Toxicological Knowledge Research Articles

In Response: The path forward for the adverse outcome pathway framework--A regulatory perspective.

In Response: The path forward for the adverse outcome pathway framework--A regulatory perspective.

Approaches and perspectives to toxicogenetics and toxicogenomics

Toxicology is one of the scientific disciplines that has most<br />evolved in recent years due to scientific and technological<br />advances that have created a deeper understanding of the<br />genetic and molecular basis for appreciative variability in<br />toxic response from one person to another. The application<br />of this knowledge in toxicology is known as toxicogenetics<br />and toxicogenomics. The latter is the discipline that studies<br />the genomic response of organisms exposed to chemical<br />agents, including drugs, environmental pollutants, food<br />additives, and other commonly used chemical products.<br />The use of emerging omic technologies, such as genomics,<br />transcriptomics, proteomics, metabolomics and bioinformatics<br />techniques, permits the analysis of many variants of genes<br />simultaneously in an organism exposed to toxic agents in order<br />to search for genes susceptible to damage, to detect patterns<br />and mechanisms of toxicity, and determine specific profiles<br />of gene expression that give origin to biomarkers of exposure<br />and risk. This constitutes predictive toxicology.

A Standard of Knowledge for the Professional Practice of Toxicology.

BackgroundEmployers, courts, and the general public judge the credibility of professionals based on credentials such as academic degrees, publications, memberships in professional organizations, board certifications, and professional registrations. However, the relevance and merit of these credentials can be difficult to determine objectively. Board certification can be a reliable indicator of proficiency if the certifying organization demonstrates, through regularly scheduled independent review, that its processes meet established standards and when a certificate holder is required to periodically demonstrate command of a body of knowledge that is essential to current professional practice.ObjectiveWe report herein a current Standard of Knowledge in general toxicology compiled from the experience and opinions of 889 certified practicing professional toxicologists.DiscussionAn examination is the most commonly used instrument for testing a certification candidate’s command of the body of knowledge. However, an examination-based certification is only creditable when the body of knowledge, to which a certification examination tests, is representative of the current knowledge, skills, and capabilities needed to effectively practice at the professional level. Thus, that body of knowledge must be the current “Standard of Knowledge” for the profession, compiled in a transparent fashion from current practitioners of the profession.ConclusionThis work was conducted toward ensuring the scientific integrity of the products produced by professional toxicologists.CitationHulla JE, Kinter LB, Kelman B. 2015. A Standard of Knowledge for the professional practice of toxicology. Environ Health Perspect 123:743–748; http://dx.doi.org/10.1289/ehp.1408643

New drugs of abuse.

Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases.

Adverse outcome pathway development II: best practices.

Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified adverse outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of "functional equivalence" can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.

A decision support system for drinking water production integrating health risks assessment.

The issue of drinking water quality compliance in small and medium scale water services is of paramount importance in relation to the 98/83/CE European Drinking Water Directive (DWD). Additionally, concerns are being expressed over the implementation of the DWD with respect to possible impacts on water quality from forecast changes in European climate with global warming and further anticipated reductions in north European acid emissions. Consequently, we have developed a decision support system (DSS) named ARTEM-WQ (AwaReness Tool for the Evaluation and Mitigation of drinking Water Quality issues resulting from environmental changes) to support decision making by small and medium plant operators and other water stakeholders. ARTEM-WQ is based on a sequential risk analysis approach that includes consideration of catchment characteristics, climatic conditions and treatment operations. It provides a holistic evaluation of the water system, while also assessing human health risks of organic contaminants potentially present in treated waters (steroids, pharmaceuticals, pesticides, bisphenol-a, polychlorobiphenyls, polycyclic aromatic hydrocarbons, petrochemical hydrocarbons and disinfection by-products; n = 109). Moreover, the system provides recommendations for improvement while supporting decision making in its widest context. The tool has been tested on various European catchments and shows a promising potential to inform water managers of risks and appropriate mitigative actions. Further improvements should include toxicological knowledge advancement, environmental background pollutant concentrations and the assessment of the impact of distribution systems on water quality variation.

Exposure of the adult population resident in Ireland to dioxins and PCBs from the diet

Irish monitoring data on PCDD/Fs, DL-PCBs and marker PCBs were collated and combined with Irish adult food consumption data to estimate dietary background exposure of adults (18–90 years of age) living in Ireland to dioxins and PCBs. The average upper-bound daily intake of dioxins total WHO TEQ (2005) (PCDD/Fs and DL-PCBs) from food contaminated via the environment was estimated as 0.3 pg kg–1 bw day–1 and at the 95th percentile at 1 pg kg–1 bw day–1. The average upper-bound daily intake of sum of six marker PCBs from food contaminated via the environment was estimated at 1.6 ng kg–1 bw day–1 and at the 95th percentile at 6.8 ng kg–1 bw day–1. Dietary background exposure estimates for both dioxins and PCBs indicate that the Irish adult population has exposures below the European average, a finding which is also supported by the relatively lower levels detected in breast milk of Irish mothers compared with breast milk levels reported for other European countries. Exposure levels are below health-based guidance values and/or body burdens associated with the tolerable weekly intake (TWI) (for dioxins) or associated with a no observable adverse effect level (NOAEL) (for PCBs). Given the current toxicological knowledge, based on biomarker data and estimated dietary exposure, the authors consider that general background exposure of the Irish adult population to dioxins and PCBs is not likely to be of human health concern.

Discriminating toxicant classes by mode of action: 4. Baseline and excess toxicity

Functional similarity of chemicals combines toxicological knowledge (which toxicity pathways can happen in which species under which exposure conditions) with chemical expertise (which parts of the chemical structures and physico-chemical properties are involved in which interactions) to discriminate between baseline and excess toxicants. The objective is to identify as many baseline toxicants as possible because their acute fish toxicities can be predicted with sufficient accuracy from their log Kow. Established tools like structural alerts are used to indicate modes of action (MOAs) that are typical causes of excess toxicity. Verhaar classifications are supplemented with additional chemical attributes and physico-chemical property thresholds to cover a larger range of compounds within the baseline toxicity domain. Our approach is precautionary to avoid false negatives with a sensitivity of 96.3%. It classifies 57.1% of the compounds of the EPA Fathead Minnow Acute Toxicity Database (EPAFHM) as baseline toxicants and suggests that more than 50% of acute fish toxicity testing could be replaced by reliable QSAR predictions. Furthermore, functional similarity can support the MOA classification of chemicals in different species. Toxicity profiles with fish, Daphnia and algae reveal specific targets for the compounds and, particularly for chemicals with multiple MOA, identify the most sensitive species.

Evaluation of Polycyclic Aromatic Hydrocarbons Using Analytical Methods, Toxicology, and Risk Assessment Research: Seafood Safety after a Petroleum Spill as an Example

Background: Polycyclic aromatic hydrocarbons (PAHs) are abundant and widespread environmental chemicals. They are produced naturally and through man-made processes, and they are common in organic media, including petroleum. Several PAHs are toxic, and a subset exhibit carcinogenic activity. PAHs represent a range of chemical structures based on two or more benzene rings and, depending on their source, can exhibit a variety of side modifications resulting from oxygenation, nitrogenation, and alkylation.Objectives: Here we discuss the increasing ability of contemporary analytical methods to distinguish not only different chemical structures among PAHs but also their concentrations in environmental media. Using seafood contamination following the Deepwater Horizon accident as an example, we identify issues that are emerging in the PAH risk assessment process because of increasing analytical sensitivity for individual PAHs, and we describe the paucity of toxicological literature for many of these compounds.Discussion: PAHs, including the large variety of chemically modified or substituted PAHs, are naturally occurring and may constitute health risks if human populations are exposed to hazardous levels. However, toxicity evaluations have not kept pace with modern analytic methods and their increased ability to detect substituted PAHs. Therefore, although it is possible to measure these compounds in seafood and other media, we do not have sufficient information on the potential toxicity of these compounds to incorporate them into human health risk assessments and characterizations.Conclusions: Future research efforts should strategically attempt to fill this toxicological knowledge gap so human health risk assessments of PAHs in environmental media or food can be better determined. This is especially important in the aftermath of petroleum spills.Citation: Wickliffe J, Overton E, Frickel S, Howard J, Wilson M, Simon B, Echsner S, Nguyen D, Gauthe D, Blake D, Miller C, Elferink C, Ansari S, Fernando H, Trapido E, Kane A. 2014. Evaluation of polycyclic aromatic hydrocarbons using analytical methods, toxicology, and risk assessment research: seafood safety after a petroleum spill as an example. Environ Health Perspect 122:6–9; http://dx.doi.org/10.1289/ehp.1306724

Empowerment of Medical Toxicology in Bangladesh: Inspiration from the APAMT

In the last issue of Asia Pacific Journal of Medical Toxicology (APJMT), editor-in-chief, Dr. Reza Afshari focused on an important contemporary issue of empowering toxicology in the Asia pacific region (1). The topic drew our attention and we would like to share the situation of Bangladesh in light of this editorial. Dr. Afshari correctly emphasized on forming national societies of medical toxicology in each country of Asia Pacific region (1). Bangladesh formed its own national society, ‘Toxicology Society of Bangladesh (TSB)’ in the year 2008 under the leadership of Prof. M. Abul Faiz (2). The society has its own website (http://www.tsbbd.org/index.php). Although in small scale, the society is trying its best to disseminate knowledge of medical toxicology throughout the country. So far, we have arranged two successful national conferences in the year 2011 at Rangpur medical college (northwest of Bangladesh) and in 2013 at Chittagong medical college (southeast of Bangladesh). The society decided to arrange a national gathering at every two years interval, and hence, the next conference is scheduled to be held at Sylhet MAG Osmani medical college (northeast of Bangladesh) in coming 2015. TSB purposefully has arranged the national meetings outside capital (Dhaka), so that medical toxicology as a subject can be ventilated to the remote corners of Bangladesh. Around four hundreds domestic and international participants attended both the conferences and some of the foreign participants were policy makers of the Asia Pacific Association of Medical Toxicology (APAMT). Bangladeshi physicians started to participate APAMT congresses since 2006 (Colombo meeting) and so far TSB sent members to each meeting of the APAMT. Dr. Afshari mentioned about travel grant as a strong step to motivate young investigators of this region (1). We also support his statement. So far, a number of participants from Bangladesh have received travel grants, and this surely encouraged them for future work. In fact, they are now the core members of the TSB. Undoubtedly, the APAMT is the encouragement behind all of our activities. Introduction of APJMT is clearly a milestone event for us. The young researcher of this region especially those who cannot publish their paper for various technical and linguistic reasons got a hope to see the evolution of APJMT. At least, now they can try their paper for possible publication even though their work needs fine tunes. As a Scientific and publication secretary of the TSB, I specially highlighted the journal to all of the members of TSB and others throughout the country and the journal is now receiving regular papers from Bangladesh. We firmly believe that in the near future, the APJMT will become the representative of the research in medical toxicology in this region.

Toxicological knowledge discovery by mining emerging patterns from toxicity data

Predicting the risk of toxic and environmental effects of chemical compounds is of great importance to all chemical industries [1]. Expert systems have shown success in predicting toxic risk by applying established knowledge of toxicology encoded as a knowledge base of structural alerts and a reasoning model. A disadvantage of expert systems is that developing new structural alerts requires considerable time and effort from domain experts. In order to expedite this process a software tool has been developed that can automatically mine representations of activating features directly from toxicity datasets and present them in an interpretable form. Our knowledge discovery tool applies emerging pattern (EP) mining [2]: a form of association rule mining [3] that is well known to computer science, but is relatively new to chemistry [4]. The EP mining algorithm accepts any data expressed as a series of binary properties, which is divided into two classes, and extracts patterns of those properties that are frequent within the data and are more frequent in one data class compared to the other. By mining emerging patterns from toxicity datasets, encoded as fingerprints of binary descriptors, the tool generates patterns of features that distinguish toxicants from innocuous compounds. These patterns represent potentially activating features of the toxic compounds that may then be used to define new alerts. The knowledge discovery tool has been tested using a public dataset of 3489 mutagens and 2981 non-mutagens, encoded as fingerprints of approximately 2000 functional groups and ring descriptors. EPs were produced and grouped into a number of hierarchical families. Six of the EPs that represented distinct chemical classes were selected for manual inspection by a toxicology expert. Relevant literature was analysed to find a mechanistic rationale for the mined features, which resulted in four new structural alerts for in vitro mutagenicity.

The role of the toxicologic pathologist in the post-genomic era(#).

The role of the toxicologic pathologist in the post-genomic era(#).

Toxicologic Pathology: An Introduction

This chapter provides an overview of toxicology pathology. Toxicologic pathology integrates the disciplines of pathology and toxicology and is generally performed in an applied experimental setting. Pathologists study the nature of disease, evaluating changes produced in cells, tissues, or organs in response to a “challenge;” whether it is infectious, neoplastic, immune-mediated, or toxic. These diseases leave significant visual “footprints” in cells and tissues. However, toxicologists tend to focus on the biochemical basis of the science of poisons. The discipline of toxicologic pathology requires knowledge of pathology and toxicology, as well as other related disciplines, so that integration of morphological, biochemical, and functional changes can be accomplished in a logical manner with respect to their biological significance. Most toxicologic pathologists are engaged in the conduct of bioassays in industry, toxicology, contract organizations, or government. The responsibility of training new toxicologic pathologists to meet the increasing demands of industry, government, and academia will fall on academic institutions with training programs. As the role of the toxicologic pathologist continues to expand, even more opportunities for employment and contribution to society can become available. However, the anticipated retirements of toxicologic pathologists in all sectors will exacerbate the already critical shortage of veterinary pathologists, let alone those to fill positions in toxicologic pathology.

Response to “Incorporating Biological, Chemical, and Toxicological Knowledge Into Predictive Models of Toxicity”

Response to “Incorporating Biological, Chemical, and Toxicological Knowledge Into Predictive Models of Toxicity”

Product Evaluation for the Control of Chemical Emissions to Indoor Air – 10 Years of Experience with the AgBB Scheme in Germany

AbstractEmissions from construction products may have a significant impact on the quality of indoor air, particularly in energy‐efficient buildings, where the normal rate of air exchange with fresh ambient air may be limited. In this context, reduction strategies to mitigate the concentration of chemicals in the indoor environment have become even more important. German authorities wanted to foster the development of low‐emission products, and as a result it was necessary to quantify and qualify these emissions in a reliable and objective manner. The core principles for evaluation of the standardized measurements in emission tests were established by the “Committee for Health‐Related Evaluation of Building Products” (AgBB) and published in the so‐called “AgBB scheme”. Relevant for evaluation are: (i) Assessment of the emission levels of substances with known toxicological properties; (ii) limits for non‐assessable or unknown substances; (iii) limits for the total amount of chemical emissions. This review describes the stepwise implementation of the test procedure in Germany and the experience gained in evaluation of product emissions over the years. A comprehensive overview of the philosophy, history, current practices, and future directions of the German AgBB scheme for VOC emissions is also provided. Special emphasis is given to the evaluation of a list of about 170 single substances which have an agreed “lowest concentration of interest” (LCI) value for the indoor environment – values that are updated periodically according to present toxicological knowledge.

Proteomic research in bivalves

Biomonitoring of aquatic environment and assessment of ecosystem health play essential roles in the development of effective strategies for the protection of the environment, human health and sustainable development. Biomarkers of pollution exposure have been extensively utilized in the last few decades to monitor the health of organisms and hence assess environmental status. However, the use of single biomarkers against biotic or abiotic stressors may be limited by the lack of sensitivity and specificity. Therefore, more recently, the search for novel biomarkers has been focused on the application of OMICS methodologies. Environmental proteomics focuses on the analysis of an organism's proteome and the detection of changes in the level of individual proteins/peptides in response to environmental stressors. Proteomics can provide a more robust approach for the assessment of environmental stress and therefore exposure to pollutants. This review aims to summarize the proteomic research in bivalves, a group of sessile and filter feeding organisms that play an important function as "sentinels" of the aquatic environment. A description of the main proteomic methodologies is provided. The current knowledge in bivalves' toxicology, achieved with proteomics, is reported describing the main biochemical markers identified. A brief discussion regarding future challenges in this area of research emphasizing the development of more descriptive gene/protein databases that could support the OMICs approaches is presented.

Mixed brominated/chlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls: Simultaneous congener-selective determination in food

Of the 4600 individual poly-halogenated (bromo-chloro) dibenzo-p-dioxins, dibenzo-furans (PXDD/Fs) and 9180 poly-halogenated biphenyls (PXBs), 19 compounds were selected for analysis in food, based on current toxicological knowledge, chemical configuration, type and degree of halogenation, and the limited knowledge on environmental occurrence levels. The selection was also tempered by the availability of reliable analytical standards. The analytical methodology designed to allow simultaneous determination of PXDD/Fs and PXBs, was based on internal standardisation with (13)C(12) labelled compounds and high resolution mass spectrometry and involved a new separation procedure using dual activated carbon column fractionation. In order to unambiguously measure these compounds a practical, higher mass resolution (13,500-15,000 res) was used, coupled with a judicious choice of analyte ions and relative ion ratios. Further specificity was incorporated by exploiting the differences in chromatographic retention from those of potential interferants. The methodology was validated and used to measure occurrence levels of these contaminants in different matrices such as milk, meat, fish, eggs, offal, shellfish and soil. The limits of detection achieved by this methodology ranged from 0.005 to 0.02ngkg(-1) fat for foods. The analyses revealed the presence of both PXDD/Fs and PXBs, with the latter occurring to a greater extent, followed by PXDFs. This work represents the first targeted approach to measuring a range of individual PXDD/Fs and PXBs simultaneously.

Project summary: a critical synopsis of mechanisms of action of low-dose xenobiotics in mammalian organisms as a basis for assessing aggregated effects of chemical mixtures and identifying "new" toxicological end points

Abstract Background European chemicals legislation (registration, evaluation, authorisation and restriction of chemical substances (REACH)) requires a broad assessment of chemicals with respect to, inter alia, their health-relevant properties. Due to the extreme number of substances to be assessed and the limited current toxicological knowledge on their respective properties, REACH implicitly requires a paradigm change: away from knowledge generated mainly from costly animal experiments towards the use of mechanistic findings. Moreover, effect mechanisms at the biochemical or cellular level are essential when conclusions shall be drawn about "new" endpoints and mixtures of xenobiotics. This study (funded by the German Federal Environment Agency) describes examples of biochemical processes in the mammalian organism and how xenobiotics interfere with them. Interference with physiological processes expected to lead to adverse health effects is characterised as "toxicity pathway". The study describes toxicological endpoints not usually covered in routine animal testing and the respective toxicity pathways. Results and conclusions Screening for chemicals which exert effects via common toxicity pathways and subsequently conducting targeted short-term tests may generate new information about the toxicity of chemicals without performing extensive substance-by-substance animal experiments. Information on common toxicity pathways may also provide input for the assessment of mixture effects. The U.S. Environmental Protection Agency is working intensely on this concept. It involves the use of enormous amounts of data on relevant biochemical and cellular processes, which are generated by "high-throughput screening" methods, and then are combined with substance-specific kinetic data, experimental apical test outcomes and modelling. Current limitations in the regulatory use of this integrated approach on risk assessment will be outlined.

The current state of engineered nanomaterials in consumer goods and waste streams: the need to develop nanoproperty-quantifiable sensors for monitoring engineered nanomaterials

As nanomaterials are harnessed for medicine and other technological advances, an understanding of the toxicology of these new materials is required to inform our use. This toxicological knowledge will be required to establish the medical and environmental regulations required to protect consumers and those involved in nanomaterial manufacturing. Nanoparticles of titanium oxide, carbon nanotubes, semiconductor quantum dots, gold, and silver represent a high percentage of the nanotechnology currently available or currently poised to reach consumers. For these nanoparticles, this review aims to identify current applications, the current methods used for characterization and quantification, current environmental concentrations (if known), and an introduction to the toxicology research. Continued development of analytical tools for the characterization and quantification of nanomaterials in complex environmental and biological samples will be required for our understanding of the toxicology and environmental impact of nanomaterials. Nearly all materials exhibit toxicity at a high enough concentration. Robust, rapid, and cost effective analytical techniques will be required to determine current background levels of anthropogenic, accidental, and engineered nanoparticles in air, water, and soil. The impact of the growing number of engineered nanoparticles used in consumer goods and medical applications can then be estimated. This will allow toxicological profiles relevant to the demonstrated or predicted environmental concentrations to be determined.

The Biodegradation of Ionic Liquids - the View from a Chemical Structure Perspective

The idea of green or sustainable chemistry is to develop highly efficient technical processes and applications using chemicals with a reduced or zero hazard potential for man and the environment. This approach is perfectly applicable to ionic liquids (ILs). These substances have potential applications in different fields (economic interests), and so far millions of possible structures have been designed, thousands of which have actually been produced, providing a broad base for the structural design of ILs with optimal technological properties and at the same time posing a reduced hazard to humans and the environment. In parallel with the rapidly growing (eco)toxicological knowledge regarding ILs, the available data regarding their biodegradability are also increasing. The following sections introduce the reader to biodegradation test procedures and present an overview of existing aerobic and anaerobic biodegradation data concerning ILs. Besides pure biodegradation kinetics, this discussion covers data on biological degradation products (metabolites) and abiotic degradation processes. Throughout this review special emphasis will be placed on structure-biodegradability relationships and the question whether the 10th principle of Green Chemistry, namely, Design chemicals and products to degrade after use: design chemical products to break down to innocuous substances after use so that they do not accumulate in the environment, is or is not fulfilled for some IL structures. The discussion of this data should help to improve the future design of inherently safer ILs, thereby reducing the risks they may pose to humans and the environment. Keywords: Biodegradation, metabolization, organic cations, structure-biodegradability relationships, sustainable design, weakly coordinating anions, cellulose dissolution, aluminum plating, gas compression, dye-sensitized solar cells, abiotic degradation processes, concentration of inoculum, rotifers