Endocrine Disruptors: A Critical Review of In Vitro and In Vivo Testing Strategies for Assessing Their Toxic Hazard to Humans

2000 ◽  
Vol 28 (1) ◽  
pp. 81-118 ◽  
Author(s):  
Robert D. Combes
Keyword(s):  
Endocrine Disruptors ◽  
Human Exposure ◽  
Mechanisms Of Action ◽  
Environmental Chemicals ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
Wide Range ◽  
The Us

Currently, there is much concern that a wide range of both synthetic and naturally occurring environmental chemicals can act as endocrine disruptors (EDs), and can adversely affect humans and wildlife. Many in vivo and in vitro tests have been proposed for screening EDs, and several regulatory agencies, including the US Environmental Protection Agency (EPA), have recommended tier-testing schemes. Unfortunately, most of the proposed toxicity tests have substantial problems, including non-specificity and lack of reproducibility. There is also uncertainty concerning their relevance for generating useful hazard data for risk assessment purposes, in view of the diversity of the possible ED mechanisms of action (for example, receptor binding, steroidogenesis and modulation of the homeostatic processes which regulate endogenous responses to hormones). Moreover, most of the suggested test methods have yet to be validated according to internationally accepted criteria, although the OECD and the US EPA have defined tests for validation, and an interlaboratory “prevalidation” exercise has been initiated by the OECD. All this is compounded by the lack of information regarding human exposure levels to EDs, and a lack of direct evidence for a causal link between exposure and the development of adverse human health effects. In addition, the regulatory testing of EDs has important negative implications for animal welfare, as some of the proposed in vivo tests require large group sizes of animals and stressful procedures. From a detailed analysis of the available published literature, it is concluded that it is impossible to assess the relative values of currently available in vitro and in vivo toxicity tests for EDs, or to recommend any test or test battery. Any plans for the widespread testing of EDs are therefore premature and might be unnecessary, at least for detecting possible human effects. Several recommendations are made for rectifying this unsatisfactory situation, including the postponement of screening programmes pending: a) more information on human exposure; b) further details of the mechanisms of action of EDs; and c) the development of improved tests, followed by their proper scientific validation.

scholarly journals Formulation of Improved Traditional Drugs against virulent species of Salmonella spp in Benin: assessment of the properties from Uvaria chamae, Lantana camara and Phyllantus amarus in Benin, West Africa

2019 ◽  
Author(s):  
Boris LEGBA ◽  
Victorien DOUGNON ◽  
Carène GBAGUIDI ◽  
Alidah ANIAMBOSSOU ◽  
Esther DEGUENON ◽  
...  
Keyword(s):  
Aqueous Extract ◽  
Bacterial Load ◽  
Scientific Data ◽  
Lantana Camara ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
Post Inoculation ◽  
Salmonella Spp

Abstract Background Uvaria chamae (Annonaceae), Phyllantus amarus (Phyllantaceae) and Lantana camara (Verbenaceae) are empirically alleged to be used as Beninese medicinal plants in the treatment of salmonellosis. This study aimed to produce scientific data on in vitro and in vivo efficacy of Uvaria chamae, Lantana camara and Phyllantus amarus on multiresistant Salmonella spp isolated in Benin.Results After in vitro tests on aqueous and ethanolic extracts of Uvaria chamae, Lantana camara and Phyllantus amarus , only the aqueous extract of Uvaria chamae (leaves) showed the best anti- Salmonella ’s activity. It has been used for the following experiments. The induction of salmonellosis revealed 9.0 10 8 CFU/ml was optimal concentration for triggering and maintaining the symptoms in chicks. This infective concentration has been used for in vivo assessment. 24 hours post inoculation later, the symptoms of salmonellosis (wet cloaca, diarrhea stool and somnolence) were observed in infected groups. After seven days of treatment, the rate of reduction of bacterial load at 100 mg / L, 200 mg / L, 400 mg / L of this extract was 85%, 52.38% and 98% respectively in the chicks groups infected with Salmonella Typhimurium ATCC 14028. About the groups infected with Salmonella spp (virulent strain), the rate of reduction of bacterial load at 100 mg / L, 200 mg / L, 400 mg / L of this extract was 0%, 98.66% and 99.33%. The toxicity tests did not show any significant effect of the Uvaria chamae ’s extract on the biochemical and hematological parameters of the chicks.Conclusion The aqueous extract of Uvaria chamae is active in vitro and in vivo on multiresistant strains of Salmonella spp . This plant is a good candidate for the development of an improved traditional medicine for the management of salmonellosis.

Making the most of sperm activation responses: experiments with boar spermatozoa and bicarbonate

2018 ◽  
Vol 30 (6) ◽  
pp. 842 ◽  
Author(s):  
William V. Holt ◽  
Nana Satake
Keyword(s):  
Semen Quality ◽  
Current Knowledge ◽  
Sperm Quality ◽  
Environmental Chemicals ◽  
Information Value ◽  
In Vitro Tests ◽  
Sperm Activation ◽  
Activation Mechanisms

Attempting to extract useful and reliable information about semen quality and its fertility potential remains a difficult exercise, partly because the sperm heterogeneity within samples often renders simple statistical analyses rather meaningless. In fact, a mean and standard deviation may reflect neither the very fast swimming activities of the most active cells nor the slow and sluggish activities of others. Herein we propose that the information value within semen samples can be maximised if current knowledge about sperm activation mechanisms is exploited before undertaking the measurements. We explain, using boar semen as an example, that estimating and defining relative sperm subpopulation sizes, after activation by bicarbonate, provides a means of quantifying sperm quality. Although such estimates may indeed be related to in vivo fertility, the general approach also suggests potential new avenues that could be exploited for the elaboration of novel in vitro tests for the characterisation of toxic environmental chemicals and, indeed, to reduce the number of animals used in such testing programs.

Regulatory Perspective on in Vitro Assays as Predictors of Phototoxicity and Photo Co-Carcinogenicity

1998 ◽  
Vol 17 (5) ◽  
pp. 571-575 ◽  
Author(s):  
Amy L. Ellis
Keyword(s):  
Mammalian Cells ◽  
Hairless Mouse ◽  
In Vitro Assays ◽  
In Vitro Tests ◽  
Drug Products ◽  
Drug Classes ◽  
Wide Range ◽  
Regulatory Perspective

Drugs from a variety of chemical classes used for a wide range of therapeutic indications can be photosensitizers in humans. Several drugs are phototoxic in animal models as well; there are no nonclinical data for many. In vitro tests have been developed as predictors of phototoxicity and although they have been used as screens, none have replaced the in vivo tests done in rodents (usually mice or guinea pigs) since these have been good predictors of clinical phototoxicity. Some phototoxic drug classes are co-carcinogens with ultraviolet radiation (UVA and/or UVB) in hairless mice, specifically psoralens, retinoids, and fluo-roquinolones. Treatment with 8-methoxypsoralen and ultraviolet A radiation for psoriasis is also carcinogenic in humans. It has been suggested that in vitro photogenotoxicity assays using microorganisms or mammalian cells may be predictive of photo co-carcinogenicity. Some attractions of these in vitro assays, compared to the hairless mouse photo co-carcinogenicity assay, are their generally shorter duration and lower cost as well as reducing the number of animals used in research. Currently, personnel at the Food and Drug Administration (FDA) are examining the available data on phototoxicity, photogenotoxicity, and photo co-carcinogenicity to determine how this information can best be used toregulate and label drug products, and considering which assays should be recommended under specific circumstances.

scholarly journals Bisphenol A Analogues: A Brief Review of their Occurrence in Food, Biological Samples and Endocrine Effects

2020 ◽  
Vol 2 (4) ◽  
pp. 89-94
Author(s):  
Nikola Knizatova ◽  
Katarína Tokárová ◽  
Hana Greifová ◽  
Tomáš Jambor ◽  
Peter Massányi ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Human Health ◽  
Human Exposure ◽  
Food Packaging ◽  
In Vitro Tests ◽  
Endocrine Disrupting Chemical ◽  
Endocrine Disrupting ◽  
Made In

Bisphenol A (BPA) is the most well-known compound from the bisphenol family. There is increasing evidence that bisphenol BPA used in plastics, receipts, food packaging, and other products might be harmful to human health due to its actions as an endocrine-disrupting chemical, therefore BPA is being replaced by compounds very similar in structure, but data on the occurrence and effects of these BPA analogs are limited. Therefore, there is increasing concern regarding human exposure to bisphenol analogs (BPs) due to their widespread use and potential adverse effects. The main objective of this work was to investigate human exposure to BPs and the associated endocrine activities. We performed a literature review of the available research made in humans, in in vivo and in vitro tests. The findings support the idea that exposure to BPs may have an impact on human health, especially in terms of endocrine disruption.

scholarly journals Bisphenol A Analogues in Food and Their Hormonal and Obesogenic Effects: A Review

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2136 ◽  
Author(s):  
Andújar ◽  
Gálvez-Ontiveros ◽  
Zafra-Gómez ◽  
Rodrigo ◽  
Álvarez-Cubero ◽  
...  
Keyword(s):  
Literature Review ◽  
Bisphenol A ◽  
Human Health ◽  
Health Effects ◽  
Human Exposure ◽  
In Vitro Tests ◽  
Adverse Health Effects ◽  
Made In

Bisphenol A (BPA) is the most well-known compound from the bisphenol family. As BPA has recently come under pressure, it is being replaced by compounds very similar in structure, but data on the occurrence of these BPA analogues in food and human matrices are limited. The main objective of this work was to investigate human exposure to BPA and analogues and the associated health effects. We performed a literature review of the available research made in humans, in in vivo and in vitro tests. The findings support the idea that exposure to BPA analogues may have an impact on human health, especially in terms of obesity and other adverse health effects in children.

scholarly journals In Vitro Tests for Assessing the Neutralizing Ability of Snake Antivenoms: Toward the 3Rs Principles

2021 ◽  
Vol 11 ◽  
Author(s):  
José María Gutiérrez ◽  
Mariángela Vargas ◽  
Álvaro Segura ◽  
María Herrera ◽  
Mauren Villalta ◽  
...  
Keyword(s):  
State Of The Art ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
Enzyme Assays ◽  
Snake Venoms ◽  
Experimental Animals ◽  
Functional Assays ◽  
3Rs Principle

There is an urgent need to strengthen the implementation of the 3Rs principle (Replacement, Reduction and Refinement) in the use of experimental animals in toxinological research and in the assessment of the neutralizing efficacy of snake antivenoms. This is a challenging task owing to the inherent complexity of snake venoms. The state of the art on this topic is hereby reviewed, with emphasis on the studies in which a correlation has been observed between in vivo toxicity tests and in vitro surrogate assays, particularly in the study of lethal activity of venoms and its neutralization. Correlations have been described with some venoms-antivenoms when using: (a) enzyme immunoassays, (b) hemagglutination, (c) enzyme assays (proteinase, phospholipase A2), (d) in vitro coagulant effect on plasma, (e) cell culture assays for cytotoxicity, (f) functional assays for assessing neurotoxicity in vitro, (g) use of hens’ eggs, and (h) antivenomics. Additionally, the routine introduction of analgesia in these assays and the design of more ‘humane’ protocols for the lethality test are being pursued. It is expected that the next years will witness a growing awareness of the relevance of the 3Rs principles in antivenom testing, and that new in vitro alternatives and more ‘humane’ experimental designs will emerge in this field.

scholarly journals Cancer Risk Assessment Strategies Based on Mechanisms of Action

1988 ◽  
Vol 7 (4) ◽  
pp. 417-425
Author(s):  
John H. Weisburger
Keyword(s):  
Risk Assessment ◽  
Cancer Risk ◽  
Neoplastic Cell ◽  
Mechanisms Of Action ◽  
Cancer Risk Assessment ◽  
In Vitro Tests ◽  
Carcinogenic Effects ◽  
Effect Level

The induction of cancer by chemicals is a complex process that involves a series of steps, proceeding from the neoplastic conversion of a normal cell, i.e., the discrete mechanistically distinct initiation of a neoplastic cell, through the steps involving promotion, development, and progression. Chemicals can act in each of these stages as initiators, cocarcinogens, promoters, or inhibitors of carcinogenesis. Chemicals must be classified as operating by genotoxic or epigenetic mechanisms. Appropriate short-term in vitro tests used as a battery can be applied to detect such properties. These abbreviated and economic tests have good qualitative decision-making potential, since they are based on mechanisms of action. Advances in molecular biology may provide additional tests to detect cancer risk. Quantitative data available from in vivo dose-response studies demonstrate that carcinogenic effects are dose dependent, and, therefore, a threshold or no-effect level probably exists that is low for potent carcinogens, especially genotoxins, and high for weaker ones, particularly epigenetic agents. A set of mechanism-oriented data must be acquired systematically to serve as basis for realistic and effective risk assessment and management.

scholarly journals Flavonoids and Stilbenoids of the Genera Dracaena and Sansevieria: Structures and Bioactivities

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2608 ◽  
Author(s):  
Zaw Min Thu ◽  
Ko Ko Myo ◽  
Hnin Thanda Aung ◽  
Chabaco Armijos ◽  
Giovanni Vidari
Keyword(s):  
Southeast Asia ◽  
In Vitro Tests ◽  
Cytotoxic Activities ◽  
Isolation And Identification ◽  
Traditional Medicines ◽  
Wide Range ◽  
Phytochemical Constituents ◽  
Anti Inflammatory

The genera Dracaena and Sansevieria (Asparagaceae, Nolinoideae) are still poorly resolved phylogenetically. Plants of these genera are commonly distributed in Africa, China, Southeast Asia, and America. Most of them are cultivated for ornamental and medicinal purposes and are used in various traditional medicines due to the wide range of ethnopharmacological properties. Extensive in vivo and in vitro tests have been carried out to prove the ethnopharmacological claims and other bioactivities. These investigations have been accompanied by the isolation and identification of hundreds of phytochemical constituents. The most characteristic metabolites are steroids, flavonoids, stilbenes, and saponins; many of them exhibit potent analgesic, anti-inflammatory, antimicrobial, antioxidant, antiproliferative, and cytotoxic activities. This review highlights the structures and bioactivities of flavonoids and stilbenoids isolated from Dracaena and Sansevieria.

Can the In Vivo Maximum Tolerated Dose be Predicted Using In Vitro Techniques? A Working Hypothesis

1991 ◽  
Vol 19 (4) ◽  
pp. 393-402
Author(s):  
Ravi Shrivastava ◽  
Gareth W. John ◽  
Ginette Rispat ◽  
Annick Chevalier ◽  
Roy Massingham
Keyword(s):  
Cell Death ◽  
Research Effort ◽  
Maximum Tolerated Dose ◽  
In Vitro Cytotoxicity ◽  
Toxicity Tests ◽  
In Vitro Toxicity ◽  
Working Hypothesis ◽  
Wide Range

All new chemical entities synthesised in our laboratories have routinely been subjected to in vitro toxicity tests. Out of curiosity, we established a working hypothesis in which the in vitro data could be empirically transformed to predict the in vivo four-week standard maximum tolerated dose (MTD) studies in rats and dogs. As a first step to verifying this hypothesis, we report here the findings of an in vitro cytotoxicity study of 25 compounds randomly selected from our files, possessing a wide range of pharmacological activities and for which data from standard four-week MTD studies were available. Single blind in vitro toxicity studies in three carefully selected types of primary and cell line cultures were carried out. In vitro CT50 (concentration inducing 50% cell death) and CT100 (concentration inducing 100% cell death) values were obtained for each of the three cell types and, using empirical assumptions, these results were used to predict the MTD in vivo in the rat and dog. The actual in vivo threshold and toxic doses were obtained from the MTD study reports. The in vivo toxicity values predicted from the in vitro toxicity results with this series of 25 compounds showed a better than 80% correlation with the actual in vivo results obtained in the MTD studies. Whether or not in vitro cytotoxicity predictions are ultimately found to be directly and consistently related to the MTD in vivo for all pharmacological classes of compounds will require many additional studies, but it is hoped that these results will stimulate the necessary research effort required to answer this question.

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