Quantitative assessment of the dose–response of alkylating agents in DNA repair proficient and deficient ames tester strains

Tang, Leilei; Guérard, Melanie; Zeller, Andreas

doi:10.1002/em.21825

Cited by 14 publications

(8 citation statements)

References 43 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The BMD concept is now proposed by authority bodies 206 and used routinely, e.g. in development toxicity studies, 207,208 mutagenicity ring-studies 209 or toxicogenomics. 196 Different software is available.…”

Section: Behavioral Testsmentioning

confidence: 99%

Statistical evaluation of toxicological bioassays – a review

Hothorn

2014

Toxicol. Res.

View full text Add to dashboard Cite

The basic conclusions in almost all reports on new drug applications and in all publications in toxicology are based on statistical methods. However, serious contradictions exist in practice: designs with small samples sizes but use of asymptotic methods (i.e. constructed for larger sample sizes), statistically significant findings without biological relevance (and vice versa), proof of hazard vs. proof of safety, testing (e.g. no observed effect level) vs. estimation (e.g. benchmark dose), available statistical theory vs. related userfriendly software. In this review the biostatistical developments since about the year 2000 onwards are discussed, mainly structured for repeated-dose studies, mutagenicity, carcinogenicity, reproductive and ecotoxicological assays. A critical discussion is included on the unnecessarily conservative evaluation proposed in guidelines, the inadequate but almost always used proof of hazard approach, and the limitation of data-dependent decision-tree approaches.

show abstract

Section: Behavioral Testsmentioning

confidence: 99%

Statistical evaluation of toxicological bioassays – a review

Hothorn

2014

Toxicol. Res.

View full text Add to dashboard Cite

show abstract

“…Determination of the lower and upper limits of the BMD (BMDL and BMDU) can be used in comparisons of chemical-induced toxicity across multiple genotoxicity endpoints (14). Recently, these approaches have been used to analyse data generated in the gpt -delta transgenic mouse (18), the in vitro micronucleus test (19,20), and the Ames mutagenicity rest (21).…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of the relative mutagenicity of five chemical constituents of tobacco smoke in the mouse lymphoma assay

Guo

Heflich

Dial

et al. 2015

MUTAGE

View full text Add to dashboard Cite

Quantifying health-related biological effects, like genotoxicity, could provide a way of distinguishing between tobacco products. In order to develop tools for using genotoxicty data to quantitatively evaluate the risk of tobacco products, we tested five carcinogens found in cigarette smoke, 4-aminobiphenyl (4-ABP), benzo[a]pyrene (BaP), cadmium (in the form of CdCl2), 2-amino-3,4-dimethyl-3H-imidazo[4,5-f]quinoline (MeIQ) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the mouse lymphoma assay (MLA). The resulting mutagenicity dose responses were analyzed by various quantitative approaches and their strengths and weaknesses for distinguishing responses in the MLA were evaluated. L5178Y/Tk (+/-) 3.7.2C mouse lymphoma cells were treated with four to seven concentrations of each chemical for 4h. Only CdCl2 produced a positive response without metabolic activation (S9); all five chemicals produced dose-dependent increases in cytotoxicity and mutagenicity with S9. The lowest dose exceeding the global evaluation factor, the benchmark dose producing a 10%, 50%, 100% or 200% increase in the background frequency (BMD10, BMD50, BMD100 and BMD200), the no observed genotoxic effect level (NOGEL), the lowest observed genotoxic effect level (LOGEL) and the mutagenic potency expressed as a mutant frequency per micromole of chemical, were calculated for all the positive responses. All the quantitative metrics had similar rank orders for the agents' ability to induce mutation, from the most to least potent as CdCl2(-S9) > BaP(+S9) > CdCl2(+S9) > MeIQ(+S9) > 4-ABP(+S9) > NNK(+S9). However, the metric values for the different chemical responses (i.e. the ratio of the greatest value to the least value) for the different chemicals ranged from 16-fold (BMD10) to 572-fold (mutagenic potency). These results suggest that data from the MLA are capable of discriminating the mutagenicity of various constituents of cigarette smoke, and that quantitative analyses are available that can be useful in distinguishing between the exposure responses.

show abstract

“…This was unsurprising, as p53 deficiency has previously been associated with reduced growth arrest and DNA repair, and therefore a higher incidence of micronuclei (Brü sehafer et al, 2014;Driessens et al, 2003;Masunaga et al, 2002). Indeed, studies with DNA repair-proficient and -deficient Ames strains emphasized the importance of efficient DNA repair in genotoxic tolerance (Tang et al, 2014). Interestingly, protein levels of p53 and phospho ser15 -p53 in p53-competent cell line TK6 remained unchanged during the chronic 5 þ 2 day study.…”

Section: Discussionmentioning

confidence: 97%

Acute Dosing and p53-Deficiency Promote Cellular Sensitivity to DNA Methylating Agents

Chapman

Doak

Jenkins

2015

Toxicological Sciences

View full text Add to dashboard Cite

Risk assessment of human exposure to chemicals is crucial for understanding whether such agents can cause cancer. The current emphasis on avoidance of animal testing has placed greater importance on in vitro tests for the identification of genotoxicants. Selection of an appropriate in vitro dosing regime is imperative in determining the genotoxic effects of test chemicals. Here, the issue of dosing approaches was addressed by comparing acute and chronic dosing, uniquely using low-dose experiments. Acute 24 h exposures were compared with equivalent dosing every 24 h over 5-day, fractionated treatment periods. The in vitro micronucleus assay was used to measure clastogenicity induced by methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU) in human lymphoblastoid cell line, TK6. Quantitative real-time (qRT) PCR was used to measure mRNA level induction of DNA repair enzymes. Lowest observed genotoxic effect levels (LOGELs) for MMS were obtained at 0.7 µg/ml for the acute study and 1.0 µg/ml for the chronic study. For acute MNU dosing, a LOGEL was observed at 0.46 µg/ml, yet genotoxicity was completely removed following the chronic study. Interestingly, acute MNU dosing demonstrated a statistically significant decrease at 0.009 µg/ml. Levels of selected DNA repair enzymes did not change significantly following doses tested. However, p53 deficiency (using the TK6-isogenic cell line, NH32) increased sensitivity to MMS during chronic dosing, causing this LOGEL to equate to the acute treatment LOGEL. In the context of the present data for 2 alkylating agents, chronic dosing could be a valuable in vitro supplement to acute dosing and could contribute to reduction of unnecessary in vivo follow-up tests.

show abstract

Quantitative assessment of the dose–response of alkylating agents in DNA repair proficient and deficient ames tester strains

Cited by 14 publications

References 43 publications

Statistical evaluation of toxicological bioassays – a review

Statistical evaluation of toxicological bioassays – a review

Quantitative analysis of the relative mutagenicity of five chemical constituents of tobacco smoke in the mouse lymphoma assay

Acute Dosing and p53-Deficiency Promote Cellular Sensitivity to DNA Methylating Agents

Contact Info

Product

Resources

About