Publications by authors named "Martin Wilks"

46 Publications

Statement of the PPR Panel on a framework for conducting the environmental exposure and risk assessment for transition metals when used as active substances in plant protection products (PPP).

EFSA J 2021 Mar 29;19(3):e06498. Epub 2021 Mar 29.

The European Commission asked the European Food Safety Authority (EFSA) to prepare a statement on a framework for the environmental risk assessment (ERA) of transition metals (e.g. iron and copper) used as active substances in plant protection products (PPPs). Non-degradability, essentiality and specific conditions affecting fate and behaviour as well as their toxicity are distinctive characteristics possibly not covered in current guidance for PPPs. The proposed risk assessment framework starts with a preliminary phase, in which monitoring data on transition metals in relevant environmental compartments are provided. They deliver the metal natural background and anthropogenic residue levels to be considered in the exposure calculations. A first assessment step is then performed assuming fully bioavailable residues. Should the first step fail, refined ERA can, in principle, consider bioavailability issues; however, non-equilibrium conditions need to be taken into account. Simple models that are fit for purpose should be employed in order to avoid unnecessary complexity. Exposure models and scenarios would need to be adapted to address environmental processes and parameters relevant to the fate and behaviour of transition metals in water, sediment and soils (e.g. speciation). All developments should follow current EFSA guidance documents. If refined approaches have been used in the risk assessment of PPPs containing metals, post-registration monitoring and controlled long-term studies should be conducted and assessed. Utilisation of the same transition metal in other PPPs or for other uses will lead to accumulation in environmental compartments acting as sinks. In general, it has to be considered that the prospective risk assessment of metal-containing PPPs can only cover a defined period as there are limitations in the long-term hazard assessment due to issues of non-degradability. It is therefore recommended to consider these aspects in any risk management decisions and to align the ERA with the goals of other overarching legislative frameworks.
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http://dx.doi.org/10.2903/j.efsa.2021.6498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006092PMC
March 2021

Approaches in metabolomics for regulatory toxicology applications.

Analyst 2021 Mar 19;146(6):1820-1834. Epub 2021 Feb 19.

School of Pharmaceutical Sciences, University of Geneva, Switzerland.

Innovative methodological approaches are needed to conduct human health and environmental risk assessments on a growing number of marketed chemicals. Metabolomics is progressively proving its value as an efficient strategy to perform toxicological evaluations of new and existing substances, and it will likely become a key tool to accelerate chemical risk assessments. However, additional guidance with widely accepted and harmonized procedures is needed before metabolomics can be routinely incorporated in decision-making for regulatory purposes. The aim of this review is to provide an overview of metabolomic strategies that have been successfully employed in toxicity assessment as well as the most promising workflows in a regulatory context. First, we provide a general view of the different steps of regulatory toxicology-oriented metabolomics. Emphasis is put on three key elements: robustness of experimental design, choice of analytical platform, and use of adapted data treatment tools. Then, examples in which metabolomics supported regulatory toxicology outputs in different scenarios are reviewed, including chemical grouping, elucidation of mechanisms of toxicity, and determination of points of departure. The overall intention is to provide insights into why and how to plan and conduct metabolomic studies for regulatory toxicology purposes.
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http://dx.doi.org/10.1039/d0an02212hDOI Listing
March 2021

Exploring the Potential of ToxCast Data in Supporting Read-Across for Evaluation of Food Chemical Safety.

Chem Res Toxicol 2021 Feb 30;34(2):300-312. Epub 2020 Nov 30.

Nestlé Research, Case Postale 44, CH-1000 Lausanne 26, Switzerland.

The intention of this study was to determine the utility of high-throughput screening (HTS) data, as exemplified by ToxCast and Tox21, for application in toxicological read-across in food-relevant chemicals. Key questions were addressed on the extent to which the HTS data could provide information enabling (1) the elucidation of underlying bioactivities associated with apical toxicological outcomes, (2) the closing of existing toxicological data gaps, and (3) the definition of the boundaries of chemical space across which bioactivity could reliably be extrapolated. Results revealed that many biological targets apparently activated within the chemical groupings lack, at this time, validated toxicity pathway associations. Therefore, as means of providing proof-of-principle, a comparatively well-characterized end point-estrogenicity-was selected for evaluation. This was facilitated through the preparation of two exploratory case studies, focusing upon groupings of paraben-gallates and pyranone-type compounds (notably flavonoids). Within both, the HTS data were seen to reflect estrogenic potencies in a manner which broadly corresponded to established structure-activity group relationships, with parabens and flavonoids displaying greater estrogen receptor affinity than benzoate esters and alternative pyranone-containing molecules, respectively. As such, utility in the identification of out-of-domain compounds was demonstrated, indicating potential for application in addressing point (3) as detailed above.
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http://dx.doi.org/10.1021/acs.chemrestox.0c00240DOI Listing
February 2021

Bringing Chemistry to Medicine - The Contribution of Paracelsus to Modern Toxicology.

Authors:
Martin F Wilks

Chimia (Aarau) 2020 Jun;74(6):507-508

Swiss Centre for Applied Human Toxicology & Dept. of Pharmaceutical Sciences, University of Basel, Missionsstrasse 64, Ch-4055 Basel;, Email:

At the heart of Paracelsus' medical theory is the belief that all matter can be reduced to three basic elements: sulphur, mercury and salt. Their unique properties can be harnessed in the preparation of specific medicines. In this way, poisons can become medicines since it is the dose that determines toxicity.
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http://dx.doi.org/10.2533/chimia.2020.507DOI Listing
June 2020

Organochlorine pesticide levels in Greek patients with Parkinson's disease.

Toxicol Rep 2020 8;7:596-601. Epub 2020 Apr 8.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Parkinson's disease (PD) is a neurodegenerative disease, mostly presenting with characteristic motor symptoms. Organochlorines (OC) are a class of widely-used pesticides that have been included among the list of environmental factors incriminated in PD pathogenesis. However, most studies reporting this association are based on questionnaires, and few have reported exposure data.

Aim: To examine the relationship between OC blood concentrations and PD risk.

Methods: In the present study, we studied the concentrations of 8 OC compounds (hexachlorobenzene, heptachlor, hepachlor epoxide, c-chlordane, a-chlordane, p,p'-DDE, DDD, DDT) in 104 Greek PD patients and 110 healthy controls.

Results: All substances studied were present in at least one sample. The most frequently detected (above the level of quantification) pesticides were p,p'-DDE (n = 214, 100 % of both groups) and hexachlorobenzene, HCB (n = 189, cases 46.5 %, controls 53.5 %). Higher levels of DDE were detected among PD patients in comparison to controls by using logistic regression analysis to control for confounders [Odds Ratio, OR (95 % confidence interval, C.I.)]: 2.592,(1.29-5.21)], whilst lower levels of HCB were detect among PD patients [OR,95 %CI:0.176(0.09-0.35)].

Conclusions: Our data suggest that exposure to specific OCs is related to the risk of PD. Further studies, using real exposure data, are needed in order to confirm and extend these findings.
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http://dx.doi.org/10.1016/j.toxrep.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225589PMC
April 2020

A case study applying pathway-oriented thinking to problem formulation for planning a systematic review.

Environ Int 2020 07 10;140:105768. Epub 2020 May 10.

Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland.

The use of evidence-based methods in chemical risk assessment (CRA) is still in its infancy. Novel approaches exploring how to implement Systematic Review (SR) principles and methods for evaluating human health risks from environmental chemical exposures are needed. This paper reports and comments on a conceptual model that was developed as part of a mapping exercise for planning a SR, using aluminium-containing antiperspirants (Al-AP) and female breast cancer risk as a case study. The work explores how knowledge-assembly tools and pathway-oriented thinking developed in systems toxicology can be applied to support problem formulation (PF) in the context of SR. A conceptual model was developed to map out key research questions, working hypotheses, routes of exposure, toxicity pathways and endpoints, and related health outcomes. The model draws on the analytic framework for screening topics of the U.S. Preventive Services Task Force and builds on the concept of a "source-to-outcome continuum", integrating knowledge gained from exposure pathway concepts such as the Aggregate Exposure Pathway and Adverse Outcome Pathways. The model can be used as a central decision and prioritization tool for scoping and framing Population, Exposure, Control, Outcome (PECO) questions in a transparent and iterative manner; as a supporting tool to guide the whole SR process; and to lay down the methodological foundation of a SR on the Al-AP breast cancer topic. Logic modelling can be easily combined with systems or pathway-oriented thinking, and allows for a more structured, objective and transparent approach to PF when applying SR methods to the CRA context.
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http://dx.doi.org/10.1016/j.envint.2020.105768DOI Listing
July 2020

Pesticides, cognitive functions and dementia: A review.

Toxicol Lett 2020 Jun 4;326:31-51. Epub 2020 Mar 4.

Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, Greece; Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece. Electronic address:

Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person's quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer's disease.
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http://dx.doi.org/10.1016/j.toxlet.2020.03.005DOI Listing
June 2020

Potential of ToxCast Data in the Safety Assessment of Food Chemicals.

Toxicol Sci 2020 04;174(2):326-340

Nestlé Research, CH-1000 Lausanne, Switzerland.

Tox21 and ToxCast are high-throughput in vitro screening programs coordinated by the U.S. National Toxicology Program and the U.S. Environmental Protection Agency, respectively, with the goal of forecasting biological effects in vivo based on bioactivity profiling. The present study investigated whether mechanistic insights in the biological targets of food-relevant chemicals can be obtained from ToxCast results when the chemicals are grouped according to structural similarity. Starting from the 556 direct additives that have been identified in the ToxCast database by Karmaus et al. [Karmaus, A. L., Trautman, T. D., Krishan, M., Filer, D. L., and Fix, L. A. (2017). Curation of food-relevant chemicals in ToxCast. Food Chem. Toxicol. 103, 174-182.], the results showed that, despite the limited number of assays in which the chemical groups have been tested, sufficient results are available within so-called "DNA binding" and "nuclear receptor" target families to profile the biological activities of the defined chemical groups for these targets. The most obvious activity identified was the estrogen receptor-mediated actions of the chemical group containing parabens and structurally related gallates, as well the chemical group containing genistein and daidzein (the latter 2 being particularly active toward estrogen receptor β as a potential health benefit). These group effects, as well as the biological activities of other chemical groups, were evaluated in a series of case studies. Overall, the results of the present study suggest that high-throughput screening data could add to the evidence considered for regulatory risk assessment of food chemicals and to the evaluation of desirable effects of nutrients and phytonutrients. The data will be particularly useful for providing mechanistic information and to fill data gaps with read-across.
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http://dx.doi.org/10.1093/toxsci/kfaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098372PMC
April 2020

Erratum to Template for the description of cell-based toxicological test methods to allow evaluation and regulatory use of the data.

ALTEX 2020 ;37(1):164

In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany.

In this manuscript, which appeared in ALTEX (2019), 36(4), 682- 699, doi:10.14573/altex.1909271 , the affiliation of Hennicke Kamp should be Experimental Toxicology and Ecology, BASF SE, Ludwigshafen, Germany. Further, the reference to an article by Bal-Price et al. (2015) should have the following doi:10.1007/s00204-015-1464-2 .
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http://dx.doi.org/10.14573/altex.1909271eDOI Listing
January 2020

Template for the description of cell-based toxicological test methods to allow evaluation and regulatory use of the data.

ALTEX 2019 ;36(4):682-699

In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany.

Only few cell-based test methods are described by Organisation for Economic Co-operation and Development (OECD) test guidelines or other regulatory references (e.g., the European Pharmacopoeia). The majority of toxicity tests still falls into the category of non-guideline methods. Data from these tests may nevertheless be used to support regulatory decisions or to guide strategies to assess compounds (e.g., drugs, agrochemicals) during research and development if they fulfill basic requirements concerning their relevance, reproducibility and predictivity. Only a method description of sufficient clarity and detail allows interpretation and use of the data. To guide regulators faced with increasing amounts of data from non-guideline studies, the OECD formulated Guidance Document 211 (GD211) on method documentation for the purpose of safety assessment. As GD211 is targeted mainly at regulators, it leaves scientists less familiar with regulation uncertain as to what level of detail is required and how individual questions should be answered. Moreover, little attention was given to the description of the test system (i.e., cell culture) and the steps leading to it being established in the guidance. To address these issues, an annotated toxicity test method template (ToxTemp) was developed (i) to fulfill all requirements of GD211, (ii) to guide the user concerning the types of answers and detail of information required, (iii) to include acceptance criteria for test elements, and (iv) to define the cells sufficiently and transparently. The fully annotated ToxTemp is provided here, together with reference to a database containing exemplary descriptions of more than 20 cell-based tests.
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http://dx.doi.org/10.14573/altex.1909271DOI Listing
April 2020

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures.

Arch Toxicol 2019 10 13;93(10):2741-2757. Epub 2019 Sep 13.

Medical School, Division of Morphology, University of Crete, Heraklion, Crete, Greece.

Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance.
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http://dx.doi.org/10.1007/s00204-019-02547-xDOI Listing
October 2019

Corrigendum to Recommendation on test readiness criteria for new approach methods in toxicology: exemplified for developmental neurotoxicity.

ALTEX 2019 ;36(3):506

Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany.

In this manuscript, which appeared in ALTEX 35 , 306-352 ( doi:10.14573/altex.1712081 ), the Acknowledgements should read: This work was supported by the Doerenkamp-Zbinden Foundation, EFSA, the BMBF, JPI-NutriCog-Selenius, and it has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 681002 (EU-ToxRisk).
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http://dx.doi.org/10.14573/altex.1904112DOI Listing
January 2019

Authors' response to the letter to the editor by Jowsey et al.

Regul Toxicol Pharmacol 2019 04 3;103:330-331. Epub 2019 Jan 3.

University of Lausanne, Institute for Work and Health (IST), Route de la Corniche 2, CH-1066, Epalinges-Lausanne, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.yrtph.2019.01.008DOI Listing
April 2019

Magnesium sulfate ameliorates carbon monoxide‑induced cerebral injury in male rats.

Mol Med Rep 2019 Feb 17;19(2):1032-1039. Epub 2018 Dec 17.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Zabol University of Medical Sciences, 9861615881 Zabol, Iran.

Carbon monoxide (CO) has been shown to induce several cardiovascular abnormalities, as well as necrosis, apoptosis and oxidative stress in the brain. Magnesium sulfate (MS) has been shown to have beneficial activities against hypoxia in the brain. In the present study, the possible protective effects of MS against CO‑induced cerebral ischemia were investigated. For this purpose, 25 male Wistar rats were exposed to 3,000 ppm CO for 1 h. The animals were divided into 5 groups (n=5 in each group) as follows: The negative control group (not exposed to CO), the positive control group (CO exposed and treated with normal saline), and 3 groups of CO‑exposed rats treated with MS (75, 150 and 300 mg/kg/day) administered intraperitoneally for 5 consecutive days. On the 5th day, the animals were sacrificed and the brains were harvested for the evaluation of necrosis, apoptosis and oxidative stress. Histopathological evaluation revealed that MS reduced the number and intensity of necrotic insults. The Bax/Bcl2 ratio and malondialdehyde (MDA) levels were significantly decreased in a dose‑dependent manner in the MS‑treated rats compared to the positive control group, while a significant dose‑dependent increase in Akt expression, a pro‑survival protein, was observed. In addition, MS administration reduced pro‑apoptotic indice levels, ameliorated histological insults, favorably modulated oxidative status and increased Akt expression levels, indicating a possible neuroprotective effect in the case of CO poisoning. On the whole, the findings of this study indicate that MS may prove to be useful in protecting against CO‑induced cerebral injury.
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http://dx.doi.org/10.3892/mmr.2018.9771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323247PMC
February 2019

A quantitative risk assessment for skin sensitizing plant protection products: Linking derived No-Effect levels (DNELs) with agricultural exposure models.

Regul Toxicol Pharmacol 2018 Oct 29;98:171-183. Epub 2018 Jul 29.

University of Lausanne, Institute for Work and Health (IST) , Route de la Corniche 2, CH-1066, Epalinges-Lausanne, Switzerland. Electronic address:

Chemical skin sensitizers produce allergic contact dermatitis, which is one of the most frequent occupational diseases associated with chemical exposures. Skin exposure is the major route of exposure when using plant protection products (PPPs). Therefore, skin sensitization is an important factor to be addressed during the regulatory risk assessment of PPPs. The main regulatory decision criterion considered when performing risk assessment for skin sensitizers is the dose applied. The equally important criteria "potency of the substance" is insufficiently considered by two potency categories as potency may vary up to five orders of magnitude. "Frequency of exposure" to the skin sensitizer is not considered at all. Consequently, an improved risk assessment methodology is essential to adequately assess health risks from skin sensitizers, especially for agricultural operators using PPPs. A quantitative risk assessment (QRA) approach for addressing PPPs sensitizing potential is proposed here. This QRA combines a methodology to derive a substance-specific threshold for skin sensitizers, a Derived No-Effect Level (DNEL), and an agricultural exposure model used for assessing chronic health risks of PPPs. The proposed QRA for skin sensitizing PPPs is a clear improvement over current risk assessment to ensure the safe use of skin sensitizers in an occupational context.
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http://dx.doi.org/10.1016/j.yrtph.2018.07.022DOI Listing
October 2018

Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity.

ALTEX 2018 23;35(3):306-352. Epub 2018 Feb 23.

Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany.

Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).
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http://dx.doi.org/10.14573/altex.1712081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545888PMC
November 2018

Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes.

Toxicol Appl Pharmacol 2018 09 12;354:3-6. Epub 2018 Feb 12.

European Commission -DG Joint Research Centre (JRC), Ispra, Italy. Electronic address:

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.
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http://dx.doi.org/10.1016/j.taap.2018.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097873PMC
September 2018

High-dose immunosuppression to prevent death after paraquat self-poisoning - a randomised controlled trial.

Clin Toxicol (Phila) 2018 07 3;56(7):633-639. Epub 2017 Nov 3.

b South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine , University of Peradeniya , Peradeniya , Sri Lanka.

Context: Intentional self-poisoning with the herbicide paraquat has a very high case-fatality and is a major problem in rural Asia and Pacific.

Objectives: We aimed to determine whether the addition of immunosuppression to supportive care offers benefit in resource poor Asian district hospitals.

Materials And Methods: We performed a randomised placebo-controlled trial comparing immunosuppression (intravenous cyclophosphamide up to 1 g/day for two days and methylprednisolone 1 g/day for three days, and then oral dexamethasone 8 mg three-times-a-day for 14 days) with saline and placebo tablets, in addition to standard care, in patients with acute paraquat self-poisoning admitted to six Sri Lankan hospitals between 1st March 2007 and 15th November 2010. The primary outcome was in-hospital mortality.

Results: 299 patients were randomised to receive immunosuppression (147) or saline/placebo (152). There was no significant difference in in-hospital mortality rates between the groups (immunosuppression 78 [53%] vs. placebo 94 [62%] (Chi squared test 2.4, p = .12). There was no difference in mortality at three months between the immunosuppression (101/147 [69%]) and placebo groups (108/152 [71%]); (mortality reduction 2%, 95% CI: -8 to +12%). A Cox model did not support benefit from high-dose immunosuppression but suggested potential benefit from the subsequent two weeks of dexamethasone.

Conclusions: We found no evidence that high dose immunosuppression improves survival in paraquat-poisoned patients. The continuing high mortality means further research on the use of dexamethasone and other potential treatments is urgently needed.
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http://dx.doi.org/10.1080/15563650.2017.1394465DOI Listing
July 2018

Contrast-induced nephropathy: Basic concepts, pathophysiological implications and prevention strategies.

Pharmacol Ther 2017 Dec 19;180:99-112. Epub 2017 Jun 19.

Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.

Contrast-induced nephropathy (CIN) is reversible acute renal failure observed following administration of iodinated contrast media (CM) during angiographic or other medical procedures such as urography. There are various mechanisms through which CM develop their nephrotoxic effects, including oxidative stress and apoptosis. CIN is a real-life, albeit not very rare, entity. Exact pathophysiology remains obscure and no standard diagnostic criteria apply. The Acute Kidney Injury Network criteria was recently employed but its incidence/clinical significance warrants further clarification based on recent methodological advancements, because most published studies to date were contaminated by bias. The current study is a comprehensive review conducted to provide an overview of the basic concepts of CIN and summarize recent knowledge on its pathophysiology and the evidence supporting potential prevention strategies. CIN is expected to increase morbidity, hospital stay and mortality, while all patients scheduled to receive CM should undergo risk assessment for CIN and high-risk patients may be considered candidates for prevention strategies. The value of using compounds with antioxidant properties other than sodium bicarbonate, remains controversial, warranting further clinical investigation.
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http://dx.doi.org/10.1016/j.pharmthera.2017.06.009DOI Listing
December 2017

Systems Toxicology: Real World Applications and Opportunities.

Chem Res Toxicol 2017 04 31;30(4):870-882. Epub 2017 Mar 31.

Department of Health Sciences and Technology, ETH Zurich , 8092 Zurich, Switzerland.

Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxicology entails the integration of in vitro and in vivo toxicity data with computational modeling. This evolving approach depends critically on data reliability and relevance, which in turn depends on the quality of experimental models and bioanalysis techniques used to generate toxicological data. Systems Toxicology involves the use of large-scale data streams ("big data"), such as those derived from omics measurements that require computational means for obtaining informative results. Thus, integrative analysis of multiple molecular measurements, particularly acquired by omics strategies, is a key approach in Systems Toxicology. In recent years, there have been significant advances centered on in vitro test systems and bioanalytical strategies, yet a frontier challenge concerns linking observed network perturbations to phenotypes, which will require understanding pathways and networks that give rise to adverse responses. This summary perspective from a 2016 Systems Toxicology meeting, an international conference held in the Alps of Switzerland, describes the limitations and opportunities of selected emerging applications in this rapidly advancing field. Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized, from empirical end points to pathways of toxicity. This requires the integration of in vitro and in vivo data with computational modeling. Test systems and bioanalytical technologies have made significant advances, but ensuring data reliability and relevance is an ongoing concern. The major challenge facing the new pathway approach is determining how to link observed network perturbations to phenotypic toxicity.
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http://dx.doi.org/10.1021/acs.chemrestox.7b00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396025PMC
April 2017

A framework for cumulative risk assessment in the 21st century.

Crit Rev Toxicol 2017 Feb 11;47(2):85-97. Epub 2016 Aug 11.

g ILSI Health and Environmental Sciences Institute , Washington , DC , USA.

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health.
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http://dx.doi.org/10.1080/10408444.2016.1211618DOI Listing
February 2017

Problem formulation for risk assessment of combined exposures to chemicals and other stressors in humans.

Crit Rev Toxicol 2016 11 11;46(10):835-844. Epub 2016 Aug 11.

g ILSI Health and Environmental Sciences Institute , Washington , DC , USA.

When the human health risk assessment/risk management paradigm was developed, it did not explicitly include a "problem formulation" phase. The concept of problem formulation was first introduced in the context of ecological risk assessment (ERA) for the pragmatic reason to constrain and focus ERAs on the key questions. However, this need also exists for human health risk assessment, particularly for cumulative risk assessment (CRA), because of its complexity. CRA encompasses the combined threats to health from exposure via all relevant routes to multiple stressors, including biological, chemical, physical and psychosocial stressors. As part of the HESI Risk Assessment in the 21st Century (RISK21) Project, a framework for CRA was developed in which problem formulation plays a critical role. The focus of this effort is primarily on a chemical CRA (i.e., two or more chemicals) with subsequent consideration of non-chemical stressors, defined as "modulating factors" (ModFs). Problem formulation is a systematic approach that identifies all factors critical to a specific risk assessment and considers the purpose of the assessment, scope and depth of the necessary analysis, analytical approach, available resources and outcomes, and overall risk management goal. There are numerous considerations that are specific to multiple stressors, and proper problem formulation can help to focus a CRA to the key factors in order to optimize resources. As part of the problem formulation, conceptual models for exposures and responses can be developed that address these factors, such as temporal relationships between stressors and consideration of the appropriate ModFs.
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http://dx.doi.org/10.1080/10408444.2016.1211617DOI Listing
November 2016

Occupational and environmental exposure to pesticides and cytokine pathways in chronic diseases (Review).

Int J Mol Med 2016 Oct 2;38(4):1012-20. Epub 2016 Sep 2.

Department of Biomedical, Odontoiatric, Morphological and Functional Images, Occupational Medicine Section, 'Policlinico G. Martino' Hospital, University of Messina, I‑98125 Messina, Italy.

Pesticides can exert numerous effects on human health as a consequence of both environmental and occupational exposures. The available knowledge base suggests that exposure to pesticides may result in detrimental reproductive changes, neurological dysfunction and several chronic disorders, which are defined by slow evolution and long-term duration. Moreover, an ever increasing amount of data have identified an association between exposure to pesticides and the harmful effects on the immune system. The real impact of alterations in humoral cytokine levels on human health, in particular in the case of chronic diseases, is still unclear. To date, studies have suggested that although exposure to pesticides can affect the immune system functionally, the development of immune disorders depends on the dose and duration of exposure to pesticides. However, many of the respective studies exhibit limitations, such as a lack of information on exposure levels, differences in the pesticide administration procedures, difficulty in characterizing a prognostic significance to the weak modifications often observed and the interpretation of obtained results. The main challenge is not just to understand the role of individual pesticides and their combinations, but also to determine the manner and the duration of exposure, as the toxic effects on the immune system cannot be separated from these considerations. There is a clear need for more well‑designed and standardized epidemiological and experimental studies to recognize the exact association between exposure levels and toxic effects and to identify useful biomarkers of exposure. This review focuses on and critically discusses the immunotoxicity of pesticides and the impact of cytokine levels on health, focusing on the development of several chronic diseases.
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http://dx.doi.org/10.3892/ijmm.2016.2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029960PMC
October 2016

Effects of resveratrol on carbon monoxide-induced cardiotoxicity in rats.

Environ Toxicol Pharmacol 2016 Sep 19;46:110-115. Epub 2016 Jul 19.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran; Students Research Committee, School of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran. Electronic address:

Carbon monoxide (CO) poisoning leads to tissue hypoxia resulting in cardiovascular disturbances. Resveratrol (RES) is considered a natural cardioprotective agent especially in the setting of ischemia/reperfusion injury. In the present study, the cardioprotective potential of RES against CO-induced cardiotoxicity was evaluated. 45 male Wistar rats, animals were randomly assigned to 5 experimental groups. The first group served as negative control and was not exposed to CO. All remaining rats were exposed to CO 3000ppm for 60min. The second group received normal saline following CO exposure, while groups 3, 4 and 5 were injected intraperitoneally with different doses of RES (1, 5 and 10mg/kg, respectively). Histopathological examination showed that RES administration reduced myocardial lesions compared to control groups. Myocardial Akt expression was significantly increased in rats treated with the highest dose of RES (p<0.05) compared to CO-exposed non-treated animals. Caspase-3 activity in rat cardiomyocytes of RES-treated animals was significantly decreased in a dose-dependent manner. ECG findings did not differ significantly among CO-exposed groups. In conclusion, the present study offers evidence of a protective effect of RES administration on CO-induced cardiotoxicity via Akt up-regulation and attenuation of caspase-3 activity in rat hearts.
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http://dx.doi.org/10.1016/j.etap.2016.07.010DOI Listing
September 2016

The European Registered Toxicologist (ERT): Current status and prospects for advancement.

Toxicol Lett 2016 Sep 22;259:151-155. Epub 2016 Jun 22.

EUROTOX President 2014-2016, Toxicology & Forensic Sciences Department, Faculty of Medicine, University of Crete, Heraklion, Greece.

Following its inception in 1994, the certification of European Registered Toxicologists (ERT) by EUROTOX has been recognized as ensuring professional competence as well as scientific integrity and credibility. Criteria and procedures for registration are contained in the ERT "Guidelines for Registration 2012". The register of ERT currently has over 1900 members. In order to continue the harmonisation of requirements and processes between national registering bodies as a prerequisite for official recognition of the ERT title as a standard, and to take account of recent developments in toxicology, an update of the ERT Guidelines has been prepared in a series of workshops by the EUROTOX subcommittees for education and registration, in consultation with representatives of national toxicology societies and registers. The update includes details of topics and learning outcomes for theoretical training, and how these can be assessed. The importance of continuing professional development as the cornerstone of re-registration is emphasised. To help with the process of harmonisation, it is necessary to collate and share best practices of registration conditions and procedures across Europe. Importantly, this information can also be used to audit compliance with the EUROTOX standards. As recognition of professionals in toxicology, including specialist qualifications, is becoming more important than ever, we believe that this can best be achieved based on the steps for harmonisation outlined here together with the proposed new Guidelines.
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http://dx.doi.org/10.1016/j.toxlet.2016.06.014DOI Listing
September 2016

Effects of 3-monochloropropane-1,2-diol (3-MCPD) and its metabolites on DNA damage and repair under in vitro conditions.

Food Chem Toxicol 2016 Mar 31;89:1-7. Epub 2015 Dec 31.

Center of Toxicology Science & Research, Medical School, University of Crete, Heraklion, Crete, Greece.

3-monochloropropane-1,2-diol (3-MCPD) is a food contaminant that occurs during industrial production processes and can be found mainly in fat and salt containing products. 3-MCPD has exhibited mutagenic activity in vitro but not in vivo, however, a genotoxic mechanism for the occurrence of kidney tumors has not so far been excluded. The main pathway of mammalian 3-MCPD metabolism is via the formation of β--chlorolactatic acid and formation of glycidol has been demonstrated in bacterial metabolism. The aim of this study was to investigate genotoxic and oxidative DNA damaging effects of 3-MCPD and its metabolites, and to provide a better understanding of their roles in DNA repair processes. DNA damage was assessed by alkaline comet assay in target rat kidney epithelial cell lines (NRK-52E) and human embryonic kidney cells (HEK-293). Purine and pyrimidine base damage, H2O2 sensitivity and DNA repair capacity were assessed via modified comet assay. The results revealed in vitro evidence for increased genotoxicity and H2O2 sensitivity. No association was found between oxidative DNA damage and DNA repair capacity with the exception of glycidol treatment at 20 μg/mL. These findings provide further insights into the mechanisms underlying the in vitro genotoxic potential of 3-MCPD and metabolites.
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http://dx.doi.org/10.1016/j.fct.2015.12.027DOI Listing
March 2016

The synthesis of recombinant membrane proteins in yeast for structural studies.

Methods 2016 Feb 30;95:26-37. Epub 2015 Sep 30.

School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK. Electronic address:

Historically, recombinant membrane protein production has been a major challenge meaning that many fewer membrane protein structures have been published than those of soluble proteins. However, there has been a recent, almost exponential increase in the number of membrane protein structures being deposited in the Protein Data Bank. This suggests that empirical methods are now available that can ensure the required protein supply for these difficult targets. This review focuses on methods that are available for protein production in yeast, which is an important source of recombinant eukaryotic membrane proteins. We provide an overview of approaches to optimize the expression plasmid, host cell and culture conditions, as well as the extraction and purification of functional protein for crystallization trials in preparation for structural studies.
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http://dx.doi.org/10.1016/j.ymeth.2015.09.027DOI Listing
February 2016

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

Arch Toxicol 2015 Feb 25;89(2):269-87. Epub 2015 Jan 25.

Systems Toxicology Unit, EURL-ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, TP 580, Via Fermi 1, 21026, Ispra, VA, Italy,

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.
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http://dx.doi.org/10.1007/s00204-015-1464-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309915PMC
February 2015