Marilyn Aardema Consulting LLC

Fairfield, OH, United States

Marilyn Aardema Consulting LLC

Fairfield, OH, United States
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Brusick D.,Toxicology Consultant | Aardema M.,Marilyn Aardema Consulting LLC | Kier L.,Private Consultant | Kirkland D.,Kirkland Consulting | Williams G.,New York Medical College
Critical Reviews in Toxicology | Year: 2016

In 2015, the International Agency for Research on Cancer (IARC) published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


Corvi R.,European Commission - Joint Research Center Ispra | Aardema M.J.,Marilyn Aardema Consulting LLC | Aardema M.J.,Procter and Gamble | Gribaldo L.,European Commission - Joint Research Center Ispra | And 6 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

The potential for a compound to induce carcinogenicity is a key consideration when ascertaining hazard and risk assessment of chemicals. Among the in vitro alternatives that have been developed for predicting carcinogenicity, in vitro cell transformation assays (CTAs) have been shown to involve a multistage process that closely models important stages of in vivo carcinogenesis and have the potential to detect both genotoxic and non-genotoxic carcinogens. These assays have been in use for decades and a substantial amount of data demonstrating their performance is available in the literature. However, for the standardised use of these assays for regulatory purposes, a formal evaluation of the assays, in particular focusing on development of standardised transferable protocols and further information on assay reproducibility, was considered important to serve as a basis for the drafting of generally accepted OECD test guidelines. To address this issue, a prevalidation study of the CTAs using the BALB/c 3T3 cell line, SHE cells at pH 6.7, and SHE cells at pH 7.0 was coordinated by the European Centre for the Validation of Alternative Methods (ECVAM) and focused on issues of standardisation of protocols, test method transferability and within- and between-laboratory reproducibility. The study resulted in the availability of standardised protocols that had undergone prevalidation [1,2]. The results of the ECVAM study demonstrated that for the BALB/c 3T3 method, some modifications to the protocol were needed to obtain reproducible results between laboratories, while the SHE pH 6.7 and the SHE pH 7.0 protocols are transferable between laboratories, and results are reproducible within- and between-laboratories. It is recommended that the BALB/c 3T3 and SHE protocols as instituted in this prevalidation study should be used in future applications of these respective transformation assays. To support their harmonised use and regulatory application, the development of an OECD test guideline for the SHE CTAs, based on the protocol published in this issue, is recommended. The development of an OECD test guideline for the BALB/c 3T3 CTA should likewise be further pursued upon the availability of additional supportive data and improvement of the statistical analysis. © 2011 Elsevier B.V.


Vanparys P.,ALTOXICON BVBA | Corvi R.,European Commission - Joint Research Center Ispra | Aardema M.J.,Marilyn Aardema Consulting LLC | Gribaldo L.,European Commission - Joint Research Center Ispra | And 3 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012

Two year rodent bioassays play a key role in the assessment of carcinogenic potential of chemicals to humans. The seventh amendment to the European Cosmetics Directive will ban in 2013 the marketing of cosmetic and personal care products that contain ingredients that have been tested in animal models. Thus 2-year rodent bioassays will not be available for cosmetics/personal care products. Furthermore, for large testing programs like REACH, in vivo carcinogenicity testing is impractical. Alternative ways to carcinogenicity assessment are urgently required. In terms of standardization and validation, the most advanced in vitro tests for carcinogenicity are the cell transformation assays (CTAs). Although CTAs do not mimic the whole carcinogenesis process in vivo, they represent a valuable support in identifying transforming potential of chemicals. CTAs have been shown to detect genotoxic as well as non-genotoxic carcinogens and are helpful in the determination of thresholds for genotoxic and non-genotoxic carcinogens. The extensive review on CTAs by the OECD (OECD (2007) Environmental Health and Safety Publications, Series on Testing and Assessment, No. 31) and the proven within- and between-laboratories reproducibility of the SHE CTAs justifies broader use of these methods to assess carcinogenic potential of chemicals. © 2012 Elsevier B.V.


Roy S.,BioReliance Corporation | Kulkarni R.,BioReliance Corporation | Hewitt N.J.,SWS | Aardema M.J.,Marilyn Aardema Consulting LLC
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2016

The in vitro human reconstructed skin micronucleus (RSMN) assay in EpiDerm™ is a promising novel animal alternative for evaluating genotoxicity of topically applied chemicals. It is particularly useful for assessing cosmetic ingredients that can no longer be tested using in vivo assays. To advance the use of this test especially for regulatory decision-making, we have established the RSMN assay in our laboratory according to Good Laboratory Practice and following the principles of the OECD test guideline 487 in vitro mammalian cell micronucleus test. Proficiency with the assay was established by correctly identifying direct-acting genotoxins and genotoxins requiring metabolism, as well as non-genotoxic/non-carcinogenic chemicals. We also report the analysis of our historical control data that demonstrate vehicle control and positive control values for %micronuclei in binucleated cells are in the ranges reported previously. Technical issues including evaluating various solvents with both 48 h and 72 h treatment regimens were investigated. For the first time, mechanistic studies using CREST analysis revealed that the RSMN assay is suitable for distinguishing aneugens and clastogens. Moreover, the assay is also suitable for measuring cytokines as markers for proliferative and toxic effects of chemicals. © 2016 Elsevier B.V.


Aardema M.J.,Marilyn Aardema Consulting LLC | Barnett B.B.,Advanced Testing Laboratories | Mun G.C.,Institute for In Vitro science Inc. | Dahl E.L.,Exponent, Inc. | And 3 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2013

The in vitro human reconstructed skin micronucleus (RSMN) assay in EpiDerm™ is a promising new assay for evaluating genotoxicity of dermally applied chemicals. A global pre-validation project sponsored by the European Cosmetics Association (Cosmetics Europe - formerly known as COLIPA), and the European Center for Validation of Alternative Methods (ECVAM), is underway. Results to date demonstrate international inter-laboratory and inter-experimental reproducibility of the assay for chemicals that do not require metabolism [Aardema et al., Mutat. Res. 701 (2010) 123-131]. We have expanded these studies to investigate chemicals that do require metabolic activation: 4-nitroquinoline-N-oxide (4NQO), cyclophosphamide (CP), dimethylbenzanthracene (DMBA), dimethylnitrosamine (DMN), dibenzanthracene (DBA) and benzo(a)pyrene (B. aP). In this study, the standard protocol of two applications over 48. h was compared with an extended protocol involving three applications over 72. h. Extending the treatment period to 72. h changed the result significantly only for 4NQO, which was negative in the standard 48. h dosing regimen, but positive with the 72. h treatment. DMBA and CP were positive in the standard 48. h assay (CP induced a more reproducible response with the 72. h treatment) and B. aP gave mixed results; DBA and DMN were negative in both the 48. h and the 72. h dosing regimens. While further work with chemicals that require metabolism is needed, it appears that the RMSN assay detects some chemicals that require metabolic activation (4 out of 6 chemicals were positive in one or both protocols). At this point in time, for general testing, the use of a longer treatment period in situations where the standard 48. h treatment is negative or questionable is recommended. © 2012 Elsevier B.V.


PubMed | SWS, BioReliance Corporation and Marilyn Aardema Consulting LLC
Type: | Journal: Mutation research. Genetic toxicology and environmental mutagenesis | Year: 2016

The in vitro human reconstructed skin micronucleus (RSMN) assay in EpiDerm is a promising novel animal alternative for evaluating genotoxicity of topically applied chemicals. It is particularly useful for assessing cosmetic ingredients that can no longer be tested using in vivo assays. To advance the use of this test especially for regulatory decision-making, we have established the RSMN assay in our laboratory according to Good Laboratory Practice and following the principles of the OECD test guideline 487 in vitro mammalian cell micronucleus test. Proficiency with the assay was established by correctly identifying direct-acting genotoxins and genotoxins requiring metabolism, as well as non-genotoxic/non-carcinogenic chemicals. We also report the analysis of our historical control data that demonstrate vehicle control and positive control values for %micronuclei in binucleated cells are in the ranges reported previously. Technical issues including evaluating various solvents with both 48h and 72h treatment regimens were investigated. For the first time, mechanistic studies using CREST analysis revealed that the RSMN assay is suitable for distinguishing aneugens and clastogens. Moreover, the assay is also suitable for measuring cytokines as markers for proliferative and toxic effects of chemicals.


Pant K.,BioReliance Corporation | Springer S.,BioReliance Corporation | Bruce S.,BioReliance Corporation | Lawlor T.,BioReliance Corporation | And 2 more authors.
Environmental and Molecular Mutagenesis | Year: 2014

There is increased interest in the in vivo comet assay in rodents as a follow-up approach for determining the biological relevance of chemicals that are genotoxic in in vitro assays. This is partly because, unlike other assays, DNA damage can be assessed in this assay in virtually any tissue. Since background levels of DNA damage can vary with the species, tissue, and cell processing method, a robust historical control database covering multiple tissues is essential. We describe extensive vehicle and positive control data for multiple tissues from rats and mice. In addition, we report historical data from control and genotoxin-treated human blood. Technical issues impacting comet results are described, including the method of cell preparation and freezing. Cell preparation by scraping (stomach and other GI tract organs) resulted in higher % tail DNA than mincing (liver, spleen, kidney etc) or direct collection (blood or bone marrow). Treatment with the positive control genotoxicant, ethyl methanesulfonate (EMS) in rats and methyl methanesulfonate in mice, resulted in statistically significant increases in % tail DNA. Background DNA damage was not markedly increased when cell suspensions were stored frozen prior to preparing slides, and the outcome of the assay was unchanged (EMS was always positive). In conclusion, historical data from our laboratory for the in vivo comet assay for multiple tissues from rats and mice, as well as human blood show very good reproducibility. These data and recommendations provided are aimed at contributing to the design and proper interpretation of results from comet assays. © 2014 Wiley Periodicals, Inc.


Kirsch-Volders M.,Vrije Universiteit Brussel | Decordier I.,Vrije Universiteit Brussel | Elhajouji A.,Novartis | Plas G.,Vrije Universiteit Brussel | And 2 more authors.
Mutagenesis | Year: 2011

The toxicological relevance of the micronucleus (MN) test is well defined: it is a multi-target genotoxic endpoint, assessing not only clastogenic and aneugenic events but also some epigenetic effects, which is simple to score, accurate, applicable in different cell types. In addition, it is predictive for cancer, amenable for automation and allows good extrapolation for potential limits of exposure or thresholds and it is easily measured in experimental both in vitro and in vivo systems. Implementation of in vitro micronucleus (IVMN) assays in the battery of tests for hazard and risk assessment of potential mutagens/carcinogens is therefore fully justified. Moreover, the final draft of an OECD guideline became recently available for this test. In this review, we discuss the prerequisites for an acceptable MN assay, including the cell as unit of observation, importance of cell membranes, the requirement of a mitotic or meiotic division and the assessment of cell division in the presence of the test substance. Furthermore, the importance of adequate design of protocols is highlighted and new developments, in particular the in vitro 3D human skin models, are discussed. Finally, we address future research perspectives including the possibility of a combined primary 3D human skin and primary human whole blood culture system, and the need for adaptation of the IVMN assays to assess the genotoxic potential of new materials, in particular nanomaterials. © The Author 2010. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved.


Poirier M.C.,U.S. National Institutes of Health | Schwartz J.L.,University of Washington | Aardema M.J.,Marilyn Aardema Consulting LLC
Environmental and Molecular Mutagenesis | Year: 2014

One of the goals of the EMGS is to help members achieve professional success in the fields they have trained in. Today, there is greater competition for jobs in genetic toxicology, genomics, and basic research than ever before. In addition, job security and the ability to advance in one's career is challenging, regardless of whether one works in a regulatory, academic, or industry environment. At the EMGS Annual Meeting in Monterey, CA (September, 2013), the Women in EMGS Special Interest Group held a workshop to discuss strategies for achieving professional success. Presentations were given by three speakers, each representing a different employment environment: Government (Miriam C. Poirier), Academia (Jeffrey L. Schwartz), and Industry (Marilyn J. Aardema). Although some differences in factors or traits affecting success in the three employment sectors were noted by each of the speakers, common factors considered important for advancement included networking, seeking out mentors, and developing exceptional communication skills. © 2014 Wiley Periodicals, Inc.


Fellows M.D.,Astrazeneca | Mcdermott A.,Astrazeneca | Clare K.R.,Astrazeneca | Doherty A.,Astrazeneca | And 2 more authors.
Environmental and Molecular Mutagenesis | Year: 2014

There has been much discussion on acceptable spontaneous mutant frequencies in the mouse lymphoma assay (MLA). This culminated in the International Workshop on Genotoxicity Testing (IWGT) recommended control limits for the microtitre version of 50-170 mutants/106 viable cells, which has now been included in the draft Organization for Economic Co-Operation and Development guideline for assays investigating mammalian cell gene mutation at the tk locus. Some of the factors affecting mutant frequency have been investigated. It was shown that when culturing methotrexate cleansed TK+/- cells, a spontaneous mutant frequency of ~100 mutants/106 viable cells was achieved after only 26 doublings. However, after further culturing for ~6 months the spontaneous mutant frequency only gradually increased. Culturing for this time did not affect the karyotype of the cell in so much as the modal chromosome number remained stable. The spontaneous mutant frequency could effectively be manipulated by cleansing with various concentrations of methotrexate. The necessity for using appropriately heat-inactivated horse serum was confirmed. Finally, following treatment with 4-nitroquinoline-N-oxide, cells did not preferentially survive when plated at high cell densities (1.6 cells plus 2,000 feeder cells/well) versus cells at low density (1.6 cells/well). It was considered that these findings confirm that the dynamics of spontaneous mutant formation in the MLA are complex. However, the karyotype of L5178Y cells is remarkably stable and assuming investigators are using cells with appropriate provenance and good culturing technique, it is clear that the IWGT recommendations are achievable. © 2013 Wiley Periodicals, Inc.

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