scholarly journals PeBiToSens™: A Platform for PBT Screening of Fragrance Ingredients Without Animal Testing

2020 ◽  
Vol 74 (3) ◽  
pp. 168-175
Author(s):  
Heike Laue ◽  
Lu Hostettler ◽  
Gordon Sanders ◽  
Georg Kreutzer ◽  
Andreas Natsch
Keyword(s):  
The Body ◽  
Trophic Levels ◽  
Chemical Toxicity ◽  
Animal Testing ◽  
Ecotoxicological Assessment ◽  
Microbial Biodegradation ◽  
Animal Tests ◽  
Safe By Design

The determination of persistence (P), bioaccumulation (B) and toxicity (T) plays a central role in the environmental assessment of chemicals. Persistence is typically evaluated via standard microbial biodegradation tests. Bioaccumulation refers to the accumulation of chemicals in organisms and is usually assessed in fish exposed to the test chemical. Toxicity is determined at three trophic levels, with fish toxicity as the highest trophic level assessed. Thus, animal tests are classically needed for both B and T assessment. In vitro systems based on fish liver cells or liver S9 fractions ('RT-S9 assay') have been recently adopted by OECD to measure the biotransformation rates for the chemicals for B assessment. Biotransformation drives clearance from the body and reduces bioaccumulation. For T assessment, an assay based on in vitro toxicity on fish gill cells has been established ('RTgill-W1 assay'). Here we summarize our findings indicating that these tests are highly predictive for fragrance ingredients, and show with two case studies of our latest new registered substances how we apply these tests in particular during development and also for chemical registration. This platform of tests (PeBiToSens™) could fully replace animal tests in ecotoxicological assessment and is key in the Givaudan Safe by Design™ approach to develop safer and environmentally compatible novel fragrance ingredients.

scholarly journals Commentary on ‘‘Toxicity Testing in the 21st Century: A vision and a Strategy’’

2010 ◽  
Vol 29 (1) ◽  
pp. 11-14 ◽  
Author(s):  
Robert F Phalen
Keyword(s):  
21St Century ◽  
Toxicity Testing ◽  
In Vitro Testing ◽  
Chemical Toxicity ◽  
Animal Testing ◽  
In Vitro Techniques ◽  
Human Monitoring ◽  
Animal Tests ◽  
In Silico Methods

Toxicity Testing in the 21st Century: A Vision and a Strategy (NRC, 2007) presents a bold plan for chemical toxicity testing that replaces whole-animal tests with cell-culture, genetic, other in-vitro techniques, computational methods, and human monitoring. Although the proposed vision is eloquently described, and recent advances in in-vitro and in-silico methods are impressive, it is difficult believe that replacing in-vitro testing is either practical or wise. It is not clear that the toxicity-related events that occur in whole animals can be adequately replicated using the proposed methods. Protecting public health is a serious endeavor that should not be limited by denying animal testing. Toxicologists and regulators are encouraged to read the report, carefully consider its implications, and share their thoughts. The vision is for too important to ignore.

scholarly journals Modern Approaches to Determination of the Biological Activity of Insulin and its

2019 ◽  
Vol 9 (2) ◽  
pp. 85-92
Author(s):  
T. A. Batuashvili ◽  
L. V. Simutenko ◽  
P. V. Shadrin ◽  
N. P. Neugodova
Keyword(s):  
Biological Activity ◽  
Animal Models ◽  
Insulin Analogues ◽  
Quality Parameters ◽  
The Body ◽  
Animal Testing ◽  
Biological Potency

The paper considers insulin’s specific action on the patient’s body, types of insulin preparations and insulin analogues which are used for the treatment of diabetes, as well as applicable requirements for these products. It was demonstrated that determination of biological activity is one of the key quality parameters of this type of medicines. The paper summarises the methods used for evaluation of insulin and its analogues, which are based both on the hormone’s general action on the body (in vivo: double crossing, euglycemic clamp, etc.), and on certain aspects of the hormone’s interaction with the body systems (in vitro: receptor-binding assay, phosphorylation, metabolic methods). Due to the appearance of insulin biosimilars on the pharmaceutical market, the article raises the issue that the «Biological potency» parameter tested in animals should be kept as part of the product specification. The analysis of the in vivo and in vitro methods of biological activity determination convincingly demonstrates that animal models can not be replaced with the modern analytical methods based on cell cultures. Consequently, animal models are still necessary, as they allow for an adequate assessment of the quality of insulins in terms of «Biological potency». Taking into account the global trend towards reduction of animal testing, the authors point out the need to develop modern methods, the results of which will be comparable to the results of in vivo determination of the biological activity.

scholarly journals Chemical toxicity prediction based on semi-supervised learning and graph convolutional neural network

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jiarui Chen ◽  
Yain-Whar Si ◽  
Chon-Wai Un ◽  
Shirley W. I. Siu
Keyword(s):  
Neural Network ◽  
Supervised Learning ◽  
Superior Performance ◽  
Chemical Toxicity ◽  
Animal Testing ◽  
Toxicity Prediction ◽  
Discovery Research ◽  
Drug Discovery Research

AbstractAs safety is one of the most important properties of drugs, chemical toxicology prediction has received increasing attentions in the drug discovery research. Traditionally, researchers rely on in vitro and in vivo experiments to test the toxicity of chemical compounds. However, not only are these experiments time consuming and costly, but experiments that involve animal testing are increasingly subject to ethical concerns. While traditional machine learning (ML) methods have been used in the field with some success, the limited availability of annotated toxicity data is the major hurdle for further improving model performance. Inspired by the success of semi-supervised learning (SSL) algorithms, we propose a Graph Convolution Neural Network (GCN) to predict chemical toxicity and trained the network by the Mean Teacher (MT) SSL algorithm. Using the Tox21 data, our optimal SSL-GCN models for predicting the twelve toxicological endpoints achieve an average ROC-AUC score of 0.757 in the test set, which is a 6% improvement over GCN models trained by supervised learning and conventional ML methods. Our SSL-GCN models also exhibit superior performance when compared to models constructed using the built-in DeepChem ML methods. This study demonstrates that SSL can increase the prediction power of models by learning from unannotated data. The optimal unannotated to annotated data ratio ranges between 1:1 and 4:1. This study demonstrates the success of SSL in chemical toxicity prediction; the same technique is expected to be beneficial to other chemical property prediction tasks by utilizing existing large chemical databases. Our optimal model SSL-GCN is hosted on an online server accessible through: https://app.cbbio.online/ssl-gcn/home.

An Evaluation of the Proposed OECD Testing Strategy for Skin Corrosion

1998 ◽  
Vol 26 (5) ◽  
pp. 709-720 ◽  
Author(s):  
Andrew P. Worth ◽  
Julia H. Fentem ◽  
Michael Balls ◽  
Philip A. Botham ◽  
Rodger D. Curren ◽  
...  
Keyword(s):  
Skin Irritation ◽  
Alternative Methods ◽  
Advisory Group ◽  
Chemical Toxicity ◽  
Testing Strategy ◽  
Animal Testing ◽  
Ph Measurements ◽  
Testing Strategies

The use of testing strategies which incorporate a range of alternative methods and which use animals only as a last resort is widely considered to provide a reliable way of predicting chemical toxicity while minimising animal testing. The widespread concern over the severity of the Draize rabbit test for assessing skin irritation and corrosion led to the proposal of a stepwise testing strategy at an OECD workshop in January 1996. Subsequently, the proposed testing strategy was adopted, with minor modifications, by the OECD Advisory Group on Harmonization of Classification and Labelling. This article reports an evaluation of the proposed OECD testing strategy as it relates to the classification of skin corrosives. By using a set of 60 chemicals, an assessment was made of the effect of applying three steps in the strategy, taken both individually and in sequence. The results indicate that chemicals can be classified as corrosive (C) or non-corrosive (NC) with sufficient reliability by the sequential application of three alternative methods, i.e., structure-activity relationships (where available), pH measurements, and a single in vitro method (either the rat skin transcutaneous electrical resistance (TER) assay or the EPISKIN™ assay). It is concluded that the proposed OECD strategy for skin corrosion can be simplified without compromising its predictivity. For example, it does not appear necessary to measure acid/alkali reserve (buffering capacity) in addition to pH for the classification of pure chemicals.

scholarly journals Drug delivery: Epithelial cell models for drug transport and toxicology studies

2014 ◽  
Vol 36 (3) ◽  
pp. 8-12
Author(s):  
Martin C. Garnett ◽  
Driton Vllasaliu ◽  
Snow Stolnik ◽  
Franco H. Falcone
Keyword(s):  
Gastrointestinal Tract ◽  
Epithelial Cell ◽  
Oral Delivery ◽  
Drug Transport ◽  
In Vitro Models ◽  
The Body ◽  
Cell Models ◽  
Animal Testing ◽  
Epithelial Barriers

The development of medicines during the 20th Century was initially based on oral delivery of drugs via the gastrointestinal tract. To enhance understanding of rate of uptake of different drugs and formulations and reduce the need for animal testing, in vitro models based on gut epithelial cell models were developed in the 1980s and 1990s. With the advent of biotechnology, an increasing number of drugs based on proteins and other biomolecules are being produced, which currently require parenteral administration (by injection). To avoid the need for injection, alternative routes of delivery are being sought for these molecules, including mucosal routes of the gastrointestinal tract and the lung. In parallel with this, the field of ‘nanotechnology’ began to develop. Nanotechnology offers both solutions and problems. ‘Nanomedicines’ over a range of nano sizes appear to offer some solutions for delivery, provided that they could cross epithelial barriers. In contrast, there remains considerable concern that the many different types of nanoparticles in development for electronics and new materials may be taken up into the body and cause harm. There are therefore clear needs for epithelial models which allow us to not only screen conventional drugs for absorption, but also assess potential non-invasive delivery of biologics and nanomedicines, as well as screen easily and reliably for nanotoxicology1. As it is the same barrier involved in all of these cases, we need a single epithelial model that can adequately reflect and give accurate answers for all of these different barrier problems. In this article, we assess the properties needed for an epithelial cellular model, the current state of the art, and some recent work developing a more accurate and comprehensive model.

scholarly journals Chemical Toxicity Prediction Based on Semi-supervised Learning and Graph Convolutional Neural Network

2021 ◽  
Author(s):  
Jiarui Chen ◽  
Yain-Whar Si ◽  
Chon-Wai Un ◽  
Shirley W. I. Siu
Keyword(s):  
Neural Network ◽  
Supervised Learning ◽  
Superior Performance ◽  
Chemical Toxicity ◽  
Animal Testing ◽  
Toxicity Prediction ◽  
Discovery Research ◽  
Drug Discovery Research

Abstract As safety is one of the most important properties of drugs, chemical toxicology prediction has received increasing attentions in the drug discovery research. Traditionally, researchers rely on in vitro and in vivo experiments to test the toxicity of chemical compounds. However, not only are these experiments time consuming and costly, but experiments that involve animal testing are increasingly subject to ethical concerns. While traditional machine learning (ML) methods have been used in the field with some success, the limited availability of annotated toxicity data is the major hurdle for further improving model performance. Inspired by the success of semi-supervised learning (SSL) algorithms, we propose a Graph Convolution Neural Network (GCN) to predict chemical toxicity and trained the network by the Mean Teacher (MT) SSL algorithm. Using the Tox21 data, our optimal SSL-GCN models for predicting the twelve toxicological endpoints achieve an average ROC-AUC score of 0.757 in the test set, which is a 6% improvement over GCN models trained by supervised learning and conventional ML methods. Our SSL-GCN models also exhibit superior performance when compared to models constructed using the built-in DeepChem ML methods. This study demonstrates that SSL can increase the prediction power of models by learning from unannotated data. The optimal unannotated to annotated data ratio ranges between 1:1 and 4:1. This study demonstrates the success of SSL in chemical toxicity prediction; the same technique is expected to be beneficial to other chemical property prediction tasks by utilizing existing large chemical databases.

Ten Years of REACH — An Animal Protection Perspective

2018 ◽  
Vol 46 (6) ◽  
pp. 347-373 ◽  
Author(s):  
Katy Taylor
Keyword(s):  
European Commission ◽  
Chemical Industry ◽  
Alternative Methods ◽  
Animal Testing ◽  
Annual Average ◽  
Animal Protection ◽  
Reach Regulation ◽  
Similar Legislation ◽  
Animal Tests

It has now been 11 years since the EU's new chemicals legislation ( Regulation No. 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals [REACH]) came into force. Two important statements in the REACH Regulation in relation to animal testing and alternatives are: Article 1(1), which states that one of its purposes is to promote alternative methods; and Article 25(1), which states that animal testing should be used as a last resort. This review looks at the mechanisms that were put in place within REACH to achieve these aims and asks, not only if they are being implemented properly, but also if they have been sufficient. Whilst the chemical industry has heavily used data-sharing and read-across, this review concludes that nevertheless over 2.2 million animals have already been used in new tests for REACH registrations. This equates to an annual average of 275,000 animals; 58,000 more per year than the best-case estimate made by the European Commission in 2004. The use of in vitro and (Q)SAR approaches as standalone replacements for animal tests has been relatively low. The levels of funding for research into alternative methods remain low, and there are concerns over the speed of formal adoption of those that have been validated. In addition, there have been issues with the recognition that testing as a last resort and the promotion of alternative methods applies to all parties, including the Commission, Member States and the agency responsible, the European Chemicals Agency. This review provides ten recommendations for better implementation of these two key aspirations, as well as lessons to be learned for future similar legislation.

An Optimized MTT Bioassay for Determination of Cytotoxicity of Fumonisins in Turkey Lymphocytes

1994 ◽  
Vol 77 (2) ◽  
pp. 512-516 ◽  
Author(s):  
Mary A Dombrink-Kurtzman ◽  
Glenn A Bennett ◽  
John L Richard
Keyword(s):  
Gradient Centrifugation ◽  
In Vitro Cytotoxicity ◽  
Tetrazolium Salt ◽  
Animal Testing ◽  
Cytotoxicity Assays ◽  
Cytoplasmic Vacuolization ◽  
Diphenyl Tetrazolium Bromide ◽  
Dose Dependent

Abstract In vitro cytotoxicity assays have been performed for detection and quantitation of fumonisins, as possible alternatives for whole animal testing. This study was undertaken to establish optimal in vitro conditions using turkey lymphocytes. Turkey lymphocytes were isolated from peripheral blood by Percoll gradient centrifugation. Cytotoxicity of fu-monisin B1 (FB1) and B2 (FB2) was determined by exposing lymphocytes to FB1 or FB2 at concentrations of 0.01–25 μg/mL for 24,48, or 72 h at 39°C. The MTT bioassay was used to measure cell viability and proliferation. In metabolically active cells, the tetrazolium salt, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide], was reduced to MTT formazan. Turkey lymphocytes that had been exposed in vitro to FB1 and FB2 for 48 and 72 h showed inhibition of cell proliferation that was dose-dependent. The 50% inhibitory dose for FB1 and FB2 was 0.4–5 μg/mL. Cells exposed to FB1 or FB2 exhibited high levels of cytoplasmic vacuolization and were unable to proliferate, whereas proliferation of control lymphocytes was observed at 48 and 72 h. FB2 was 3- to 4-fold more cytotoxic than FB1.

Mechanisms of adaptation of motor «fast» and «slow» locomotor muscles in mice under conditions of allergic reorganization of the body

2021 ◽  
pp. 64-72
Author(s):  
Aleksandr Yurievich Teplov
Keyword(s):  
Sports Medicine ◽  
Contractile Function ◽  
The State ◽  
The Body ◽  
Mechanisms Of Adaptation ◽  
Locomotor Muscles ◽  
Action Taking ◽  
Mandatory Vaccination

The state of the contractile function of transversely striated locomotor muscles under conditions of allergic reorganization remains relevant for modern sports medicine. In particular, it is known that the mandatory vaccination of athletes before the competition leads to changes in the state of the muscular system. The mechanisms of these changes are not fully understood. In the presented work, the following research methods were used: the registration of: a) the contractile function of various locomotor «fast» and «slow» muscles of the mouse in vitro on humoral initiators of contraction — carbacholine (CCh) and potassium chloride (KCI); b) indicators of the systems of pro- and antioxidant balance in the blood and in the tissues of these muscles and the determination of the level of malondialdehyde (MDA) in them. The differences in the ratios of the dynamics of the contraction force and the MDA level in both muscles demonstrate the degree of their resistance to oxidative stress, which determines the differences in the mechanisms of their adaptation to allergic reorganization. The materials of the article can be used to correct the function of locomotor muscles during vaccination, as well as to determine the strategy of therapeutic action, taking into account their fiber composition. The purpose of the article is to determine the mechanisms of adaptation of skeletal muscles (SM) of the mouse («fast» (m.EDL) and «slow» (m.Soleus)) during allergic reorganization.

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