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A Class Approach to Hazard Assessment of Organohalogen Flame Retardants (2019)

Chapter: Appendix D: Summary of Zebrafish Studies

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Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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D

Summary of Zebrafish Studies

Chapter 3 provided two case examples that illustrate the committee’s scoping plan for evaluating nonpolymeric, additive organohalogen flame retardants (OFRs) as a single class for the purpose of hazard assessment. Two OFR subclasses, the polyhalogenated organophosphates and the polyhalogenated bisphenol aliphatics, were selected as the case examples. Each example considered zebrafish data. This appendix provides summaries of studies identified by the committee.

Tables D-1 and D-2 provide summaries of zebrafish studies of the polyhalogenated organophosphates: Table D-1, data from developmental-toxicology studies, including changes in behavior; and Table D-2, data from other types of toxicology studies.

Tables D-3 through D-5 provide summaries of zebrafish studies of the polyhalogenated bisphenol aliphatics: Table D-3, data on the effects of tetrabromobisphenol A (TBBPA) on thyroid homeostasis in zebrafish; Table D-4, data from studies of the effects of polyhalogenated bisphenols on zebrafish development or behavior; and Table D-5, data from other types of toxicology studies.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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TABLE D-1 Summary of Zebrafish Studies That Evaluated Teratogenic or Developmental Neurotoxic Effects after Exposure to a Polyhalogenated Organophosphate Flame Retardant

Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TDCPP [1] 5.25–96 hpf; [2] 0.75–96, 2.25–96, 5.25–96, 10–96, and 24–96; [3] 0.75–2, 2.25–5, 5.25–10, 10–24 and 24–48 hpf Larval (96 hpf) 0.05–50 µM; 0.5–9 µM Mortality, malformations, global DNA methylation. Overt toxicity at <50 µM and 100% mortality at 50 µM at 96 hpf; no change in mortality in second set of exposure periods; exposure during 0.75–2 hpf (cleavage period) most susceptible; delays in remethylation of genome at 2 hpf but not at 10 or 24 hpf. Exposure to 3 µM TDCPP at 0.75–96 hpf resulted in a significant increase in mortality and developmental abnormalities. McGee et al. (2012)
TDCPP 0.75–96 hpf Embryonic (4 hpf) or larval (96 hpf) 0.2, 1, 3 µM Developmental toxicity, microarray and qRT-PCR for transcript expression and protein expression, proteomics. Increase in mortality at 96 hpf in 1- and 3-µM treatment groups; 17 genes with altered expression at 4 hpf in 3-µM treatment group; qRT-PCR and Western blot analysis confirmed transcript- and protein-expression changes in 8 target genes; proteomics on 96 hpf larvae in 0.2,- 1-, and 3-µM treatment groups showed 15 proteins with altered expression. Fu et al. (2013)
TDCPP 2–120 hpf Embryonic (behavior 18–28 hpf) or larval (96 and 120 hpf) 100, 300, 600, 900 µg/L Locomotor activity, imaging of Tg(Huc-GFP) line, transcript expression, immunofluorescence, ACh concentration, and AChE activity. Decreased hatching rate (96 hpf), decreased survival (120 hpf), and increased malformations (120 hpf) significant at 900 µg/L; decrease in body length (120 hpf) at 600 and 900 µg/L; embryonic (24 hpf) hyperactivity at 300, 600, and 900 µg/L; reduction in neuron-specific expression (120 hpf) at 900 µg/L; decreased transcript expression (120 hpf) of elavl3 at 300, 600, and 900 µg/L and ngn1 at 900 µg/L; hyperactivity (120 hpf) in dark period at 300 and 600 µg/L and hypoactivity in light period at 900 µg/L; reduction in length of dorsal and ventral axon from secondary motor neuron at 900 µg/L; up-regulation of transcript expression of a1-tubulin, shha, and nestrin2 (120 hpf) at 900 µg/L; reduced ACh concentration (120 hpf) at 900 µg/L and reduced AChE activity (120 hpf) at 600 and 900 µg/L. Cheng et al. (2017)
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TDCPP 4–96 hpf Larval (96 hpf) 1–1,000 µM Lethality, behavior, hepatotoxicity, cardiotoxicity. NOAEL of 3 µM (48 hpf) and 2 µM (96 hpf); EC50 of 4.11 µM (48 hpf) and 3.08 µM (96 hpf); LC50 of 8.29 µM (48 hpf) and 6.53 µM (96 hpf); teratogenic index of 2.02 (48 hpf) and 2.12 (96 hpf); no cardiotoxicity or hepatotoxicity; no change in behavior. Alzualde et al. (2018)
TDCPP 4.5–144 hpf or 0–28 dpf 6 or 28 dpf 19 µg/L (1% of LC50) Swim bladder and body size, transcript expression, locomotor activity. Decreased length at 28 dpf; increase in fish without anterior swim bladder at 28 dpf; increase in transcript expression at 6 dpf of ttf-1, sp-a, sp-c, and tpo and at 28 dpf of sp-c; no alterations in locomotor activity at 6 dpf. Godfrey et al. (2017a)
TDCPP 6–120 hpf Larval (144 hpf) 0.04–120 µM Lethality, hatching, malformations. Point of departure at 8.9 µM with dependence on mortality. Behl et al. (2015)
TDCPP 6–120 hpf Embryonic (24 hpf) and larval (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Behavior. 24 hpf change in photomotor response at 64 µM. Reif et al. (2016)
TDCPP 6–120 hpf Embryonic (24 hpf) and larval (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Malformations and behavior. Mortality and delayed progression at 64 µM; hypoactivity at 24 hpf at 64 µM; at 120 hpf, hyperactivity at 0.64 µM in dark stimulation, hypoactivity at 64 µM in dark acclimation, and hyperactivity at 6.4 µM in light phase. Noyes et al. (2015)
TDCPP 6–120 hpf Embryonic (24 hpf) and larval (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Malformations and behavior. Developmental defects at 64 µM. Truong et al. (2014)
TDCPP 6–120 hpf Larval (120 hpf) 5, 50, 500 µg/L Behavior, AChE and BChE activity, LC3 immunofluorescence, measurement of acidic vesicular organelles, and gene and protein expression. No significant effects on hatching or survival; increase in malformations in highest treatment group; decreased swimming speed in highest treatment group in dark periods; down-regulation of transcripts of mbp, syn2a, and a1-tubulin at 50 and 500 µg/L and up-regulation of gap-43 at 500 µg/L; down-regulation of protein expression of mbp in all treatments, of syn2a at 50 and 500 µg/L and of a1-tubulin at 500 µg/L; no changes in AChE or BChE activity; increase in LC3 expression in brain and up-regulation of atg5 and map1lc3b at 50 and 500 µg/L and of becn1 and atg3 at 500 µg/L. Li et al. (2018)
TDCPP 5–120 hpf Larval (144 hpf) 3 or 6 µM Locomotor activity. Hypoactivity in light and dark. Oliveri et al. (2018)
TDCPP 6–144 hpf Larval (144 hpf) 0.56–5.6 µm Morphology and behavior. Overt toxicity threshold of 10 µM; teratogenic; neurobehavioral effect threshold of 3.14 µm. Dishaw et al. (2014)
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TDCPP 6–120 hpf Larval (150–154 hpf) 0.04–120 µM Locomotor activity. Hyperactivity in the light phase and hypoactivity in the dark phase. Jarema et al. (2015)
TDCPP 5–144 hpf 144 hpf and 12 wks 0.3 and 3 µM Larval locomotor assay and adult behavioral test battery. Increased movement at 0.03 µM in the dark phase; fish exposed at 0.3 µM swam faster only in the novel environment test. Oliveri et al. (2015)
TDCPP 2 hpf up to 6 mo Larval (120 hpf), adults (6 mos) 4, 20, 100 µg/L Locomotion, AChE activity, neurotransmitter levels, and gene and protein expression in larval fish; AChE activity, neurotransmitter levels, and gene and protein expression in adult brain tissue. No significant effects on hatching, malformations, survival, or growth rates at 5 dpf; up-regulation of gap-43 in 5-dpf larvae; no change in protein levels of a1-tubulin or mbp in 5-dpf larvae; no changes in dopamine, serotonin, or AChE activity in larvae; no locomotor changes in larvae; growth inhibition in all treatments in both adult sexes; down-regulation of a1-tubulin and mbp in 20- and 100-µg/L treatment groups (transcript and protein), down-regulation of syn2a in 100-µg/L treatment group (transcript/protein not assessed), and up-regulation of gap-43 (transcript/protein not assessed) in 100-µg/L treatment group in adult female brain; down-regulation of a1-tubulin in 20-µg/L (transcript only) and 100-µg/L (transcript and protein) treatment groups and up-regulation of gap-43 (transcript/protein not assessed) in 100-µg/L treatment group in adult male brain; dopamine and serotonin reduced in all treatment groups in female brain, but no changes in adult male brain or in AChE activity in both sexes. Wang et al. (2015a)
TDCPP 1 mo old for 240 d (~8 mo) Adults ~9 mos of age (F0), larval progeny at 3 or 5 dpf (F1) 0.5 or 5 µg/L Bioconcentration, life-history traits, and transcript levels of brain and liver in adult females; developmental toxicity in larvae; transcript levels in F1 BCF were 26 for 0.5-µg/L and 317 for 5-µg/L treatments in females and 45 for 0.5-µg/L and 42 for 5-µg/L treatments in males; 2.8 ng/g at 0.5 µg/L and 11 ng/g at 5 µg/L in F1 eggs; significant decrease in body mass and length in females in 5-µg/L treatment; females, down-regulation of gh in both treatments in brain and down-regulation of ghra, ghrb, igf1, and igf1ra in both treatments and of igf1rb at higher treatment in liver; decrease in survival in 3- and 5-dpf F1 larvae in higher treatment group; decreased heart rate in 3-dpf larvae in both treatment groups; decreased body length in 5-dpf larvae in both treatment groups; in 5 dpf larvae: down-regulation of gh and igf1 in offspring of higher treatment group. Yu et al. (2017)
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TDCPP 2 hpf through sexual maturation Adults (age not specified) 4, 20, 100 µg/L Developmental toxicity of F1; fecundity; plasma hormone concentrations; GSI, transcript expression of brain, gonad, and liver; gonad histology. Increase in malformations in F1 larvae from 20- and 100-µg/L treatment groups with no change in hatching, survival, or growth; decreased weight of adult females and males in all treatment groups; decreased GSI in males in highest treatment group and increased GSI in females in 20- and 100-µg/L treatment groups; decreased egg production in 20- and 100-µg/L treatment groups; E2 and T increased in 20- and 100-µg/L treatment groups in females; in brain, fshβ was upregulated in highest treatment group in both sexes, lhβ and gnrh2 up-regulated in females in 100-µg/L treatment group, and cyp19β up-regulated in all treatment groups in females and in 20- and 100-µg/L treatment groups in males; in liver, erβ and vtg3 were up-regulated in females in 20-and 100-µg/L treatment groups and erα and vtg1 in 100-µg/L treatment group in females, whereas vtg1 was up-regulated in 20-and 100-µg/L treatment groups and erβ and vtg3 in 100-µg/L treatment group in males; in gonads, in females 3β-hsd was upregulated in all treatment groups, fshr, star, Activin-βA2, and ActRIIA were up-regulated in the 20- and 100-µg/L treatment groups, and lhr was up-regulated only in the highest treatment group, whereas in males 3β-hsd was down-regulated in all three treatment groups, 17β-hsd and ActivinβA2 were down-regulated in the 20- and 100-µg/L treatment groups, and ActRIIA was down-regulated and cyp19α upregulated only in the highest treatment group; in females in the 20- and 100-µg/L treatment groups, the percentage of primary oocytes was decreased and the percentage of late/mature oocytes and atretic oocytes was increased; in males, the percentage of spermatogonia was increased in the 20- and 100-µg/L treatment groups. Wang et al. (2015b)
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TDCPP Adult 4 mo old for 3 mo Adult (7 mos, F0), progeny aged 5 or 10 dpf (F1) 4, 20, 100 µg/L Developmental toxicity in larvae, thyroid end points in F0 and F1, ROS in F1. Decreased hatching rate at 20 and 100 µg/L; growth inhibition, increased malformations, and decreased survival at 100 µg/L; T4 (at 20 and 100 µg/L) and T3 (at 100 µg/L) reduced in adult females; T4 reduced in eggs and 5-dpf larvae from 100- µg/L females and in 10-dpf larvae from 20- and 100-µg/L females, whereas T3 reduced in 100-µg/L group; 5-dpf larvae showed decreased mbp in 20-µg/L (transcript only) and 100-µg/L (transcript and protein) groups, α1-tubulin in 20-µg/L (protein only) and 100-µg/L (transcript and protein) groups, and syn2a in 20- and 100-µg/L groups (protein only); 10-dpf larvae had decreased mbp in 20-µgL (protein only) and 100-µg/L (transcript and protein) groups, decreased syn2a in 20-µgL (protein only) and 100-µg/L (transcript and protein) groups, decreased α1-tubulin in 20- and 100-µg/L groups (transcript and protein), and increased gap-43 in 100-µg/L group (transcript only); 5-dpf larvae had decreased dopamine and GABA in 20- and 100-µg/L groups and decreased serotonin in 100-µg/L group; 10-dpf larvae had decreased dopamine and histamine in 20- and 100-µg/L groups and decreased GABA and serotonin in 100-µg/L group; no change in AChE activity in larvae; swimming speed reduced in 100-µg/L group at 5 and 10 dpf; ROS was increased in 100-µg/L group at 5 and 10 dpf. Wang et al. (2015c)
TCEP 5.25–96 hpf Larval (96 hpf) 0.05–50 µM Malformations. No overt toxicity up to 50 µM. McGee et al. (2012)
TCEP 2–120 hpf Larval (120 hpf) 50, 250, 1,250, 6,250 µg/L Locomotor, gene transcript expression, AChE activity. Hypoactivity at 6,250 µg/L; no change in AChE activity; down-regulation of gfap expression at 1,250 and 6,260 µg/L, of mbp expression at 50, 250, and 1,250 µg/L, and of shha and syn2a at 1,250 µg/L. Sun et al. (2016)
TCEP 3–120 hpf Embryonic, larval through 120 hpf 2,85, 28.5, 285, 14,250, 28,500 µg/L LC50, morphology, gene transcript expression. 72-h LC50: 3,748 µg/L; increased mortality at 28.5 µg/L and above; developmental delay and malformations at 14,250 and 28,500 µg/L; increased transcript expression of vtg2, ncoa1, ncoa2, ncoa3, er1, and er2b at 2.85, 28.5, and 285 µg/L, of er2a at 28.5 and 285 µg/L, and of pgr, vtg1, and vtg4 at 2.85 and 285 µg/L . Wu et al. (2017)
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TCEP 4–96 hpf Larval (96 hpf) 1–1,000 µM Lethality, behavior, hepatotoxicity, cardiotoxicity. NOAEL of 400 µM at 48 and 96 hpf; EC50 521 µM at 48 hpf and 415 µM at 96 hpf; LC50 >1,000 µM at 48 hpf and 977 µM at 96 hpf; teratogenic index >1.92 at 48 hpf and 2.35 at 96 hpf; no cardiotoxicity or hepatoxicity; hypoactivity only at highest concentration at which systemic toxicity was observed. Alzualde et al. (2018)
TCEP 24, 48, 72, 96, 120 hpf Embryonic (24, 48 hpf), larval (72, 96, 120 hpf) 0.3, 1, 3, 10, 30 µM Lethality, malformations, photomotor behavior. No malformations; hypoactivity at 96 and 120 hpf at 30 µM. Dach et al. (2019)
TCEP 6–120 hpf Larval (144 hpf) 0.04–120 µM Lethality, hatching, malformations. No adverse effects observed. Behl et al. (2015)
TCEP 6–120 hpf Embryonic (24 hpf), larval (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Behavior. No behavioral changes. Reif et al. (2016)
TCEP 6–120 hpf Embryonic (24 hpf), larval (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Malformations, behavior. No mortality or delayed progression at 24 hpf; hyperactivity at 24 hpf at 0.0064 and 0.064 µM; hypoactivity at 120 hpf at 64 µM in dark acclimation and light phase. Noyes et al. (2015)
TCEP 6–120 hpf Embryonic (24 hpf), larval (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Malformations, behavior. Mortality at 0.0064 µM. Truong et al. (2014)
TCEP 6–120 hpf Larval (150–154 hpf) 0.04–120 µM Locomotor activity. No overt developmental toxicity; decreased activity down to 12 µM. Jarema et al. (2015)
TCEP 6–144 hpf Larval (144 hpf) 10–100 µM Morphology, behavior. Overt toxicity threshold NA; not teratogenic; neurobehavioral effect threshold 31.4 µM. Dishaw et al. (2014)
TCPP 5.25–96 hpf Larval (96 hpf) 0.05–50 µM Malformations. No overt toxicity up to 50 µM. McGee et al. (2012)
TCPP 24, 48, 72, 96, 120 hpf Embryonic (24, 48 hpf), larval (72, 96, 120 hpf) 0.3, 1, 3, 10, 30 µM Lethality, malformations, photomotor behavior. No malformations; hypoactivity at 96 and 120 hpf at 30 µM. Dach et al. (2019)
TCPP 6–120 hpf Embryonic (24 hpf), larval (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Malformations, behavior. No mortality or malformations at 24 or 120 hpf; no behavioral change at 24 hpf; at 120 hpf, hypoactivity at 64 µM in dark acclimation and light phase. Noyes et al. (2015)
TCPP 6–144 hpf Larval (144 hpf) 10–100 µM Morphology, behavior. Overt toxicity threshold NA; not teratogenic; neurobehavioral effect threshold 100 µm. Dishaw et al. (2014)
TDBPP 6–144 hpf Larval (144 hpf) 0.1–1 µM Morphology, behavior. Overt toxicity threshold 3.3 µM; not teratogenic; neurobehavioral effect threshold 0.56 µM. Dishaw et al. (2014)

Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; AhR, aryl hydrocarbon receptor; dpf, days post-fertilization; BChE, butyrylcholine esterase; EC50, effect concentration at which 50% of the population is affected; ER, estrogen receptor; GABA, γ-aminobutyric acid; GR, glycocorticoid receptor; hpf, hours post-fertilization; LC50, lethal concentration at which 50% of the population is killed; mpf, months post-fertilization; MR, mineralocorticoid receptor; NA, not available; NOAEL, no-observed-adverse-effect level; NOEL, no-observed-effect level; PPARα, peroxisome proliferator-activated receptor alpha; qRT-PCR, quantitative real-time polymerase chain reaction; TCEP, tris(2-chloroethyl) phosphate; TCPP, tris(1-chloro-2-propyl) phosphate; TDBPP, tris(2,3-dibromopropyl) phosphate; TDCPP, tris(1,3-dichloro-2-propyl) phosphate; TRα, thyroid-hormone receptor alpha.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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TABLE D-2 Summary of Additional Zebrafish Studies after Exposure to a Polyhalogenated Organophosphate Flame Retardant

Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TDCPP 0.75–2 hpf Embryonic (2 hpf) 2 µM Whole-genome bisulfite sequencing for methylation. Chromosome-specific alterations in cytosine methylation. Volz et al. (2016)
TDCPP 0.75–4, 6, 8, 10, 12, and 24 hpf Embryonic (4, 6, 8, 10, 12, and 24 hpf) 1.56, 3.12 µM Transcriptomics; immunohistochemistry; hemoglobin staining; pericardial area and cardiac assessments; ocular area and pigmentation assessments. Most sensitive developmental toxicity stage 2-3-hpf window; minimal effects on transcriptome at lower concentration; higher concentration altered expression of genes associated with gastrulation and mesoderm development and differentiation, decreased hemoglobin, increased pericardial area, and decreased ocular area and pigmentation. Dasgupta et al. (2018)
TDCPP 2–96 hpf Larval (96 hpf) Not stated 96-h LC50, 96-h cardiotoxicity EC50. 96-h LC50 0.418 mg/L; 96-h EC50 for pericardial edema 1.65 mg/L. Du et al. (2015)
TDCPP 4–120 hpf Larval (120 hpf) [1] 0.8, 4, 20, 100, 500 mg/L; [2] 0.02, 0.2, 2 mg/L Developmental toxicity, transcript expression. Survival and hatching rate decreased at 20 mg/L and greater; concentration-dependent alterations in transcript expression of genes associated with AhR, PPARα, ER, TRa, GR, and MR receptor networks. Liu et al. (2013a)
TDCPP 6–96 hpf 96 hpf 1.25–10 mg/L 96-h LC50. 1.9 mg/L. Godfrey et al. (2017b)
TDCPP 9–14 dpf Larval (14 dpf) 0.5 µmol/L Lipid staining in trunk. Demonstrated obesogenic effects. Kopp et al. (2017)
TDCPP 1 wk old through 4 mo old Adult (4 mo) 0.05, 0.5, 5 µg/L Fecundity, plasma hormone concentrations, GSI, transcript expression in brain, gonad, and liver. Dose-dependent reduction in egg production with significant decrease at 5 µg/L; decrease in length and body weight in females in 0.5- and 5-µg/L treatment groups and decrease in GSI in 5-µg/L treatment group; no changes in gonad histology or hormone concentrations in both sexes; no changes in HPGL axis transcript expression of fshβ and lhβ in the brain, of cyp19a, activin-βa2, or 3βhsd in gonad, or in vtg1 in liver in both sexes; in GH/IGF axis, down-regulation of gh in brain and igf1 in liver in all three treatment groups in males; in GH/IGF axis, down-regulation of gh in brain, igf1 in ovary, and igf1, igf2a, and igf2a in liver in all three treatment groups and down-regulation of igf2b in ovary in highest treatment group. Zhu et al. (2015)
TDCPP 1 mo old for 120 d (4 mo) Adult females (5 mo) 0.05, 0.5, 5 µg/L Fish morphology and gene expression associated with muscle and bone. Significant morphologic changes and decreased muscle density in the 5-µg/L treatment group; down-regulation of myf5 and myog and up-regulation of bmp2b and bmp4 in the 5-µg/L treatment group. Zhu et al. (2018)
TDCPP Adult 4 mo old for 7 d Adult (4 mo) 229 µg/L (1/20 96-h LC50—high), 45.81 µg/L (1/100 96-h LC50—low) Biochemical, transcript expression, and SCGE in liver. In females, ROS and CAT increased after low treatment, and GSH decreased and Mn-SOD increased after low treatment and decreased after high treatment; in males, ROS increased and GSH decreased after both treatments and Mn-SOD and Cu/Zn-SOD decreased after high treatment; transcript expression of genes related to the defense system increased in both sexes after low treatment and decreased in both sex after high treatment; decrease in transcript expression in females (except an increase in cyclin 1A) and an increase in transcript expression in males (except a decrease in cyclin B) after low treatment occurred in genes associated with cell-cycle regulation; expression of genes associated with cell-cycle regulation decreased after high treatment for most genes in both sexes (except an increase in chik2 in females); Chen et al. (2018)
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
fen1 (DNA repair) decreased in females and increased in males after low treatment; after high treatment, rpa3 decreased in both sexes and fen1 decreased in males; after low treatment, most apoptosis-related genes increased in both sexes (except a decrease in bax in females); after high treatment, most apoptosis-related genes decreased in both sexes (except increases in bcl-2 and bax in females); DNA damage increased after both treatments in both sexes.
TDCPP Adult 4 mo old for 14 d Adult 4 mo (each sex) 0.04, 0.2, 1 mg/L Plasma hormones and gene transcription. E2 and T increased in males and females at 1 mg/L; 11-KT decreased in males at 0.04, 0.2, and 1 mg/L; cyp17 and cyp19a expression increased at 1 mg/L in males and females; vtg increased at 1 mg/L in males and decreased at 0.2 and 1 mg/L in females. Liu et al. (2012)
TDCPP Adults 4–5 mo old for 21 d Adult (4–6 mo) 0.04, 0.2, 1 mg/L Fecundity, plasma hormones and gene transcription of brain and gonads. Egg/female spawning and fertilization success decreased at 1 mg/L, and spawning events per female and hatchability decreased at 0.2 and 1 mg/L; in females, E2 increased at 1 mg/L, T decreased at 0.2 and 1 mg/L, 11-KT decreased at 0.2 mg/L, and vtg increased at 0.2 and 1 mg/L; in males, E2 increased at 1 mg/L, T decreased at all three concentrations, 11-KT decreased at 0.04 mg/L, and vtg increased in all three treatment groups; transcription levels of HPG-associated genes were sex- and tissue-dependent. Liu et al. (2013b)
TDCPP Adult 4 mo old for up to 22 d Adult (4 mo) Not stated Accumulation. Half-life in five tissues <6.5 h but 9 h in roe; steady state by 14–19 d. Wang et al. (2017a)
TDCPP Adult 5 mo old for up to 19 d Adult (5 mo) 1/150 96-h LC50 (low), 1/30 96-h LC50 (high) Metabolism in liver. Dechlorination pathway. Wang et al. (2017b)
TDCPP Adult 5 mo old for 4 d Male adult (5 mo) 1 mg/L Transcriptomics in liver; confirmation of hepatoxicity biomarkers, and histologic examination of transgenic larvae for liver toxicity. Up-regulation of genes associated with endoplasmic reticulum stress and toll-like receptor pathway indicating hepatic inflammation; histologic evaluation showed increase in infiltrated neutrophils, hepatic vacuolization, and apoptosis with increase in liver size. Liu et al. (2016)
TCEP 2–96 hpf Larval (96 hpf) Not stated 96-h LC50, 96-h cardiotoxicity EC50. 96-h LC50, 202 mg/L; 96-h EC50 for pericardial edema, 179 mg/L. Du et al. (2015)
TCEP Adult 4 mo old for up to 22 d Adult (4 mo) Not stated Accumulation. Half-life in six tissues, <6.5 h; steady state by 3 d. Wang et al. (2017a)
TCEP Adult 5 mo old for up to 19 d Adult (5 mo) 1/150 96-h LC50 (low), 1/30 96-h LC50 (high) Metabolism in liver. Dechlorination pathway. Wang et al. (2017b)
TCPP 2–96 hpf Larval (96 hpf) Not stated 96-h LC50, 96-h cardiotoxicity EC50. 96-h LC50, 13.5 mg/L; 96-h EC50 for pericardial edema, 22.8 mg/L. Du et al. (2015)

Abbreviations: dpf, days post-fertilization; EC50, effect concentration at which 50% of the population is affected; hpf, hours post-fertilization; LC50, lethal concentration at which 50% of the population is killed; mpf, months post-fertilization; TCEP, tris(2chloroethyl) phosphate; TCPP, tris(1-chloro-2-propyl) phosphate; TDCPP, tris(1,3-dichloro-2-propyl) phosphate.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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TABLE D-3 Effects of Tetrabromobisphenol A on Thyroid Homeostasis in Zebrafish

Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
1–72 hpf Larva (72 hpf) 0.01, 0.1, 1 µM Transcript expression of trβ. No change in transcript expression of trβ. Lu et al. (2018)
1–96 hpf or 96 h started after hatching Larva (96 hpf or 96 h after hatching) 10, 25, 50, 75% of 96-h LC50 or 96-h EC50 96-h LC50, 96-h EC50 (hatching); transcript expression of tg, ttr, tshβ, trα, trβ for both exposures. 1–96 hpf: LC50 5.27 mg/L and EC50 1.09 mg/L; up-regulation of trα (75%) and down-regulation of tshβ (75%); in larvae (96 h post-hatch), up-regulation of trα (75%), ttr (75%), and tshβ (10, 25, 50, 75%). Chan and Chan (2012)
2–120 hpf Larva (120 hpf) 100, 200, 300, 400 µg/L Transcript expression, histology. Up-regulation of trα (100, 200 µg/L) and down-regulation of tpo (100, 200, 300 µg/L); no change in trb, dio1, dio2, dio3, tsh; linked to changes in ocular development and behavior. Baumann et al. (2016)
2–122 hpf Larva (122 hpf) 0.15, 0.3, 0.6, 1.2, 2.4, 4.8 µM Morphology, transcript expression of thr, er, ar, ahr pathways’ potential to dock thrα. Delay in embryogenesis at 0.6 µM and above; down-regulation of expression of ccnd1, ar, thrα, er2a, er2b. Liu et al. (2018)
2–144 hpf Larva (144 hpf) 50, 100, 200, 400 µg/L Survival, morphology, thyroid hormone, transcript expression, acetylcholinesterase activity, behavior. Increased T4; decreased T3; up-regulation of tshβ, tg; down-regulation of ttr, trβ; decreased swimming activity. Zhu et al. (2018)
4.5–144 hpf or 0–28 dpf Larva (6 or 28 dpf) 13 µg/L (1% of LC50) Swim bladder, body size; transcript expression, locomotor activity. No significant changes in body size or locomotor activity; no changes in expression of thyroid-related genes Godfrey et al. (2017a)
Adult Adult (14-d exposure) 0.75, 1.5 µM Transcriptomics and proteomics of liver. Interference of thyroid, vitamin A homeostasis; oxidative stress response and cellular metabolism pathways. De Wit et al. (2008)
Adult; juvenile (1–42 d post-hatch) Adults (30-d exposure); juvenile [42 dph (~45 dpf)] 0.023, 0.047, 0.094, 0.188, 0.375, 0.75, 1.5, 3, 6 µM (no 3- or 6-µM treatments of juveniles) Adults: observed behavior, reproduction, histology of gonads and thyroid; juveniles: growth, development, survival, histology of gonads and thyroid. Adults: abnormal adult behavior (3 and 6 µM) within 24 h, including reduced respiration and stress leading to euthanasia for ethical reasons; reduction in egg number in all chemical-treated groups; fertilization not affected; hatching decreased in all but 0.375-µM group (0.023-1.5 µM); increase in previtellogenic oocytes at 1.5 µM; early oocyte atresia in all treatment groups; thyroid tissue similar.

Juveniles: increased female characteristics at 1.5 µM with no changes in other measures.
Kuiper et al. (2007)
NA NA 1, 3, 10 µM Used a species-specific reporter system based on fusion of LBD trα to GAL4 DNA-binding domain to measure displacement of T3. Displaced T3 from trα. Fini et al. (2012)

Abbreviations: dpf, days post-fertilization; dph, days posthatching; mpf, months post-fertilization; NA, not available; T3, triiodothyronine; T4, thyroxine.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×

TABLE D-4 Effects of Polyhalogenated Bisphenols on Zebrafish Development or Behavior

Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TBBPA 2–120 hpf Larva (120 hpf) 100, 200, 300, 400 µg/L Behavior, histology Changes in trb, dio1, dio2, dio3, tsh were not linked to changes in ocular development or behavior. Baumann et al. (2016)
TBBPA 2–122 hpf Larva (122 hpf) 0.15, 0.3, 0.6, 1.2, 2.4, 4.8 µM Morphology Delay in embryogenesis at ≥0.6 µM. Liu et al. (2018)
TBBPA 2–144 hpf Larva (144 hpf) 50, 100, 200, 400 µg/L Morphology, behavior Decreased swimming activity. Zhu et al. (2018)
TBBPA 3–120 hpf Larva (24, 48 hpf, transcript expression, enzyme activity; 48 hpf, heart beat; 28 dpf, survival) 0.75, 1.5, 3 µM Mortality, malformation 100% mortality at 1.5, 3 µM; decreased heart rate, edema of the trunk, tail malformations. McCormick et al. (2010)
TBBPA 4–96 hpf Larva (96 hpf) 1–1,000 µM Lethality, behavior, hepatotoxicity, cardiotoxicity NOAEL 1.5 µM at 48 hpf, 1 µM at 96 hpf; EC50, 1.81 µM at 48 hpf, 1.48 µM at 96 hpf; LC50, 3.26 µM at 8 hpf, 1.90 µM at 96 hpf; teratogenic index, 1.8 at 48 hpf, 1.28 at 96 hpf; cardiotoxicity, arrhythmia/ventricular failure; no hepatoxicity; no change in behavior. Alzualde et al. (2018)
TBBPA 4–96 hpf Embryo (24, 48 hpf) larva, (96 hpf) 0.05, 0.1, 0.5, 1 mg/L Survival, morphology Decreased survival (96 hpf) at 0.5, 1 mg/L; increased malformations (96 hpf) at 0.5, 1 mg/L; blood flow disorder (24 hpf) at 0.1, 0.5, 1 mg/L; spawn coagulation (24 hpf) at 0.5, 1 mg/L; increased pericardial edema (48 hpf) at 0.5, 1 mg/L. Yang et al. (2015)
TBBPA 4.5–144 hpf or 0-28 dpf Larva (6, 28 dpf) 13 µg/L (1% of LC50) Swim bladder and body size; locomotor activity No significant changes in body size or locomotor activity. Godfrey et al. (2017a)
TBBPA 24, 48, 72, 96, 120 hpf Embryo (24, 48 hpf), larva (72, 96, 120 hpf) 0.03, 0.1, 0.3, 1, 3 µM Lethality, malformations, photomotor behavior Malformation, mortality at 3 µM at all time points; no effects on behavior at nonlethal concentrations. Dach et al. (2019)
TBBPA TBBPA 6–120 hpf 6–120 hpf Embryo (24 hpf), larva (120 hpf) Larva (144 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM 0.04–120 µM Behavior Lethality, hatching, malformations 24 hpf, change in photomotor response at 64 µM, Point of departure at 4.6 µM with dependence on mortality, Reif et al. (2016) Behl et al. (2015)
TBBPA 6–120 hpf Embryo (24 hpf), larva (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Malformations, behavior Greatest teratogenic effects of all chemicals tested at 24, 120 hpf; significant hyperactivity at 24 hpf; at 120 hpf, hypoactivity in both dark stimulatory and acclimation phases. Noyes et al. (2015)
TBBPA 6–120 hpf Embryo (24 hpf), larva (120 hpf) 0.0064, 0.064, 0.64, 6.4, 64 µM Malformations, behavior Mortality at 6 µM with no defects. Truong et al. (2014)
TBBPA 6–120 hpf Larva (150–154 hpf) 0.04–120 µM Locomotor activity Acute exposure changed behavior, but developmental exposure resulted in no behavioral change. Jarema et al. (2015)
TBBPA 6–168 hpf Larva (168 hpf) 1.25, 2.5, 5, 10, 20 mg/L Mortality, malformations, behavior LC50, 1.45 mg/L; EC50, 0.99 mg/L; fin malformations, pericardial edema at 2.5 mg/L; decreased spontaneous movement with movement ceasing at 10 mg/L. Usenko et al. (2016)
TBBPA 8–48 or 48–96 hpf Embyro (48 hpf), larva (96 or 120 hpf) 5, 10 µM Malformations, behavior, apoptosis, motor neuron development, muscle fiber patterning Increased mortality, morphologic alterations at higher concentration at earlier exposure window; no morphologic alterations at 5 µM; behavior at 120 hpf showed hypoactivity for earlier exposure period at 5 µM; increase in apoptotic cells, delayed motor neuron development, loose muscle fibers. Chen et al. (2016)
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TBBPA-BHEE or TBBPA-OHEE 6-168 hpf Larva (168 hpf) 1.25, 2.5, 5, 10, 20 mg/L Mortality, malformations, behavior LC50, 2.2 mg/L; EC50, 1.85 mg/L; fin malformations and pericardial edema at 10 mg/L;decreased spontaneous movement with movement ceasing at 10 mg/L. Usenko et al. (2016)
TBBPA-BDBPE or TBBPA-DBPE 6-120 hpf Embryo (24 hpf), larva (120 hpf) 0.00064, 0.0064, 0.064, 0.64, 6.4 µM Malformations, behavior No mortality or malformations at 24, 120 hpf; no behavioral change at 24, 120 hpf. Noyes et al. (2015)
TBBPA-BME or TBBPA-DME 3-120 hpf Larva (24, 48 hpf, transcript expression, enzyme activity; 48 hpf heartbeat; 28 dpf, survival) 1, 5, 10 µM Mortality, malformations No mortality; some edema and hemorrhage, but less than after exposure toTBBPA. McCormick et al. (2010)

Abbreviations: dpf, days post-fertilization; dph, days posthatching; EC50, effect concentration at which 50% of the population is affected; hpf, hours post-fertilization; LC50, lethal concentration at which 50% of the population is killed; mpf, months post-fertilization; TBBPA, tetrabromobisphenol A; TBBPA-BHEE, tetrabromobisphenol A bis(2-hydroxyethyl) ether; TBBPA-BDBPE, 3,3′,5,5′-tetrabromobisphenol A bis(2,3-dibromopropyl) ether; TBBPA-BME, tetrabromobisphenol A bismethyl ether; T4, thyroxine; T3, triiodothyronine.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×

TABLE D-5 Additional Zebrafish Studies of Polyhalogenated Bisphenol

Chemical Life Stage at Exposure Life Stage Analyzed Concentrations Outcomes Assessed Results Reference
TBBPA 1–72, 1–96, 1–120 hpf Larva (72, 96, 120 hpf) 0.01–1,000 µg/L Transcript expression of vtg, cyp19a, cyp19b No changes in transcript expression. Wang et al. (2011)
TBBPA 1–144 hpf; 21 d in 2-mo-old males Larva (144 hpf), 2-mo-old males (21 d) 0.5, 1.0, 1.5 mg/L Lethality, hatching rate Less lethal than TCBPA with 100% mortality at 1.5 mg/L by 144 hpf; LC50 144 hpf, 1.24 mg/L; hatching delayed at 0.5, 1, 1.5 mg/L; increased hemorrhage, edema at 1.5 mg/L; adults, no change in mortality or vtg. Song et al. (2014)
TBBPA 1? –192 hpf Embryo (48 hpf), larva (96, 144, 192 hpf)—note: possible discrepancy in hpf in methods and dpf reported in results (1, 3, 5, 8 dpf) 0.1, 0.4, 0.7, 1.0 mg/L Biochemical assays (Cu/Zn-SOD, CAT, GPx), transcript expression (cat, cu- zn-sod, gpx1a), apoptosis, histology At 192 hpf: decreased survival at 0.7, 1 mg/L, decreased hatching at 1 mg/L, increased malformations at 0.4, 0.7, 1 mg/L, decreased length at 0.7, 1.0 mg/L; decreased Cu/Zn-SOD, CAT, Gpx1a activity at 0.4 (3, 5, 8 dpf), 0.7 (3, 5, 8 dpf), 1 mg/L (1, 3, 5, 8 dpf); decreased expression of Cu/Zn-SOD 0.1 (5 dpf), 0.4 (3 dpf), 0.7 (3, 8 dpf), 1 mg/L (1, 3, 5, 8 dpf); decreased expression of CAT at 0.1 (3 dpf), 0.7 (1 dpf), 1 mg/L (1, 3, 5, 8 dpf); decreased expression of GPx1a at 1 mg/L (1, 3, 5, 8 dpf); increase in apoptosis at 5 dpf in brain, heart, tail; 1 mg/L led to decrease in myocardial cells and heart linearization. Wu et al. (2015)
TBBPA 2–48 hpf Embryo (48 hpf) 1, 10, 100, 1,000 µg/L Embryo toxicity Lowest effect concentration 1,000 µg/L; lack of spontaneous movement and decline in heart rate. Carlsson and Norrgren (2014)
TBBPA 2–96 hpf Larva (96 hpf) Up to 10 mg/L Lethality, vtg1 expression LC50 at 96 h, 5.27 mg/L; EC50 at 96h, 1.09 mg/L (hatching rate); 75% of EC50 = 61.2-fold increase in vtg1 expression. Chow et al. (2013)
TBBPA 2–96 hpf Larva (96 hpf) 0.002, 0.01, 0.05, 0.25, 0.75, 1.5 mg/L Lethality; SOD, LPO, Hsp70 Lethality at concentrations >0.75 mg/L; superoxide dismutase, lipid peroxidation increased with increasing concentration. Hu et al. (2009)
TBBPA 6–96 hpf Larva (96 hpf) 0.625–5 mg/L 96-h LC50 1.3 mg/L. Godfrey et al. (2017b)
TBBPA 120 hpf for 30 min Larva (121 hpf) 2.5, 5, 10, 20 mg/L Zebrafish neuromast cells Decreased P1, OC neuromast hair cells in dose-dependent manner. Park et al. (2016)
TBBPA NA NA (72-h cell exposure) 5 µM Proteomic analysis of zebrafish liver cells Protein related to folding. NADPH production. Kling and Förlin (2009)
TBBPA NA NA 10-9–10-5 M Ligands of estrogen receptors and/or peroxisome proliferator activated receptors PPARγ ligand (same as TCBPA). Riu et al. (2011)
TCBPA 1–144 hpf; 21 d in 2-mo-old males Larva (144 hpf), 2-mo-old males (21 d) 0.5, 1.0, 1.5 mg/L Lethality, hatching rate More lethal than TBBPA with 100% mortality at 1 mg/L by 120 hpf, 1.5 mg/L by 96 hpf; LC50 144h, 0.75 mg/L; hatching delayed at 1.5 mg/L; increased hemorrhage, edema at 1 and 1.5 mg/L; adults, increased mortality at 1.5 mg/L; no change in vtg. Song et al. (2014)
TCBPA NA NA 10-9–0-5 M Ligands of estrogen receptors and/or peroxisome proliferator activated receptors PPARγ ligand (same as TBBPA). Riu et al. (2011)

Abbreviations: dpf, days post-fertilization; dph, days posthatching; hpf, hours post-fertilization; Hsp, heat-shock protein; LC50, lethal concentration at which 50% of the population is killed; LPO, lipid peroxidation; mpf, months post-fertilization; NA, not available; TBBPA, tetrabromobisphenol A; TCBPA, tetrachlorobisphenol A; vtg, vitellogenin.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×

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Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Wang, Q., J.C. Lam, J. Han, X. Wang, Y. Guo, P.K. Lam, and B. Zhou. 2015b. Developmental exposure to the organophosphorus flame retardant tris(1,3-dichloro-2-propyl) phosphate: estrogenic activity, endocrine disruption and reproductive effects on zebrafish. Aquat. Toxicol. 160:163-171.

Wang, Q., N.L. Lai, X. Wang, Y. Guo, P.K. Lam, J.C. Lam, and B. Zhou. 2015c. Bioconcentration and transfer of the organophorous flame retardant 1,3-dichloro-2-propyl phosphate causes thyroid endocrine disruption and developmental neurotoxicity in zebrafish larvae. Environ. Sci. Technol. 49(8):5123-5132.

Wang, G., H. Shi, Z. Du, H. Chen, J. Peng, and S. Gao. 2017a. Bioaccumulation mechanism of organophosphate esters in adult zebrafish (Danio rerio). Environ. Pollut. 229:177-187.

Wang, G., H. Chen, Z. Du, J. Li, Z. Wang, and S. Gao. 2017b. In vivo metabolism of organophosphate flame retardants and distribution of their main metabolites in adult zebrafish. Sci. Total Environ. 590-591:50-59.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×

Wu, S., G. Ji, J. Liu, S. Zhang, Y. Gong, and L. Shi. 2015. TBBPA induces developmental toxicity, oxidative stress, and apoptosis in embryos and zebrafish larvae (Danio rerio). Environ. Toxicol. 31(10):1241-1249.

Wu, Y., G. Su, S. Tang, W. Liu, Z. Ma, X. Zheng, H. Liu, and H. Yu. 2017. The combination of in silico and in vivo approaches for the investigation of disrupting effects of tris (2-chloroethyl) phosphate (TCEP) toward core receptors of zebrafish. Chemosphere 168:122-130.

Yang, S., S. Wang, F. Sun, M. Zhang, F. Wu, F. Xu, and Z. Ding. 2015. Protective effects of puerarin against tetrabromobisphenol a-induced apoptosis and cardiac developmental toxicity in zebrafish embryo-larvae. Environ. Toxicol. 30(9):1014-1023.

Yu, L., Y. Jia, G. Su, Y. Sun, R.J. Letcher, J.P. Giesy, H. Yu, Z. Han,andC.Liu.2017.Parentaltransferoftris(1,3-dichloro2-propyl) phosphate and transgenerational inhibition of growth of zebrafish exposed to environmentally relevant concentrations. Environ. Pollut. 220(Pt. A):196-203.

Zhu, Y., X. Ma, G. Su, L. Yu, R.J. Letcher, J. Hou, H. Yu, J.P. Giesy, and C. Liu. 2015. Environmentally relevant concentrations of the flame retardant tris(1,3-dichloro-2propyl) phosphate inhibit growth of female zebrafish and decrease fecundity. Environ. Sci. Technol. 49(24):14579-14587.

Zhu, Y., D. Lin, D. Yang, Y. Jia, and C. Liu. 2018. Environmentally relevant concentrations of the flame retardant tris(1,3-dichloro-2-propyl) phosphate change morphology of female zebrafish. Chemosphere 212:358-364.

Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
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Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
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Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 77
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 78
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 79
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 80
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 81
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 82
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 83
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 84
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 85
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 86
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 87
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 88
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
Page 89
Suggested Citation:"Appendix D: Summary of Zebrafish Studies." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
×
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A Class Approach to Hazard Assessment of Organohalogen Flame Retardants Get This Book
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In the 1970s, flame retardants began to be added to synthetic materials to meet strict flammability standards. Over the years, diverse flame retardants have been manufactured and used in various products. Some flame retardants have migrated out of the products, and this has led to widespread human exposure and environmental contamination. There also is mounting evidence that many flame retardants are associated with adverse human health effects. As a result, some flame retardants have been banned, restricted, or voluntarily phased out of production and use.

This publication develops a scientifically based scoping plan to assess additive, nonpolymeric organohalogen flame retardants as a class for potential chronic health hazards under the Federal Hazardous Substances Act, including cancer, birth defects, and gene mutations.

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