Publications by authors named "Deferme Lize"

11 Publications

  • Page 1 of 1

An in vitro air-liquid interface inhalation platform for petroleum substances and constituents.

ALTEX 2021 04 20. Epub 2021 Apr 20.

VITO NV (Flemish Institute for Technological Research), Unit HEALTH, Mol, Belgium.

The goal is to optimize and show the validity of an in vitro method for inhalation testing of petroleum substances and its constituents at the air-liquid interface (ALI). The approach is demonstrated in a pilot study with ethylbenzene (EB), a mono-constituent petroleum substance using a human alveolar epithelial cell line model. This included the development and validation of a generation facility to obtain EB vapors and the optimization of an exposure system for a negative control (clean air, CA), positive control (nitrogen dioxide), and EB vapors. The optimal settings for the VITROCELL® 24/48 system were defined. Cytotoxicity, cell viability, inflammation, and oxidative stress were assessed in A549 after exposure to EB vapors. A concentration-dependent significant decrease in mean cell viability was observed after exposure, which was confirmed by a cytotoxicity test. The oxidative stress marker superoxide dismutase 2 was significantly increased, but no concentration-response was observed. A concentration-dependent significant increase in pro-inflammatory markers C-C motif chemokine ligand 2, interleukin (IL)6, and IL8 was observed for EB-exposed A549 cells compared to CA. The data demonstrated consistency between in vivo air concentrations at which adverse respiratory effects were observed and ALI-concentrations affecting cell viability, provided that the actual measured in vitro delivery efficiency of the compound were included. It can be concluded that extrapolating in vitro air concentrations (adjusted for delivery efficiency and absorption characteristics and applied for testing cell viability) to simulate in vivo air concentrations may be a promising method to screen for acute inhalation toxicity.
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http://dx.doi.org/10.14573/altex.2010211DOI Listing
April 2021

Prenatal developmental toxicity studies on fumes from oxidised asphalt (OA) in the rat.

Reprod Toxicol 2021 Jun 26;102:67-79. Epub 2021 Mar 26.

Nynas, P.O. Box 10 700, SE-121 29 Stockholm, Sweden; Toxicology Group in CONCAWE, Brussels, Belgium. Electronic address:

The prenatal developmental toxicity of the fumes of oxidised asphalt (OA) was tested by nose-only inhalation in the rat. The test material was generated by collecting fumes from the headspace of storage tanks filled with OA. The composition of these fumes was matched to fumes sampled at a workplace where the same OA was applied in a pour-and-roll operation, representing occupational exposure with high concentrations of fumes to not underestimate the possible hazard. In the main study, dams were exposed to 0, 53, 158 and 536 mg/m of fume (as total organic mass), for 6 h/day for 19 days p.c. The maternal NOAEC was 53 mg/m³ (lowest dose tested). In the high-dose group treatment-related effects on body weight gain were seen. In the mid- and high-dose groups treatment-related effects on food consumption, lung weights, and histopathological changes in lungs and the upper respiratory tract were observed. The NOAEC for prenatal developmental toxicity was 536 mg/m³ since no exposure-related effects were found in any of the exposure groups for any of the investigated reproductive endpoints. Furthermore, nose-only exposure to OA fumes in concentrations up to 536 mg/m³ from days 1-19 p.c. did not induce any significant fetal abnormalities.
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http://dx.doi.org/10.1016/j.reprotox.2021.03.003DOI Listing
June 2021

Prenatal developmental toxicity studies on fumes from bitumen in the rat.

Reprod Toxicol 2021 01 26;99:15-26. Epub 2020 Nov 26.

Nynas AB, P.O. Box 10 700, Stockholm, SE-121 29, Sweden; Toxicology Group in CONCAWE, Belgium. Electronic address:

The prenatal developmental toxicity of bitumen fume was tested by nose-only inhalation in the rat. The fumes for exposure were collected from the headspace of a storage tank filled with a bitumen corresponding in composition to an anticipated worst-case occupational exposure. The composition of these fumes was compared to actual paving site fumes to ensure its representativeness for workplace exposures. In a dose-range-finding study male and female rats were exposed to 0, 103, 480 or 1043 mg/m of fume (as total organic mass), for 6 h/day during 20 days post conception (p.c.). Dose-related effects on body weight and lungs were observed in the mid- and high-dose groups. In the main study, dams were exposed to 0, 52, 151 and 482 mg/m of fume, for 6 h/day during 19 days p.c. The maternal NOAEL was 52 mg/m³. In the high-dose group treatment-related effects on body weight (gain), food consumption, lung weights, and histopathological changes in lungs and larynx were observed. In the mid-dose group only histopathological changes in the larynx and lungs were found. The NOAEL for prenatal developmental toxicity was 151 mg/m³ based on reduced fetal weight in the high-dose group (482 mg/m³). However, these changes are most likely a consequence of the maternal toxicity, in particular the reduction of maternal body weight gain by 26 % as compared to control. Nose-only exposure to bitumen fumes in concentrations up to 482 mg/m³ from days 1-19 p.c. did not induce any significant fetal anomalies.
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http://dx.doi.org/10.1016/j.reprotox.2020.11.009DOI Listing
January 2021

Alternative air-liquid interface method for inhalation toxicity testing of a petroleum-derived substance.

MethodsX 2020 8;7:101088. Epub 2020 Oct 8.

VITO NV (Flemish Institute for Technological Research), Unit HEALTH, Mol, Belgium.

-based new approach methodologies (NAMs) provide a pragmatic solution to animal testing of petroleum substances and their constituents. A previous study exposed an in vitro model (A549 cells) at the air-liquid interface (ALI) to assess inhalation toxicity of a single compound, ethylbenzene. Experimental conditions using VITROCELL 24/48 exposure system were optimized to achieve a deposition efficiency that resulted in dose-dependent biological changes. The feasibility of this set-up was evaluated for testing the complex substance gasoline, which, at only high concentrations, can induce mild respiratory irritation in animals and cough in humans.•Results showed that perpendicular ALI exposure flow systems (VITROCELL® 6/4 and 24/48) may not be appropriate for testing gasoline because it was not possible to achieve enough deposition onto the cells and in the culture medium to measure dose and to determine dose-dependent biological changes (more information can be found in 'Supplementary material and/or Additional information' section).•Structural features ( aromatic or saturated hydrocarbon structure) and high hydrophobicity, together with the low concentrations of individual components in gasoline, may have caused the low deposition.•To achieve a higher deposition on the cells, A549 cells were exposed to gasoline at the ALI by passive dosing.The results demonstrate that the presented methodology is a promising NAM for inhalation toxicity testing of (semi-)volatile complex substances with low aqueous solubility.
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http://dx.doi.org/10.1016/j.mex.2020.101088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581970PMC
October 2020

A cross-omics approach to investigate temporal gene expression regulation by 5-hydroxymethylcytosine via TBH-derived oxidative stress showed involvement of different regulatory kinases.

Toxicol In Vitro 2018 Apr 9;48:318-328. Epub 2018 Feb 9.

Department of Toxicogenomics, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200, MD, Maastricht, The Netherlands.

Regulation of DNA methylation plays a crucial role in biological processes and carcinogenesis. The formation of 5-hydroxymethylcytosine (5hmC) by oxidation of 5-methylcytosine (5mC) has been proposed as an intermediate of active demethylation. However, whether and how active demethylation is regulated by oxidative stress-related processes is not well understood. Here we investigated whether free oxygen radicals are capable of directly forming 5hmC and how this enhanced whole genome gene expression. We applied LC-MS/MS technology for the analysis of 5mC, 5hmC, 5-formylcytosine (5fC) and 5-hydroxymethyluracyl (5hmU) in HepG2 cells exposed to hydroxyl- and methyl radicals, formed by tert-butyl hydroperoxide (TBH) at multiple time points. We observed that TBH is able to induce a significant increase in 5hmC. A detailed evaluation of the hydroxymethylome using a combination of 5hmC-immunoprecipitation and microarrays resulted in the identification of highly dynamic modifications that appear to increase during prolonged oxidant exposure. Analyses of temporal gene expression changes in combination with network analysis revealed different subnetworks containing differentially expressed genes (DEGs) with differentially hydroxyl-methylated regions (DhMRs) in different regulatory kinases enriched with serine-threonine kinases. These serine-threonine kinases compromises MAPK14, RPSK6KA1, RIPK1, and PLK3 and were all previously identified as key-regulators in hepatocarcinogenesis and subject of study for chemotherapeutic interventions.
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http://dx.doi.org/10.1016/j.tiv.2018.02.006DOI Listing
April 2018

Framework for the quantitative weight-of-evidence analysis of 'omics data for regulatory purposes.

Regul Toxicol Pharmacol 2017 Dec 14;91 Suppl 1:S46-S60. Epub 2017 Oct 14.

Systox Ltd., UK.

A framework for the quantitative weight-of-evidence (QWoE) analysis of 'omics data for regulatory purposes is presented. The QWoE framework encompasses seven steps to evaluate 'omics data (also together with non-'omics data): (1) Hypothesis formulation, identification and weighting of lines of evidence (LoEs). LoEs conjoin different (types of) studies that are used to critically test the hypothesis. As an essential component of the QWoE framework, step 1 includes the development of templates for scoring sheets that predefine scoring criteria with scores of 0-4 to enable a quantitative determination of study quality and data relevance; (2) literature searches and categorisation of studies into the pre-defined LoEs; (3) and (4) quantitative assessment of study quality and data relevance using the respective pre-defined scoring sheets for each study; (5) evaluation of LoE-specific strength of evidence based upon the study quality and study relevance scores of the studies conjoined in the respective LoE; (6) integration of the strength of evidence from the individual LoEs to determine the overall strength of evidence; (7) characterisation of uncertainties and conclusion on the QWoE. To put the QWoE framework in practice, case studies are recommended to confirm the relevance of its different steps, or to adapt them as necessary.
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http://dx.doi.org/10.1016/j.yrtph.2017.10.010DOI Listing
December 2017

Framework for the quality assurance of 'omics technologies considering GLP requirements.

Regul Toxicol Pharmacol 2017 Dec 5;91 Suppl 1:S27-S35. Epub 2017 Oct 5.

BASF SE, Germany. Electronic address:

'Omics technologies are gaining importance to support regulatory toxicity studies. Prerequisites for performing 'omics studies considering GLP principles were discussed at the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Workshop Applying 'omics technologies in Chemical Risk Assessment. A GLP environment comprises a standard operating procedure system, proper pre-planning and documentation, and inspections of independent quality assurance staff. To prevent uncontrolled data changes, the raw data obtained in the respective 'omics data recording systems have to be specifically defined. Further requirements include transparent and reproducible data processing steps, and safe data storage and archiving procedures. The software for data recording and processing should be validated, and data changes should be traceable or disabled. GLP-compliant quality assurance of 'omics technologies appears feasible for many GLP requirements. However, challenges include (i) defining, storing, and archiving the raw data; (ii) transparent descriptions of data processing steps; (iii) software validation; and (iv) ensuring complete reproducibility of final results with respect to raw data. Nevertheless, 'omics studies can be supported by quality measures (e.g., GLP principles) to ensure quality control, reproducibility and traceability of experiments. This enables regulators to use 'omics data in a fit-for-purpose context, which enhances their applicability for risk assessment.
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http://dx.doi.org/10.1016/j.yrtph.2017.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816020PMC
December 2017

Applying 'omics technologies in chemicals risk assessment: Report of an ECETOC workshop.

Regul Toxicol Pharmacol 2017 Dec 25;91 Suppl 1:S3-S13. Epub 2017 Sep 25.

BASF SE, Germany.

Prevailing knowledge gaps in linking specific molecular changes to apical outcomes and methodological uncertainties in the generation, storage, processing, and interpretation of 'omics data limit the application of 'omics technologies in regulatory toxicology. Against this background, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop Applying 'omics technologies in chemicals risk assessment that is reported herein. Ahead of the workshop, multi-expert teams drafted frameworks on best practices for (i) a Good-Laboratory Practice-like context for collecting, storing and curating 'omics data; (ii) the processing of 'omics data; and (iii) weight-of-evidence approaches for integrating 'omics data. The workshop participants confirmed the relevance of these Frameworks to facilitate the regulatory applicability and use of 'omics data, and the workshop discussions provided input for their further elaboration. Additionally, the key objective (iv) to establish approaches to connect 'omics perturbations to phenotypic alterations was addressed. Generally, it was considered promising to strive to link gene expression changes and pathway perturbations to the phenotype by mapping them to specific adverse outcome pathways. While further work is necessary before gene expression changes can be used to establish safe levels of substance exposure, the ECETOC workshop provided important incentives towards achieving this goal.
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http://dx.doi.org/10.1016/j.yrtph.2017.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816021PMC
December 2017

The challenge of the application of 'omics technologies in chemicals risk assessment: Background and outlook.

Regul Toxicol Pharmacol 2017 Dec 18;91 Suppl 1:S14-S26. Epub 2017 Sep 18.

Centre for Radiation, Chemical and Environmental Hazards (CRCE), Harwell Science and Innovation Campus, Public Health England (PHE), UK. Electronic address:

This survey by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) highlights that 'omics technologies are generally not yet applied to meet standard information requirements during regulatory hazard assessment. While they are used within weight-of-evidence approaches to investigate substances' modes-of-action, consistent approaches for the generation, processing and interpretation of 'omics data are not applied. To date, no 'omics technology has been standardised or validated. Best practices for performing 'omics studies for regulatory purposes (e.g., microarrays for transcriptome profiling) remain to be established. Therefore, three frameworks for (i) establishing a Good-Laboratory Practice-like context for collecting, storing and curating 'omics data; (ii) 'omics data processing; and (iii) quantitative WoE approaches to interpret 'omics data have been developed, that are presented in this journal supplement. Application of the frameworks will enable between-study comparison of results, which will facilitate the regulatory applicability of 'omics data. The frameworks do not constitute prescriptive protocols precluding any other data analysis method, but provide a baseline for analysis that can be applied to all data allowing ready cross-comparison. Data analysis that does not follow the frameworks can be justified and the resulting data can be compared with the Framework-based common analysis output.
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http://dx.doi.org/10.1016/j.yrtph.2017.09.020DOI Listing
December 2017

Dynamic Interplay between the Transcriptome and Methylome in Response to Oxidative and Alkylating Stress.

Chem Res Toxicol 2016 09 24;29(9):1428-38. Epub 2016 Aug 24.

Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.

In recent years, it has been shown that free radicals not only react directly with DNA but also regulate epigenetic processes such as DNA methylation, which may be relevant within the context of, for example, tumorigenesis. However, how these free radicals impact the epigenome remains unclear. We therefore investigated whether methyl and hydroxyl radicals, formed by tert-butyl hydroperoxide (TBH), change temporal DNA methylation patterns and how this interferes with genome-wide gene expression. At three time points, TBH-induced radicals in HepG2 cells were identified by electron spin resonance spectroscopy. Total 5-methylcytosine (5mC) levels were determined by liquid chromatography and tandem mass spectrometry and genome-wide changes in 5mC and gene expression by microarrays. Induced methylome changes rather represent an adaptive response to the oxidative stress-related reactions observed in the transcriptome. More specifically, we found that methyl radicals did not induce DNA methylation directly. An initial oxidative and alkylating stress-related response of the transcriptome during the early phase of TBH treatment was followed by an epigenetic response associated with cell survival signaling. Also, we identified genes of which the expression seems directly regulated by DNA methylation. This work suggests an important role of the methylome in counter-regulating primary oxidative and alkylating stress responses in the transcriptome to restore normal cell function. Altogether, the methylome may play an important role in counter-regulating primary oxidative and alkylating stress responses in the transcriptome presumably to restore normal cell function.
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http://dx.doi.org/10.1021/acs.chemrestox.6b00090DOI Listing
September 2016

Oxidative Stress Mechanisms Do Not Discriminate between Genotoxic and Nongenotoxic Liver Carcinogens.

Chem Res Toxicol 2015 Aug 4;28(8):1636-46. Epub 2015 Aug 4.

Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.

It is widely accepted that in chemical carcinogenesis different modes-of-action exist, e.g., genotoxic (GTX) versus nongenotoxic (NGTX) carcinogenesis. In this context, it has been suggested that oxidative stress response pathways are typical for NGTX carcinogenesis. To evaluate this, we examined oxidative stress-related changes in gene expression, cell cycle distribution, and (oxidative) DNA damage in human hepatoma cells (HepG2) exposed to GTX-, NGTX-, and noncarcinogens, at multiple time points (4-8-24-48-72 h). Two GTX (azathriopine (AZA) and furan) and two NGTX (tetradecanoyl-phorbol-acetate, (TPA) and tetrachloroethylene (TCE)) carcinogens as well as two noncarcinogens (diazinon (DZN, d-mannitol (Dman)) were selected, while per class one compound was deemed to induce oxidative stress and the other not. Oxidative stressors AZA, TPA, and DZN induced a 10-fold higher number of gene expression changes over time compared to those of furan, TCE, or Dman treatment. Genes commonly expressed among AZA, TPA, and DZN were specifically involved in oxidative stress, DNA damage, and immune responses. However, differences in gene expression between GTX and NGTX carcinogens did not correlate to oxidative stress or DNA damage but could instead be assigned to compound-specific characteristics. This conclusion was underlined by results from functional readouts on ROS formation and (oxidative) DNA damage. Therefore, oxidative stress may represent the underlying cause for increased risk of liver toxicity and even carcinogenesis; however, it does not discriminate between GTX and NGTX carcinogens.
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http://dx.doi.org/10.1021/acs.chemrestox.5b00222DOI Listing
August 2015