chemical research in toxicology abbreviation

Chemical Research in Toxicology

Subject Area and Category

• Medicine (miscellaneous)

Publication type

0893228X, 15205010

Information

How to publish in this journal

[email protected]

The set of journals have been ranked according to their SJR and divided into four equal groups, four quartiles. Q1 (green) comprises the quarter of the journals with the highest values, Q2 (yellow) the second highest values, Q3 (orange) the third highest values and Q4 (red) the lowest values.

The SJR is a size-independent prestige indicator that ranks journals by their 'average prestige per article'. It is based on the idea that 'all citations are not created equal'. SJR is a measure of scientific influence of journals that accounts for both the number of citations received by a journal and the importance or prestige of the journals where such citations come from It measures the scientific influence of the average article in a journal, it expresses how central to the global scientific discussion an average article of the journal is.

Evolution of the number of published documents. All types of documents are considered, including citable and non citable documents.

This indicator counts the number of citations received by documents from a journal and divides them by the total number of documents published in that journal. The chart shows the evolution of the average number of times documents published in a journal in the past two, three and four years have been cited in the current year. The two years line is equivalent to journal impact factor ™ (Thomson Reuters) metric.

Evolution of the total number of citations and journal's self-citations received by a journal's published documents during the three previous years. Journal Self-citation is defined as the number of citation from a journal citing article to articles published by the same journal.

Evolution of the number of total citation per document and external citation per document (i.e. journal self-citations removed) received by a journal's published documents during the three previous years. External citations are calculated by subtracting the number of self-citations from the total number of citations received by the journal’s documents.

International Collaboration accounts for the articles that have been produced by researchers from several countries. The chart shows the ratio of a journal's documents signed by researchers from more than one country; that is including more than one country address.

Not every article in a journal is considered primary research and therefore "citable", this chart shows the ratio of a journal's articles including substantial research (research articles, conference papers and reviews) in three year windows vs. those documents other than research articles, reviews and conference papers.

Ratio of a journal's items, grouped in three years windows, that have been cited at least once vs. those not cited during the following year.

Evolution of the percentage of female authors.

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Evoution of the number of documents related to Sustainable Development Goals defined by United Nations. Available from 2018 onwards.

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Author guidelines.

Last updated: December 29, 2023

Scope of the Journal

Manuscript types, submit with fast format, document templates and format, acceptable software, file designations, and tex/latex, cover letter, manuscript text components, supporting information, research data policy, data requirements, language and editing services, preparing graphics, figure and illustration services, prior publication policy, editorial policies, providing potential reviewer names, manuscript transfer, proofs via acs direct correct, publication date and patent dates, asap publication, post-publication policies, sharing your published article.

Chemical Research in Toxicology publishes Articles, Communications, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques. Representative research includes:

• Studies concerning the molecular mechanisms by which physical, chemical, or biological agents or materials, interact with and perturb the normal function and/or structure of biological systems, including living organisms, cells, or biomolecules.
• Studies that address hypotheses concerning mechanisms of adverse or therapeutic responses, or contribute to the development of models of toxic/biological function on the basis of quantifying chemical, molecular and cellular responses to physical, chemical, or biological agents or materials.
• Studies involving data resulting from high content characterization of molecular responses to agents from the use of bioanalytical approaches such as proteomics, metabolomics, lipidomics, genomics, high content imaging, multi-omics, etc. to characterize targeted patterns or global cellular responses, as well as studies that use novel or existing data to create new models for quantifying exposures or building predictive models of biological pathways or networks.
• The identification and characterization of potentially hazardous agents such as environmental contaminants, industrial chemicals, drugs and drug-like molecules, natural products, biological toxins and engineered nanomaterials, and the development and application of novel methodologies for their detection and/or characterizations of their interactions with biological systems or biomolecules.
• Studies concerning pathological biochemistry and molecular mechanisms of disease etiology involving exogenous as well as endogenous agents and/or molecular pathways or networks.

In the case of uncertainty regarding the suitability of a manuscript, authors may send a pre- submission inquiry to the Editor that includes an abstract and cover letter indicating the intended manuscript format by e-mail ( [email protected] ).

Reviews, Perspectives, Letters to the Editor, and ToxWatch. See the Manuscript Organization section for details concerning the technical organization for each manuscript type.

• Articles : <300 word abstract; no limit on length, figures/tables, or references
• Communications : 3000 word limit; <100 word abstract; ~5 or fewer figures/tables; ~30 references
• Reviews : <300 word abstract; no limit on length, figures/tables, or references
• Perspectives : 3000-6000 words; <300 word abstract; no limits on figures/tables or references
• 1 figure: 7 in width x 9 in. height (or 504 pt x 648 pt)
• Letters to the Editor : 2000 words; no abstract; 0-1 figures/tables; maximum 5 references

Comprehensive accounts of significant original research should be submitted as Articles.

Communications

Timely topics that are important and of urgent interest should be submitted as Communications. We aim for a decision within three weeks of receipt. Only minor revisions, completed within ten days, are possible. Any manuscript deemed publishable but requiring a major revision may be further considered as an article. Authors should review the Journal’s Preparation of Manuscripts (below) prior to submission of a manuscript. Communications are strictly limited to 3,000 words.

Comprehensive reviews of topics within the scope of the journal and supported by significant literature should be submitted as reviews. Short reviews of recent literature that update a topic are also considered. The information in Reviews should be presented objectively, not limited to the contributions of the authors, and written with the intent of familiarizing the general reader with the broad current state of knowledge of a topic of active interest. The length of reviews should be commensurate with the information available; there are no formal limitations on length.

Perspectives

Manuscripts that discuss particular issues about which the author has expertise, for example introducing new concepts, proposing original models, offering the author’s interpretation of statistical trends, or weighing in on a controversy, should be submitted as perspectives. Perspectives contain approximately 3,000-6,000 words and have no limitations on figures, tables or references.

Letters to the Editor

Communication with the readership of the journal, for example, highlighting important concerns or differences of interpretation of scientific or policy matters relevant to all areas of Toxicology should be submitted as Letters to the Editor. In topics of controversy, contributions from investigators with differing viewpoints may be invited by the Editors. Letters to the Editor should be limited to 2,000 words and are subject to editorial, but not peer review.

Forum in which interesting perspectives and opinions on current issues in Toxicology including aspects of policy, risk assessment practices, and in explaining how particular research findings in toxicology are anticipated to impact society. These pieces are written in a way that they are accessible by a wide audience, clearly explaining key background information. These articles should also provide a critical evaluation of policies, practices, or scientific work they are addressing. ToxWatch contain approximately 1000 words, a single unnumbered high resolution image without caption that is 7 in. width x 9 in. height (vertical), 7 in. height x 9 in. width (horizontal) or 504 pt x 648 pt graphic, and a maximum of 5 references. This graphic should be used as TOC graphic. ToxWatch is subject to editorial, but not peer review.

While this document will provide basic information on how to prepare and submit the manuscript as well as other critical information about publishing, we also encourage authors to visit the ACS Publishing Center for additional information on everything that is needed to prepare (and review) manuscripts for ACS journals and partner journals, such as

• Mastering the Art of Scientific Publication , which shares editor tips about a variety of topics including making your paper scientifically effective, preparing excellent graphics, and writing cover letters.
• Resources on how to prepare and submit a manuscript to ACS Paragon Plus, ACS Publications’ manuscript submission and peer review environment, including details on selecting the applicable Journal Publishing Agreement .
• Sharing your research with the public through the ACS Publications open access program.
• ACS Reviewer Lab , a free online course covering best practices for peer review and related ethical considerations. 
• ACS Author Lab , a free online course that empowers authors to prepare and submit strong manuscripts, avoiding errors that could lead to delays in the publication process.
• ACS Inclusivity Style Guide , a guide that helps researchers communicate in ways that recognize and respect diversity in all its forms.

Manuscript Preparation

All ACS journals and partner journals have simplified their formatting requirements in favor of a streamlined and standardized format for an initial manuscript submission. Read more about the requirements and the benefits these serves authors and reviewers here .

Manuscripts submitted for initial consideration must adhere to these standards:

• Submissions must be complete with clearly identified standard sections used to report original research, free of annotations or highlights, and include all numbered and labeled components.
• Figures, charts, tables, schemes, and equations should be embedded in the text at the point of relevance. Separate graphics can be supplied later at revision, if necessary.
• When required by a journal's structure or length limitations, manuscript templates should be used.
• References can be provided in any style, but they must be complete, including titles. For information about the required components of different reference types, please refer to the  ACS Style Quick Guide .
• Supporting Information must be submitted as a separate file(s).

The templates facilitate the peer review process by allowing authors to place artwork and tables close to the point where they are discussed within the text. Learn more about document templates here .

General information on the preparation of manuscripts may also be found in the ACS Guide to Scholarly Communication .

See the list of Acceptable Software and appropriate File Designations to be sure your file types are compatible with ACS Paragon Plus. Information for manuscripts generated from TeX/LaTeX is also available.

A cover letter must accompany every manuscript submission. During the submission process, you may type it or paste it into the submission system, or you may attach it as a file.

We encourage you to view  Publishing Your Research 101- Episode 2 on Writing Your Cover Letter.

Title Page . A brief and informative title (preferably fewer than 12 words) will aid in the classification and indexing of the paper. Do not use trade names of drugs, jargon, or abbreviations. Include keywords. List full names and institutional affiliations of all authors, and if differentiation is necessary, indicate the affiliations of each author by the superscript symbols  † , ‡ , § , ║ , ┴ , etc. These symbols should also be used to indicate author affiliations different from those stated on the title page and present address information. The author to whom correspondence should be addressed is indicated by an asterisk. It is implicit in listing a person as an author that this individual has agreed to appear as an author of the manuscript.

Table of Contents Graphic . A Table of Contents (TOC) graphic is published with each manuscript. It is submitted for use in the table of contents and is also used for multiple purposes, including the document abstract and other situations where a representative graphic is required. Create an image that represents the work while adhering to size constraints. Keeping in mind that various devices may be involved, some of the best images are simple, relatively free of text and technical characters, and make use of color for visual impact. It is best to avoid complex structure schemes and small-sized details. The author must submit a graphic in the actual size to be used for the TOC that will fit in an area 8.47 cm by 4.76 cm (3.33 in. by 1.88 in.). Larger images will be reduced to fit within those dimensions. Type size of labels, formulas, or numbers within the graphic must be legible at the specified size. Tables or spectra are not acceptable. Place the TOC graphic after the title page and before the abstract page of the manuscript. All elements of the TOC graphic must be (1) entirely original and (2) created by one or more of the authors. Lastly, this graphic should have no legend.

Abstract . An abstract should be included with all Articles, Communications, Reviews, and Perspectives. For Articles and Communications, the abstract should briefly (300 word maximum) present, in one paragraph, the problem and experimental approach and state the findings and conclusions. For Reviews and Perspectives, the abstract should introduce the topic, summarize key points, and state the major conclusions. In all cases, the abstract should be self- explanatory and suitable for reproduction without rewriting. Footnotes or undefined abbreviations may not be used. Avoid the use of jargon, but include keywords relevant to the field to improve indexing and discoverability to potential readers. If a reference must be cited, complete publication data must be given.

Introduction .   The introduction should state the purpose of the investigation and its relation to other work in the field. Background material should be brief and relevant to the research described. Detailed or lengthy reviews of the literature should be avoided.

Experimental Procedures .  Procedures for experimental methods should be described in sufficient detail to enable other investigators to repeat the experiments. Names of product manufacturers (with city, state address, catalog number) should be included if alternate sources are deemed unsatisfactory or if the product is of limited availability. Novel experimental procedures should be described in detail, but previously published procedures should be referred to by literature citation of the original detailed explanation, and should include description of any modifications.

Results . The results should be presented concisely. Tables and figures should be designed to maximize the presentation and comprehension of the experimental data. The same data should not be presented in more than one figure or in both a figure and a table. Detailed interpretation of results should be reserved for the discussion section of an Article.

Discussion . The purpose of the discussion is to interpret the results and to relate them to existing knowledge in the field in as clear and brief a fashion as possible. Information given elsewhere in the manuscript should not be repeated in the discussion. Extensive reviews of the literature should be avoided.

Funding Information . Authors are required to report ALL funding sources and grant/award numbers relevant to this manuscript. Enter all sources of funding for ALL authors relevant to this manuscript in BOTH the Open Funder Registry tool in ACS Paragon Plus and in the manuscript to meet this requirement. See http://pubs.acs.org/page/4authors/funder _options.html for complete instructions.

Acknowledgment . This section should acknowledge technical assistance, advice from colleagues, gifts, etc. Permission should be sought from persons whose contribution to the work is acknowledged in the manuscript.

Abbreviations . Abbreviations are used in ACS Journals without periods. Standard abbreviations should be used throughout the manuscript. All nonstandard abbreviations should be kept to a minimum and must be defined in the text following their first use.

Footnotes . When footnotes are necessary to express some relevant thoughts, these should be included as a parenthetical statement, placed next to the related text to ensure visibility. Footnotes should not be included in the reference list.

Tables . Tabulation of experimental results is encouraged when this leads to more effective presentation or to more economical use of space. Tables may be created using a word processor’s text mode or table format feature. The table format feature is preferred. Ensure each data entry is in its own cell; no listing of data by using bullets or numbering. If the text mode is used, separate columns with a single tab and use a line feed (return) at the end of each row. Tables should be numbered consecutively with Arabic numerals. Provide a brief title with each table and a brief heading for each column. Clearly indicate the units of measure (preferably SI). Data should be rounded to the nearest significant figure. Explanatory material referring to the whole table is to be included as a footnote to the title ( a ). Footnotes in tables should be given lower case letter designations and cited in the tables as italicized superscripts. All tables should be cited in the text in consecutive order.

Previously published tables that are being borrowed or adapted from another source require permission from the copyright holder. Once permission is obtained, the permission letter should be uploaded to the submission under the tag “Other Files for Editors Only.” Also, the copyright holder’s preferred credit line should be included in the table’s legend.

Figures and Figure Legends .  Line drawings, graphs, stereograms, histograms, and black and white (or color) photographs are all classified as figures and should be numbered consecutively with Arabic numerals in order of citation. Figure legends should be placed after the tables as a single list with the figures following. The figures must be embedded in the same document as the article and not submitted separately as Supporting Information. It may help to print the manuscript on a laser printer to ensure all artwork is clear and legible. See below for guidelines for preparing publication quality illustrations.

*Authors Photos and Biographies . All authors of Reviews and Perspectives (but not other publication formats) should provide a short biography (100 words or less) to be published with the articles.

Headshots (i.e., photos) of the authors may also be provided for publication with the biography. Photos and accompanying biography should be inserted below the reference list in the manuscript. Each photo must be high resolution (at least 300 ppi). No logos may appear in the photo. Before publication, each author must sign (1) a Model Release Form and (2) either a Copyright Transfer Form, which transfers copyright to ACS, or the Nonexclusive Rights Agreement, by which the copyright holder keeps the copyright but grants ACS permission to use the photo. Please choose either the Copyright Transfer Form or the Nonexclusive Rights Agreement; do not sign both forms.

This information is provided to the reviewers during the peer-review process (for Review Only) and is available to readers of the published work (for Publication). Supporting Information must be submitted at the same time as the manuscript. See the list of Acceptable Software by File Designation and confirm that your Supporting Information is viewable .

If the manuscript is accompanied by any supporting information files for publication, these files will be made available free of charge to readers. A brief, nonsentence description of the actual contents of each file, including the file type extension, is required. This description should be labeled Supporting Information and should appear before the Acknowledgement and Reference sections.  Examples of sufficient and insufficient descriptions are as follows:

Examples of sufficient descriptions: “Supporting Information: 1 H NMR spectra for all compounds (PDF)” or “Additional experimental details, materials, and methods, including photographs of experimental setup (DOC)”.

Examples of insufficient descriptions: “Supporting Information: Figures S1-S3” or “Additional figures as mentioned in the text”.

When including supporting information for review only, include copies of references that are unpublished or in-press. These files are available only to editors and reviewers.

All ACS journals strongly encourage authors to make the research data underlying their articles publicly available at the time of publication.

Research data is defined as materials and information used in the experiments that enable the validation of the conclusions drawn in the article, including primary data produced by the authors for the study being reported, secondary data reused or analyzed by the authors for the study, and any other materials necessary to reproduce or replicate the results.

The ACS Research Data Policy provides additional information on Data Availability Statements, Data Citation, and Data Repositories.

Chemical Identity and Purity . The identity and purity of key compounds, including those used for toxicological testing, and description(s) of the method(s) used to determine purity, which should generally include HPLC and NMR, should be included in the experimental procedures section. Characterization data for key compounds should include HPLC, 1 H NMR/ 13 C NMR (peak lists), and HRMS. For instructions on submitting NMR data, refer to ACS guidelines:  https://publish.acs.org/publish/manu_prep_sub . HRMS data should be reported to support the molecular formula assignment and should include the molecular formulas on which the theoretical (calcd) values are based. HRMS molecular formulas and calcd values should include any added atoms (usually H or Na). Found values should be close enough to the calcd values, and have sufficiently small estimated uncertainties, to exclude alternative plausible formulas. The ionization method and the mass detector type should be reported.

Nanomaterials. The physico-chemical properties of nanomaterials used for toxicological studies should be characterized appropriately in order to support the conclusions of the study. This applies to commercially available materials as well as to designed materials. Where applicable, the information included should comprise primary size and shape, aspect ratio, size distribution, agglomeration or aggregation state, rigidity, elemental composition, surface modification, zeta potential, redox potential, surface reactivity, and/or crystalline phase. A description or reference to the synthetic procedure used to prepare the materials should be included. Furthermore, the stability and reactivity of the nanomaterials as well as influence of external parameters like the composition of cell culture media, buffers etc. on the nanomaterials properties should be addressed, for example by measurements of dissolution or dissolution rate, formation of reactive oxygen species or agglomeration under experimental conditions. Finally, the techniques used to characterize the materials should be described sufficiently or referenced, including the description of algorithms and methods used to analyze the data.

Hazardous Materials. Authors must emphasize any unexpected, new, and/or significant hazards or risks associated with the reported work. This information should be in the experimental details section of the full article or communication. All hazardous chemicals should be clearly identified as such. Precautions for handling dangerous materials or for performing hazardous procedures should be explicitly stated and referenced. Identification of and precautions for handling hazardous chemicals and dangerous procedures should be placed at the beginning of this section. An example would be: “ Caution: The following chemicals are hazardous and should be handled carefully: (list of chemicals and handling procedures or references )”.

Biological models: The identity and source of the biological model used (i.e. organism, cells) should be specified (collection and collection number) and referenced (primary description). Where appropriate, information on the state of cell lines (e.g. passage number, doubling number) and information regarding how they were authenticated to ensure identity and validity for use, should be given. A rationale for selecting the specific model relevant to the aims of the study should be given.

Biological Assays . Exposure protocols and methods must be referenced or described in sufficient detail to permit the experiments to be repeated by other investigators. This includes for example information on the preparation of the test materials, medium components, and duration of exposure. In addition, the applied dose or dose range should be given in a meaningful unit and the relevance of the applied dose should be substantiated. Doses and concentrations should be expressed as molar quantities (e.g., μmol/kg, mM, etc.), particularly when comparisons of potencies are made on compounds having large differences in molecular weights. The routes of administration of test compounds and vehicles should be indicated. Benchmarks should be included in form of appropriate positive or negative control substances or reference materials. Especially for studies on nanomaterials, assays should be checked for interference induced by nanomaterials, e.g. optical or chemical interference, masking of the analyte or other interference mechanisms by inclusion of appropriate controls. Also for studies on nanomaterials, sterilization procedures and specification of dilution steps as well as the order of addition should be provided, and as far as possible, various measuring units related to dose (e.g. surface area, mass, particle number per surface area, volume, cell number) should be given to increase comparability with other studies. Data may be presented as numerical expressions or in graphical form. Statistical limits (statistical significance) for the biological data are usually required. If statistical limits cannot be provided, the number of determinations and some indication of the variability and reliability of the results should be given. References to statistical methods of calculation should be included.

In vivo studies: For research involving animals: An indication that all animal experiments have undergone ethical review and were carried out with appropriate permissions or licences from national or institutional committees that cover the research must be provided. Relevant details listed in the latest version of the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines should be given, especially the description of animals (e.g. source, sex, age, species, and strain), experimental design (e.g. number of groups, number of animals in each group, how animals were divided, and a flow chart of the study protocol) and procedures (e.g. drug or chemical formulation, dose, treatment time and frequency). The numbers of animals for each experiment used in the research should be clearly stated in the Materials and Methods section in manuscript and legends of relevant Tables and Figures.

Justifications for the doses used in the research should be included, and where appropriate, the relationship between these doses and relevant environmental or human exposure or intake levels is encouraged to be provided.

For research involving human subjects: A statement confirming that the research has been approved by relevant ethical committees and performed under The Code of Ethics of the World Medical Association (Declaration of Helsinki) must be provided. Details listed in the latest version of the STROBE (The Strengthening the Reporting of Observational Studies in Epidemiology) guidelines and description of informed consent protocols  must also be provided.

Data Deposition. Large data sets, such as those from structure determination, omics or sequencing data must be submitted to discipline-appropriate repositories recognized by the corresponding scientific community, and made publically available by the time of publication. A statement must appear in the submitted manuscript confirming submission of the data and indicating the data bank and any pertinent accession codes/ID.

Any set of atomic coordinates for structural data referred to in the manuscript, including atomic coordinates and structure factors for proteins determined by X-ray crystallography and coordinates determined by NMR, should be deposited with the Protein Data Bank, Research Collaboratory for Structural Bioinformatics at Rutgers University whenever appropriate. (Theoretical model depositions are no longer accepted for inclusion in the PDB archive.) If the coordinate files are not deposited in the PDB, or if the PDB files are on hold until publication, then the coordinate files must be included in the Supporting Information submitted concurrently with the manuscript. Requirements are similar for structures of nucleic acids, which should be deposited with the Nucleic Acid Database. A manuscript that does not provide coordinates at the time of submission will not be sent out for review. It is the responsibility of the author to obtain a file name (PDB ID or NDB ID) for the molecule; the file name must appear in the published manuscript. If a file name has not yet been obtained upon acceptance of a paper, it must be added in proof. Atomic coordinates and structure factors for all structures mentioned must be available immediately upon publication of the paper, either directly in the Supporting Information or as a data bank deposition. Similar requirements also apply to any chemical shifts referred to in the paper, whether they are only for assignment of resonances or used for any form of structure calculation. Those chemical shifts must be available to the reviewer at time of submission, either as an available entry in the Biological Magnetic Resonance Data Bank or included directly as Supplementary Information.

Any sequencing data should be submitted to a public repository prior to submission and include accession numbers in the manuscript where appropriate. Examples of suitable public repositories for DNA and RNA sequences include GenBank or Protein DataBank ; nucleic acid sequencing data can be deposited in NCBI Trace Archive or NCBI Sequence Read Archive (SRA). Protein sequences can be submitted to Uniprot .

Binding DB: Authors may wish to submit binding constants and associated information to the public database BindingDB.

Contributor Roles Taxonomy (CRediT)

CRediT is a high-level taxonomy used to identify and acknowledge the roles played by contributors to scientific scholarly output. During original submission and/or revision, there are 14 standard roles from which the submitting author can select to describe the specific contributions of each author. At this time, CRediT is optional for authors. Please note that author CRediT information will not transfer if the manuscript is transferred to a non-pilot journal. Click here to learn more about the ACS CRediT pilot .

A well-written paper helps share your results most clearly. ACS Publications’ English Editing Service is designed to help scientists communicate their research effectively. Our subject-matter expert editors will edit your manuscript for grammar, spelling, and other language errors so your ideas are presented at their best.

The quality of illustrations in ACS journals and partner journals depends on the quality of the original files provided by the authors. Figures are not modified or enhanced by journal production staff. All graphics must be prepared and submitted in digital format.

Graphics should be inserted into the main body whenever possible. Please see Appendix 2 for additional information.

Any graphic (figure chart, scheme, or equation) that has appeared in an earlier publication should include a credit line citing the original source. Authors are responsible for obtaining written permission to re-use this material.

The impact of your research is not limited to what you can express with words. Tables and figures such as graphs, photographs, illustrations, diagrams, and other visuals can play a significant role in effectively communicating your findings. Our Artwork Editing and Graphical Abstract services generate publication-ready figures and Table of Contents (TOC) graphics that conform to your chosen journal’s specifications. For figures, this includes changes to file type, resolution, color space, font, scale, line weights, and layout (to improve readability and professional appearance). For TOC graphics, our illustrators can work with a rough sketch or concept or help extract the key findings of your manuscript directly for use as a visual summary of your paper.

Preparing for Submission

Manuscripts, graphics, supporting information, and required forms, as well as manuscript revisions, must all be submitted in digital format through ACS Paragon Plus , which requires an ACS ID to log in. Registering for an ACS ID is fast, free, and does not require an ACS membership. Please refer to Appendix 1 for additional information on preparing your submission

Chemical Research in Toxicology authors are allowed to deposit an initial draft of their manuscript in a preprint service such as ChemRxiv , arXiv, bioRxiv or similar repository relevant to the research. Please note any use of a preprint server, as well as patents, dissertations, published conference proceedings or related dissemination, in the cover letter, and as appropriate, state how the manuscript has been adjusted/updated between deposition and submission. All other prior/redundant publications are forbidden.

Upon publication in Chemical Research in Toxicology , authors are advised to add a link from the preprint to the published paper via the Digital Object Identifier (DOI).

When a manuscript is received, Editors first judge whether its content is appropriate for publication in Chemical Research in Toxicology. Manuscripts that are primarily descriptive, confirmative of previous work, or those that do not address fundamental aspects of mechanisms or are not, in the judgment of the Editors, of sufficient interest to the general readers of Chemical Research in Toxicology will be returned to the author without further review. Following this initial evaluation, manuscripts are assigned to an Editor (the Editor-in-Chief or an Associate Editor) for review. The author will receive an e- mail notification indicating the Editor who will be processing the manuscript.

Manuscripts are evaluated for scientific content and significance by independent reviewers and the Editors. Reviewers are selected by the editors for their competence relevant to the manuscript. Authors also are required to provide the names of a minimum of three individuals who are competent to review the work. Authors should take care not to recommend reviewers who have a real or perceived conflict of interest (e.g., a collaborator or someone who has recently published with one of the authors), and all reviewers are expected to disqualify themselves if they have a conflict of interest. Authors may also express a preference that certain reviewers not be chosen. The reviewers are advisory to the Editor, who makes the final decision. If the reviewers disagree or, if in the judgment of the Editor, the manuscript has not received adequate consideration, a member of the Editorial Advisory Board may arbitrate. Editorial decisions that result from this process are final.

When a manuscript is returned to the author for revision, the author should reply, point by point, to reviewers’ and editors’ comments and, in an accompanying letter, indicate those recommendations that have been incorporated into the revision and the reasons for any that have been disregarded. When submitting a revised manuscript, authors should include a version of the manuscript that has the Tracked Changes feature turned on, so editors and reviewers can see the revisions that were made to the original manuscript. Please upload this version of the manuscript under the tag “Supporting Information for Review Only”. Authors should still indicate page and line numbers when referring to edited text in their response letter to the reviewers. An unmarked, final version of the manuscript should be uploaded under the tag “Manuscript File.” Manuscripts requiring a minor revision should be returned within 30 days (10 days for Communications). Manuscripts requiring a major revision should be returned within 60 days (no major revisions possible for Communications). Usually only one major revision will be considered. Authors requiring longer periods may request an extension, which will be granted at the discretion of the Editor. In general, a revised manuscript received beyond the specified deadline will be considered a new submission, will receive a new manuscript number, and will usually undergo a new review process.

Please suggest 5 reviewers. Authors are encouraged to avoid suggesting reviewers from the authors’ institutions. Do not suggest reviewers who may have a real or perceived conflict of interest . Whenever possible, suggest academic email addresses rather than personal email addresses.

If your submission is declined for publication by this journal, the editors might deem your work to be better suited for another ACS Publications journal or partner journal and suggest that the authors consider transferring the submission. Manuscript Transfer simplifies and shortens the process of submitting to another ACS journal or partner journal, as all the coauthors, suggested reviewers, manuscript files, and responses to submission questions are copied by ACS Paragon Plus to the new draft submission. Authors are free to accept or decline the transfer offer.

Note that each journal is editorially independent. Transferring a manuscript is not a guarantee that the manuscript will be accepted, as the final publication decision will belong to the editor of the next journal.

PRODUCTION AND PUBLICATION

Correction of the galley proofs is the responsibility of the Corresponding Author. The Corresponding Author of an accepted manuscript will receive e-mail notification and complete instructions when page proofs are available for review via ACS Direct Correct . Extensive or important changes on page proofs, including changes to the title or list of authors, are subject to review by the editor.

It is the responsibility of the Corresponding Author to ensure that all authors listed on the manuscript agree with the changes made on the proofs. Galley proofs should be returned within 48 hours in order to ensure timely publication of the manuscript.

Accepted manuscripts will be published on the ACS Publications Web site as soon as page proofs are corrected and all author concerns are resolved. The first date on which the document is published on the Web is considered the publication date.

Publication of manuscripts on the Web may occur weeks in advance of the cover date of the issue of publication. Authors should take this into account when planning their patent and intellectual property activities related to a document and should ensure that all patent information is available at the time of first publication, whether ASAP or issue publication.

All articles published ahead of print receive a unique Digital Object Identifier (DOI) number, which is used to cite the manuscript before and after the paper appears in an issue. Additionally, any supplemental information submitted along with the manuscript will automatically be assigned a DOI and hosted on Figshare to promote open data discoverability and use of your research outputs.

Manuscripts will be published on the “ASAP Articles” page on the web as soon as page proofs are corrected and all author concerns are resolved. ASAP publication usually occurs within a few working days of receipt of page proof corrections, which can be several weeks in advance of the cover date of the issue.

The American Chemical Society follows guidance from the Committee on Publication Ethics (COPE) when considering any ethical concerns regarding a published article, Retractions, and Expressions of Concern.

Additions and Corrections

Additions and Corrections may be requested by the author(s) or initiated by the Editor to address important issues or correct errors and omissions of consequence that arise after publication of an article. All Additions and Corrections are subject to approval by the Editor, and should bring new and directly relevant information and corrections that fix scientific facts. Minor corrections and additions will not be published. Readers who detect errors of consequence in the work of others should contact the corresponding author of that work.

Additions and Corrections must be submitted as new manuscripts via ACS Paragon Plus by the Corresponding Author for publication in the “Addition/Correction” section of the Journal. The corresponding author should obtain approval from all coauthors prior to submitting or provide evidence that such approval has been solicited. The manuscript should include the original article title and author list, citation including DOI, and details of the correction.

Retractions

Articles may be retracted for scientific or ethical reasons and may be requested by the article author(s) or by the journal Editor(s), but are ultimately published at the discretion of the Editor. Articles that contain seriously flawed or erroneous data such that their findings and conclusions cannot be relied upon may be retracted in order to correct the scientific record. When an article is retracted, a notice of Retraction will be published containing information about the reason for the Retraction. The originally published article will remain online except in extraordinary circumstances (e.g. where deemed legally necessary, or if the availability of the published content poses public health risks).

Expressions of Concern

Expressions of Concern may be issued at the discretion of the Editor if:

• there is inconclusive evidence of research or publication misconduct by the authors;
• there is evidence that the findings are unreliable but the authors’ institution will not investigate the case;
• an investigation into alleged misconduct related to the publication either has not been, or would not be, fair and impartial or conclusive;
• an investigation is underway but a judgment will not be available for a considerable time.

Upon completion of any related investigation, and when a final determination is made about the outcome of the article, the Expression of Concern may be replaced with a Retraction notice or Correction.

At ACS Publications, we know it is important for you to be able to share your peer reviewed, published work with colleagues in the global community of scientists. As sharing on sites known as scholarly collaboration networks (SCNs) is becoming increasingly prevalent in today’s scholarly research ecosystem, we would like to remind you of the many ways in which you, a valued ACS author, can share your published work .

Publishing open access makes it easy to share your work with friends, colleagues, and family members. In addition, ACS Publications makes it easy to share your newly published research with ACS Articles on Request (see below). Don’t forget to promote your research and related data on social media, at conferences, and through scholarly communication networks. Increase the impact of your research using the following resources: Altmetrics , Figshare , ACS Certified Deposit

When your article is published in an ACS journal or partner journal, corresponding authors are provided with a link that offers up to 50 free digital prints of the final published work. This link is valid for the first 12 months following online publication, and can be shared via email or an author’s website. After one year, the access restrictions to your article will be lifted, and you can share the Articles on Request URL on social media and other channels. To access all your Articles on Request links, log in to your ACS Publishing Center account and visit the “My Published Manuscripts” page.

Article , journal , and commercial reprints are available to order.

Appendix 1: PREPARING FOR SUBMISSION

We’ve developed ACS’ publishing and editorial policies in consultation with the research communities that we serve, including authors and librarians. Browse our policies below to learn more.

Ethical Guidelines

ACS editors have provided Ethical Guidelines for persons engaged in the publication of chemical research—specifically, for editors, authors, and reviewers. Each journal also has a specific policy on prior publication .

OFAC Compliance

As a U.S.-based non-profit organization, the American Chemical Society (ACS) is required to comply with U.S. sanctions laws and regulations administered by the U.S. Treasury Department’s Office of Foreign Assets Control (OFAC). While these laws and regulations permit U.S.-based publishers like ACS to engage in publishing-related activities with authors located in sanctioned regions in many cases, ACS may be prohibited under U.S. law from engaging in publishing-related activities in some cases, including, but not limited to, instances where an author or the institution with which an author is affiliated is located in a particular sanctioned region or has been designated by OFAC as a Specially Designated National (SDN) pursuant to certain U.S. sanctions programs. ACS reserves the right to refrain from engaging in any publishing-related activities that ACS determines in its sole discretion may be in violation of U.S. law.

Safety Considerations

Authors must emphasize any unexpected, new, and/or significant hazards or risks associated with the reported work. This information should be in the Experimental Section of a full article and included in the main text of a letter. Statement examples can be found in the Safety Statement Style Sheet  and additional information on communicating safety information from the  ACS Guide to Scholarly Communication is freely available here .

Conflict of Interest Disclosure

A statement describing any financial conflicts of interest or lack thereof is published in each ACS journal and partner journal article.

During the submission process, the Corresponding Author must provide a statement on behalf of all authors of the manuscript, describing all potential sources of bias, including affiliations, funding sources, and financial or management relationships, that may constitute conflicts of interest. If the manuscript is accepted, the statement will be published in the final article.

If the manuscript is accepted and no conflict of interest has been declared, the following statement will be published in the final article: “The authors declare no competing financial interest.”

In publishing only original research, ACS is committed to deterring plagiarism, including self-plagiarism. ACS Publications uses CrossCheck's iThenticate software to screen submitted manuscripts for similarity to published material. Note that your manuscript may be screened during the submission process.

Further information about plagiarism can be found in Part B of the Ethical Guidelines to Publication of Chemical Research . See also the press release regarding ACS' participation in the CrossCheck initiative.

Authorship, Author List, and Coauthor Notification

Authors are required to obtain the consent of all their coauthors prior to submitting a manuscript. The submitting author accepts the responsibility of notifying all coauthors that the manuscript is being submitted.

During manuscript submission, the submitting author must provide contact information (full name, email address, institutional affiliation, and mailing address) for all of the coauthors. Because all of the author names are automatically imported into the electronic Journal Publishing Agreement , the names must be entered into ACS Paragon Plus. (Note that coauthors are not required to register in ACS Paragon Plus.) Author affiliation should reflect where the work was completed, even if the author has since left that institution. Authors may include a note with a current address if their institution has changed since the work was completed.

To expedite the processing of your manuscript, please format your author and affiliation information according the guidelines in this link: https://pubsapp.acs.org/paragonplus/submission/author-address-information.pdf .

Criteria for authorship can be found in Part B of the Ethical Guidelines to Publication of Chemical Research . Artificial intelligence (AI) tools do not qualify for authorship. The use of AI tools for text or image generation should be disclosed in the manuscript within the Acknowledgment section with a description of when and how the tools were used. For more substantial use cases or descriptions of AI tool use, authors should provide full details within the Methods or other appropriate section of the manuscript.

If any change in authorship is necessary after a manuscript has been submitted, confirmation is required that all of the authors (including those being added or removed) have been notified and have agreed to the change. To provide this confirmation, authors are asked to complete and sign an authorship change form and provide the completed form to the appropriate editorial office.

Authors with a single name:  If you, or any of your coauthors, have only one name, please follow these steps for proper submission to ACS Paragon Plus:

• First (Given) Name Field: Enter an asterisk (*) into the "First (Given) Name" field.
• Last (Family) Name Field: Enter your single name into the "Last (Family) Name" field.

If your paper is accepted, the asterisk (*) will be removed from the published version of the paper.

Patent Activities and Intellectual Property

Authors are responsible for ensuring that all patent activities and intellectual property issues are satisfactorily resolved prior to first publication (ASAP or in issue). Acceptance and publication will not be delayed for pending or unresolved issues of this nature.

Open Researcher and Contributor ID (ORCID)

Authors submitting manuscript revisions are required to provide their own personal, validated ORCID iD before completing the submission, if an ORCID iD is not already associated with their ACS Paragon Plus user profiles. This ID may be provided during original manuscript submission or when submitting the manuscript revision. All authors are strongly encouraged to register for an ORCID iD, a unique researcher identifier. The ORCID iD will be displayed in the published article for any author on a manuscript who has a validated ORCID iD associated with ACS when the manuscript is accepted.

ORCID iDs should not be typed into the manuscript. ACS publishes only those ORCID iDs that have been properly verified and linked before the manuscript is accepted . After your ORCID iD is linked, it will be displayed automatically in all subsequently accepted manuscripts for any/all ACS journals. We do not publish ORCID iDs provided during proof review or via other communications after a manuscript is accepted for publication.

With an ORCID iD, you can create a profile of your research activities to distinguish yourself from other researchers with similar names, and make it easier for your colleagues to find your publications. If you do not yet have an ORCID iD, or you wish to associate your existing ORCID iD with your ACS Paragon Plus account, you may do so by clicking on “Edit Your Profile” from your ACS Paragon Plus account homepage and following the ORCID-related links. Learn more at www.orcid.org .

Copyright and Permissions

To obtain forms and guidelines for completing the Journal Publishing Agreement or obtaining permissions from copyright owners, and to explore a Copyright Learning Module for chemists, click here .

Funder Reporting Requirement

Authors are required to report funding sources and grant/award numbers. Enter ALL sources of funding for ALL authors in BOTH the Funder Registry Tool in ACS Paragon Plus and in your manuscript to meet this requirement.

Open Access Compliance

ACS offers options by which authors can fulfill the requirements for open access and deposition into repositories for funded research. Visit our ACS Open Science site to see how to fulfill requirements for specific funders  and to find out if you are eligible to publish under a Read + Publish agreement between ACS and your institution. You can also find out more about Open Access Compliance and ACS Open Science initiatives .

Diversity and Inclusion Statement

During manuscript submission, ACS journal authors have the option to submit a statement sharing information related to diversity and inclusion that is relevant for their paper. If supplying a diversity and inclusion statement, the corresponding author must provide this on behalf of all authors of the manuscript during the submission process. These statements include but are not limited to analysis of citation diversity and acknowledgment of indigenous land on which research was conducted. Statements expressing political beliefs are not permitted and may be removed by the journal office. All statements are subject to final review by the Editor.

• Citation Diversity Statement: The citation diversity statement should appear in the Acknowledgements section of the manuscript. ACS recommends including the following: (1) the importance of citation diversity, (2) the proportion of citations by gender and race/ethnicity for the first and last authors, (3) the method used to determine those proportions and its limitations, and (4) steps taken to by the authors to improve citation diversity in the article. We recognize that one limitation of the current methods is that it cannot account for intersex, non-binary, and transgender people, or Indigenous and mixed-race authors. (Adapted from BMES/Springer Guidelines )
• Land acknowledgment: The land acknowledgment statement should appear in the Acknowledgements section of the manuscript. The statement should link to the institutions’ formal land acknowledgments on which the research took place, if possible. Further guidance for creating these statements can be found here: https://nativegov.org/news/a-guide-to-indigenous-land-acknowledgment/ .

Appendix 2: Preparing Graphics

Digital graphics pasted into manuscripts should have the following minimum resolutions:

• Black and white line art, 1200 dpi
• Grayscale art, 600 dpi
• Color art, 300 dpi

Graphics must fit a one- or two-column format. Single-column graphics can be sized up to 240 points wide (3.33 in.) and double-column graphics must be sized between 300 and 504 points (4.167 in. and 7 in.). The maximum depth for all graphics is 660 points (9.167 in.) including the caption (allow 12 pts. For each line of caption text). Lettering should be no smaller than 4.5 points in the final published format. The text should be legible when the graphic is viewed full-size. Helvetica or Arial fonts work well for lettering. Lines should be no thinner than 0.5 point.

Color may be used to enhance the clarity of complex structures, figures, spectra, and schemes, etc., and color reproduction of graphics is provided at no additional cost to the author. Graphics intended to appear in black and white or grayscale should not be submitted in color.

Type of Graphics

Table of contents (toc)/abstract graphic.

Consult the Guidelines for Table of Contents/Abstract Graphics for specifications.

Our team of subject-matter experts and graphical designers can also help generate a compelling TOC graphic to convey your key findings. Learn more about our Graphical Abstract service .

A caption giving the figure number and a brief description must be included below each figure. The caption should be understandable without reference to the text. It is preferable to place any key to symbols used in the artwork itself, not in the caption. Ensure that any symbols and abbreviations used in the text agree with those in the artwork.

Charts (groups of structures that do not show reactions) may have a brief caption describing their contents.

Each table must have a brief (one phrase or sentence) title that describes the contents. The title should be understandable without reference to the text. Details should be put in footnotes, not in the title. Tables should be used when the data cannot be presented clearly in the narrative, when many numbers must be presented, or when more meaningful inter-relationships can be conveyed by the tabular format. Tables should supplement, not duplicate, information presented in the text and figures. Tables should be simple and concise.

Each scheme (sequences of reactions) may have a brief caption describing its contents.

Chemical Structures

Chemical structures should be produced with the use of a drawing program such as ChemDraw.

Chemical Research in Toxicology encourages authors to submit images to be considered for use on the journal’s front cover or Supplementary Covers at the time of the submission of their revised manuscript. If your article is accepted for publication, your suggestion may also be selected for use on one of the journal’s covers. Images chosen for the front cover will be published at no cost to the author. If your art is selected for front cover, ACS will send you information about how to request one complimentary 18” by 24” printed poster featuring your work.

Your cover image submissions should be colorful and visually engaging, with minimal text. The cover image should be an artistic and scientifically accurate representation of your manuscript. The editors prefer artistic renditions of structures, function, and data - it should not resemble a graphical abstract or data figure. Submit your cover image, along with a clear caption (less than 50 words) explaining the image, as supplementary files to ACS Paragon Plus with your revised manuscript. Image files should be submitted as TIF, JPG, PNG or EPS files with a resolution of at least 300 dpi for pixel-based images. Images should be 8.19 in × 10 in. (or 20.80 cm × 25.40 cm). Please note that the journal title will cover the top 3 in. (7.62 cm) of the image.

If you wish to be considered only for the front cover, and not a paid supplementary cover, please respond NO accordingly to the Journal Covers question in ACS Paragon Plus. For more information on the Supplementary Covers program, please see this webpage . All art submitted for consideration for a supplementary cover will also be considered for a front cover.

Web Enhanced Objects (WEO)

The Web editions of ACS journals allow readers to view multimedia attachments such as animations and movies that complement understanding of the research being reported.

WEOs should be uploaded in ACS Paragon Plus with ‘Web Enhanced Object’ selected as the file designation. Consult the list of compatible WEO formats .

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Chemical Research in Toxicology - Impact Score, Ranking, SJR, h-index, Citescore, Rating, Publisher, ISSN, and Other Important Details

Published By: American Chemical Society

Abbreviation: Chem. Res. Toxicol.

Impact Score The impact Score or journal impact score (JIS) is equivalent to Impact Factor. The impact factor (IF) or journal impact factor (JIF) of an academic journal is a scientometric index calculated by Clarivate that reflects the yearly mean number of citations of articles published in the last two years in a given journal, as indexed by Clarivate's Web of Science. On the other hand, Impact Score is based on Scopus data.

Important details, about chemical research in toxicology.

Chemical Research in Toxicology is a journal published by American Chemical Society . This journal covers the area[s] related to Medicine (miscellaneous), Toxicology, etc . The coverage history of this journal is as follows: 1988-2022. The rank of this journal is 5160 . This journal's impact score, h-index, and SJR are 3.87, 169, and 0.878, respectively. The ISSN of this journal is/are as follows: 15205010, 0893228X . The best quartile of Chemical Research in Toxicology is Q1 . This journal has received a total of 3203 citations during the last three years (Preceding 2022).

Chemical Research in Toxicology Impact Score 2022-2023

The impact score (IS), also denoted as the Journal impact score (JIS), of an academic journal is a measure of the yearly average number of citations to recent articles published in that journal. It is based on Scopus data.

Prediction of Chemical Research in Toxicology Impact Score 2023

Impact Score 2022 of Chemical Research in Toxicology is 3.87 . If a similar upward trend continues, IS may increase in 2023 as well.

Impact Score Graph

Check below the impact score trends of chemical research in toxicology. this is based on scopus data., chemical research in toxicology h-index.

The h-index of Chemical Research in Toxicology is 169 . By definition of the h-index, this journal has at least 169 published articles with more than 169 citations.

What is h-index?

The h-index (also known as the Hirsch index or Hirsh index) is a scientometric parameter used to evaluate the scientific impact of the publications and journals. It is defined as the maximum value of h such that the given Journal has published at least h papers and each has at least h citations.

Chemical Research in Toxicology ISSN

The International Standard Serial Number (ISSN) of Chemical Research in Toxicology is/are as follows: 15205010, 0893228X .

The ISSN is a unique 8-digit identifier for a specific publication like Magazine or Journal. The ISSN is used in the postal system and in the publishing world to identify the articles that are published in journals, magazines, newsletters, etc. This is the number assigned to your article by the publisher, and it is the one you will use to reference your article within the library catalogues.

ISSN code (also called as "ISSN structure" or "ISSN syntax") can be expressed as follows: NNNN-NNNC Here, N is in the set {0,1,2,3...,9}, a digit character, and C is in {0,1,2,3,...,9,X}

Chemical Research in Toxicology Ranking and SCImago Journal Rank (SJR)

SCImago Journal Rank is an indicator, which measures the scientific influence of journals. It considers the number of citations received by a journal and the importance of the journals from where these citations come.

Chemical Research in Toxicology Publisher

The publisher of Chemical Research in Toxicology is American Chemical Society . The publishing house of this journal is located in the United States . Its coverage history is as follows: 1988-2022 .

Call For Papers (CFPs)

Please check the official website of this journal to find out the complete details and Call For Papers (CFPs).

Abbreviation

The International Organization for Standardization 4 (ISO 4) abbreviation of Chemical Research in Toxicology is Chem. Res. Toxicol. . ISO 4 is an international standard which defines a uniform and consistent system for the abbreviation of serial publication titles, which are published regularly. The primary use of ISO 4 is to abbreviate or shorten the names of scientific journals using the technique of List of Title Word Abbreviations (LTWA).

As ISO 4 is an international standard, the abbreviation ('Chem. Res. Toxicol.') can be used for citing, indexing, abstraction, and referencing purposes.

How to publish in Chemical Research in Toxicology

If your area of research or discipline is related to Medicine (miscellaneous), Toxicology, etc. , please check the journal's official website to understand the complete publication process.

Acceptance Rate

• Interest/demand of researchers/scientists for publishing in a specific journal/conference.
• The complexity of the peer review process and timeline.
• Time taken from draft submission to final publication.
• Number of submissions received and acceptance slots
• And Many More.

The simplest way to find out the acceptance rate or rejection rate of a Journal/Conference is to check with the journal's/conference's editorial team through emails or through the official website.

Frequently Asked Questions (FAQ)

What is the impact score of chemical research in toxicology.

The latest impact score of Chemical Research in Toxicology is 3.87. It is computed in the year 2023.

What is the h-index of Chemical Research in Toxicology?

The latest h-index of Chemical Research in Toxicology is 169. It is evaluated in the year 2023.

What is the SCImago Journal Rank (SJR) of Chemical Research in Toxicology?

The latest SCImago Journal Rank (SJR) of Chemical Research in Toxicology is 0.878. It is calculated in the year 2023.

What is the ranking of Chemical Research in Toxicology?

The latest ranking of Chemical Research in Toxicology is 5160. This ranking is among 27955 Journals, Conferences, and Book Series. It is computed in the year 2023.

Who is the publisher of Chemical Research in Toxicology?

Chemical Research in Toxicology is published by American Chemical Society. The publication country of this journal is United States.

What is the abbreviation of Chemical Research in Toxicology?

This standard abbreviation of Chemical Research in Toxicology is Chem. Res. Toxicol..

Is "Chemical Research in Toxicology" a Journal, Conference or Book Series?

Chemical Research in Toxicology is a journal published by American Chemical Society.

What is the scope of Chemical Research in Toxicology?

• Medicine (miscellaneous)

For detailed scope of Chemical Research in Toxicology, check the official website of this journal.

What is the ISSN of Chemical Research in Toxicology?

The International Standard Serial Number (ISSN) of Chemical Research in Toxicology is/are as follows: 15205010, 0893228X.

What is the best quartile for Chemical Research in Toxicology?

The best quartile for Chemical Research in Toxicology is Q1.

What is the coverage history of Chemical Research in Toxicology?

The coverage history of Chemical Research in Toxicology is as follows 1988-2022.

Credits and Sources

• Scimago Journal & Country Rank (SJR), https://www.scimagojr.com/
• Journal Impact Factor, https://clarivate.com/
• Issn.org, https://www.issn.org/
• Scopus, https://www.scopus.com/

Note: The impact score shown here is equivalent to the average number of times documents published in a journal/conference in the past two years have been cited in the current year (i.e., Cites / Doc. (2 years)). It is based on Scopus data and can be a little higher or different compared to the impact factor (IF) produced by Journal Citation Report. Please refer to the Web of Science data source to check the exact journal impact factor ™ (Thomson Reuters) metric.

Impact Score, SJR, h-Index, and Other Important metrics of These Journals, Conferences, and Book Series

Check complete list

Chemical Research in Toxicology Impact Score (IS) Trend

Top journals/conferences in medicine (miscellaneous), top journals/conferences in toxicology.

Reference management. Clean and simple.

Journal abbreviation: Toxicology

The abbreviation of the journal title " Toxicology " is " Toxicology ". It is the recommended abbreviation to be used for abstracting, indexing and referencing purposes and meets all criteria of the ISO 4 standard for abbreviating names of scientific journals.

Abbreviation rules

The table below outlines in detail the ISO 4 rules and matches to the ISSN maintained list of title word abbreviations ( TWA ) to derive the abbreviation.

Abbreviation systems

ISO 4 abbreviation is a uniform system created by the International Organization for Standardization to abbreviate journal titles in a consistent manner. It serves to facilitate effective communication and reference within the academic community.

Journal title abbreviations are divided into ISO (International Organization for Standardization) for broad disciplines, NLM (National Library of Medicine) for biomedical and life sciences, and CASSI (CAS Source Index) for chemistry and related fields.

About the journal

Other journal abbreviations.

• International journal of petroleum engineering
• Global journal of traditional medicine
• Arkansas law review

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A primer on systematic reviews in toxicology

Sebastian hoffmann.

1 Evidence-Based Toxicology Collaboration at Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA

13 seh consulting + services, Paderborn, Germany

Rob B. M. de Vries

2 SYRCLE (SYstematic Review Centre for Laboratory Animal Experimentation), Department for Health Evidence (section HTA), Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

Martin L. Stephens

Nancy b. beck.

3 American Chemistry Council, Washington, DC USA

Hubert A. A. M. Dirven

4 Norwegian Institute of Public Health, Oslo, Norway

John R. Fowle, III

5 Science to Inform, LLC, Pittsboro, NC USA

Julie E. Goodman

6 Gradient, Cambridge, MA USA

Thomas Hartung

7 Center for Alternatives to Animal Testing at Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA

8 University of Manchester, Manchester, UK

Manoj M. Lalu

9 Clinical Epidemiology Program, Regenerative Medicine Program, Department of Anesthesiology and Pain Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada

Kristina Thayer

10 US Environmental Protection Agency, Washington, DC USA

Paul Whaley

11 Lancaster Environment Centre, Lancaster University, Lancaster, UK

Daniele Wikoff

12 ToxStrategies, Asheville, NC USA

Katya Tsaioun

Systematic reviews, pioneered in the clinical field, provide a transparent, methodologically rigorous and reproducible means of summarizing the available evidence on a precisely framed research question. Having matured to a well-established approach in many research fields, systematic reviews are receiving increasing attention as a potential tool for answering toxicological questions. In the larger framework of evidence-based toxicology, the advantages and obstacles of, as well as the approaches for, adapting and adopting systematic reviews to toxicology are still being explored. To provide the toxicology community with a starting point for conducting or understanding systematic reviews, we herein summarized available guidance documents from various fields of application. We have elaborated on the systematic review process by breaking it down into ten steps, starting with planning the project, framing the question, and writing and publishing the protocol, and concluding with interpretation and reporting. In addition, we have identified the specific methodological challenges of toxicological questions and have summarized how these can be addressed. Ultimately, this primer is intended to stimulate scientific discussions of the identified issues to fuel the development of toxicology-specific methodology and to encourage the application of systematic review methodology to toxicological issues.

Evidence-based approaches are received growing attention in toxicology due to their potential to improve the field’s transparency, objectivity, consistency and reproducibility, and to inform regulatory decisions and policy more effectively (Guzelian et al. 2005 ; Hoffmann and Hartung 2006 ; Schreider et al. 2010 ; Woodruff and Sutton 2014 ; Thayer et al. 2014 ; National Toxicology Program 2015 ; Stephens et al. 2016 ). By analogy to evidence-based medicine (EBM), the umbrella term evidence-based toxicology (EBT) has been coined to group all approaches intended to implement more effectively evidence-based principles in toxicology in general, and in toxicological decision making in particular. Such approaches include inter alia the establishment and universal use of a common ontology, justified design and rigorous conduct of studies, consistently structured and detailed reporting of experimental evidence, structured frameworks for evidence synthesis that characterize confidence in the evidence, probabilistic uncertainty and risk assessment, and the development of synthesis methodology to integrate evidence from diverse streams, e.g., from human observational studies, animal studies, in vitro studies and in silico/mathematical modeling.

The core evidence-based tool is the systematic review. Much attention has been focused on the application of systematic review methodology to toxicological questions in line with the efforts of government institutions from both sides of the Atlantic, such as the European Food Safety Authority (EFSA 2010 ) and the US National Toxicology Program’s (NTP) (Birnbaum et al. 2013 ). The work of these organizations has triggered the adoption and adaptation of systematic review approaches as a tool for conducting evidence-based assessments (EFSA 2010 ; Rooney et al. 2014 ; National Research Council 2014 ). As these initiatives are focused on the requirements and mandates of the respective institutions, the Evidence-Based Toxicology Collaboration (EBTC) and its stakeholders have identified the need to build on these recent developments and to provide a general introduction to systematic reviews for the broader toxicology community.

Building on calls for systematic reviews, e.g., by Stephens et al. ( 2013 ), Silbergeld and Scherer ( 2013 ) and Whaley et al. ( 2015 ), this primer is intended to serve as a starting point for toxicologists interested in understanding or conducting systematic reviews. While not a manual or handbook, sufficient detail is provided to allow basic understanding of the principles, process, and resources required to conduct a systematic review. The review process has been broken down into ten sequential steps identified by Stephens et al. ( 2016 ), which were used to structure this guidance (Fig.  1 ). The application of systematic reviews in toxicology is still in its early days and will continue to evolve. In particular, many methodological aspects are being discussed and consensus still needs to be reached. Consequently, this primer attempts to summarize existing proposals by identifying commonalities to introduce a common terminology (see Glossary), and to highlight the challenges ahead.

Steps of a systematic review

Historically, reviews in toxicology have been predominantly narrative in approach, whereby an expert uses literature to summarize a particular field, or attempts to address a specific research question, for example, regarding the potential toxicity of a chemical or drug for humans. A narrative review typically uses an implicit process to compile evidence to support the statements being made in the review. The reader often cannot tell how the available literature was identified, selected and compiled, why some studies were given more weight than others, and how the evidence was summarized to arrive at conclusions. It is often uncertain whether the author of a narrative review selectively cited reports that reinforced his or her preconceived ideas, or promoted specific views of a topic. Also, a quantitative summary of the literature is often absent in a narrative review.

Overall, these issues increase the risk that a review will produce misleading results through selective use and/or interpretation of the available evidence, and transmission of bias and error in the reviewed evidence to the final summary results. Lack of transparency in reporting of review methods can make it very difficult for the reader to detect such shortcomings. Given the numerous sources of potential bias, and the lack of transparency and methodological rigor, traditional “narrative” toxicological reviews are at an increased risk of being biased and often cannot be independently reproduced. This makes it difficult to confirm a review’s conclusions and runs the risk of misdirecting future research. In worst cases, risk management decisions based ostensibly on the same evidence base may differ significantly, as summarized by Whaley et al. ( 2015 ) for Bisphenol A or by Rudén ( 2001 ) for trichloroethylene, leading to a variety of issues, including uncertainty for all stakeholders. This undermines trust in decision makers’ and impedes consumers’ decision making, potentially jeopardizing public health. It should be noted, however, that notwithstanding their shortcomings for purposes such as summarizing toxicological knowledge or informing decision making, narrative reviews have their place in toxicology, e.g., when an expert view on a topic is needed or when time to make a decision is limited, as long as the nature of the review is made explicit. Table  1 , adapted from de Vries et al. ( 2014 ), summarizes how various features differ between narrative and systematic reviews. While this summary provides a general overview and is in most features a relative comparison of the review types, it demonstrates that the rigor of systematic reviews often requires increased time and resources.

Table 1

Some differences between systematic and narrative reviews

Note that these are just generalized estimates and true costs are likely to be variable for both narrative and systematic reviews

a Narrative reviews of authorities may take years, which are associated with high costs

Historically, clinical research reviews were expert-written narrative reviews as well, before the advent of the evidence-based medicine/healthcare (EBM/EBHC) movement. This movement established systematic review methodology as the best practice for summarizing all available evidence bearing on a research question. The need for reproducible, transparent, and comprehensive syntheses of the ever-growing volume of medical evidence triggered the development of increasingly rigorous approaches to review question formulation, literature search, evidence selection, and evidence integration. The field of clinical systematic reviews has grown into a large discipline with offshoot products, such as PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses; www.prisma-statement.org ), which is a guideline for reporting systematic reviews. In addition, working groups such as GRADE (Grading of Recommendations Assessment, Development and Evaluation) have developed to better understand and interpret the results of systematic reviews. The Cochrane group ( http://www.cochrane.org ), previously known as the Cochrane Collaboration, has played an instrumental role in fostering the continued development of systematic review methodologies since 1993. The Cochrane Handbook for Systematic Reviews of Interventions provides detailed guidance and instructions for conducting systematic reviews in a medical context (Higgins and Green 2011 ). Cochrane is also drafting a handbook for systematic reviews of diagnostic test accuracy (DTA) that adapts the evidence-based approaches to the challenges associated with evaluating diagnostic testing. Many of the methods in both handbooks are widely applicable, so they can be directly adopted for conducting systematic reviews in non-clinical areas, such as toxicology, while other methods need to be adapted for the toxicology context.

However, it is important to mention the specific differences between toxicology and clinical research, and the unique challenges associated with the application of this framework to toxicological questions (Wikoff and Britt 2016 ). These include multiple evidence streams and the challenges of their integration, multiple animal species (and strains), multiple outcomes and endpoints that characterize hazards, exposures to complex mixtures and the frequent lack of human data engendering the need to extrapolate from other species to human outcomes. Further, the objectives in a toxicological review often involve the evaluation of adversities as compared to clinical interventions. These complexities make it clear that the process developed for systematically reviewing randomized clinical trials for medical interventions, while serving as a foundational framework, will have to be substantially adapted to be applicable and useful in toxicology.

This primer relies heavily on existing authoritative documents, such as guidance and handbooks. We considered documents that were known to us, identified by a (non-systematic) internet search or included in the references of already identified guidance documents. This process yielded eight guidance documents (Table  2 ). We distilled the information from them by extracting the relevant details for each of the ten systematic review steps in our framework, focusing primarily on the Cochrane Handbook (Higgins and Green 2011 ), the EFSA guidance (EFSA 2010 ), the OHAT guidance (National Toxicology Program 2015 ) and the Collaboration for Environmental Evidence guidance (CEE 2013 ). The guidance provided by the Institute of Medicine (IOM 2011 ), Agency for Healthcare Research and Quality (AHRQ 2014 ) and Centre for Reviews and Dissemination (CRD 2009 ) is largely similar to the Cochrane Handbook, but with special focus on the needs and requirements of the individual organizations. The National Research Council’s (NRC’s) analysis of the US Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS) process reviewed inter alia current methods for evidence-based reviews. Other guidances, such as the systematic review methodology of the Navigation Guide (Woodruff and Sutton 2014 ) and the recommendations for systematic review and evidence integration by the Texas Commission on Environmental Quality (TCEQ 2014 ), are generally in agreement with the guidances considered here. In many cases, the approaches put forward in the individual guidance documents were similar to each other and consequently to that presented here. However, we also found some specific issues, on which not all guidance documents were aligned. In these cases, we either choose to present the approach proposed by the majority or describe the divergent views.

Table 2

The guidance documents that were considered

Reliance on these guidance documents should not be interpreted as an endorsement of any particular approach at this point in time as the field and methodology are continuing to develop. In addition, it should be noted that we deliberately did not conduct a systematic review on this topic. As the purpose was rather to provide a survey of available guidance and characterize the key components in the conduct of a systematic review and in doing so, highlight some of the challenges in applying existing frameworks to toxicological questions, we considered a narrative approach to be more suitable.

To date, the application of systematic review methodology to toxicological issues has focused primarily on questions regarding the impact of chemicals on human health, e.g., for perfluorooctanoic acid (PFOA) (Johnson et al. 2014 ; Koustas et al. 2014 ) or metals (Navas-Acien et al. 2007 ; Meyer-Baron et al. 2009 ). However, many other toxicological questions are suitable for systematic review. Examples are, the risk associated with a specific exposure (Tsuji et al. 2014 ), the (eco-)toxicity of mixtures of substances (Cedergreen 2014 ), the relevance of a toxicity biomarker (Dello et al. 2013 ), the assessment of new toxicological test methods, the determination of toxicological mechanism, e.g., in the frame of the Adverse Outcome Pathways (AOP) approach, the status of technology development relevant for toxicological questions (de Vries et al. 2013 ), and the evaluation of risks to human health posed by a chemical under specific regulations, such as the Regulation, Evaluation and Authorisation of Chemicals (REACH) in Europe (Whaley et al. 2015 ). Note that the examples given here claimed to be systematic reviews. However, it is important to note that our citing of those examples here does not imply that these publications met the systematic review criteria in all cases. Indeed, an increasing number of publications claim to be systematic reviews, but upon a closer examination, fail to meet basic criteria such as the production of a review protocol, the documentation of the literature search, or the appraisal of studies (Haddaway et al. 2017 ).

The application of many of the individual framework steps in a systematic review, e.g., the approach and reporting for evidence search, will be very similar for any review question. However, as outlined above, toxicological reviews have specific challenges that call for adaptation of the established systematic review methodology, especially the potential diversity of evidence. This primer summarizes the systematic review process and methods in a way intended to be primarily useful for assessing the toxicity of chemical substances. However, it will also be useful when considering other types of review questions, such as the assessment of test methods for hazard identification, characterization and the elucidation of a toxicological mechanism as well as the establishment of health-based toxicity values. In addition, it identifies some important methodological and structural challenges we are currently facing. It is anticipated that this primer will serve as a helpful introduction for those unfamiliar with the tool, as well contribute to a common acceptance of the rigor involved with the conduct of systematic reviews in support of toxicological assessments.

• Review team
• Advisory group

Because minimizing bias is a guiding principle of systematic reviews, even the initial planning should be conducted as rigorously, objectively, and transparently as possible. This step may involve iterative consideration of sponsor and stakeholder needs, scoping of the topic—including considerations of feasibility, and input and participation from a multidisciplinary team sharing a variety of roles.

The motivation to conduct a systematic review should be documented to provide a summary of what is known on a given topic, e.g., to summarize a large amount of evidence, to explore reasons for inconsistency in the results of studies, resolve controversies or uncertainty about what the existing evidence is demonstrating, or to identify data gaps. Once the plan to conduct a review assumes shape, it has to be decided which type of review to perform. In some cases, a narrative approach may be chosen for any of a variety of reasons, such as limited available time or resources, limited data or to express an expert opinion. However, if the goal is to provide an objective and comprehensive summary of the evidence on a certain topic, a systematic review approach should be conducted. Table  1 (see “ Preamble ”) suggests that it is conceivable to adopt a mixed review approach that addresses some features in the manner of a narrative review and others in the manner of a systematic review. It is emphasized, however, that only a review conducted systematically in all steps is a systematic review. To avoid improper use of terminology, a mixed review approach should not be called a systematic review.

Various motivations exist to conduct a systematic review in toxicology. It is conceivable that the motivated party is researchers, who conduct systematic reviews to answer questions in their specific field of interest, or governmental, nonprofit or commercial organizations, which may conduct systematic reviews themselves or sponsor them. In the frameworks that have been created by agencies, including the NTP and EFSA, the motivation is driven by the respective public health mandates and needs of the conducting entity. Whether conducted by an agency or not, a systematic review may seek to clarify the health effects of an evidence-rich chemical. In other cases, a systematic review may be undertaken when evidence is scarce to identify data gaps or to assess the accuracy of a toxicological test method. Given that the systematic review framework is still an emerging practice in toxicology, it is also possible in these early days that a systematic review may be conducted, in part, to explore the proper translation of this methodology to the toxicological arena.

The questions addressed by systematic reviews should be meaningful to relevant stakeholders. Once the question and objective(s) for a systematic review have been at least roughly formulated, an effort should be made to make certain that no systematic review of sufficient quality and timeliness already exists. If a systematic review addressing a similar question is currently in progress, the results should be awaited prior to considering the undertaking of another one. In this regard, a registry of ongoing or completed systematic reviews in toxicology would be helpful. The PROSPERO database ( http://www.crd.york.ac.uk/PROSPERO/ ), may serve as such a registry as the inclusion criteria have been expanded to systematic reviews with a health-related outcome. Other options are available, such as the publication of protocols for systematic reviews of laboratory animal studies offered by SYRCLE (SYstematic Review Centre for Laboratory animal Experimentation).

While not necessarily required, scoping the literature on the topic could be helpful in assessing the need for a systematic review. This approach is particularly useful in fields where little is known regarding the current state of the literature and previous systematic reviews have not been performed. Scoping may range from a simple non-systematic search in one or two databases to a more formalized, resource intensive scoping review (described in Levac et al. 2010 and in Peters et al. 2015 ). If a more formalized approach is adopted, it is recommended to consult with or involve a trained information specialist in conducting comprehensive literature searches for systematic reviews (McGowan and Sampson 2005 ). The findings of a scoping exercise may reveal that the question has already been adequately addressed or may confirm that better understanding of the evidence could provide clarity. A scoping search can inform the planning process by revealing important details such as the expertise required, the stakeholders that have interest in the topic, and the resources needed. Scoping may be conducted before or after a review team is formed, but the approach used should be transparent and objective.

A review team should be created and the roles and responsibilities of the team members should be defined during the planning phase. This team should be multidisciplinary and combine appropriate expertise and experience to conduct the systematic review. It should include expertise on (1) the topic, (2) systematic review methodology, (3) literature search and retrieval, and if required, (4) quantitative methods and statistics. Two or more members of the team should collaborate to allow cross-checking of essential systematic review steps, many of which require parallel work independently conducted. The team should establish a leader who understands the task in detail and is skilled in facilitating multidisciplinary projects. Among the first tasks of the review team should be detailed planning of required resources, distribution of tasks and planning of the time frame. Furthermore, the team should engage with expected users of the review’s results and diverse stakeholders to collect their input. Bias in the review team should be minimized and disclosed. Members should be independent of parties with potential conflicts of interest. All members should complete a formal conflict of interest statement, e.g., using the International Committee of Medical Journal Editors (ICMJE) Conflict of Interest form (COI). (available at http://www.icmje.org ), which may need to be re-visited throughout the review, e.g., using a COI management plan.

An advisory group that includes representation of relevant stakeholders, especially potential users of the systematic review outcome with appropriate interests, skills and commitment, should be considered. The availability of an advisory group may prove especially valuable in supporting the review team by informing key decisions, particularly those that arise from the need to adapt general systematic review methodology to the needs of toxicology. In addition, the advisory group can help interpret and disseminate results, and collect stakeholder and user input.

If not yet available, potential sponsors that provide financial resources may be approached. Sponsors of systematic reviews can be governmental, nonprofit or commercial, noting, however, that in the clinical field, some (e.g., Cochrane) prohibit commercial sponsors. They should not interfere with the independence of the review team. While allowed to give direction in the very early stages of a systematic review, sponsors should not exert any influence once the (broad) review question is defined. However, input on the scope as well as oversight of the review to ensure progress and timeliness should be allowed. All sponsorships should be acknowledged. It is advisable that the motivation of the sponsor to support a specific systematic review should be made known to all parties involved. Best practices regarding sponsorship are likely to evolve with the acceptance and application of systematic reviews in toxicology.

By the end of the planning stage, the decision to conduct the review will have been confirmed (or not). The resources and the timeframe will have been established, and the review team and advisory group will be in place.

For toxicological systematic reviews, the major challenge in the planning phase will be to compose a skilled review team. In particular, systematic review experience among toxicologists is scarce. Until sufficient systematic review capacity is built in toxicology, clinical or pre-clinical systematic review experts may need to be engaged. Also, the issue of sponsorship is delicate. While such sponsorship may be essential to progress in this field, this needs to be weighted against the potential bias introduced. Clear boundaries for sponsor interaction need to be established very early in the review process and detailed documentation of the sponsor’s role may present a solution.

• Review question(s)
• Components (PICO/PECO)
• Modifications

Once the need for a systematic review has been established, that need should be translated into the review question(s) for conducting the review. Framing the review question(s) is a crucial step in a systematic review.

When reviewing clinical questions/interventions, the process of formulating a review question follows a structured framework that consists of a few essential components . One of the approaches for formulating systematic review questions used in medicine is captured in the PICO framework. This framework calls for the systematic review question to address the Population/participants, the Intervention, the Comparison or Control, and, if considered relevant, the Outcome. In addition, the review question may also specify the types of studies to be considered, e.g., randomized clinical trials, and may include the (clinical) setting, which is sometimes reflected by amending the framework to PICOTS.

In general, this framework should also be applicable to the toxicological context; it has been adapted to exposure-related review questions as PECO , replacing the Intervention component with Exposure, defined by exposure conditions, e.g., a substance or radiation, the route (e.g., oral, dermal, intravenous), the duration (ranging from once (acute) to daily for a lifetime (chronic)) and the relevant exposure range. Appropriate definition of the exposure component is essential for the relevance of the review results for public health protection. An example of a PECO for a chemical health effect is to investigate if chronic oral exposure to chemical X (exposure) induces health effect Y (outcome) in adult rats (population) as compared to not exposed adult rats (control). The population should clearly define the evidence stream(s) and the subjects considered (e.g., adult, juvenile/children, pregnant, healthy, diseased, etc.).

For systematic reviews assessing the accuracy of a test method compared with another, one would need to specify an index test and a comparator test. Note that not all components are relevant to every systematic review and that specific questions may require different components. Regardless of specifics, framework components are a general requirement and are specified in the systematic review protocol. The review team should plan sufficient time for framing the review question, including the generation of the associated rationale and context, and possibly for iterative modifications, as decisions made during problem formulation have significant impact on the scope and form of the systematic review.

Examples of toxicological review questions addressed in recent systematic reviews or intended for systematic reviews include:

• What is the effect of exposure to fluoride used as additive for water fluoridation, compared to vehicle-only treatment, on neurobehavioral outcomes in whole non-human mammalian animals? (National Toxicology Program 2016 ).
• What is the epidemiological evidence for an association of low-level arsenic exposure in drinking water with cardiovascular disease? (Tsuji et al. 2014 ).
• What is the animal and human evidence for the usefulness of ophthalmate as a biomarker for oxidative stress and hepatic glutathione homeostasis? (Dello et al. 2013 ).
• What is the association between intake of isoflavones from food supplements and adverse effects on the three target organs (mammary gland, uterus and thyroid) in peri- and post-menopausal women? (EFSA Panel ANS 2015 ).
• Is developmental exposure to air pollution associated with autism spectrum disorder? (Lam et al. 2016 ).
• For healthy adults, is caffeine intake above 400 mg/day, compared to intakes of 400 mg/day or less, associated with adverse effects on cardiovascular outcomes? (PROSPERO 2015: CRD42015026673; available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015026673 ).

While secondary review question(s) may be addressed, a clear single primary review question should drive the formulation of the review. Because this question will be the systematic review’s guiding element and principal goal, defining it precisely and appropriately is of crucial importance; the entire review team should be involved in the process. A properly framed review question will facilitate all the review’s subsequent steps, including the definition of the eligibility criteria and the literature search, how the evidence/data will be collected, and how the results will be presented and integrated. In particular, the question should help define the criteria for the inclusion and exclusion of research studies in a way that ensures that all relevant evidence is included to answer a particular question. For example, the review question could focus on a specific study type, such as chronic toxicity studies in animals, and would exclude any other study type, such as acute or sub-acute toxicity studies. An example of a question about a specific hazard of a substance would be ‘What is the current evidence from animal studies that substance X compared to substance Y (e.g., vehicle or no treatment) can induce effect Y?’

Once the review question has been formulated, it can be modified if more detailed insight into the topic demands it. However, all modifications should be well documented and justified, agreed to by the entire review team, eventually approved by the advisory group and reported, preferably, both in a protocol and in the final publication. Any introduction of bias, such as modifying the review question after data extraction should be strictly avoided. Modifications to the question during protocol development may be indicated, for example, when the scope of the review question proves to be too narrow or wide, the study type(s) to be considered need to be restricted or extended, or the outcome of interest is too specific or nonspecific (e.g., developmental effects vs malformations vs delayed ossification).

A major challenge will be to frame questions in a way that they are amenable to systematic reviews. The initiating problem might be too broad for a single systematic review, e.g., to perform a human health risk assessment for chemical X. In this case, the broad question needs to be distilled into various smaller PECO questions allowing for a systematic review, for example, focusing on specific risk, a single human health endpoints and/or a limited number of outcomes/endpoints.

• Protocol development
• Essential steps
• Protocol publication and registration

Once the review question has been defined, the protocol needs to be developed. Protocol development is often an iterative process. To minimize bias, the protocol should specify the methods to conduct the systematic review in such detail that the review could be independently reproduced. This reduces the potential for introducing bias, because the process is defined without detailed knowledge of the evidence. As the review team’s understanding of the topic evolves, issues may arise that make the need for adjustments to the protocol apparent. To ensure the transparency of any protocol modifications, the review team needs to document and justify them. Developing the protocol may require regular communication within the review team and with the advisory group. Standardized protocol formats are available for clinical systematic reviews (e.g., in Higgins JPT and Green S (2011)) and for animal intervention studies (e.g., by de Vries et al. 2015 ), but not for systematic reviews of toxicological issues.

The protocol should address how the systematic review’s essential steps will be carried out to maximize transparency and consistency and to reduce biases. Special care must be taken to avoid the possibility of having biases introduced by the review team, e.g., simply by being aware of this potential bias or by requesting the support of the advisory group. At least some members of the team are by definition knowledgeable about the review topic and may therefore have predetermined opinions and expectations. In addition to presenting the review question to be addressed in detail, including background information and any secondary questions, and administrative information, the protocol should specify (see e.g., PRISMA-P (Moher et al. 2015 ):

• The literature search strategy, including the databases and other sources to be searched, the languages to be considered, the publication period to be covered as well as database-specific search syntax.
• The inclusion/exclusion criteria detailing how the studies/hits identified during the search, which can be in the thousands, will be screened for relevance, and a description of the process how these will be applied. Usually, at least two reviewers screen the studies independently in duplicate, initially based on title and abstracts, and later on full texts.
• The data to be extracted and the process of data extraction, including an explanation of how it will be retrieved from disparate data sources. This should involve at least two trained extractors that abstract data independently in duplicate using standardized forms/templates.
• The criteria that will be used to assess each evaluated study’s quality, including internal validity/risk of bias, i.e., the degree to which a result of a study is likely to be true and free of bias, such as selection bias, performance bias or detection bias, but also other quality aspects, e.g., related to exposure, and a description of the process how these will be applied. Usually, at least two reviewers screen the studies independently in duplicate. Instructions for assessing the entire body of evidence’s risk of bias should also be included.
• How the data will be summarized and synthesized relative to develop conclusions, which may or may not include a quantitative analysis, e.g., a meta-analysis. Here, it is helpful to anticipate the likely data types to be encountered, e.g., ordinal or dichotomous, one- or multi-dimensional, and to determine how the (summary) data will be represented when the data are synthesized.
• The process of determining confidence in the final result distilled out of the included studies considering aspects such as precision, consistency, directness, magnitude, dose–response relationship, publication bias and aspects of quality, including external validity, and internal validity/risk of bias).

Once the review team considers the protocol as complete, it should be made publicly available. This allows interested parties that were not involved or consulted in the preparation of the systematic review, such as additional experts or stakeholders, to provide constructive input at this stage that still allows the team to accommodate suggestions. The review team should be, within limits, responsive to the comments received. Additionally, protocol publication or registration serves as documentation of a priori decisions—a critical component of systematic reviews. For example, it safeguards against introduction of bias via changing methods part-way through the review process, as it requires justifying the points in which the actual report of results deviates from the protocol. Protocols can be submitted at various stages, ranging from the very initial stages of problem formulation, but prior to the completion of data extraction. Several venues for protocol publication or registration are available. Aside from PROSPERO, HAWC (Health Assessment Workspace Collaborative), which is designed to facilitate development of human health assessments of chemicals, provides an opportunity for authors to document and make protocols publicly available. Other sources to publish protocols include: Open Science Framework ( www.osf.io ), CAMARADES for animal systematic reviews ( http://www.dcn.ed.ac.uk/camarades/ ), or any electronic repository that is publicly available and searchable (e.g., UOttawa repository— https://www.ruor.uottawa.ca/ ).

While a central site for registration of toxicological systematic review protocols is a long-term goal, it will be a challenge in these early days to publish protocols that are highly visible to stakeholders and interested parties, unless they are conducted by governmental agencies with established dissemination channels. In addition, ways to ensure timely communication of protocol publication to the intended audiences need to be established, e.g., through presentation at relevant conferences.

• Design of a search strategy
• Implementation of the search
• Sources to search
• Documentation

The literature search is at the heart of systematic review. It needs to be sensitive enough that it does not inadvertently exclude evidence, which is relevant to the review question, without returning an unmanageably large amount of irrelevant information. Care must be taken not to introduce bias during the literature search (for example, by accidentally searching only sources that tend to report significant findings). Therefore, the design of a search strategy needs to be developed thoughtfully with the help of an information specialist experienced in systematic review searches and documented in the protocol.

A comprehensive search strategy should:

• be guided by the primary question, e.g., in the selection of search terms
• minimize potential sources for biases, e.g., by specifying the information sources to be searched
• be in-line with the pertinent inclusion criteria, e.g., publication date or language(s) to be considered
• be developed using syntax specific to databases (e.g., MeSH terms in PubMed)
• strike a balance between sensitivity, i.e., the ability to identify relevant evidence, specificity, i.e., the ability to exclude irrelevant information
• be double-checked for appropriateness, e.g., in a pilot phase
• be appropriately documented in the protocol.

Because including population(s) and outcome(s) in a search can render it too complex to be conducted efficiently, these parameters are not usually considered in clinical systematic review searches. However, a search strategy for a toxicology topic can be expected to include the evidence stream assessed, e.g., animal, human, in vitro or mechanistic studies, and often also the toxicological endpoint(s) of interest.

The search should be implemented in an objective manner. In this way, some biases , e.g., inclusions of studies known to the authors, or supporting the authors’ view (frequently observed in traditional narrative reviews) can be minimized. Furthermore, authors need to be especially aware of issues such as publication bias, i.e., systematic differences between the findings of published and unpublished research, selective outcome reporting, time-lag bias (time of publication depending on the results), citation bias [(non-) citations driven by the results], gray literature bias (publication in gray literature depending on the results) or multiple publication (Song et al. 2014 ). It remains to be explored which biases play a role for toxicological systematic reviews.

Some biases can be minimized by an appropriate choice of sources to search . Searches will be most efficient in bibliographic databases such as PubMed, EMBASE or Toxline, as they offer advanced search options and will in many cases include at least a substantial proportion of the relevant evidence. A BIOSIS preview, which inter alia includes proceedings, provides access to a certain proportion of gray literature. To determine which sources to search, review teams may wish to contact other experts in the topic of interest, such as research groups or manufacturers. Citation searching may be necessary to complement the database search using tools such as science citation index (SCI) or SCI Expanded, as e.g., implemented by SciSearch or the Web of Science or Scopus. These tools can be used to support the identification of relevant backward citations, i.e., references in eligible studies, as well as forward citations, i.e., later studies referring to an eligible study. It should clearly be stated what level of detail will be required for inclusion, e.g., if posters or abstracts will be considered.

In addition, other sources of evidence may be considered, including general search engines (e.g., Google Scholar), subject-specific or regional databases (e.g., National Toxicology Program study databases), or dissertation and thesis databases.

Gray literature—here defined as material either unpublished or not controlled by commercial publishers, often differing in form, e.g., not a scientific article or report, and the way it is available, i.e., not in journals or databases—may comprise a variety of sources, such as government reports, theses, dissertations, conference proceedings, regulatory databases, case reports or interest group media, such as websites. Gray literature is potentially as important for toxicological systematic reviews as it is for those in the clinical field, but with different emphasis. While in the clinical field gray literature has been shown to include more ‘negative’ results (Hopewell et al. 2007 ), no evidence on any possible pattern in gray toxicological literature is available. However, it can be expected that it will be associated with intellectual properties. Therefore, some of the original toxicological studies might not be readily accessible for the review team since these are owned by the study sponsors. It is essential to clearly define the gray literature sources to be searched and the type of information to be included (experimental studies, case studies, collection of information (e.g., on websites)). Note that with the new channels of scientific communications, i.e., all forms of web publishing, including blogs, newsletters and websites, the definition of gray literature is currently undergoing adaptation that potentially may require a review of the use of this term in the context of systematic reviews.

Proper documentation of the search is required to allow its replication. While the overall strategy design is reported in the protocol, the database-specific search strategies should be included in an appendix to the review. Consequently, the exact strategies should be stored electronically with the date of the search and the number of unique records found. This information should be reported in the first step of a study flow diagram.

The major challenge of the evidence search for toxicological systematic reviews will be to identify the right sources, including gray literature sources, so that the vast majority of relevant evidence is identified. In addition, it will be crucial to provide the means to conduct searches balancing sensitivity and specificity. This could, e.g., be improved by better annotation of the toxicological literature using a widely agreed terminology/ontology. Another issue is that information specialists are often not very familiar with toxicological evidence and databases.

• Eligibility criteria
• Selection process

Literature searches usually yield thousands of records. Many of these will either not be relevant or will have specific characteristics that disqualify them for evidence synthesis. To prevent subjectivity in the evidence selection, systematic reviews include definition of eligibility criteria that are used to identify the proportion of relevant studies that will ultimately be included in the systematic review. Driven by the review question, it is important to define the criteria as unambiguously as possible to allow consistent interpretation and application by the assessors. To minimize biases and to ensure reproducibility of the process of selecting the studies, the eligibility criteria need to be defined in advance in such a way that the scope for subjective judgment is reduced to a minimum.

Generally, the eligibility criteria for a systematic review will address the pivotal aspects of the framed question, i.e., in case of PECO, its four defining elements. Depending on the scope of the systematic review, the population may refer to a human study population (e.g., in terms of sex, age, geographical region); to animal species, strains and other characteristics for in vivo studies; or to cell source(s) for in vitro studies. Exposure criteria may address the preparation of the doses/concentrations or the administration/treatment (route, characterization, stability, frequency, duration, optimal treatment window, etc.) scheme. Criteria related to the comparison will specify requirements related to experimental controls (e.g., for animal and in vitro studies, the need for a negative or vehicle control) and aspects like randomization and blinding. The eligibility of outcomes needs to be carefully considered in order not to bias the review. Systematic exclusion of outcomes may bias the results, such as excluding evidence that opposes the effect determined by the included outcomes. By contrast, inclusion of a wide range of outcomes may result in a spectrum too broad for a meaningful synthesis, e.g., when considering all types of developmental effects. Other study characteristics that may be used as eligibility criteria include the animal species, reporting of required data and—although often discouraged—the language and date ranges. Studies’ internal validity/risk of bias may be used to exclude studies. However, this has the potential (a) to discard too much evidence perceived low internal validity that may nevertheless be useful and/or (b) to inject a substantial risk of bias, as studies first need to undergo detailed assessment, which may influence reviewers. Therefore, the internal validity of studies is usually accounted for in a sensitivity or subgroup analysis later in the review process.

Another bias may be introduced at this stage of a review if the reviewers’ knowledge results in the formulation of eligibility criteria potentially biased to meet the experts’ expectations. A further potential pitfall at this stage is random error associated with reading and reviewing records.

The selection process should be described in detail in the protocol. It should specify the qualification and/or training of the reviewers and how the quality of the selection is controlled (usually by independent duplicate review, i.e., requiring that two reviewers independently carry out the selection, with a procedure to resolve disagreements). In addition, it should provide instruction to document the selection in a way that allows its reproduction. The selection is usually carried out in two stages. First, all identified records are screened, e.g., on the basis of title and abstract, to exclude obviously irrelevant records. Although reviewers should be conservative, and when in doubt, not to exclude studies, screening substantially reduces the number of records. Rejected studies will either be completely off-topic or fail to meet one or more eligibility criteria. These rejections should be clearly documented including a justification. The second stage involves retrieving full reports of the remaining records and determining their eligibility. The task of obtaining full study reports poses challenges to the review team, as both the process and eligibility assessment may be time consuming. For toxicological issues, reports may be scientific articles, but can also be study reports usually in the possession of the study sponsor or conducting agency, which may be difficult to obtain.

Duplicate records should be identified and excluded, usually before the eligibility is evaluated. While some duplicates may be straightforward to identify (e.g., identical records retrieved from different sources), especially when using reference managing software, or other software designed to facilitate systematic reviews, others may be very difficult to detect. Duplicates may be especially hard to detect when only parts of the data have been duplicated.

Researchers may want to consider the appropriateness of the selection process in a pilot exercise. Therefore, a representative subset of studies identified through the literature search should be selected. To assess the reproducibility and appropriateness, two reviewers should independently apply the selection criteria. This practice can identify and remedy ambiguities both in the eligibility criteria themselves or in the way the reviewers interpret them.

Detailed documentation of the decision(s) made in the selection process is essential for the transparency of the review. Reviewers’ assessments should be captured, as well as the solutions in case of disagreements. The reasons for exclusion of records at the screening stage should be documented in a dedicated place, where distinguishing the irrelevant cases from the cases that failed eligibility criteria is considered sufficient. Similarly, exclusion at the full-text level should be documented. All full texts retrieved should be kept in a database.

A widely accepted and valuable tool for summarizing the selection process is the PRISMA statement flow chart on study selection presented in Fig.  2 (Moher et al. 2009 ). Koustas et al. ( 2014 ) provide a practical example of its use for a toxicological systematic review.

Flow chart of the study selection (from Moher et al. 2009 ) (screening is based on title and abstracts)

At this stage, it may be most challenging to learn to handle the possibly vast amount of identified records and appropriately document the selection process. Software applications are available and will likely allow reviewers to implement an efficient and transparent record management. Tsafnat et al. ( 2014 ) provided an overview of informatics solutions to support various processes of a systematic review and the systematic review toolbox contains more than 100 software tools for a broad range of systematic review task ( http://systematicreviewtools.com/advancedsearch.php ).

• Data to collect
• Data extraction process

Data extraction is the process of collecting relevant information from the full-text version of selected studies for the subsequent data summary and analysis steps of a systematic review. Thorough planning of the extraction is required to minimize biases, reduce human errors, and allow for reproducibility. A priori planning of tables and figures to be included the final report can help ensure that all data relevant for the intended analyses will be collected.

Proper documentation, the use of user-friendly extraction tables or software, and a piloting exercise (see below) will maximize reproducibility of the extraction. Striking the right balance between over- and under-extracting is the key, as failing to collect relevant data may require additional reviews of the full texts of all eligible studies, while extraction of irrelevant data will unnecessarily consume valuable time and resources.

Relevant information includes study characteristics, information pertinent to quality assessment, and study results to be synthesized and meta-analyzed, if needed. Data to collect for each study must be defined in advance, and include:

• eligibility, including reasons for both inclusion and exclusion (see above)
• data for quality/risk of bias assessment
• study characteristics (regarding all components, e.g., PECO)
• other information, such as funding source, study authors’ conclusions or if study authors were contacted.

Collected data need to be augmented with general information, e.g., reviewer ID and date of extraction, and with unambiguous study identifiers, such as the citation and a study ID. For some cases, e.g., when only study types with a well-harmonized way of reporting are considered, it is efficient to also extract the data required for the study quality/risk of bias assessment, as described in the next step, during this step. For fields with lesser standardization such as toxicology, it may be more prudent to conduct three different extractions—one for the study characteristics, one for the quality/risk of bias assessment, and one for the results—as each of them requires a different focus and level of interpretation by the extractor.

Usually, most data should be extracted from study reports that allow the data source to be traced. Some journals have included the raw data as supplementary material. In some cases, the funding agencies have a requirement that raw data are submitted to a central database. In some cases, the review team may decide to seek clarification or missing data by contacting study authors. As such obtained information will not be directly accessible to others, it needs to be explicitly annotated. Moreover, this procedure creates the risk of introducing bias, as only some authors will respond. Author response rate should be reported in the final review.

The data extraction process is greatly facilitated using electronic data extraction forms. Various nonspecific (e.g., spreadsheet or database application) or specific (e.g., DRAGON, HAWC, RevMan, or DistillerSR) software solutions are available. The extraction form, a sample of which should be included in the study protocol, compiles the relevant data for the review in a clear and unambiguous manner. A clear structure and features such as pre-specified entries increase efficiency as well as user-friendliness, which in turn will reduce human error. It is important to design an efficient extraction process, e.g., using pre-defined lists of values for specific information to be extracted, and by minimizing free text fields.

The extraction itself is a time-consuming process and standardized approaches will help to decrease burdens. Certain study document formats of studies, e.g., PDFs, can facilitate the process by allowing electronic searching. Dual independent review by trained review authors is strongly recommended, while extraction by one reviewer and quality control by a second may be acceptable. Consistency and reproducibility of extraction can be evaluated by a piloting exercise with some representative studies; experience shows that this often leads to modifications of the form. A process to resolve reviewer disagreements should be specified at the outset.

Also, at this stage, efficient and transparent data management might pose the biggest challenge. In our experience, the above-mentioned software solutions allow for efficient and transparent data management.

• Terminology
• Internal validity/risk of bias
• Reporting quality

In a systematic review, the quality of the individual pieces of evidence is assessed systematically. In this context, some authorities, especially Cochrane, purposefully avoid use of the term ‘quality,’ owing to the potential for misunderstanding. Consequently, this section briefly introduces the terminology used in this context

The term ‘methodological quality’ or ‘study quality’ can refer to study validity as well as to other methodological criteria such as ethical approval and reporting or lack of power (Krauth et al. 2013 ). An individual study’s validity is composed of its external validity, or relevance, i.e., the extent to which a study provides a correct basis to be generalized to other circumstances, and its internal validity, which is concerned with the reliability of the study itself, regardless of whether it is relevant to other circumstances. A study is internally valid if the differences in results observed between the experimental groups can, apart from random error, be attributed to the intervention under investigation. Certain characteristics of a study may threaten its internal validity, namely if these characteristics introduce systematic differences between the experimental groups other than the intervention of interest. These differences may result in either systematic over- or underestimation of the true effect size, i.e., bias. However, the actual bias (magnitude and direction) in a study can usually not be assessed. Therefore, the term ‘risk of bias’ (RoB) is now widely used in the clinical field to assess the degree of bias susceptibility of a study.

Given that we do not have space to discuss all aspects of methodological quality and given that internal validity/RoB is considered to be a crucial element of quality assessments in toxicological reviews (Krauth et al. 2013 ; Lam et al. 2014 ), we will focus in the remainder of this section on internal validity/RoB. However, external validity and possibly other quality aspects of toxicological studies are also important and should be evaluated systematically. Samuel et al. ( 2016 ), who provided a systematic compilation of available approaches for assessing methodological and reporting quality of toxicologically relevant studies, present a good starting point for exploring study quality more broadly.

The internal validity/RoB assessment evaluates the extent, to which study conduct may have introduced systematic error (i.e., bias) into its results and/or interpretation. This assessment is ultimately one of the several factors that determine the confidence in the systematic review results. The various biases that may affect a study’s internal validity can be assigned to one of the six bias types:

• Selection bias refers to systematic differences between baseline characteristics of the groups that are compared. In experimental studies, this type of bias can be reduced or prevented by randomized allocation and allocation concealment.
• Performance bias refers to systematic differences between groups in the care that is provided, or in exposure to factors other than the interventions of interest. It can be minimized by, for example, blinding researchers and caretakers or by randomizing the order in which the groups receive the experimental exposure.
• Detection bias refers to systematic differences in the way the outcomes are assessed, e.g., when outcome assessors are aware to which experimental group the subject/specimen being assessed belongs. It can be avoided by appropriate blinding and randomization of the outcome assessment.
• Attrition bias refers to systematic differences between the experimental groups in withdrawals or drop-outs from the study. Withdrawals or drop-outs lead to incomplete outcome data. Because the outcomes of the study can only be based on the available data, the reported outcomes may not reflect the true effect of the intervention. Attrition bias can be taken into account by detailed reporting of the number of withdrawals/drop-outs per experimental group and the reason for withdrawing/dropping out.
• Reporting bias refers to systematic differences between reported and unreported findings. For instance, in a published report, those analyses with statistically significant differences between intervention groups, are more likely to be reported than non-significant differences. This sort of ‘within-study publication bias’ is usually known as outcome-reporting bias or selective-reporting bias. The risk of this type of bias can only by assessed if protocols for primary studies are registered or made publicly available before the data analysis. For animal studies, for example, such registration is still highly uncommon.
• Other biases: there may be other sources of bias that are relevant only in certain circumstances or for particular study designs. It is up to the review authors to judge whether for the studies that will be included in their systematic review other factors are likely to cause structural underestimation or overestimation. However, to prevent bias in the application of the criteria for this sixth type of bias, these criteria should be prespecified and clearly defined in the protocol, preferably with an explanation why the criterion in question is likely to reflect an actual risk of bias.

It must be kept in mind that the method for appraising study validity by assessing risk of bias was initially developed in the clinical field, at first for randomized controlled trials. While some of the concepts can directly be transferred to toxicological systematic reviews, e.g., reporting bias, others need to be adapted. Furthermore, for some (aspects of) study types, e.g., in vitro studies on toxicological mechanisms, potential “threats” to internal validity need to be identified.

The RoB assessment is based on specific questions that are defined in advance to address the various bias types. The utility of these questions strongly depends on the kind of evidence to be reviewed. When dealing with human toxicological data, it is possible to adopt the clinical approaches (see e.g., Johnson et al. 2014 ). With some modifications, the approaches used in clinical systematic reviews have been used for animal experiments, including pre-clinical (see e.g., Wever et al. 2012 ) and toxicological studies (see e.g., Koustas et al. 2014 ). For pre-clinical studies, a risk of bias tool has been proposed (Hooijmans et al. 2014a ) that focuses on one or more domains for each bias type, e.g., performance bias is addressed by the domains of ‘random housing’ and ‘blinding of caregivers.’ The proposed tool comprises ten specific questions, such as ‘Was the outcome assessor blinded?’ or ‘Are reports of the study free of selective outcome reporting?’ Half of the tool’s questions were in agreement with the Cochrane risk of bias tool (Cochrane handbook) stressing that much can be learned from the role model of clinical systematic review practice. This tool could also be applicable to systematic review of toxicological animal studies. Guidance or examples of risk of bias assessment for in vitro studies are, to our knowledge, not yet available, but the NRC report (2014) addresses this aspect in some detail. Ongoing efforts in toxicology to improve existing scoring systems may be helpful in the future (Segal et al. 2015 ).

It is important to predefine answers to the questions used to evaluate the risk of bias for each outcome, e.g., low, high, no or unknown risk of bias. This produces results that lend themselves to straightforward summary and improves the consistency and reproducibility of answers from different reviewers. The answer spectrum to the questions should be harmonized across questions as much as possible and should be transparent and clearly described to foster reproducibility. In this process, guidance and/or examples for the answer choices for each question further reduces reviewer disagreement. In addition, answers should be justified, which will help resolving reviewer disagreement.

The results of the risk of bias assessment for individual study should be reported, e.g., as a tabular matrix of risk of bias questions and included studies (see, e.g., Fig.  3 a). Such a matrix facilitates the summary of the risk of bias for each question across all included studies, which is often displayed as a bar chart (see Fig.  3 b). In addition, the rationales leading to this assessment should be available. These summary data are to be considered in the synthesis of the results, either narratively or by meta-analysis.

Representative summary table ( a ) for the risk of bias assessment [ green cells with ( plus ): low risk of bias; yellow cells with ( question mark ): unknown risk of bias; red cells with ( hyphen ): high risk of bias] and representative summary ( b ) of risk of bias analysis across studies (reproduced from Wever et al. 2015 )

The importance of the various bias domains or questions varies depending on the outcome. For example, detection bias is likely to be less important, i.e., will more unlikely result in bias, for animal studies with death as the primary outcome. Detailed discussions of the applicability of certain domains to toxicological animal studies are available (see e.g., National Research Council (NRC) ( 2014 ); National Toxicology Program ( 2015 )).

For all potential sources of bias, it is important to consider the likely magnitude and the likely direction of the bias. For example, if all methodological limitations of studies were expected to bias the results towards a lack of effect, and the evidence indicates that the intervention is effective, then it may be concluded that the intervention is effective even in the presence of these potential biases.

General lack of scientists’ awareness of the risk of bias concept in the toxicological community results in reporting that omits details important for risk of bias assessment. This may seriously hamper assessing the actual risk of bias of the included studies and therefore of the systematic review. Guidance to improve reporting quality is available for toxicological animal studies, notably the ARRIVE guidelines (Kilkenny et al. 2010 ) and others (Hooijmans et al. 2010 ; Landis et al. 2012 ). However, harmonization of guidance and focus on potential use in systematic reviews is required. As more toxicological systematic reviews are conducted, their authors will identify which aspects need to be reported (or not), possibly creating an iterative feedback loop motivating authors and even journals.

With regard to use in a systematic review, inadequate reporting per se does not reduce internal validity, but is an obstacle to the assessment of this validity. It remains to be seen if the solution of contacting authors to retrieve missing information is a feasible and useful approach in toxicology. This solution is often applied in the clinical fields, but is generally not very successful because of low response rates. An approach that is likely to work better is education in and adherence to reporting standards, with proper enforcement by journals.

A major challenge for the community is both to find agreement on the importance of the various potential quality (including risk of bias) criteria and to support their importance by empirical evidence as well as determining how best to integrate these measures into developing and supporting conclusions. A good example of a type of bias of which the presence and importance in toxicology is still a topic of debate is sponsorship bias (or funding bias). Although there have been studies that pay attention to this issue (e.g., Wandall et al. 2007 ; Bero et al. 2015 ), it has not yet been investigated systematically whether a similar type of bias exists in toxicology.

• Planning the analysis
• Narrative analysis
• Meta-analysis
• Heterogeneity, sensitivity analysis and reporting bias

It is important that the analysis is planned a priori, in the context of the review question. To prevent selective outcome reporting, the protocol should describe the planned analysis as precisely as possible, notably the outcome measures to be analyzed as well as the ways to deal with heterogeneity (statistical model, subgroups). The data type (binary, ordinal or continuous) of the measured effects to be analyzed will inform the analytical methods. Because it is not always easy to anticipate all details of the analysis steps, the analysis section of a systematic review protocol sometimes has to be revised once the analysis has been started. It is important that these revisions are clearly indicated and justified both in the protocol and the published systematic review. Consultation with a statistician is strongly recommended, particularly if the data analysis takes the form of a meta-analysis.

A narrative analysis (or narrative synthesis) is a descriptive summary of the included studies’ results. It is an essential ingredient of any systematic review that should provide sufficient detail, usually using tables.

A meta-analysis is a structured quantitative analysis of outcome data from comparable studies leading to a quantitative summary of results. Note that a systematic review does not have to contain a meta-analysis. If, for instance, the number of studies is too low, the outcome measures vary substantially between the included studies or the studies are too dissimilar in design, a meta-analysis does not make sense. The benefits of a meta-analysis include increased statistical power and improved precision in the estimation of an effect. However, the reliability of the results of a meta-analysis depend on the reliability of the included studies. If a meta-analysis contains many low quality studies (e.g., a high risk of bias), the results can be misleading.

While meta-analysis is the predominant approach in the clinical field, it still has to be explored to what extent and to which type of toxicological review questions meta-analytical techniques can be applied (Goodman et al. 2015 ). Possibly, lessons can be learned from the experiences made when adapting and applying meta-analyses to pre-clinical animal studies (Vesterinen et al. 2014 , Hooijmans et al. 2014b ). Meta-analysis of human epidemiological studies has been applied to assess neurobehavioral effects of metal or organic solvent exposure in an occupational setting (e.g., Goodman et al. 2002 ; Meyer-Baron 2005 ). Also, unique to toxicology is that many assessments involve quantitative characterization of hazard via toxicological benchmark values, such as daily reference doses or occupational limit values—values that the process of systematic review can support, but the approach for doing so is not yet clear.

Heterogeneity in a meta-analytical context refers to statistical heterogeneity, i.e., variation in the results of studies greater than would be expected from chance alone. This heterogeneity may be caused by several types of differences between the included studies. Such differences may be present in study characteristics such as the population, e.g., when different species, strains or cell lines are used; the exposure, e.g., when various exposure routes or durations have been used; the control, e.g., when different solvent vehicles were employed; or the outcome. Furthermore, study designs and methodological factors, as addressed in the risk of bias assessment may vary between included studies, potentially leading to heterogeneous effect sizes.

The protocol should describe how heterogeneity will be identified and dealt with. An important method of exploring the sources of heterogeneity is performing subgroup analyses, in which the studies included in the meta-analysis are split according to basic characteristics that might lead to differences in effect. For example, it might be of toxicological interest to study in a subgroup analysis whether studies that only used a negative control had different results compared to those employing a solvent control and whether these differences (partly) explain the heterogeneity found in the analysis. Subgroup analyses need to be pre-specified in the protocol to prevent selective reporting and should be limited in numbers to allow meaningful interpretation and to keep control of the multiple testing.

To assess the robustness of the results of the systematic review/meta-analysis, i.e., the extent to which these results depend on the decisions made during the review process, a sensitivity analysis can be performed. Although a major aim of systematic reviews is to be as objective as possible, in the conduct of a review decisions have to be made that to some extent depend on subjective preferences. Examples of such ‘subjective’ decisions are the definition of a numerical value (e.g., NOEL vs LOEL) or the choice of statistical methods (e.g., Chi-square test vs Fisher’s exact test). Documentation and justification of these decisions will ensure transparency. In a sensitivity analysis, however, the impact of these decisions can be shown. Such an analysis studies whether the overall results would have been different, if another choice had been made, for example, if a LOEL rather than a NOEL had been used. If the overall results are the same, the conclusions of the meta-analysis are more robust.

In the clinical field, publication bias , i.e., bias in the published literature because studies with neutral or negative results are less likely to be published, is a frequently suspected problem. Tools that provide an indication of the presence and/or impact of publication bias, such as funnel plots and trim-and-fill analysis, have been developed. Moreover, the practice of prospective registration of trials, which makes studies traceable, has been established as a countermeasure.

It will be interesting to see whether and in what way meta-analyses can and will be applied in toxicological systematic reviews, whereas a major challenge will be to grasp publication bias in toxicology, i.e., the frequency, the direction and the causes. In the field of clinical studies, what counts as a positive (treatment effective), a neutral (treatment no effect) and a negative result (treatment harmful) is relatively straightforward and similar for all stakeholders involved. In toxicology, it is not that simple. It is even conceivable that publication bias may be present in both directions; while some may not publish unexpected negative results, others may not publish unexpected positive results. In addition, investigation of the external validity of subgroups, e.g., animal species, by a subgroup analysis, which has been used, e.g., by Lalu et al. ( 2016 ) for a pre-clinical systematic review, may present a valuable approach for toxicological questions. Consistency in results over subgroups may increase external validity, while inconsistencies may flag the need to identify the evidence most relevant to the review question.

• Evidence streams
• Confidence in a body of evidence
• Integration of evidence streams
• Conclusions

The interpretation (or synthesis) of the results found and the conclusion of the systematic review should be clear, precise, and comprehensive in light of the review question. The components of this final section of the systematic review should be presented in a way that can be easily understood by scientists, the public, and decision makers.

In toxicology, often data from the various so-called evidence streams , i.e., sets of studies representing the same type or level of evidence, e.g., human (observational) studies, animal studies, in vitro or mechanistic studies, need to be integrated. For methodological reasons, it is advisable to conduct systematic reviews for each evidence stream separately. Consequently, interpretation will have to be done at at least two levels; for the individual systematic reviews/evidence streams and for the combination of all evidence streams.

Within each systematic review, the interpretation should be carried out for the so-called bodies of evidence, i.e., sets of studies of the same type or level of evidence grouped by outcome measure. The interpretation is qualitative and aims at determining the confidence (or certainty) in the evidence. The confidence in the evidence expresses the level of certainty that the findings from a group of studies reflect the true relationship between exposure to a substance and the outcome measure in question.

There is no consensus yet on the details of how the confidence in a body of evidence should be determined in the field of toxicology. For systematic reviews for environmental health assessments, Rooney et al. ( 2014 ) proposed a system for rating confidence in the body of evidence based on GRADE, where GRADE stands for: Grading of Recommendations Assessment, Development and Evaluation (Guyatt et al. 2011 ; Balshem et al. 2011 ). The GRADE approach was developed for healthcare systematic reviews. It starts by setting an initial level of confidence depending on study type, e.g., randomized controlled trials start high and observational studies start low. This initial level of confidence may be decreased or increased if certain attributes are present. Attributes that can reduce the confidence in the body of evidence include overall risk of bias, publication bias, imprecision, inconsistency and indirectness, whereas characteristics such as large effect sizes and a dose–response gradient may increase the confidence. The outcomes of this grading process inform a rating of the final confidence in body of evidence, which will guide the conclusions. It is acknowledged that this rating may be subjective. However, the rating is considered helpful as it increases the transparency of the final conclusions.

The approach developed by the National Toxicology Program ( 2015 ), and the approach used by the Navigation Guide (Woodruff and Sutton 2014 ), are similar to the original GRADE approach, but use slightly different criteria for setting initial levels of confidence and for upgrading and downgrading. For example, in the Navigation Guide, observational studies start at a moderate rather than a low level of confidence and NTP uses consistency across species as an extra-upgrading criterion. However, it is re-emphasized that there is not yet consensus in the toxicology field regarding this approach.

Ideally, the confidence in the different bodies of evidence (i.e., per outcome) should be integrated into a confidence across outcomes for the evidence stream in question.

As indicated above, a complexity of toxicology, in contrast to healthcare, is the potential need for integration of evidence streams . It has been proposed to distinguish the following three evidence streams: ‘human’; ‘animal’; and ‘mechanistic/in vitro’ (National Toxicology Program, 2015 ). It remains to be seen if this categorization of evidence based on the test species/system is sufficiently coherent, as mechanistic evidence may also be derived from animal studies and in vitro studies may provide other information than mechanistic. However, mechanistic understanding is essential in the assessment of external validity, especially of non-human evidence. Although the integration of these evidence streams is not part of the systematic review process (it is more about the integration of the results of different systematic reviews), it is desirable that this process is conducted in a structured, transparent and pre-specified way.

The methods to integrate different evidence streams are even less established than the methods to interpret and rate bodies of evidence. An important reason for this is that, at this level, not only the confidence in each evidence stream may be important but also its relevance, e.g., for the human exposure of interest, or external validity.

Questions that arise at this level are: Should all evidence streams get the same weight or should the evidence streams be weighted by their external validity, for example, the evidence from mechanistic in vitro studies, by definition, have a lower weight because these data might have lower relevance for the human situation? This is especially relevant, since more Adverse Outcome Pathways are available as well as data from programs like US EPA ToxCast™ and TOX21, providing a wealth of data on a molecular level. For example, if the human evidence stream has a low confidence level (e.g., because these studies contain many confounding factors) and the mechanistic stream has a high level (e.g., because it consists of well-designed and well-conducted experimental studies with very similar results), should the latter get more weight than the former?

NTP has developed a framework that translates confidence ratings per evidence stream into evidence of health effects, which is then used to integrate evidence from human and animal studies into a hazard identification conclusion. The mechanistic evidence is used to support the decision to turn the initial hazard conclusion into a final hazard conclusion. Rhomberg ( 2015 ) has suggested a different approach for integrating data from different evidence streams, called a hypothesis-based weight-of-evidence approach. However, a standardized approach does not yet exist.

The conclusions of the systematic review should detail the implications of the findings. These may vary depending on the study question(s), but should not go beyond the review scope. For example, in cases where a specific hazardous property of a substance was investigated, the conclusions should make a clear statement about that hazard. Other potential topics to address in the conclusions section include the implications for research, e.g., how to address identified data gaps or how to solve methodological issues, and the reflection on limitations in design and conduct of the review itself.

The data analysis is posing two main challenges. It remains to be seen how to determine to best adapt the GRADE approach to toxicological questions, as discussed by Morgan et al. ( 2016 ), or whether an alternative system is more appropriate. In addition, further methodological discussions and case studies are needed to explore how to integrate bodies of evidence within an evidence stream and across evidence streams.

• Basic requirements
• Reporting elements
• Presentation of findings

Regardless of the specific form of a systematic review report, some basic requirements exist that are applicable to the reporting of toxicological findings in general. General authorship rules apply, such as identifying a corresponding or lead author. These decisions are likely to be made as part of protocol development and establishment of team members and roles. Of particular importance to systematic reviews, conflict of interest statements for all authors are required. Most, if not all, systematic reviews will be reported in English. Correct spelling and grammar, and clear, concise language should be used, keeping in mind that audiences will often include non-toxicologists. Toxicological systematic reviews should undergo peer review and should be made publicly available.

Systematic reviews can be written up in the form of a stand-alone report (perhaps published on a website) and/or a publication in a peer-reviewed journal. While these two reporting forms may differ in length due to journal restrictions, both should cover essential reporting elements . If important information cannot be included in a journal publication, this should be made available elsewhere, e.g., as supplementary documentation, with a level of detail that allows reproduction of the review, or through data repositories.

Systematic review reporting guidelines are available for human studies, especially for intervention studies, but there is less established information on reporting toxicological systematic reviews. However, the structural elements that are generally recommended for systematic reviews provide valuable guidance relevant for toxicological systematic reviews. For example, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement is a well-recognized source (Moher et al. 2009 ). Its checklist elements include the following:

• Structured abstract/executive summary
• Introduction including the rationale and the review question
• Methods according to the review protocol including evidence search and selection, data extraction, quality assessment and data analysis
• Discussion summarizing results and including a conclusion
• Funding sources

This checklist, with minor amendments, has been adopted by others (Sena et al. 2014 ; Whaley et al. 2016 ). In addition, commissioning bodies or organizations conducting systematic reviews may have or may develop specific reporting requirements.

The results should present findings in a clear and structured manner, using tables and figures. For example, two tables may be derived from the extracted study data: one for the characteristics of included studies (such as authors and year of publication, source, study design aspects, essential components (e.g., PECO)), as well as one for the study data and results. The most important findings should be summarized narratively, and if possible, complemented by a tabular summary. A flow chart on the study selection process (Fig. ​ (Fig.2) 2 ) should be included.

The challenge in reporting toxicological systematic reviews will be to include all information that is relevant to allow independent replication of the review. Meeting such requirements may be facilitated by the use of online repositories for protocols, as well as other reporting materials (e.g., extraction and quality tables), particularly for large assessments.

This primer is an introduction to the application of the systematic review process to toxicological issues. It is intended primarily for those unfamiliar with systematic reviews, who would like to understand them better and/or conduct their own. It draws on existing guidance from the fields of clinical medicine, environmental sciences, food and feed safety as well as the emerging guidance in toxicology. The existing guidance documents compartmentalize a systematic review into different numbers of individual steps. In this primer, a fine-grained approach to parsing the various review steps was chosen to deliver the information in succinct components. For each step, the most important aspects to be considered are highlighted. To summarize, our framework for a systematic review consists of ten steps and their associated topics:

• Framing the question
• Developing and publishing of the protocol
• Searching for evidence
• Selecting the evidence
• Extracting (the data)
• Assessing the evidence
• Analyzing data
• Interpreting the results

Conducting a systematic review is not a trivial task, often specifically funded as independent studies, especially for healthcare interventions. The process differs substantially from that involved in narrative reviews, which are commonly used in toxicology. Although systematic reviews have clear advantages, such as their explicit methodology and transparency, they require diverse expertise, substantial resources, time and for most questions the availability of sufficient data. Therefore, it is advisable to carefully consider the intentions and aims of a toxicological review to decide on the type of review to be conducted. When a systematic review is not feasible, a narrative review may be justifiable. However, even in such cases, reviewers should consider the feasibility of implementing at least some of the individual systematic review steps. For example, an explicit, clear and unambiguous statement of the review question should always be provided. In addition, some basic elements of a systematic literature search, such as specifying the databases searched, the search date and the search terms and strategy, can be easily implemented. These steps nevertheless increase the transparency of the process of study selection and the search criteria, and ultimately would improve the reproducibility and quality of narrative reviews.

We hope the increased awareness of systematic review will result in a shift towards including more systematic review elements into toxicological reviews. This shift should also help to identify challenges specific to toxicology that do not allow adoption or simple adaptation of available systematic review methodology. We identified some of those challenges and summarized them in Table  3 . They may require new solutions compatible with the evidence-based principles of transparency, consistency, and objectivity, which provide the foundation of evidence-based approaches.

Table 3

Challenges in adapting systematic review methodology to toxicology

We recognize that any brief introduction to such a complicated topic will have limitations. Many of the topics addressed above are quite complex, and will require further guidance for complete understanding and practical tools for their implementation in the systematic review methodology. Some experts may question the systematic review steps proposed here, preferring instead an alternate framework. Such issues are only natural, as the application of systematic review to toxicological issues is just emerging. Consequently, there is little direct experience and empirical evidence available to guide these types of systematic reviews, although the knowledge base is rapidly increasing. It is the aim of this primer, and in particular of the challenges highlighted, to stimulate development of tools that facilitate the application of systematic review in toxicology, and to encourage the application of the methodology. The systematic review process will be instrumental in guiding toxicology to a more evidence-based science that is rooted in transparency, objectivity and consistency.

Acknowledgements

We thank Richard Judson (US Environmental Protection Agency, Washington, DC, USA) and Johanna Rochester (The Endocrine Disruption Exchange, Washington, DC, USA) for their review of an early draft version of the manuscript.

Compliance with ethical standards

Conflict of interest.

The contents of this manuscript are solely the responsibility of the authors and do not necessarily reflect the views or policies of their employers. Sebastian Hoffmann, a self-employed consultant, was paid by the Evidence-Based Toxicology Collaboration (EBTC) for his work on this manuscript. Nancy B. Beck was employed by the American Chemistry Council, a trade association of U.S. chemical manufacturers. Sebastian Hoffmann, Martin L. Stephens, John R. Fowle III, Ian Kimber, Nancy B. Beck, Rob de Vries and Katya Tsaouin are members of the Board of Trustees of the EBTC, which is funded by Center for Alternatives to Animal Testing at Johns Hopkins Bloomberg School of Public Health and ExxonMobil Foundation. Hubert Dirven, Julie E. Goodman, Manoj M. Lalu, Kristina Thayer, Paul Whaley and Daniele Wikoff are members of the Scientific Advisory Council of the EBTC. Manoj Lalu was supported by The Ottawa Hospital Anesthesia Alternate Funds Association.

1 The glossary mainly consists of adopted and adapted definitions from the Cochrane glossary ( http://community-archive.cochrane.org/glossary ) and the EFSA glossary (EFSA 2010 ) and new definitions.

Contributor Information

Nancy B. Beck, Email: moc.liamg@44banu .

Katya Tsaioun, Phone: +1-410-456-2032, Email: ude.uhj@1uoiastk .

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