/plate was determined for TA1535. With curve fitting using a benchmark model (PROAST) we estimated the efficiency of error-free repair by the ogt system at the different EMS exposures. The likelihood of erroneous repair approaches 0 with decreasing EMS concentrations. Together with recent studies on other alkylating agents our data argue for a change of paradigm concerning risk assessment of the exposure to simple DNA-alkylating genotoxins.
Background
Carcinogenic risk assessment studies have been repeatedly improved and are still being debated to find a goal. Evaluation might be changed if new approaches would be applied to some chemicals which means that new approaches may change the final assessment. In this paper, the risk assessment of a chemical, in particular the proper carcinogenicity, is examined using the long-banned food additive, 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide, AF-2, as a case study.
Results
First, Ames tests were carried out using strains TA1535, TA100, TA1538, and TA98 and their nitroreductase-deficient strains YG7127, YG7128, YG7129, and YG7130. The results showed that mutagenic activity was reduced by about 50% in the nitroreductase-deficient strains, indicating that part of the mutagenic activity shown in Ames test was due to bacterial metabolism. Second, in vivo genotoxicity tests were conducted, including the one that had not been developed in 1970’s. Both a micronucleus test and a gene mutation assay using transgenic mice were negative. Third, assuming it is a genotoxic carcinogen, the virtual safety dose of 550 μg/day was calculated from the TD 50 in rats with a probability of 10 ⁻⁵ .
Conclusion
AF-2 has been shown to be carcinogenic to rodents and has previously been indicated to be genotoxic in vitro. However, the present in vivo genotoxicity study, it was negative in the forestomach, a target organ for cancer, particularly in the gene mutation assay in transgenic mice. Considering the daily intake of AF-2 in the 1970s and its virtually safety dose, the carcinogenic risk of AF-2 could be considered acceptable.
Diaminotoluenes (DATs), including aromatic amines with
industrial importance, were commercially produced in the
United States since 1919 by nitration process of toluene into
the dinitrotoluene isomers, and consequent reduction of the
resultant mixtures to DATs (2,3-, 2,4-, 2,6-, and 3,4-DAT).Among them, 2,4-DAT was used as an ingredient of some
oxidative hair dyes until 1971. Toxicity of this substance was
established in rats as a hepatocarcinogen. Currently, 2,5-DAT is
used in commercial hair dyes, and it is one of the preferred
additives because it is less toxic. The compound 2,6-DAT (CAS
RN: 823-40-5) is reported to induce genotoxicity, while
2,4-DAT (CAS RN: 95-80-7) can cause both genotoxicity and
carcinogenicity in experimental animals. 2,4-DAT is reasonably
anticipated to be a human carcinogen based on sufficient
evidence of carcinogenicity from studies in experimental
animals. Additionally, fetal toxicity of 2,5-DAT was observed in
the pre-exposed pregnant mice.....
