scholarly journals Advancing Chemical Risk Assessment through Human Physiology-Based Biochemical Process Modeling

Fluids ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 4 ◽  
Author(s):  
Dimosthenis Sarigiannis ◽  
Spyros Karakitsios
Keyword(s):  
Risk Assessment ◽  
Effective Dose ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Daily Intake ◽  
Adverse Outcomes ◽  
Internal Exposure ◽  
Biological Pathway ◽  
Exposure Levels

Physiology-Based BioKinetic (PBBK) models are of increasing interest in modern risk assessment, providing quantitative information regarding the absorption, metabolism, distribution, and excretion (ADME). They focus on the estimation of the effective dose at target sites, aiming at the identification of xenobiotic levels that are able to result in perturbations to the biological pathway that are potentially associated with adverse outcomes. The current study aims at the development of a lifetime PBBK model that covers a large chemical space, coupled with a framework for human biomonitoring (HBM) data assimilation. The methodology developed herein was demonstrated in the case of bisphenol A (BPA), where exposure analysis was based on European HBM data. Based on our calculations, it was found that current exposure levels in Europe are below the temporary Tolerable Daily Intake (t-TDI) of 4 μg/kg_bw/day proposed by the European Food Safety Authority (EFSA). Taking into account age-dependent bioavailability differences, internal exposure was estimated and compared with the biologically effective dose (BED) resulting from translating the EFSA temporary total daily intake (t-TDI) into equivalent internal dose and an alternative internal exposure reference value, namely biological pathway altering dose (BPAD); the use of such a refined exposure metric, showed that environmentally relevant exposure levels are below the concentrations associated with the activation of biological pathways relevant to toxicity based on High Throughput Screening (HTS) in vitro studies.

scholarly journals Biomonitoring and Subsequent Risk Assessment of Combined Exposure to Phthalates in Iranian Children and Adolescents

2018 ◽  
Vol 15 (11) ◽  
pp. 2336 ◽  
Author(s):  
Maryam Zare Jeddi ◽  
Mohamad Eshaghi Gorji ◽  
Ivonne Rietjens ◽  
Jochem Louisse ◽  
Yuri Bruinen de Bruin ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Children And Adolescents ◽  
Health Risks ◽  
Safety Concern ◽  
Hazard Quotient ◽  
Daily Intake ◽  
Hazard Index ◽  
Internal Exposure ◽  
Combined Exposure ◽  
Iranian Children

This study aimed to estimate the exposure and related health risks of phthalates, and to assess the health risks from combined exposure to three of the phthalates sharing the same mode of action (anti-androgenicity) in children. We determined the internal exposure of 56 Iranian children and adolescents aged 6 to 18 years by analyzing seven urinary metabolites of five phthalates. The estimated daily intake values derived from the biomonitoring data ranged from 0.01 µg/kg bw/day for butyl benzyl phthalate (BBP), to 17.85 µg/kg bw/day for di(2-ethylhexyl) phthalate (DEHP). The risk assessment revealed that not only the exposure to the individual phthalates, but also the combined exposure to the three anti-androgenic phthalates (DEHP, DBP, BBP) did not raise a safety concern (hazard index values averaged 0.2). The range of maximum cumulative ratio values varied from around 1 for most individuals to around 2 in some individuals, indicating that the combined exposures were dominated by one and in some cases by two of the three anti-androgenic phthalates, especially dibutyl phthalate (DBP) and/or DEHP. Based on biomonitoring data, the overall combined exposure of Iranian children to phthalates does not raise a concern, while reduction of exposure is best focused on DEHP and DBP that showed the highest hazard quotient.

Estimation of daily intake and risk assessment of organophosphorus pesticides based on biomonitoring data – The internal exposure approach

2019 ◽  
Vol 123 ◽  
pp. 57-71 ◽  
Author(s):  
Ioanna Katsikantami ◽  
Claudio Colosio ◽  
Athanasios Alegakis ◽  
Manolis N. Tzatzarakis ◽  
Elena Vakonaki ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Organophosphorus Pesticides ◽  
Daily Intake ◽  
Internal Exposure

scholarly journals Internal Threshold of Toxicological Concern (iTTC): Where We Are Today and What Is Possible in the Near Future

2021 ◽  
Vol 2 ◽  
Author(s):  
Corie A. Ellison ◽  
Anne Marie Api ◽  
Richard A. Becker ◽  
Alina Y. Efremenko ◽  
Sanket Gadhia ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Assessment Tool ◽  
Plasma Concentrations ◽  
Hepatic Metabolism ◽  
Internal Exposure ◽  
Pbpk Modeling ◽  
Pharmacokinetic Data ◽  
Stakeholder Collaboration ◽  
Threshold Of Toxicological Concern

The Threshold of Toxicological Concern (TTC) is a risk assessment tool for evaluating low-level exposure to chemicals with limited toxicological data. A next step in the ongoing development of TTC is to extend this concept further so that it can be applied to internal exposures. This refinement of TTC based on plasma concentrations, referred to as internal TTC (iTTC), attempts to convert the chemical-specific external NOAELs (in mg/kg/day) in the TTC database to an estimated internal exposure. A multi-stakeholder collaboration formed, with the aim of establishing an iTTC suitable for human safety risk assessment. Here, we discuss the advances and future directions for the iTTC project, including: (1) results from the systematic literature search for metabolism and pharmacokinetic data for the 1,251 chemicals in the iTTC database; (2) selection of ~350 chemicals that will be included in the final iTTC; (3) an overview of the in vitro caco-2 and in vitro hepatic metabolism studies currently being generated for the iTTC chemicals; (4) demonstrate how PBPK modeling is being utilized to convert a chemical-specific external NOAEL to an internal exposure; (5) perspective on the next steps in the iTTC project.

scholarly journals High Throughput Screening of the NatureBank ‘Marine Collection’ in a Haemonchus Bioassay Identifies Anthelmintic Activity in Extracts from a Range of Sponges from Australian Waters

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5846
Author(s):  
Aya C. Taki ◽  
Joseph J. Byrne ◽  
Abdul Jabbar ◽  
Kah Yean Lum ◽  
Sasha Hayes ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Marine Invertebrates ◽  
Chemical Space ◽  
Anthelmintic Activity ◽  
Distinct Species ◽  
Parasitic Nematodes ◽  
Wild Type ◽  
Control Programs

Widespread resistance in parasitic nematodes to most classes of anthelmintic drugs demands the discovery and development of novel compounds with distinct mechanisms of action to complement strategic or integrated parasite control programs. Products from nature—which assume a diverse ‘chemical space’—have significant potential as a source of anthelmintic compounds. In the present study, we screened a collection of extracts (n = 7616) derived from marine invertebrates sampled from Australian waters in a high throughput bioassay for in vitro anti-parasitic activity against the barber’s pole worm (Haemonchus contortus)—an economically important parasitic nematode of livestock animals. In this high throughput screen (HTS), we identified 58 active extracts that reduced larval motility by ≥70% (at 90 h), equating to an overall ‘hit rate’ of ~0.8%. Of these 58 extracts, 16 also inhibited larval development by ≥80% (at 168 h) and/or induced ‘non-wild-type’ (abnormal) larval phenotypes with reference to ‘wild-type’ (normal) larvae not exposed to extract (negative controls). Most active extracts (54 of 58) originated from sponges, three from chordates (tunicates) and one from a coral; these extracts represented 37 distinct species/taxa of 23 families. An analysis of samples by 1H NMR fingerprinting was utilised to dereplicate hits and to prioritise a set of 29 sponge samples for future chemical investigation. Overall, these results indicate that a range of sponge species from Australian waters represents a rich source of natural compounds with nematocidal or nematostatic properties. Our plan now is to focus on in-depth chemical investigations of the sample set prioritised herein.

scholarly journals Application of hepatocyte-like cells to enhance hepatic safety risk assessment in drug discovery

2018 ◽  
Vol 373 (1750) ◽  
pp. 20170228 ◽  
Author(s):  
Dominic P. Williams
Keyword(s):  
Risk Assessment ◽  
Drug Discovery ◽  
High Throughput Screening ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Genetic Characteristics ◽  
Short Period ◽  
Donor Variation ◽  
Discovery Pipeline

Hepatic stress and injury from drugs continues to be a major concern within the pharmaceutical industry, leading to preclinical and clinical attrition precautionary warnings and post-market withdrawal of drugs. There is a requirement for more predictive and mechanistically accurate models to aid risk assessment. Primary human hepatocytes, subject to isolation stress, cryopreservation, donor-to-donor variation and a relatively short period of functional capability in two-dimensional cultures, are not suitable for high-throughput screening procedures. There are two areas within the drug discovery pipeline that the generation of a stable, metabolically functional hepatocyte-like cell with unlimited supply would have major impact. First, in routine, cell health risk-assessment assays where hepatic cell lines are typically deployed. Second, at later stages of the drug discovery pipeline approaching candidate nomination where bespoke/investigational studies refining and understanding the risk to patients use patient-derived induced pluripotent stem cell (iPSC) hepatocytes retaining characteristics from the patient, e.g. HLA susceptibility alleles, iPSC hepatocytes with defined disease phenotypes or genetic characteristics that have the potential to make the hepatocyte more sensitive to a particular stress mechanism. Functionality of patient-centric hepatocyte-like cells is likely to be enhanced when coupled with emerging culture systems, such as three-dimensional spheroids or microphysiological systems. Ultimately, the aspiration to confidently use human-relevant in vitro models to predict human-specific hepatic toxicity depends on the integration of promising emerging technologies. This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.

Abstracts

2008 ◽  
Vol 27 (6) ◽  
pp. 405-405
Author(s):  
David J. Dix
Keyword(s):  
Risk Assessment ◽  
High Throughput ◽  
Environmental Protection Agency ◽  
High Throughput Screening ◽  
Human Health Risk ◽  
Environmental Chemicals ◽  
In Vitro Assays ◽  
The Impact ◽  
Toxicity Pathways

The U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), and National Institutes of Health (NIH) Chemical Genomics Center (NCGC) have complementary research programs designed to improve chemical toxicity evaluations by developing high throughput screening (HTS) methods that evaluate the impact of environmental chemicals on key toxicity pathways. These federal partners are coordinating an extension of the EPA’s ToxCast program, the NTP’s HTS initiative, and the NCGC’s Molecular Libraries Initiative into a collaborative research program focused on identifying toxicity pathways and developing in vitro assays to characterize the ability of chemicals to perturb those pathways. The goal is to develop new paradigm for high throughput toxicity testing that collects mechanistic and quantitative data from in vitro assays measuring chemical modulation of biological processes involved in the progression to toxicity. As toxicity pathways are identified, the in vitro assays can be optimized for comparison to in vivo animal studies, and for predicting effects in humans. Subsequent computational modeling of toxicity pathway responses and appropriate chemical dosimetry will need to be developed to make these predictions relevant for human health risk assessment. This work was reviewed by EPA and approved for publication but does not necessarily reflect official Agency policy. Index Terms: Toxicogenomics, High Throughput Screening/Testing, EPA ToxCast, Chemical Risk Assessment

scholarly journals The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies

2020 ◽  
Vol 21 (7) ◽  
pp. 2387 ◽  
Author(s):  
Rong-Jane Chen ◽  
Yu-Ying Chen ◽  
Mei-Yi Liao ◽  
Yu-Hsuan Lee ◽  
Zi-Yu Chen ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Health And Safety ◽  
Adverse Outcomes ◽  
Testing Strategy ◽  
C Elegans ◽  
Testing Strategies ◽  
Alternative Testing ◽  
Alternative Testing Strategies

Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.

scholarly journals Novel Methods and Approaches for Safety Evaluation of Nanoparticle Formulations: A Focus Towards In Vitro Models and Adverse Outcome Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Mounika Gayathri Tirumala ◽  
Pratibha Anchi ◽  
Susmitha Raja ◽  
Mahesh Rachamalla ◽  
Chandraiah Godugu
Keyword(s):  
Risk Assessment ◽  
Adverse Outcome ◽  
Safety Concern ◽  
Single Cells ◽  
High Surface ◽  
Adverse Outcomes ◽  
Novel Methods ◽  
Adverse Outcome Pathways

Nanotoxicology is an emerging field employed in the assessment of unintentional hazardous effects produced by nanoparticles (NPs) impacting human health and the environment. The nanotoxicity affects the range between induction of cellular stress and cytotoxicity. The reasons so far reported for these toxicological effects are due to their variable sizes with high surface areas, shape, charge, and physicochemical properties, which upon interaction with the biological components may influence their functioning and result in adverse outcomes (AO). Thus, understanding the risk produced by these materials now is an important safety concern for the development of nanotechnology and nanomedicine. Since the time nanotoxicology has evolved, the methods employed have been majorly relied on in vitro cell-based evaluations, while these simple methods may not predict the complexity involved in preclinical and clinical conditions concerning pharmacokinetics, organ toxicity, and toxicities evidenced through multiple cellular levels. The safety profiles of nanoscale nanomaterials and nanoformulations in the delivery of drugs and therapeutic applications are of considerable concern. In addition, the safety assessment for new nanomedicine formulas lacks regulatory standards. Though the in vivo studies are greatly needed, the end parameters used for risk assessment are not predicting the possible toxic effects produced by various nanoformulations. On the other side, due to increased restrictions on animal usage and demand for the need for high-throughput assays, there is a need for developing and exploring novel methods to evaluate NPs safety concerns. The progress made in molecular biology and the availability of several modern techniques may offer novel and innovative methods to evaluate the toxicological behavior of different NPs by using single cells, cell population, and whole organisms. This review highlights the recent novel methods developed for the evaluation of the safety impacts of NPs and attempts to solve the problems that come with risk assessment. The relevance of investigating adverse outcome pathways (AOPs) in nanotoxicology has been stressed in particular.

Toxicological Risk Assessment of Soil Contaminants

1997 ◽  
Vol 16 (4-5) ◽  
pp. 495-508 ◽  
Author(s):  
Fritz Kalberlah ◽  
Martin Hassauer ◽  
Nicole Frijus-Plessen ◽  
Klaus Schneider
Keyword(s):  
Risk Assessment ◽  
Environmental Protection Agency ◽  
Daily Intake ◽  
Absorbed Dose ◽  
Quality Criteria ◽  
Internal Exposure ◽  
World Health ◽  
Soil Contaminants ◽  
Toxicological Risk ◽  
Toxicological Risk Assessment

International bodies such as the World Health Organization (WHO) and national governmental agencies like the U.S. Environmental Protection Agency (EPA) use the same basic concept to derive acceptable daily intake (ADI) and reference dose (RfD). This customary concept is used in toxicological risk assessment of soil contaminants in Germany. It is used in the following ways: with extension to new substances not yet assessed by, for example, WHO or EPA; with reevaluations for substances with new toxicologically relevant input data; with explicitly stated absorption rates used to calculate internal exposure; its results are presented differently and are better suited to multipathway situations of exposure such as in contaminated sites; and with extensions in assessment by assigning quality criteria to unit risk quantifications to carcinogenic substances. The respective derived doses are called TRD (tolerable resorbiente dosis—tolerable absorbed dose) values, that is, reference values equivalent to a no observed adverse effect level in sensitive human subpopulations. TRD values are proposed for approximately 85 soil contaminants and 20 warfare substances with high priority in Germany up to now. The article outlines some of the specific problems in deriving TRD values and gives examples for comparison with ADI (WHO) or RfD (EPA) values.

A Comparative Ex Vivo Study of Plasminogen Activators and Proteases for Fibrinolytic Activity and Side Effects in Rabbits

1977 ◽  
Vol 37 (01) ◽  
pp. 154-161 ◽  
Author(s):  
B. A Janik ◽  
S. E Papaioannou
Keyword(s):  
Side Effects ◽  
Effective Dose ◽  
Fibrinolytic Activity ◽  
Ex Vivo ◽  
Plasminogen Activators ◽  
Assay System ◽  
Coagulation Parameters ◽  
Ex Vivo Assay

SummaryUrokinase, streptokinase, Brinase, trypsin, and SN 687, a bacterial exoprotease, have been evaluated in an ex vivo assay system. These enzymes were injected into rabbits and the fibrinolytic activity as well as other coagulation parameters were measured by in vitro techniques. Dose-response correlations have been made using the euglobulin lysis time as a measure of fibrinolytic activity and the 50% effective dose has been determined for each enzyme. Loading doses, equal to four times the 50% effective dose, were administered to monitor potential toxicity revealing that Brinase, trypsin, and SN 687 were very toxic at this concentration.Having established the 50% effective dose for each enzyme, further testing was conducted where relevant fibrinolytic and coagulation parameters were measured for up to two days following a 50% effective dose bolus injection of each enzyme. Our results have demonstrated that urokinase and streptokinase are plasminogen activators specifically activating the rabbit fibrinolytic system while Brinase, trypsin and SN 687 increase the general proteolytic activity in vivo.The advantages of this ex vivo assay system for evaluating relative fibrinolytic potencies and side effects for plasminogen activators and fibrinolytic proteases have been discussed.

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