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  1. Thesis ; Online: The role of polycyclic aromatic hydrocarbons in developmental toxicity of petroleum substances

    Kamelia, Lenny

    2019  

    Abstract: REACH requires prenatal developmental toxicity (PDT) testing for substances registered in the EU at a volume of ≥100 tonnes/year. One of the consequences is that many petroleum substances (PS) will need to be tested for their potential adverse effect on ... ...

    Abstract REACH requires prenatal developmental toxicity (PDT) testing for substances registered in the EU at a volume of ≥100 tonnes/year. One of the consequences is that many petroleum substances (PS) will need to be tested for their potential adverse effect on prenatal development according to the current OECD 414 testing guidelines. This will involve a huge number of experimental animals and a considerable amount of resources. Therefore, the application of in vitro alternative testing strategies may reduce the animal experimentation and resources needed to study PDT potencies of PS. Furthermore, since some PS with high concentrations of polycyclic aromatic hydrocarbons (PAH) may induce PDT whilst their gas-to-liquid (GTL) analogues, which are synthetic products completely devoid of aromatics, do not induce PDT, it was hypothesized that PDT observed for some PS is caused by certain types of PAH in these products. This hypothesis was tested in the present thesis using a battery of in vitro alternative assays. Chapter 1 provided background information and presented the aim of the thesis. In addition, the selected test substances and in vitro alternative assays used in the present thesis were also introduced. In total, 19 samples derived from 6 PS and 2 GTL product categories were tested. These samples were selected because i) they represent a series with a systematic variation in PAH content, being substances containing a range of 3- to 7-ring PAHs including extremes regarding their PAH content (with and without PAHs) and ii) in vivo PDT data for these product categories were available, enabling in vitro-in vivo comparisons. The selected in vitro alternative assays were presented, including the embryonic stem cell test (EST), the zebrafish embryotoxicity test (ZET), and a panel of CALUX reporter gene assays. Finally, the general outline of the thesis was also provided. Chapter 2 assessed the applicability of the EST to evaluate in vitro embryotoxic potencies of the DMSO extracts of 9 PS (varying in their PAH content, ...
    Keywords cum laude
    Subject code 500
    Language English
    Publisher Wageningen University
    Publishing country nl
    Document type Thesis ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Developmental toxicity testing of the fume condensate extracts of bitumen and oxidized asphalt in a series of in vitro alternative assays.

    Kamelia, Lenny / Rietjens, Ivonne M C M / Boogaard, Peter J

    Toxicology in vitro : an international journal published in association with BIBRA

    2021  Volume 75, Page(s) 105195

    Abstract: The potential developmental toxicity and mode-of-action of fume condensate extracts of bitumen and oxidized asphalt were evaluated in the aryl hydrocarbon receptor (AhR) CALUX assay, the zebrafish embryotoxicity test (ZET), and the mouse embryonic stem ... ...

    Abstract The potential developmental toxicity and mode-of-action of fume condensate extracts of bitumen and oxidized asphalt were evaluated in the aryl hydrocarbon receptor (AhR) CALUX assay, the zebrafish embryotoxicity test (ZET), and the mouse embryonic stem cell test (mEST). In the AhR CALUX assay, both fume condensate extracts showed a concentration-dependent AhR induction following 6-h of exposure, but this activity was substantially reduced after 24-h, indicating a transient AhR activation. The main effect observed in the ZET was early embryonic lethality that occurred mostly in the 24 h-post-fertilization (hpf). This typically reflects non-specific toxicity rather than in vitro developmental toxicity of the fume condensate extracts tested since this effect was not seen as a result of the whole cumulative exposure period in the ZET (up to 96 hpf). No malformations were seen in any zebrafish embryo exposed to these fume condensate extracts, although some developed pericardial and/or yolk-sac edemas. Furthermore, both fume condensate extracts tested negative in the mEST. In conclusion, the results show that fume condensate extracts of bitumen and oxidized asphalt do not induce any in vitro developmental toxicity, which is in line with the results observed in the in vivo prenatal developmental toxicity studies performed with the same materials.
    MeSH term(s) Animal Testing Alternatives ; Animals ; Biological Assay ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Complex Mixtures/toxicity ; Embryo, Nonmammalian/anatomy & histology ; Embryo, Nonmammalian/drug effects ; Embryonic Development/drug effects ; Genes, Reporter ; Hydrocarbons/toxicity ; Mice ; Mouse Embryonic Stem Cells/drug effects ; Receptors, Aryl Hydrocarbon/genetics ; Toxicity Tests ; Zebrafish/anatomy & histology
    Chemical Substances Complex Mixtures ; Hydrocarbons ; Receptors, Aryl Hydrocarbon ; asphalt (8052-42-4)
    Language English
    Publishing date 2021-05-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
    DOI 10.1016/j.tiv.2021.105195
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  3. Article ; Online: Evaluating the in vitro developmental toxicity potency of a series of petroleum substance extracts using new approach methodologies (NAMs).

    Fang, Jing / Rietjens, Ivonne M C M / Carrillo, Juan-Carlos / Boogaard, Peter J / Kamelia, Lenny

    Archives of toxicology

    2023  Volume 98, Issue 2, Page(s) 551–565

    Abstract: The present study evaluates the in vitro developmental toxicity and the possible underlying mode of action of DMSO extracts of a series of highly complex petroleum substances in the mouse embryonic stem cell test (mEST), the zebrafish embryotoxicity test ...

    Abstract The present study evaluates the in vitro developmental toxicity and the possible underlying mode of action of DMSO extracts of a series of highly complex petroleum substances in the mouse embryonic stem cell test (mEST), the zebrafish embryotoxicity test (ZET) and the aryl hydrocarbon receptor reporter gene assay (AhR CALUX assay). Results show that two out of sixteen samples tested, both being poorly refined products that may contain a substantial amount of 3- to 7-ring polycyclic aromatic compounds (PACs), induced sustained AhR activation in the AhR CALUX assay, and concentration-dependent developmental toxicity in both mEST and ZET. The other samples tested, representing highly refined petroleum substances and petroleum-derived waxes (containing typically a very low amount or no PACs at all), were negative in all assays applied, pointing to their inability to induce developmental toxicity in vitro. The refining processes applied during the production of highly refined petroleum products, such as solvent extraction and hydrotreatment which focus on the removal of undesired constituents, including 3- to 7-ring PACs, abolish the in vitro developmental toxicity. In conclusion, the obtained results support the hypothesis that 3- to 7-ring PACs are the primary inducers of the developmental toxicity induced by some (i.e., poorly refined) petroleum substances and that the observed effect is partially AhR-mediated.
    MeSH term(s) Mice ; Animals ; Petroleum/toxicity ; Petroleum/analysis ; Zebrafish ; Mouse Embryonic Stem Cells ; Polycyclic Aromatic Hydrocarbons
    Chemical Substances Petroleum ; Polycyclic Aromatic Hydrocarbons
    Language English
    Publishing date 2023-12-12
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-023-03645-7
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  4. Article ; Online: Evaluating the in vitro developmental toxicity potency of a series of petroleum substance extracts using new approach methodologies (NAMs)

    Fang, Jing / Rietjens, Ivonne M.C.M. / Carrillo, Juan Carlos / Boogaard, Peter J. / Kamelia, Lenny

    Archives of Toxicology

    2024  Volume 98, Issue 2

    Abstract: The present study evaluates the in vitro developmental toxicity and the possible underlying mode of action of DMSO extracts of a series of highly complex petroleum substances in the mouse embryonic stem cell test (mEST), the zebrafish embryotoxicity test ...

    Abstract The present study evaluates the in vitro developmental toxicity and the possible underlying mode of action of DMSO extracts of a series of highly complex petroleum substances in the mouse embryonic stem cell test (mEST), the zebrafish embryotoxicity test (ZET) and the aryl hydrocarbon receptor reporter gene assay (AhR CALUX assay). Results show that two out of sixteen samples tested, both being poorly refined products that may contain a substantial amount of 3- to 7-ring polycyclic aromatic compounds (PACs), induced sustained AhR activation in the AhR CALUX assay, and concentration-dependent developmental toxicity in both mEST and ZET. The other samples tested, representing highly refined petroleum substances and petroleum-derived waxes (containing typically a very low amount or no PACs at all), were negative in all assays applied, pointing to their inability to induce developmental toxicity in vitro. The refining processes applied during the production of highly refined petroleum products, such as solvent extraction and hydrotreatment which focus on the removal of undesired constituents, including 3- to 7-ring PACs, abolish the in vitro developmental toxicity. In conclusion, the obtained results support the hypothesis that 3- to 7-ring PACs are the primary inducers of the developmental toxicity induced by some (i.e., poorly refined) petroleum substances and that the observed effect is partially AhR-mediated.
    Keywords Developmental toxicity ; Highly refined petroleum substances ; New approach methodologies ; Petroleum-derived waxes ; Polycyclic aromatic compounds ; Poorly refined petroleum substances
    Subject code 500
    Language English
    Publishing country nl
    Document type Article ; Online
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
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  5. Article ; Online: Developmental toxicity testing of unsubstituted and methylated 4- and 5-ring polycyclic aromatic hydrocarbons using the zebrafish embryotoxicity test.

    Fang, Jing / Dong, Shutong / Boogaard, Peter J / Rietjens, Ivonne M C M / Kamelia, Lenny

    Toxicology in vitro : an international journal published in association with BIBRA

    2022  Volume 80, Page(s) 105312

    Abstract: The present study evaluates the in vitro developmental toxicity of 4- and 5-ring polycyclic aromatic hydrocarbons (PAHs) including benz[a]anthracene (BaA) and benzo[a]pyrene (BaP) and six of their monomethylated congeners, and dibenz[a,h]anthracene (DB[a, ...

    Abstract The present study evaluates the in vitro developmental toxicity of 4- and 5-ring polycyclic aromatic hydrocarbons (PAHs) including benz[a]anthracene (BaA) and benzo[a]pyrene (BaP) and six of their monomethylated congeners, and dibenz[a,h]anthracene (DB[a,h]A) using the zebrafish embryotoxicity test (ZET). In general, the tested PAHs induced various developmental effects in the zebrafish embryos including unhatched embryos, no movement and circulation, yolk sac and pericardial edemas, deformed body shape, and cumulative mortality at 96 h post fertilization (hpf). The methyl substituent on different positions of the aromatic ring of the PAHs appeared to change their in vitro developmental toxicity. Comparison to a previously reported molecular docking study showed that the methyl substituents may affect the interaction of the PAHs with the aryl hydrocarbon receptor (AhR) which is known to play a role in the developmental toxicity of some PAHs. Taken together, our results show that methylation can either increase or decrease the developmental toxicity of PAHs, and suggest this may in part relate to effects on the molecular dimensions and resulting consequences for interactions with the AhR.
    MeSH term(s) Animals ; Embryo, Nonmammalian ; Embryonic Development/drug effects ; Methylation ; Polycyclic Aromatic Hydrocarbons/toxicity ; Toxicity Tests/methods ; Zebrafish
    Chemical Substances Polycyclic Aromatic Hydrocarbons
    Language English
    Publishing date 2022-01-14
    Publishing country England
    Document type Journal Article
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
    DOI 10.1016/j.tiv.2022.105312
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  6. Article ; Online: The role of receptor-mediated activities of 4- and 5-ring unsubstituted and methylated polycyclic aromatic hydrocarbons (PAHs) in developmental toxicity.

    Fang, Jing / Wang, Danlei / Kramer, Nynke I / Rietjens, Ivonne M C M / Boogaard, Peter J / Kamelia, Lenny

    Journal of applied toxicology : JAT

    2023  Volume 43, Issue 6, Page(s) 845–861

    Abstract: The present study evaluated the aryl hydrocarbon receptor (AhR), estrogen receptor-α (ER-α), and retinoic acid receptor (RAR) mediated activities of nine 4- and 5-ring unsubstituted and monomethylated polycyclic aromatic hydrocarbons (PAHs) using a ... ...

    Abstract The present study evaluated the aryl hydrocarbon receptor (AhR), estrogen receptor-α (ER-α), and retinoic acid receptor (RAR) mediated activities of nine 4- and 5-ring unsubstituted and monomethylated polycyclic aromatic hydrocarbons (PAHs) using a series of Chemical-Activated LUciferase gene eXpression (CALUX) assays. The potential role of these aforementioned receptors in relation to the developmental toxicity of these PAHs was further assessed in the zebrafish embryotoxicity test (ZET). The results show that all nine tested PAHs were AhR agonists, benz[a]anthracene (BaA) and 8-methyl-benz[a]anthracene (8-MeBaA) were ER-α agonists, and none of the tested PAHs induced ER-α antagonistic or RAR (ant)agonistic activities. In the AhR CALUX assay, all the methylated PAHs showed higher potency (lower EC50) in activating the AhR than their respective unsubstituted PAHs, implying that the addition of a methyl substituent on the aromatic ring of PAHs could enhance their AhR-mediated activities. Co-exposure of zebrafish embryos with each individual PAH and an AhR antagonist (CH223191) counteracted the observed developmental retardations and embryo lethality to a certain extent, except for 8-methyl-benzo[a]pyrene (8-MeBaP). Co-exposure of zebrafish embryos with either of the two estrogenic PAHs (i.e., BaA and 8-MeBaA) and an ER-α antagonist (fulvestrant) neutralized embryo lethality induced by 50 μM BaA and the developmental retardations induced by 15 μM 8-MeBaA. Altogether, our findings suggest that the observed developmental retardations in zebrafish embryos by the PAH tested may partially be AhR- and/or ER-α-mediated, whereas the RAR seems not to be relevant for the PAH-induced developmental toxicity in the ZET.
    MeSH term(s) Animals ; Polycyclic Aromatic Hydrocarbons/toxicity ; Polycyclic Aromatic Hydrocarbons/metabolism ; Zebrafish/metabolism ; Anthracenes/metabolism ; Receptors, Aryl Hydrocarbon/metabolism
    Chemical Substances Polycyclic Aromatic Hydrocarbons ; Anthracenes ; Receptors, Aryl Hydrocarbon
    Language English
    Publishing date 2023-01-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604625-3
    ISSN 1099-1263 ; 0260-437X
    ISSN (online) 1099-1263
    ISSN 0260-437X
    DOI 10.1002/jat.4428
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  7. Article ; Online: Developmental toxicity testing of the fume condensate extracts of bitumen and oxidized asphalt in a series of in vitro alternative assays

    Kamelia, Lenny / Rietjens, Ivonne M.C.M. / Boogaard, Peter J.

    Toxicology in Vitro

    2021  Volume 75

    Abstract: The potential developmental toxicity and mode-of-action of fume condensate extracts of bitumen and oxidized asphalt were evaluated in the aryl hydrocarbon receptor (AhR) CALUX assay, the zebrafish embryotoxicity test (ZET), and the mouse embryonic stem ... ...

    Abstract The potential developmental toxicity and mode-of-action of fume condensate extracts of bitumen and oxidized asphalt were evaluated in the aryl hydrocarbon receptor (AhR) CALUX assay, the zebrafish embryotoxicity test (ZET), and the mouse embryonic stem cell test (mEST). In the AhR CALUX assay, both fume condensate extracts showed a concentration-dependent AhR induction following 6-h of exposure, but this activity was substantially reduced after 24-h, indicating a transient AhR activation. The main effect observed in the ZET was early embryonic lethality that occurred mostly in the 24 h-post-fertilization (hpf). This typically reflects non-specific toxicity rather than in vitro developmental toxicity of the fume condensate extracts tested since this effect was not seen as a result of the whole cumulative exposure period in the ZET (up to 96 hpf). No malformations were seen in any zebrafish embryo exposed to these fume condensate extracts, although some developed pericardial and/or yolk-sac edemas. Furthermore, both fume condensate extracts tested negative in the mEST. In conclusion, the results show that fume condensate extracts of bitumen and oxidized asphalt do not induce any in vitro developmental toxicity, which is in line with the results observed in the in vivo prenatal developmental toxicity studies performed with the same materials.
    Keywords Alternative testing strategy ; Bitumen fume condensate ; Developmental toxicity ; Oxidized asphalt fume condensate ; Petroleum UVCB substances ; Polycyclic aromatic hydrocarbons
    Subject code 590
    Language English
    Publishing country nl
    Document type Article ; Online
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
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  8. Article ; Online: Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro-in silico approach.

    Wang, Danlei / Rietdijk, Maartje H / Kamelia, Lenny / Boogaard, Peter J / Rietjens, Ivonne M C M

    Archives of toxicology

    2021  Volume 95, Issue 10, Page(s) 3323–3340

    Abstract: Developmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro-in silico approach for predicting developmental toxicity of a range of ... ...

    Abstract Developmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro-in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration-response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose-response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED
    MeSH term(s) Animals ; Benzo(a)pyrene/administration & dosage ; Benzo(a)pyrene/pharmacokinetics ; Benzo(a)pyrene/toxicity ; Benzopyrenes/metabolism ; Computer Simulation ; Dose-Response Relationship, Drug ; Male ; Models, Biological ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests/methods
    Chemical Substances Benzopyrenes ; Benzo(a)pyrene (3417WMA06D) ; 3-hydroxybenzo(a)pyrene (672ICH1Q4L)
    Language English
    Publishing date 2021-08-25
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-021-03128-7
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  9. Article ; Online: Comparison of PAC and MOAH for understanding the carcinogenic and developmental toxicity potential of mineral oils.

    Carrillo, Juan-Carlos / Kamelia, Lenny / Romanuka, Julija / Kral, Olaf / Isola, Allison / Niemelä, Helena / Steneholm, Anna

    Regulatory toxicology and pharmacology : RTP

    2022  Volume 132, Page(s) 105193

    Abstract: The carcinogenicity and developmental toxicity of unrefined mineral oil is related to its 3-7 ring polycyclic aromatic compounds (PAC) content. Therefore, refining operations focus on the targeted removal PAC from mineral oil that may contain aromatics ... ...

    Abstract The carcinogenicity and developmental toxicity of unrefined mineral oil is related to its 3-7 ring polycyclic aromatic compounds (PAC) content. Therefore, refining operations focus on the targeted removal PAC from mineral oil that may contain aromatics of low toxicological concern. There are thus, two types of aromatic substances in mineral oil: hazardous and non-hazardous. The first type consists of 3-7 ring PAC which may be naked (unsubstituted) or lowly alkylated. The second type or non-hazardous consists of 1-7 ring aromatics with high degree of alkylation or lack of bay or fjord regions. Although these are toxicologically different, they may both elute in the same fraction when using chromatography. To understand how these two aromatic types are related we have assessed the entire mineral oil refinement process by measuring total mineral oil aromatic hydrocarbons (MOAH) content by chromatography next to regulatory hazard tests which focus on 3-7 ring PAC. MOAH content is positively correlated to its molecular weight resulting in aromatic content bias for high viscosity substances. Hazard to 3-7 ring PAC is best controlled by the validated IP346 or modified Ames test. We explain the concept of high vs low alkylation by shortly reviewing new data on alkylated PAC.
    MeSH term(s) Carcinogenesis ; Carcinogens/toxicity ; Humans ; Hydrocarbons, Aromatic/analysis ; Mineral Oil/chemistry ; Mineral Oil/toxicity ; Minerals ; Oils ; Polycyclic Compounds
    Chemical Substances Carcinogens ; Hydrocarbons, Aromatic ; Minerals ; Oils ; Polycyclic Compounds ; Mineral Oil (8020-83-5)
    Language English
    Publishing date 2022-05-23
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 604672-1
    ISSN 1096-0295 ; 0273-2300
    ISSN (online) 1096-0295
    ISSN 0273-2300
    DOI 10.1016/j.yrtph.2022.105193
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  10. Article ; Online: Developmental toxicity testing of unsubstituted and methylated 4- and 5-ring polycyclic aromatic hydrocarbons using the zebrafish embryotoxicity test

    Fang, Jing / Dong, Shutong / Boogaard, Peter J. / Rietjens, Ivonne M.C.M. / Kamelia, Lenny

    Toxicology in Vitro

    2022  Volume 80

    Abstract: The present study evaluates the in vitro developmental toxicity of 4- and 5-ring polycyclic aromatic hydrocarbons (PAHs) including benz[a]anthracene (BaA) and benzo[a]pyrene (BaP) and six of their monomethylated congeners, and dibenz[a,h]anthracene (DB[a, ...

    Abstract The present study evaluates the in vitro developmental toxicity of 4- and 5-ring polycyclic aromatic hydrocarbons (PAHs) including benz[a]anthracene (BaA) and benzo[a]pyrene (BaP) and six of their monomethylated congeners, and dibenz[a,h]anthracene (DB[a,h]A) using the zebrafish embryotoxicity test (ZET). In general, the tested PAHs induced various developmental effects in the zebrafish embryos including unhatched embryos, no movement and circulation, yolk sac and pericardial edemas, deformed body shape, and cumulative mortality at 96 h post fertilization (hpf). The methyl substituent on different positions of the aromatic ring of the PAHs appeared to change their in vitro developmental toxicity. Comparison to a previously reported molecular docking study showed that the methyl substituents may affect the interaction of the PAHs with the aryl hydrocarbon receptor (AhR) which is known to play a role in the developmental toxicity of some PAHs. Taken together, our results show that methylation can either increase or decrease the developmental toxicity of PAHs, and suggest this may in part relate to effects on the molecular dimensions and resulting consequences for interactions with the AhR
    Keywords Aryl hydrocarbon receptor ; Developmental toxicity ; Methylated polycyclic aromatic hydrocarbons ; New approach methodologies ; Zebrafish embryotoxicity test
    Subject code 590
    Language English
    Publishing country nl
    Document type Article ; Online
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
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