A novel cryptand was synthesized which contained a 3,5-disubstituted-4- oxahexacyclo[5.4.1.02,6.03,10.05,9.08,11] dodecane "cage" moiety. In alkali metal picrate extraction experiments the cryptand exhibited high avidity towards Rb+ and Cs+, when compared with the corresponding model compound. A computational study of a series of cage-functionalized cryptands and their alkali metal-complexes was performed. The X-ray crystal structure of a K+-complexed bis-cage-annulated 20-crown-6 was obtained. The associated picrate anion was found to be intimately involved in stabilization of the host-guest complex. The interaction energy between the host-guest complex and picrate anion has been calculated, and the energy thereby obtained has been corrected for basis set superposition error.

Symmetrical cage-annulated podands were synthesized via highly efficient synthetic strategies. Mechanisms to account for the key reaction steps in the syntheses are proposed; the proposed mechanisms receive support from the intermediates that have been isolated and characterized. An unusual complexation-promoted elimination reaction was studied, and a mechanism is proposed to account for the course of this reaction. This unusual elimination may generalized to other rigid systems and thus may extend our understanding of the role played by the host molecules in "cation-capture, anion-activation" via complexation with guest molecules. Thus, host-guest interaction serves not only to activate the anion but also may activate the leaving groups that participate in the complexation. Complexation-promoted elimination provides a convenient method to desymmetrize the cage while avoiding protection/deprotection steps. In addition, it offers a convenient method to prepare a chiral cage spacer by introducing 10 chiral centers into the host system in a single synthetic step. Cage-annulated monocyclic hosts that contain a cage-butylenoxy spacer were synthesized. Comparison of their metal ion complexation behavior as revealed by the results of electrospray ionization mass spectrometry (ESI-MS), alkali metal picrate extraction, and pseudohydroxide extraction with those displayed by the corresponding hosts that contain cage-ethylenoxy or cage-propylenoxy spacers reveals the effect of the length of the cage spacer upon the host-guest behavior. A series of cage-annulated cryptands, cavitands and the corresponding non-cage-annulated model compounds have been synthesized. These host molecules display unusual behavior when examined by using ESI-MS techniques, i.e., they bind selectively to smaller alkali metal ions (i.e., Li+ and Na+), a result that deviates significantly from expectations based solely upon consideration of the size-fit principle. It seems likely that this behavior results from the effect of the host topology on host-guest behavior. A series of non-cage-annulated cryptands also have been synthesized. These compounds can serve as starting materials for cavitand construction.

This thesis concerns the development of metal-free applications using diaryliodonium salts. The first project describes an arylation protocol of allylic and benzylic alcohols in aqueous media. The method proceeds under mild conditions and the ether products were obtained in moderate to good yields. The methodology was also expanded to include arylation of phenols, giving diaryl ethers in good to excellent yields. In the second project, an arylation method that included a wider range of aliphatic alcohols was developed. The scope of accessible alkyl aryl ethers was studied and included a comparative study of phenylation and nitrophenylation of various alcohols. Finally, a formal metal-free synthesis of butoxycain was performed, illustrating the applicability of the developed method. The third project focused on the limitations and side reactions occurring in Chapter 2 and 3. First, an approach to access symmetric diaryl ethers via arylation of hydroxide was presented. This reaction gave rise to a number of side products, which we hypothesized to originate from aryne-type intermediates. A mechanism for the formation of these side products was suggested, supported by trapping and deuterium labeling experiments. Oxidation of the alcohol to the corresponding ketone was also observed and the mechanism of this interesting side reaction was investigated. The latter was suggested to proceed via an intramolecular oxidation without the involvement of radicals or arynes. The fourth project covers a method to synthesize highly sterically congested alkyl aryl ethers via arylation of tertiary alcohols using diaryliodonium salts. The method displayed a broad scope of tertiary alcohols and was also suitable for fluorinated alcohols. The final project detailed in this thesis deals with C-arylation with diaryliodonium salts, showcasing nitroalkanes as well as a nitro ester as suitable nucleophiles for metal-free arylation. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.</p>

Os retardantes de chama bromados são substâncias utilizadas nos mais variados bens de consumo para aumentar sua resistência ao fogo e/ou altas temperaturas em casos de incêndio, aumentando assim, as chances de escape e reduzindo a gravidade das queimaduras. Para este fim os éteres difenílicos polibromados (PBDEs) representam a classe mais utilizada tendo em vista sua eficiência no controle da propagação da chama e seu baixo custo. Estes compostos se incluem entre os recentemente denominados contaminantes ambientais emergentes que apresentam uma carência de dados toxicológicos, principalmente em relação aos efeitos danosos e aos biomarcadores de exposição, além do potencial dano ao ambiente, sendo esta uma preocupação recente da comunidade científica. Pelo fato da mitocôndria ser reconhecida como a principal organela produtora de energia celular, além de exercer um papel fundamental na manutenção de inúmeras funções celulares, ela foi utilizada como modelo experimental para avaliar os efeitos dos congêneres de BDE- 100; -153; -154 e -209 na faixa de concentração de 0,1 ?mol/L a 50 ?mol/L. Nossos resultados mostram que os efeitos em mitocôndrias isoladas podem ocorrer em menores concentrações para os congêneres BDE-153; -154 (Hexa-BDE) e -209 (Deca-BDE) e em maiores concentrações para o BDE-100 (Penta-BDE). Desta forma, foi observado que os compostos possuem capacidade de interagir com membrana mitocondrial, induzir inchamento mitocondrial, desregular a homeostase cálcica e dissipar o potencial de membrana mitocondrial em concentrações diferentes, entretanto não são capazes de induzir estresse oxidativo na mitocôndria. Assim, os resultados indicam que a ação dos PBDEs sobre mitocôndrias pode ser um dos mecanismos de toxicidade desta classe de compostos. / The brominated flame retardants are substances used in various consumer goods to increase their fire resistance and / or higher temperatures in case of fire, thus increasing the chances of escape and reducing the severity of burns. To this end polybrominated diphenyls ethers (PBDEs) are the most used class in view of its efficiency in controlling the spread of flame and its low cost. These compounds are among the newly emerging environmental contaminants known to exhibit a lack of toxicological data, especially regarding the harmful effects and biomarkers of exposure and potential harm to the environment, which is a recent concern of the scientific community. Because the mitochondrion is recognized as the main energy-producing cell organelles, as well as play a vital role in the maintenance of many cellular functions, it was used as an experimental model to evaluate the effects of the congeners BDE-100 (Penta- BDE), -153, -154 (Hexa-BDE) and -209 (Deca-BDE), in concentration range ranging from 0.1 ?mol/L to 50 ?mol/L. The results show that the effects on isolated mitochondria may occur at lower concentrations for the BDE-153, -154 and -209 and high concentrations to the BDE-100. Thus, it was observed that the compounds have the ability to interact with mitochondrial membrane, inducing swelling, dysregulation of calcium homeostasis and dissipation of membrane potential at different concentrations, however they cannot change factors related to oxidative stress in mitochondria. Furthermore, the induction of mitochondrial swelling, and added significant depletion of ATP levels may contribute to the toxic effects observed. Thus, we conclude that the action of PBDESS on mitochondria is one of the mechanisms of toxicity of this class of compounds.

In this dissertation, we discuss the development of new phase transfer agents, which are capable of rapid fluorination of silicon. These are 18-C-6 derivatives containing a hydroxyl group in the side arm (podand), also known as C-pivot lariats. The syntheses of these lariats including several that have not been previously reported and their efficient purification are described. The synthesis route leads to a robust and generalized approach to obtain these lariats on the gram scale. These agents were initially designed for applications in positron emission tomography (PET). In this medical imaging modality, tracer agents containing silicon have found promising utility as fluoride receptors for more rapid radiolabeling. Phase transfer agents are generally required for 18F-labeling due to the low solubility in organic reaction media and reactivity of cyclotron-generated [18F]potassium fluoride. We envisioned that 18-C-6 derivatives may serve as both phase transfer agents as well as nucleophilic catalysts (CENCs). In this conception, CENCs were rapidly pre-complexed with KF followed by silicon fluorination, which takes advantage of a previously established silicon dianion mechanism. In collaboration with researchers at the NIH, we studied the effect of various linkers connecting the metal chelating unit to the nucleophilic hydroxyl group on the radiofluorination of silicon under mild condition. A hydrolysis resistant aryl silicon fragment has also been developed that contains various functional groups for convenient attachment to the potential PET radiotracer agents. In a second project, we demonstrate the unique reactivity of γ-silyl allenyl esters. Taking advantage of the silyl group as a fluoride acceptor, these allenoates readily underwent addition to a variety of carbon electrophiles, including aryl fluorides, to afford all-carbon quaternary centers bearing an ethynyl group. Surprisingly, in the presence of aldehydes, exclusive bis-substitution occurs at the γ-position to afford the dicarbinol. Details relating to reaction optimization and substrate scope for both the reactions are presented. Dicarbinol allenes were subsequently converted to highly substituted δ-lactones, a novel 6-hydro-2-pyrone as single diastereomers. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

A química verde, que tem a preocupação com o desenvolvimento de tecnologias e processos incapazes de causar poluição, tem sido citada cada vez mais em destaque, pela mídia, como mais uma das iniciativas para prevenção da poluição desenfreada. Neste estudo tem-se buscado a redução ou eliminação de solventes, adaptação dos sistemas reacionais para operação em temperatura ambiente e aumento do rendimento em processos de reações guiados pelos doze princípios da química verde. O objetivo deste trabalho consiste na síntese de intermediários de princípios ativos para uso industrial, através de processos de formação de oximas e oximas éteres. O trabalho foi dividido em duas etapas principais, preparação de oximas e preparação de oximas éteres. Na primeira preparou-se oximas através da reação de aldeídos (benzaldeído, furfuraldeído, salicilaldeído e p-anisaldeído) e cetonas (ciclopentanona, ciclohexanona, metil etil cetona, benzofenona e acetofenona) com cloreto de hidroxilamina, sem a utilização de solventes orgânicos e sem adição de água. Na segunda o objetivo foi preparar oximas éteres (O-butil benzaldeído oxima, O-butil furfuraldeído oxima, N-butoxi-(2-butoxifenil) metanimina, O-butil p-anisaldeído oxima, O-butil ciclohexanona oxima, O-butil ciclopentanona oxima e O-butil metil etil cetona oxima) a partir da alquilação de oximas utilizando um suporte sólido de KF/Al2O3 como catalisador. Todos os compostos foram caracterizados por RMN 13C (apt) e alguns por infravermelho e RMN 1H. / Green chemistry, which is concerned with the development of technologies and processes incapable of causing pollution, has been cited increasingly highlighted, by the media, as another of the initiatives to prevent pollution rampant. This study has sought a reduction or elimination of solvents, reaction to adjust the systems operating at room temperature and yield increase in reactive processes that are guided by the twelve principles of green chemistry. The objective of this work is the synthesis of active intermediates for industrial use, through processes of formation of oximes, oximes ethers. The work was divided into two phases, preparation of oximes and preparation of oximes ethers. In the first was prepared oximes by reaction of aldehydes (benzaldehyde, furfuraldeyde, salicylaldehyde and p-anisaldeyde) and ketones (cyclopentanone, cyclohexanone, methyl ethyl ketone, benzophenone and acetophenone) with hydroxylamine chloride without the use of organic solvents and without adding water. For the second was prepared oximes ethers (O-butyl benzaldheyde oxime, O-butyl furfuraldeyde oxime, N-butoxy-(2-butoxyphenyl) methanimine, O-butyl p-anisaldeyde oxime, O-butyl cyclohexanone oxime, O-butyl cyclopentanone oxime e O-butyl methyl ethyl ketone oxime) from the alkylation of oximes, using a solid support as catalyst KF/Al2O3. All compounds were characterized by 13C NMR (apt) and some infrared and 1H NMR.

Background & Objectives: This dissertation is comprised of two independent projects that seek to answer the research questions outlined in Aims 1 and 2. The first project is focused on measuring exposure to polybrominated diphenyl ethers (PBDE) throughout the early lifecourse, as well as investigating how exposure at different developmental periods relates to neuroendocrine endpoints. PBDEs are flame retardant chemicals that were used extensively in furniture and furnishings sold throughout the United States until their phase-out in 2004. Human exposure occurs primarily through incidental ingestion of PBDE-contaminated dust present in the indoor environment. The second project aimed to characterize telomere dynamics in maternal-child pairs and to evaluate associations between telomere dynamics and indicators of stress and stressful conditions. Telomeres are non-coding nucleotide repeats located at chromosome ends; they serve several functions, such as buffering against loss of important protein coding DNA regions during cell division. Both projects are focused on exposure-response relationships during early life and a central theme throughout this dissertation relates to the intersection of date, time and age in longitudinal cohort studies. Finally, the third aim seeks to integrate findings from Projects I and II and is focused on investigating whether telomere dynamics can be used as a biological indictor of stress in epidemiological research examining associations between low-level environmental chemical exposures and neurodevelopmental endpoints. Methods: Both projects were conducted using data and samples collected as part of the Columbia Center for Children’s Environmental Health (CCCEH) Mothers and Newborns study. In Project I, PBDEs were measured by the Centers for Disease Control and Prevention (CDC) using gas chromatography-mass spectrometry (GC-MS) in plasma samples collected repeatedly between birth and age 9 years. We examined determinants of 1) prenatal exposure to PBDEs (Chapter 2), and 2) trajectories of PBDE exposure over childhood, which we estimated using latent class growth analysis (LCGA) (Chapter 3). We also examined PBDE trajectories in relation to performance on tests of visual, verbal and working memory among early adolescents (Chapter 4) and investigated associations between prenatal exposure to PBDEs and thyroid hormone parameters, which were measured by radioimmunoassay in plasma samples collected at multiple ages (Chapter 5). In Project II, we used monochrome multiplex quantitative polymerase chain reaction (MMqPCR) to measure relative leukocyte telomere length (rLTL) in samples collected from mothers and newborns (umbilical cord blood) at the child’s delivery and from children at ages 2, 3, 5, 7 and 9-years (Chapter 6). We aimed to characterize rLTL dynamics over early life, examine the correlation between paired maternal-newborn rLTL, and examine associations between rLTL with measures of financial strain, perceived stress and maternal distress. Results: In Project I, we detected PBDEs in over 80% of cord blood samples and in multivariable models, sociodemographic and lifestyle factors explained 12% of cord blood PBDE variability. The largest determinant of exposure was ethnicity, with Dominican newborns having lower exposure compared to African American newborns, likely due to the reduced amount of time Dominican mothers had spent in the United States when they gave birth to the study child. Across postnatal life (2000 to 2013), PBDE concentrations in child blood decreased by approximately 12% per year, suggesting that exposure has continually declined since the PBDE phase-out in 2004. Trajectory analyses revealed several unique patterns of PBDE exposure over the early lifecourse, with the majority of children characterized by exposure that was persistently low or that peaked during toddler years. Smaller groups of children were characterized by exposure that was highest during the prenatal period and decreased after birth or by a pattern of high exposure during toddler years that remained elevated into middle childhood. We identified several important predictors of childhood PBDE exposure patterns, including modifiable factors, such as cleaning behaviors. In relation to neurodevelopmental outcomes, we found that children with sustained high exposure to PBDEs scored approximately 5-8 points lower on tests of visual memory. Associations between prenatal exposure and working memory significantly varied by sex, with inverse associations (approximately 8 points lower) observed only among girls. Children with PBDE plasma concentrations that peaked during toddler years performed better on verbal domains, however, these associations were significant only among children breastfed for more than 12 weeks. Finally, in relation to thyroid hormone levels, children with BDE-47 concentrations in the third and fourth quartiles of the exposure distribution (versus first quartile) had significantly lower TSH and free T4 levels, respectively. We did not detect associations between BDE-47 and total T4 levels; likewise, we did not detect associations between other pentaBDE congeners and any thyroid parameter. In Project II, we found that maternal-newborn rLTL in paired samples was moderately correlated and that maternal rLTL at delivery explained 8% of the variability (R2) in newborn rLTL. In relation to measures of hardship, perceived stress and demoralization, we found an inverse, albeit not statistically significant, association between maternal perceived stress and newborn rLTL. We did not detect an association with maternal rLTL, nor did we detect associations between material hardship or demoralization and maternal or newborn rLTL. When examining rLTL in child blood samples collected between birth and age 9 years, we observed a U-shaped pattern characterized by rapid shortening of rLTL between birth and 2 years, followed by gradual lengthening between ages 3 and 9 years. It remains unresolved whether this pattern reflects a true biological phenomenon or if it is an artifact of measurement error introduced by analytic or pre-analytic conditions. Conclusions: Despite the phase-out of PBDEs in 2004, exposure among children residing in New York City remained nearly ubiquitous through 2013, however, concentrations did decline over time. Our finding of several PBDE trajectories suggests that, despite the relatively long half-lives of PBDEs, a single measure may not accurately reflect exposure throughout childhood. Our findings of reduced scores on tests of working and visual memory during the prenatal and postnatal periods, respectively, support a growing body of literature linking early life PBDE exposure to disrupted neurodevelopment. The results of our analysis examining thyroid hormone disruption during childhood revealed a pattern consistent with hypothalamic or pituitary-level disruption during prenatal programming of the thyroid regulatory system. This is the first study to examine prenatal PBDE exposure in relation to childhood thyroid hormone levels, therefore, it is important that this finding is replicated by future research. Our finding of an inverse association between newborn rLTL and maternal perceived stress is consistent with results from previous research and suggests that the developing fetus may be sensitive to maternal stress perception during pregnancy, however, additional research is needed to more fully understand the mechanisms through which this transmission occurs. Our finding of increasing telomere length between toddler years and middle childhood is unexpected and raises questions about the suitability of the qPCR assay for analyzing telomere length in archived samples. Additional analyses are needed to determine whether the observed patterns reflect true biological changes or relate to measurement error introduced during sample processing, storage or analysis. Given these outstanding issues, we were ultimately unable to draw conclusions about the usefulness of telomere dynamics as a stress-sensitive biomarker.

<p>Brominated flame retardants (BFRs) are a diverse group of chemicals, which are used to slow down or inhibit the development of fires. BFRs are incorporated into a wide range of consumer products that are considered as potential fire hazards, such as TV-sets, household appliances, computers, and textiles. The production and use of BFRs is extensive and consists of mainly tetrabromobisphenol A (TBBPA), polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecan (HBCD). BFRs in general, but in particular the PBDEs, have led to both scientific and public concern since they have been found to bioaccumulate in humans and wildlife. The general population is targeted by the PBDEs due to their applications and via the food web. Occupational exposure occurs not only during direct handling of BFRs, but also during handling, repair and dismantling of flame retarded goods.</p><p>This thesis is aimed to assess occupational exposure to BFRs. It is mainly focused PBDEs and especially the PBDEs with high bromine content, such as decabromodiphenyl ether (BDE-209). The work has been accomplished by analysis of BFRs in indoor air at industries handling BFRs or flame retarded goods, and by analysis of blood drawn from workers with potential exposure to BFRs. A referent group, abattoir workers with no occupational exposure to PBDEs, was also investigated. Data from these cross-sectional investigations and from serum sampling during vacation in PBDE-exposed workers have been used for calculation of apparent halflives of hepta- to decaBDE in serum.</p><p>The results clearly show that the workers were exposed to PBDEs when handling PBDE containing products or goods. The serum PBDE levels in computer technicians were found to correlate to the estimated cumulative work hours with computers. Exceptionally high concentrations of BDE-209, almost up to 300 pmol/g lipid weight (l.w.) were observed in serum from rubber workers manufacturing or handling rubber compound that was flame retarded with a technical mixture of decabromodiphenyl ether (DecaBDE). Elevated concentrations of PBDEs with eight or nine bromine substituents were also observed. In an electronics dismantling plant, where elevated levels of PBDEs previously had been observed, reduced serum levels of some, but not all PBDE congeners were observed after industrial hygiene improvements. Notably, it was observed that the BDE-209 concentrations in referents with no occupational exposure were similar to the concentrations of 2,2’,4,4’- tetrabromodiphenyl ether (BDE-47), often referred to as the most abundant PBDE congener in humans and wildlife. Additionally, PBDEs with high bromine content were found to have a fast rate of elimination or transformation in humans, based on serum analysis. BDE-209 had an apparent half-life in serum of only 15 days.</p><p>The possibility of quantifying BFRs, such as PBDEs, in human serum at low levels of detection has been achieved by reducing the contamination of the samples and procedural blanks. Major efforts have been done to develop routines and clean up methodology to enable an almost contamination-free environment at the laboratory. The use of a clean room has decreased PBDE levels in the blanks to acceptable limits. The modifications of the original analytical method have made it possible to quantify almost all PBDE congeners of interest in one GC/MS run.</p><p>Occupational and general background exposure of BFRs to humans will continue as long as these chemicals are a part of our daily life and present as environmental contaminants. The present scientific knowledge of the potential health risks of these BFRs still needs to be further developed. It should be stressed that health effects to PBDEs have not been assessed in this work. It is the author's wish that this thesis should add another piece of knowledge to the puzzle of BFRs and BFR exposure to humans and that these data will be used in future risk assessments of PBDEs in particular.</p>

Brominated flame retardants (BFRs) are a diverse group of chemicals, which are used to slow down or inhibit the development of fires. BFRs are incorporated into a wide range of consumer products that are considered as potential fire hazards, such as TV-sets, household appliances, computers, and textiles. The production and use of BFRs is extensive and consists of mainly tetrabromobisphenol A (TBBPA), polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecan (HBCD). BFRs in general, but in particular the PBDEs, have led to both scientific and public concern since they have been found to bioaccumulate in humans and wildlife. The general population is targeted by the PBDEs due to their applications and via the food web. Occupational exposure occurs not only during direct handling of BFRs, but also during handling, repair and dismantling of flame retarded goods. This thesis is aimed to assess occupational exposure to BFRs. It is mainly focused PBDEs and especially the PBDEs with high bromine content, such as decabromodiphenyl ether (BDE-209). The work has been accomplished by analysis of BFRs in indoor air at industries handling BFRs or flame retarded goods, and by analysis of blood drawn from workers with potential exposure to BFRs. A referent group, abattoir workers with no occupational exposure to PBDEs, was also investigated. Data from these cross-sectional investigations and from serum sampling during vacation in PBDE-exposed workers have been used for calculation of apparent halflives of hepta- to decaBDE in serum. The results clearly show that the workers were exposed to PBDEs when handling PBDE containing products or goods. The serum PBDE levels in computer technicians were found to correlate to the estimated cumulative work hours with computers. Exceptionally high concentrations of BDE-209, almost up to 300 pmol/g lipid weight (l.w.) were observed in serum from rubber workers manufacturing or handling rubber compound that was flame retarded with a technical mixture of decabromodiphenyl ether (DecaBDE). Elevated concentrations of PBDEs with eight or nine bromine substituents were also observed. In an electronics dismantling plant, where elevated levels of PBDEs previously had been observed, reduced serum levels of some, but not all PBDE congeners were observed after industrial hygiene improvements. Notably, it was observed that the BDE-209 concentrations in referents with no occupational exposure were similar to the concentrations of 2,2’,4,4’- tetrabromodiphenyl ether (BDE-47), often referred to as the most abundant PBDE congener in humans and wildlife. Additionally, PBDEs with high bromine content were found to have a fast rate of elimination or transformation in humans, based on serum analysis. BDE-209 had an apparent half-life in serum of only 15 days. The possibility of quantifying BFRs, such as PBDEs, in human serum at low levels of detection has been achieved by reducing the contamination of the samples and procedural blanks. Major efforts have been done to develop routines and clean up methodology to enable an almost contamination-free environment at the laboratory. The use of a clean room has decreased PBDE levels in the blanks to acceptable limits. The modifications of the original analytical method have made it possible to quantify almost all PBDE congeners of interest in one GC/MS run. Occupational and general background exposure of BFRs to humans will continue as long as these chemicals are a part of our daily life and present as environmental contaminants. The present scientific knowledge of the potential health risks of these BFRs still needs to be further developed. It should be stressed that health effects to PBDEs have not been assessed in this work. It is the author's wish that this thesis should add another piece of knowledge to the puzzle of BFRs and BFR exposure to humans and that these data will be used in future risk assessments of PBDEs in particular.

Poly Brominated Diphenyl Ethers (PBDEs) are known flame retardants with highly persistent and lipophilic in nature. The continued usage of PBDE in various products amplifies the human burden of PBDEs. It is therefore, important to study the potential toxicological and/or biological effects of PBDE exposure in human. In this study we investigated the mode of action of PBDE induced toxicity in human liver by exposing human hepatocarcinoma cells in a time (24-72h) and dose (0-100μM) dependent manner. The highest test dose caused an inhibition in cell viability up to 50% after 72h, whereas lower doses (<50μM) showed slight increase in cell viability. Likewise, higher doses caused significant accumulation of intracellular ROS over time. Further, increase in caspase-3 enzyme levels and DNA fragmentation showed that, lower brominated PBDEs induce liver toxicity through accumulation of toxic metabolites and reactive oxygen species over time leading to caspase-mediated apoptotic cell death.