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2. Error-corrected next generation sequencing – Promises and challenges for genotoxicity and cancer risk assessment

Author

Marchetti, Francesco, Cardoso, Renato, Chen, Connie L., Douglas, George R., Elloway, Joanne, Escobar, Patricia A., Harper, Tod, Jr, Heflich, Robert H., Kidd, Darren, Lynch, Anthony M., Myers, Meagan B., Parsons, Barbara L., Salk, Jesse J., Settivari, Raja S., Smith-Roe, Stephanie L., Witt, Kristine L., Yauk, Carole L., Young, Robert, Zhang, Shaofei, and Minocherhomji, Sheroy

Published
2023
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3. Error-corrected next-generation sequencing to advance nonclinical genotoxicity and carcinogenicity testing

Author

Marchetti, Francesco, Cardoso, Renato, Chen, Connie L., Douglas, George R., Elloway, Joanne, Escobar, Patricia A., Harper Jr, Tod, Heflich, Robert H., Kidd, Darren, Lynch, Anthony M., Myers, Meagan B., Parsons, Barbara L., Salk, Jesse J., Settivari, Raja S., Smith-Roe, Stephanie L., Witt, Kristine L., Yauk, Carole, Young, Robert R., Zhang, Shaofei, and Minocherhomji, Sheroy

Published
2023
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4. Improving the Assessment of Risk Factors Relevant to Potential Carcinogenicity of Gene Therapies: A Consensus Article.

Author

Klapwijk, Jan C., Del Rio Espinola, Alberto, Libertini, Silvana, Collin, Philippe, Fellows, Mick D., Jobling, Susan, Lynch, Anthony M., Martus, HansJoerg, Vickers, Catherine, Zeller, Andreas, Biasco, Luca, Brugman, Martijn H., Bushmann, Frederic D., Cathomen, Toni, Ertl, Hildegrund C.J., Gabriel, Richard, Gao, Guangping, Jadlowsky, Julie K., Kimber, Ian, and Lanz, Thomas A.

Published
2024
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5. N-Nitrosodimethylamine investigations in Muta™Mouse define point-of-departure values and demonstrate less-than-additive somatic mutant frequency accumulations

Author

Lynch, Anthony M, primary, Howe, Jonathan, additional, Hildebrand, Deon, additional, Harvey, James S, additional, Burman, Mark, additional, Harte, Danielle S G, additional, Chen, Liangfu, additional, Kmett, Casey, additional, Shi, Wei, additional, McHugh, Charles F, additional, Patel, Kinnari K, additional, Junnotula, Venkat, additional, Kenny, Julia, additional, Haworth, Richard, additional, and Wills, John W, additional

Published
2024
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6. Inter-laboratory automation of the in vitro micronucleus assay using imaging flow cytometry and deep learning

Author

Wills, John W., Verma, Jatin R., Rees, Benjamin J., Harte, Danielle S. G., Haxhiraj, Qiellor, Barnes, Claire M., Barnes, Rachel, Rodrigues, Matthew A., Doan, Minh, Filby, Andrew, Hewitt, Rachel E., Thornton, Catherine A., Cronin, James G., Kenny, Julia D., Buckley, Ruby, Lynch, Anthony M., Carpenter, Anne E., Summers, Huw D., Johnson, George E., and Rees, Paul

Published
2021
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7. Ames test study designs for nitrosamine mutagenicity testing: qualitative and quantitative analysis of key assay parameters.

Author

Thomas, Dean N, Wills, John W, Tracey, Helen, Baldwin, Sandy J, Burman, Mark, Williams, Abbie N, Harte, Danielle S G, Buckley, Ruby A, and Lynch, Anthony M

Subjects
AMES test, MUTAGENICITY testing, NITROSOAMINES, TEST design, QUANTITATIVE research, SALMONELLA typhimurium
Abstract

The robust control of genotoxic N -nitrosamine (NA) impurities is an important safety consideration for the pharmaceutical industry, especially considering recent drug product withdrawals. NAs belong to the 'cohort of concern' list of genotoxic impurities (ICH M7) because of the mutagenic and carcinogenic potency of this chemical class. In addition, regulatory concerns exist regarding the capacity of the Ames test to predict the carcinogenic potential of NAs because of historically discordant results. The reasons postulated to explain these discordant data generally point to aspects of Ames test study design. These include vehicle solvent choice, liver S9 species, bacterial strain, compound concentration, and use of pre-incubation versus plate incorporation methods. Many of these concerns have their roots in historical data generated prior to the harmonization of Ames test guidelines. Therefore, we investigated various Ames test assay parameters and used qualitative analysis and quantitative benchmark dose modelling to identify which combinations provided the most sensitive conditions in terms of mutagenic potency. Two alkyl-nitrosamines, N -nitrosodimethylamine (NDMA) and N -nitrosodiethylamine (NDEA) were studied. NDMA and NDEA mutagenicity was readily detected in the Ames test and key assay parameters were identified that contributed to assay sensitivity rankings. The pre-incubation method (30-min incubation), appropriate vehicle (water or methanol), and hamster-induced liver S9, alongside Salmonella typhimurium strains TA100 and TA1535 and Escherichia coli strain WP2uvrA(pKM101) provide the most sensitive combination of assay parameters in terms of NDMA and NDEA mutagenic potency in the Ames test. Using these parameters and further quantitative benchmark dose modelling, we show that N -nitrosomethylethylamine (NMEA) is positive in Ames test and therefore should no longer be considered a historically discordant NA. The results presented herein define a sensitive Ames test design that can be deployed for the assessment of NAs to support robust impurity qualifications. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Next Generation Sequencing Workshop at the Royal Society of Medicine (London, May 2022): how genomics is on the path to modernizing genetic toxicology

Author

Lynch, Anthony M, primary, Zanoni, Thalita B, additional, Salk, Jesse J, additional, Martincorena, Inigo, additional, Young, Robert R, additional, Kucab, Jill, additional, Valentine, Charles C, additional, Yauk, Carole, additional, Escobar, Patricia A, additional, Witt, Kristine L, additional, Frötschl, Roland, additional, Reed, Simon H, additional, and Ashford, Anne, additional

Published
2023
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14. Workshop summary: Top concentration for in vitro mammalian cell genotoxicity assays; and report from working group on toxicity measures and top concentration for in vitro cytogenetics assays (chromosome aberrations and micronucleus)

Author

Galloway, Sheila, Lorge, Elisabeth, Aardema, Marilyn J., Eastmond, David, Fellows, Mick, Heflich, Robert, Kirkland, David, Levy, Dan D., Lynch, Anthony M., Marzin, Daniel, Morita, Takeshi, Schuler, Maik, and Speit, Günter

Published
2011
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15. APSS Yearbook 1974-75. A Compilation of Current Educational Practices.

Author

Associated Public School Systems, New York, NY. and Lynch, Anthony M.

Abstract

This yearbook is a compilation of educational practices recently implemented by member schools of the Associated Public School Systems. The practices included are organized into sections concerning communication, curriculum, staff, organization, and special-client programs. Forty-three programs describing a wide range of educational activities are included. The sections on organization and curriculum contain the most entries. (DW)

Published
1974

16. Responsibility for Educational Tasks: Role Perceptions in West Virginia.

Author

West Virginia State Dept. of Education, Charleston. and Lynch, Anthony M.

Abstract

Schools are influenced by the attitudes and behaviors of a wide variety of people within the home and community as well as the school itself, and an important aspect of efficient and productive school management is the need for key publics to agree as to whom is responsible for which tasks. The first step, however, must be to identify how key publics feel about the importance of basic types of tasks conducted in a school system and, further, to clarify the extent to which those same publics agree as to whom should have responsibility for each task. Sixteen educational tasks were chosen for inclusion in a questionnaire, which was sent to a sample population that included high school principals, 11th grade students, parents of 11th grade students, members of county boards of education, county superintendents, high school teachers, and State Department of Education personnel. Analysis of the survey showed the tasks are considered important by all of the publics, and that for each task there are unique patterns of expectations regarding task responsibility. The role that a given public expects itself to play is not necessarily the same as the role that other publics expect of it. These conflicts in role expectations may signal possible confusion and misunderstanding in accomplishing educational tasks. (DS)

Published
1978

20. Inter-laboratory automation of thein vitromicronucleus assay using imaging flow cytometry and deep learning

Author

Wills, John W., primary, Verma, Jatin R., additional, Rees, Benjamin J., additional, Harte, Danielle S. G., additional, Haxhiraj, Qiellor, additional, Barnes, Claire M., additional, Barnes, Rachel, additional, Rodrigues, Matthew A., additional, Doan, Minh, additional, Filby, Andrew, additional, Hewitt, Rachel E., additional, Thornton, Catherine A., additional, Cronin, James G., additional, Kenny, Julia D., additional, Buckley, Ruby, additional, Lynch, Anthony M., additional, Carpenter, Anne E., additional, Summers, Huw D., additional, Johnson, George, additional, and Rees, Paul, additional

Published
2021
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27. The 3T3 neutral red uptake phototoxicity test: Practical experience and implications for phototoxicity testing – The report of an ECVAM–EFPIA workshop

Author

Ceridono, Mara, Tellner, Pär, Bauer, Daniel, Barroso, João, Alépée, Nathalie, Corvi, Raffaella, De Smedt, Ann, Fellows, Mick D., Gibbs, Neil K., Heisler, Eckhard, Jacobs, Abigail, Jirova, Dagmar, Jones, David, Kandárová, Helena, Kasper, Peter, Akunda, Jacqueline Kinyamu, Krul, Cyrille, Learn, Douglas, Liebsch, Manfred, Lynch, Anthony M., Muster, Wolfgang, Nakamura, Kazuichi, Nash, Frank J., Pfannenbecker, Uwe, Phillips, Gareth, Robles, Catherine, Rogiers, Vera, Van De Water, Femke, Liminga, Ulla Wändel, Vohr, Hans-Werner, Wattrelos, Olivier, Woods, Julie, Zuang, Valérie, Kreysa, Joachim, and Wilcox, Phil

Published
2012
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29. International Pig-a gene mutation assay trial: Evaluation of transferability across 14 laboratories

Author

Dertinger, Stephen D., Phonethepswath, Souk, Weller, Pamela, Nicolette, John, Murray, Joel, Sonders, Paul, Vohr, Hans-Werner, Shi, Jing, Krsmanovic, Ljubica, Gleason, Carol, Custer, Laura, Henwood, Andrew, Sweder, Kevin, Stankowski, Leon F., Jr., Roberts, Daniel J., Giddings, Amanda, Kenny, Julia, Lynch, Anthony M., Defrain, Céline, Nesslany, Fabrice, van der Leede, Bas-jan M., Van Doninck, Terry, Schuermans, Ann, Tanaka, Kentaro, Hiwata, Yoshie, Tajima, Osamu, Wilde, Eleanor, Elhajouji, Azeddine, Gunther, William C., Thiffeault, Catherine J., Shutsky, Thomas J., Fiedler, Ronald D., Kimoto, Takafumi, Bhalli, Javed A., Heflich, Robert H., and MacGregor, James T.

Published
2011
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31. New and emerging technologies for genetic toxicity testing

Author

Lynch, Anthony M., Sasaki, Jennifer C., Elespuru, Rosalie, Jacobson-Kram, David, Thybaud, Véronique, De Boeck, Marlies, Aardema, Marilyn J., Aubrecht, Jiri, Benz, Daniel R., Dertinger, Stephen D., Douglas, George R., White, Paul A., Escobar, Patricia A., Fornace, Albert, Honma, Masamitsu, Naven, Russell T., Rusling, James F., Schiestl, Robert H., Walmsley, Richard M., Yamamura, Eiji, van Benthem, Jan, and Kim, James H.

Published
2011
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33. Targets and mechanisms of chemically induced aneuploidy. Part 1 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases

Author

Lynch, Anthony M., primary, Eastmond, David, additional, Elhajouji, Azeddine, additional, Froetschl, Roland, additional, Kirsch-Volders, Micheline, additional, Marchetti, Francesco, additional, Masumura, Kenichi, additional, Pacchierotti, Francesca, additional, Schuler, Maik, additional, and Tweats, David, additional

Published
2019
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34. Role of aneuploidy in the carcinogenic process: Part 3 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases

Author

Tweats, David, primary, Eastmond, David A., additional, Lynch, Anthony M., additional, Elhajouji, Azeddine, additional, Froetschl, Roland, additional, Kirsch-Volders, Micheline, additional, Marchetti, Francesco, additional, Masumura, Kenichi, additional, Pacchierotti, Francesca, additional, and Schuler, Maik, additional

Published
2019
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45. The 3T3 neutral red uptake phototoxicity test: Practical experience and implications for pototoxicity testing

Author

Ceridono, Mara, Tellner, Pär, Bauer, Daniel, Barroso, Joao, Alépée, Nathalie, Corvi, Raffaella, Fellows, Mick D., Gibbs, Neil K., Heisler, Eckhard, Jacobs, Abigail, Jirova, Dagmar, Jones, David, Kandarova, Helena, Kasper, Peter, Kinyamu Akunda, Jacqueline, Krul, Cyrille, Learn, Douglas, Liebsch, Manfred, Lynch, Anthony M., Muster, Wolfgang, Nakamura, Kazuichi, Nash, J. Frank, Pfannenbecker, Uwe, Phillips, Gareth, Robles, Catherine, Rogiers, Vera, Van De Water, Femke, Liminga, Ulla Wändel, Vohr, Hans-Werner, Wattrelos, Olivier, Woods, Julie, Zuang, Valérie, Kreysa, Joachim, Wilcox, Phil, De Smedt, Ann, Pharmaceutical and Pharmacological Sciences, Experimental in vitro toxicology and dermato-cosmetology, and Connexin Signalling Research Group

Abstract

This is the report from the "ECVAM-EFPIA workshop on 3T3 NRU Phototoxicity Test: Practical Experience and Implications for Phototoxicity Testing", jointly organized by ECVAM and EFPIA and held on the 25-27 October 2010 in Somma Lombardo, Italy. The European Centre for the Validation of Alternative Methods (ECVAM) was established in 1991 within the European Commission Joint Research, based on a Communication from the European Commission (1991). The main objective of ECVAM is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine and replace the use of laboratory animals. The European Federation of Pharmaceuticals Industries and Association (EFPIA) represent the pharmaceutical industry operating in Europe. Through its direct membership of 31 national associations and 40 leading pharmaceutical companies, EFPIA is the voice on the EU scene of 2200 companies committed to researching, developing and bringing to patients new medicines that improve health and the quality of life around the world. The workshop, co-chaired by Joachim Kreysa (ECVAM) and Phil Wilcox (GSK, EFPIA) involved thirty-five experts from academia, regulatory authorities and industry, invited to contribute with their experiences in the field of phototoxicology. The main objectives of the workshop were: -to present 'in use' experience of the pharmaceutical industry with the 3T3 Neutral Red Uptake Phototoxicity Test (3T3 NRU-PT), -to discuss why it differs from the results in the original validation exercise, -to discuss technical issues and consider ways to improve the usability of the 3T3 NRU-PT for (non-topical) pharmaceuticals, e.g., by modifying the threshold of chemical light absorption to trigger photo-toxicological testing, and by modifying technical aspects of the assay, or adjusting the criteria used to classify a positive response. During the workshop, the assay methodology was reviewed by comparing the OECD Test Guideline (TG 432) with the protocols used in testing laboratories, data from EFPIA and JPMA 'surveys' were presented and possible reasons for the outcomes were discussed. Experts from cosmetics and pharmaceutical industries reported on their experience with the 3T3 NRU-PT and evidence was presented for phototoxic clinical symptoms that could be linked to certain relevant molecules. Brainstorming sessions discussed if the 3T3 NRU-PT needed to be improved and whether alternatives to the 3T3 NRU-PT exist. Finally, the viewpoint from EU and US regulators was presented. In the final session, the conclusions of the meeting were summarized, with action points. It was concluded that the 3T3 NRU-PT identifies phototoxicological hazards with a 100% sensitivity, and thus is accepted as the tier one test that correctly identifies the absence of phototoxic potential. Consequently, positive results in the 3T3 NRU-PT often do not translate into a clinical phototoxicity risk. Possible ways to improve the practical use of this assay include: (i) adaptation of changedUV/vis-absorption criteria as a means to reduce the number of materials tested, (ii) reduction of the highest concentration to be tested, and (iii) consideration of modifying the threshold criteria for the prediction of a positive call in the test.

Published
2012

46. The in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup

Author

Gollapudi, B. Bhaskar, primary, Lynch, Anthony M., additional, Heflich, Robert H., additional, Dertinger, Stephen D., additional, Dobrovolsky, Vasily N., additional, Froetschl, Roland, additional, Horibata, Katsuyoshi, additional, Kenyon, Michelle O., additional, Kimoto, Takafumi, additional, Lovell, David P., additional, Stankowski, Leon F., additional, White, Paul A., additional, Witt, Kristine L., additional, and Tanir, Jennifer Y., additional

Published
2015
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47. Brain function predictors and outcome of weight loss and weight loss maintenance

Author

Szabo-Reed, Amanda N., primary, Breslin, Florence J., additional, Lynch, Anthony M., additional, Patrician, Trisha M., additional, Martin, Laura E., additional, Lepping, Rebecca J., additional, Powell, Joshua N., additional, Yeh, Hung-Wen (Henry), additional, Befort, Christie A., additional, Sullivan, Debra, additional, Gibson, Cheryl, additional, Washburn, Richard, additional, Donnelly, Joseph E., additional, and Savage, Cary R., additional

Published
2015
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49. Genotoxicity assessment of peptide/ protein-related biotherapeutics: points to consider before testing.

Author

Thybaud, Veronique, Kasper, Peter, Sobol, Zhanna, Elhajouji, Azeddine, Fellows, Mick, Guerard, Melanie, Lynch, Anthony M., Sutter, Andreas, and Tanir, Jennifer Y.

Subjects
GENETIC toxicology, PEPTIDE drugs, AMINO acids, BIOCONJUGATES, ENVIRONMENTAL health, DECISION trees
Abstract

The ICH S6(R1) recommendations on safety evaluation of biotherapeutics have led to uncertainty in determining what would constitute a cause for concern that would require genotoxicity testing. A Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee Workgroup was formed to review the current practice of genotoxicity assessment of peptide/ protein-related biotherapeutics. There are a number of properties of peptide/protein-related biotherapeutics that distinguish such products from traditional 'small molecule' drugs and need to be taken into consideration when assessing whether genotoxicity testing may be warranted and if so, how to do it appropriately. Case examples were provided by participating companies and decision trees were elaborated to determine whether and when genotoxicity evaluation is needed for peptides containing natural amino acids, non-natural amino acids and other chemical entities and for unconjugated and conjugated proteins. From a scientific point of view, there is no reason for testing peptides containing exclusively natural amino acids irrespective of the manufacturing process. If non-natural amino acids, organic linkers and other non-linker chemical components have already been tested for genotoxicity, there is no need to re-evaluate them when used in different peptide/protein-related biotherapeutics. Unless the peptides have been modified to be able to enter the cells, it is generally more appropriate to evaluate the peptides containing the nonnatural amino acids and other non-linker chemical moieties in vivo where the cleavage products can be formed. For linkers, it is important to determine if exposure to reactive forms are likely to occur and from which origin. When the linkers are anticipated to be potential mutagenic impurities they should be evaluated according to ICH M7. If linkers are expected to be catabolic products, it is recommended to test the entire conjugate in vivo, as this would ensure that the relevant 'free' linker forms stemming from in vivo catabolism are tested. [ABSTRACT FROM AUTHOR]

Published
2016
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