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  1. Article ; Online: A general theory of effect size, and its consequences for defining the benchmark response (BMR) for continuous endpoints.

    Slob, Wout

    Critical reviews in toxicology

    2017  Volume 47, Issue 4, Page(s) 342–351

    Abstract: A general theory on effect size for continuous data predicts a relationship between maximum response and within-group variation of biological parameters, which is empirically confirmed by results from dose-response analyses of 27 different biological ... ...

    Abstract A general theory on effect size for continuous data predicts a relationship between maximum response and within-group variation of biological parameters, which is empirically confirmed by results from dose-response analyses of 27 different biological parameters. The theory shows how effect sizes observed in distinct biological parameters can be compared and provides a basis for a generic definition of small, intermediate and large effects. While the theory is useful for experimental science in general, it has specific consequences for risk assessment: it solves the current debate on the appropriate metric for the Benchmark response in continuous data. The theory shows that scaling the BMR expressed as a percent change in means to the maximum response (in the way specified) automatically takes "natural variability" into account. Thus, the theory supports the underlying rationale of the BMR 1 SD. For various reasons, it is, however, recommended to use a BMR in terms of a percent change that is scaled to maximum response and/or within group variation (averaged over studies), as a single harmonized approach.
    MeSH term(s) Benchmarking ; Dose-Response Relationship, Drug ; Humans ; Models, Statistical ; No-Observed-Adverse-Effect Level ; Risk Assessment ; Toxicity Tests/methods
    Language English
    Publishing date 2017-04
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1097071-x
    ISSN 1547-6898 ; 1040-8444
    ISSN (online) 1547-6898
    ISSN 1040-8444
    DOI 10.1080/10408444.2016.1241756
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Benchmark dose and the three Rs. Part II. Consequences for study design and animal use.

    Slob, Wout

    Critical reviews in toxicology

    2014  Volume 44, Issue 7, Page(s) 568–580

    Abstract: OECD test guidelines for standard toxicity studies prescribe (minimal) numbers of animals, but these are not substantiated by a quantitative analysis of the relationship between number of animals and the required performance of the associated study ... ...

    Abstract OECD test guidelines for standard toxicity studies prescribe (minimal) numbers of animals, but these are not substantiated by a quantitative analysis of the relationship between number of animals and the required performance of the associated study design. This paper provides a general approach of how this relationship may be established and discusses the approach in more detail by focusing on the three typical repeated-dose studies (subacute, subchronic, and chronic). Quantitative results derived from simulation studies, including some new results, are summarized and their consequences for study guidelines are discussed. The currently prescribed study designs for repeated-dose studies do not appear to be sufficient when the NOAEL is used for evaluating the data--the probability of not detecting toxicologically significant effects is high. The ensuing need for increasing the number of animals may be avoided by replacing the NOAEL approach by the BMD approach as it increases the probability of detecting the same effects without increasing the number of animals. Hence, applying the BMD approach will result in a virtual reduction in the number of animals. Further, the BMD approach allows for a real reduction in the number of animals on various grounds. It allows for analyzing combined similar datasets, resulting in an increase in precision, which can be translated in animal reduction while keeping the same precision. In addition, applying the BMD approach may be expected to result in animal reduction in the long run, as it allows for distributing the same number of animals over more doses without loss of precision. The latter will reduce the need to repeat studies due to unfortunate dose location.
    MeSH term(s) Animals ; Benchmarking ; Datasets as Topic ; Dose-Response Relationship, Drug ; Female ; Male ; No-Observed-Adverse-Effect Level ; Probability ; Research Design
    Language English
    Publishing date 2014-08
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1097071-x
    ISSN 1547-6898 ; 1040-8444
    ISSN (online) 1547-6898
    ISSN 1040-8444
    DOI 10.3109/10408444.2014.925424
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Benchmark dose and the three Rs. Part I. Getting more information from the same number of animals.

    Slob, Wout

    Critical reviews in toxicology

    2014  Volume 44, Issue 7, Page(s) 557–567

    Abstract: Evaluating dose-response data using the Benchmark dose (BMD) approach rather than by the no observed adverse effect (NOAEL) approach implies a considerable step forward from the perspective of the Reduction, Replacement, and Refinement, three Rs, in ... ...

    Abstract Evaluating dose-response data using the Benchmark dose (BMD) approach rather than by the no observed adverse effect (NOAEL) approach implies a considerable step forward from the perspective of the Reduction, Replacement, and Refinement, three Rs, in particular the R of reduction: more information is obtained from the same number of animals, or, vice versa, similar information may be obtained from fewer animals. The first part of this twin paper focusses on the former, the second on the latter aspect. Regarding the former, the BMD approach provides more information from any given dose-response dataset in various ways. First, the BMDL (= BMD lower confidence bound) provides more information by its more explicit definition. Further, as compared to the NOAEL approach the BMD approach results in more statistical precision in the value of the point of departure (PoD), for deriving exposure limits. While part of the animals in the study do not directly contribute to the numerical value of a NOAEL, all animals are effectively used and do contribute to a BMDL. In addition, the BMD approach allows for combining similar datasets for the same chemical (e.g., both sexes) in a single analysis, which further increases precision. By combining a dose-response dataset with similar historical data for other chemicals, the precision can even be substantially increased. Further, the BMD approach results in more precise estimates for relative potency factors (RPFs, or TEFs). And finally, the BMD approach is not only more precise, it also allows for quantification of the precision in the BMD estimate, which is not possible in the NOAEL approach.
    MeSH term(s) Animals ; Benchmarking ; Dose-Response Relationship, Drug ; No-Observed-Adverse-Effect Level
    Language English
    Publishing date 2014-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1097071-x
    ISSN 1547-6898 ; 1040-8444
    ISSN (online) 1547-6898
    ISSN 1040-8444
    DOI 10.3109/10408444.2014.925423
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  4. Article ; Online: "Conundrums?".

    Slob, Wout

    Risk analysis : an official publication of the Society for Risk Analysis

    2011  Volume 31, Issue 1, Page(s) 3–4; author reply 5–6

    MeSH term(s) Animals ; Humans ; Models, Statistical ; No-Observed-Adverse-Effect Level ; Quantitative Structure-Activity Relationship ; Risk ; Uncertainty
    Language English
    Publishing date 2011-01
    Publishing country United States
    Document type Comment ; Letter
    ZDB-ID 778660-8
    ISSN 1539-6924 ; 0272-4332
    ISSN (online) 1539-6924
    ISSN 0272-4332
    DOI 10.1111/j.1539-6924.2010.01553.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The Relationship Between Internal and External Dose: Some General Results Based on a Generic Compartmental Model.

    Slob, Wout / Zeilmaker, Marco J / Hoogenveen, Rudolf T

    Toxicological sciences : an official journal of the Society of Toxicology

    2020  Volume 177, Issue 1, Page(s) 60–70

    Abstract: Statements on how the internal-to-external-dose (IED) relationship looks like are often based on qualitative toxicokinetic arguments. For example, the recently proposed kinetically derived maximum dose (KMD) states that the IED relationship must have an ... ...

    Abstract Statements on how the internal-to-external-dose (IED) relationship looks like are often based on qualitative toxicokinetic arguments. For example, the recently proposed kinetically derived maximum dose (KMD) states that the IED relationship must have an inflection point, due to saturation of underlying processes like metabolism or absorption. However, such statements lack a solid quantitative foundation. Therefore, we derived expressions for the IED relationship for a number of scenarios based on a generic compartmental model involving saturation. The scenarios included repeated or single dose, and saturable metabolism or saturable absorption. For some of these scenarios, an explicit expression for the IED relationship can be derived, for others only implicit expressions can be established, which need to be evaluated numerically. The results show that saturable processes will lead to an IED relationship that is nonlinear over the whole dose range, ie, it can be approximated by a linear relationship at the lower end, whereas the approximation will become gradually poorer with increasing doses. The finding that saturation does not lead to an inflection point in the IED relationship, as assumed in the KMD, implies that the KMD is not a valid approach for selecting the top dose in toxicological studies. An additional use of our results is that the derived explicit expressions of the IED relationship can be fitted to IED data, and, possibly, for extrapolation outside the observed dose range.
    MeSH term(s) Dose-Response Relationship, Drug ; Drugs, Generic
    Chemical Substances Drugs, Generic
    Language English
    Publishing date 2020-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfaa082
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  6. Article ; Online: Defining embryonic developmental effects of chemical mixtures using the embryonic stem cell test.

    van Oostrom, Conny Tm / Slob, Wout / van der Ven, Leo Tm

    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

    2020  Volume 140, Page(s) 111284

    Abstract: The embryonic stem cell test (EST) was applied to evaluate dose addition in combined exposures of teratogenic compounds in the EFSA-defined cumulative assessment group "craniofacial malformations", which was one of the selected cases in the EU-H2020 ... ...

    Abstract The embryonic stem cell test (EST) was applied to evaluate dose addition in combined exposures of teratogenic compounds in the EFSA-defined cumulative assessment group "craniofacial malformations", which was one of the selected cases in the EU-H2020 project "EuroMix". Test compounds were selected through reported effects in rodents, and represented a wide variety of chemical families and modes of action (MOA), including triazoles to inhibit CYP26; (synthetic) retinoids, to activate RAR/RXR; valproic acid, to inhibit histone deacetylase; dithiocarbamates, to disrupt extracellular matrix formation; dioxin (-like) compounds, to activate the aryl hydrocarbon receptor; 17alpha-ethynylestradiol, to activate the estrogen receptor; 5-fluorouracil, to disrupt DNA-synthesis; MEHP and PFOS, to activate peroxisome proliferation activated receptors; and methyl mercury, to induce oxidative stress and inhibit protein function. The EST appeared particularly useful to evaluate differentiation-inhibiting effects of compounds targeting early processes in craniofacial development, possibly related to the early fate of neural crest cells. Mixtures, designed as equipotent concentrations of two compounds with similar or dissimilar MOA, and single compounds showed overlapping dose-responses. This observation is consistent with dose addition in the EST in all studied binary mixtures, irrespective of MOA, and thereby supports the application of dose-addition as a default in cumulative risk assessment.
    MeSH term(s) Animals ; Complex Mixtures/toxicity ; Dose-Response Relationship, Drug ; Embryonic Development/drug effects ; Embryonic Stem Cells/drug effects ; Oxidative Stress/drug effects ; Risk Assessment ; Teratogens/toxicity
    Chemical Substances Complex Mixtures ; Teratogens
    Language English
    Publishing date 2020-03-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 782617-5
    ISSN 1873-6351 ; 0278-6915
    ISSN (online) 1873-6351
    ISSN 0278-6915
    DOI 10.1016/j.fct.2020.111284
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  7. Article: What is a practical threshold?

    Slob, Wout

    Toxicologic pathology

    2007  Volume 35, Issue 6, Page(s) 848–849

    MeSH term(s) Animals ; Carcinogens/toxicity ; Dose-Response Relationship, Drug ; Glutathione S-Transferase pi/analysis ; Liver/drug effects ; Liver/enzymology ; Liver/pathology ; Quinoxalines/toxicity ; Rats
    Chemical Substances Carcinogens ; Quinoxalines ; 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (77500-04-0) ; Glutathione S-Transferase pi (EC 2.5.1.18)
    Language English
    Publishing date 2007-10
    Publishing country United States
    Document type Comment ; Letter
    ZDB-ID 841009-4
    ISSN 0192-6233
    ISSN 0192-6233
    DOI 10.1080/01926230701714844
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

    Chiu, Weihsueh A / Slob, Wout

    Environmental health perspectives

    2015  Volume 123, Issue 12, Page(s) 1241–1254

    Abstract: Background: When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches ... ...

    Abstract Background: When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework.
    Objectives: We developed a unified framework for probabilistic dose-response assessment.
    Methods: We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets.
    Results: Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes.
    Conclusions: Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.
    MeSH term(s) Animals ; Dose-Response Relationship, Drug ; Hazardous Substances/toxicity ; Humans ; Models, Statistical ; Risk Assessment/methods ; Toxicology/methods ; Uncertainty
    Chemical Substances Hazardous Substances
    Language English
    Publishing date 2015-05-22
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 195189-0
    ISSN 1552-9924 ; 0091-6765 ; 1078-0475
    ISSN (online) 1552-9924
    ISSN 0091-6765 ; 1078-0475
    DOI 10.1289/ehp.1409385
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  9. Article ; Online: Rebuttal to the letter to the editors regarding Heringa et al. (2020).

    Heringa, Minne B / Cnubben, Nicole H P / Slob, Wout / Pronk, Marja E J / Muller, Andre / Woutersen, Marjolijn / Hakkert, Betty C

    Regulatory toxicology and pharmacology : RTP

    2020  Volume 116, Page(s) 104730

    Language English
    Publishing date 2020-07-05
    Publishing country Netherlands
    Document type Letter ; Comment
    ZDB-ID 604672-1
    ISSN 1096-0295 ; 0273-2300
    ISSN (online) 1096-0295
    ISSN 0273-2300
    DOI 10.1016/j.yrtph.2020.104730
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  10. Article ; Online: Rebuttal to the letters to the editors by Terry et al. and Sewell et al. regarding.

    Heringa, Minne B / Cnubben, Nicole H P / Slob, Wout / Pronk, Marja E J / Muller, Andre / Woutersen, Marjolijn / Hakkert, Betty C

    Regulatory toxicology and pharmacology : RTP

    2020  Volume 118, Page(s) 104803

    Language English
    Publishing date 2020-10-19
    Publishing country Netherlands
    Document type Letter ; Comment
    ZDB-ID 604672-1
    ISSN 1096-0295 ; 0273-2300
    ISSN (online) 1096-0295
    ISSN 0273-2300
    DOI 10.1016/j.yrtph.2020.104803
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