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Linda S Birnbaum

Publications and source records attributed to Linda S Birnbaum.

At least 19 recordsLinked to original sources
PubMed2006

Toxicokinetics of polybrominated diphenyl ether congeners 47, 99, 100, and 153 in mice.

The congener profiles of polybrominated diphenyl ethers (PBDEs) in human and wildlife samples are dominated by brominated diphenyl ether (BDE) congeners 47, 99, 100, 153, and 154, all of which are components of the commercial pentaBDE mixtures commonly used in a variety of flammable consumer products. Very little information is available on the toxicokinetics of these congeners and no studies are available directly comparing these BDE congeners in mice. Therefore, the objective of this study was to compare the distribution, metabolism, and excretion of BDEs 47, 99, 100 and 153. Female C57BL/6 mice were administered a single dose of BDE (1 mg/kg: 2.1, 1.9, 1.9, and 1.8 mumol/kg, respectively) intravenously. Excretion was monitored daily, and terminal tissue disposition was examined 5 days following exposure. All BDE congeners in this study distribute with similar patterns into lipophilic tissues; however, tissue concentrations 5 days following exposure were much higher for BDE-153 than for 100, 99, and 47, respectively. Excretion rates were inversely related to tissue concentrations as BDE-47 was the most rapidly excreted congener, followed by BDE-99, -100, and -153. Differences in tissue concentrations were largely driven by congener-specific urinary elimination rates which were associated with protein binding in the urine. While the overall rate of metabolism appeared to be low, analysis of metabolites in daily feces samples revealed that BDE-99 was the most rapidly metabolized congener in this study. The results of this study demonstrate that congener substitution plays a role in the distribution, metabolism, and excretion of PBDEs in mice and it is therefore important to consider the differential toxicokinetic parameters associated with each congener when assessing the risk to human health from these PBDE congeners.

Animals↗
PubMed2006

The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds.

In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and "systemic" TEFs for blood and adipose tissue and TEQ for body burden.

Animals↗
PubMed2006

Disposition of BDE 47 in developing mice.

Despite its minor contribution to global polybrominated diphenyl ether (PBDE) production and usage, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) is the dominant congener found in most biotic samples in North America. The majority of public health concern has focused on potential hazardous effects resulting from exposure of infants and young children to BDE 47 because of previous studies reporting adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to BDE 47. This study was designed with two objectives: (1) to investigate the disposition of BDE 47 in infantile mice reported to be susceptible to BDE 47 and (2) to investigate the disposition and excretion of BDE 47 at various developmental stages in an attempt to further identify the mechanism responsible for rapid urinary excretion. The disposition of (14)C-BDE 47 was monitored in C57BL/6 mice following a single oral dose of BDE 47 (1 mg/kg) at different stages of development. The results show that the toxicokinetics of BDE 47 are different in developing mice than in adult mice; whereas disposition patterns are similar, concentrations of BDE 47 are higher in pups because they have a reduced capacity to excrete BDE 47. These differences lead to higher concentrations of BDE 47 at target tissues during critical windows of development.

Animals↗
PubMed2006

Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t1/2 after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t1/2 reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue.

Adipose Tissue↗
PubMed2006

Polybrominated diphenyl ethers: a case study for using biomonitoring data to address risk assessment questions.

The use of biomonitoring data holds promise for characterizing exposure and informing risk assessment. Biomonitoring data have been used successfully to track population trends, identify susceptible populations, and provide indications of emerging environmental health issues. However, there remain challenges associated with interpreting biomonitoring data for risk assessment. An international biomonitoring workshop was convened in September 2004 to explore the use of biomonitoring data in the context of risk assessment. Six compounds were examined as case studies for this workshop, including polybrominated diphenyl ethers (PBDEs). The PBDE case study was developed to provide an example of a persistent compound for which relatively few data are available for human exposure, biomonitoring, and health outcomes. PBDEs are used in hard plastics, electronics, textiles, and polyurethane foam products. The congener pattern downstream of production facilities often resembles the commercial mixture. However, because these compounds persist in the environment and in biota, the patterns of congeners evolve. PBDEs partition into body lipids, and direct measurement of bromodiphenyl ether congeners in biologic specimens provides a good marker of exposure. Data indicate significant variability (> 100-fold range) in lipid-adjusted levels for PBDEs in the general population. It is hypothesized that both exposure and pharmacokinetics may play a role in observed congener profiles. Significant gaps in our ability to interpret PBDE biomonitoring data to address public health and risk assessment questions include limited knowledge of environmental fate and transport of PBDE congeners, limited population-based data for adults, and lack of data for potentially vulnerable populations such as children.

Animals↗
PubMed2005

Chemically activated luciferase gene expression (CALUX) cell bioassay analysis for the estimation of dioxin-like activity: critical parameters of the CALUX procedure that impact assay results.

The chemically activated luciferase gene expression (CALUX) in vitro cell bioassay is a bioanalytical tool that is increasingly being used by research and commercial laboratories for the screening and relative quantification of dioxins and dioxin-like compounds in sample extracts. Since CALUX analyses provide a biological response to all aryl hydrocarbon receptor active compounds present in a given sample extract containing a complex mixture of chemicals, interpretation of results is significantly more complexthan of chemical analyses. Operators in the laboratory can adjust many parameters when performing CALUX analyses, and the applied procedure strongly affects the result and, hence, the interpretation of the results. This paper examines critical methodological parameters and aspects of the CALUX bioassay that can affect the quality and accuracy of the analyses. Moreover, the study aims to identify the ways that alteration of these parameters influences CALUX measurements. A greater understanding of these characteristics will lead to increased accuracy, precision, and reproducibility of the widely used CALUX bioassay within and between research laboratories.

Biological Assay↗
PubMed2005

Development of a refined database of mammalian relative potency estimates for dioxin-like compounds.

The toxic equivalency factor (TEF) approach has been widely accepted as the most feasible method available at present for evaluating potential health risks associated with exposure to mixtures of dioxin-like compounds (DLCs). The current mammalian TEFs for the DLCs were established by the World Health Organization (WHO) following the meeting of an international expert panel in June of 1997. The TEFs recommended by WHO were determined based on a consensus of scientific judgment and were presented as point estimates. However, the relative potency estimates (REPs) underlying the TEFs were derived from a heterogeneous data set and often span several orders of magnitude. In this article, we present a refined database of mammalian REPs that we believe will facilitate better characterization of the variability and uncertainty inherent in the data. The initial step involved reviewing the REP database used by the WHO panel during its review in 1997. A set of criteria was developed to identify REPs that were determined to be the most representative measure of a biological response and of adequate quality for use in quantitative analyses. REPs were determined to be inappropriate for use in quantitative analyses if any of the established exclusion criteria were met. Comparison of data records to the established exclusion criteria resulted in the identification of a substantial number of REPs believed to be inappropriate for use in quantitative analyses. Next, studies published after 1997 were added to the database. The availability of such a refined database will improve risk assessment for this class of compounds by including additional information from new studies and facilitating the use of quantitative approaches in the further development of TEFs.

Animals↗
PubMed2005

Polybrominated diphenyl ether (PBDE) effects in rat neuronal cultures: 14C-PBDE accumulation, biological effects, and structure-activity relationships.

Polybrominated diphenyl ethers (PBDEs), widely used as flame-retardants, are now recognized as globally distributed pollutants, and are detected in most environmental and biological samples, including human blood, adipose tissue, and breast milk. Due to their wide use in commercial products and their persistent nature, long-term exposure to PBDEs may pose a human health risk, especially to children. Our previous reports showed that the commercial PBDE mixture, DE-71, affected protein kinase C (PKC) and calcium homeostasis in a similar way to those of a structurally-related polychlorinated biphenyl (PCB) mixture. These intracellular signaling events are associated with neuronal development and learning and memory function. The objectives of the present study were to test whether environmentally relevant PBDE congeners, with different position and number of bromines, affected PKC translocation in cerebellar granule neuronal cultures and compare the potency and efficacy of PBDE congeners with their 14C-accumulation. All the tested PBDE congeners increased 3H-phorbol ester (PDBu) binding, and a significant effect was seen as low as 10 microM. Among the congeners tested, 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47) increased 3H-PDBu binding in a concentration-dependent manner and to a greater extent than other congeners. These effects were seen at concentrations and exposure times where no cytotoxicity was observed. The efficacy of PBDE congeners varied with their structural composition, and the effects seen on 3H-PDBu binding with some PBDE congeners are similar to those of PCB congeners. Cerebellar granule neurons accumulated all three PBDE congeners (PBDEs 47, 99, and 153) following exposure. At the lowest concentration (0.67 microM), about 13-18% of the total dose of 14C-PBDE congeners was accumulated by these neurons. There were distinct differences in the pattern of 14C-PBDE accumulation among the PBDE congeners. The 14C-PBDE accumulation, either represented as percent basis or nanomole basis, was much lower for the 30.69 microM PBDE 99 and 10.69-30.69 microM PBDE 153 than at the lower concentrations, which may be due to low solubility of these congeners. The accumulation pattern with PBDE 47 did not vary with concentration. On a nanomole accumulation basis, PBDEs 47, 99, and 153 accumulation was linear with time. While the nanomole accumulation was linear with concentration for PBDE 47, it is nonlinear for PBDEs 99 and 153. The pattern of PBDE accumulation seems to correlate with the effects on PKC translocation, with regression values of 0.773-0.991. These results indicate that PBDEs affected PKC translocation in neurons in a similar way to those of other organohalogens, some PBDE congeners are equally efficacious as the respective PCB congeners, and PBDE accumulation correlated well with PKC translocation, suggesting a common mode of action for this group of chemicals.

Animals↗
PubMed2005

Comparison of the use of a physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure assessments.

In epidemiologic studies, exposure assessments of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) assume a fixed elimination rate. Recent data suggest a dose-dependent elimination rate for TCDD. A physiologically based pharmacokinetic (PBPK) model, which uses a body-burden-dependent elimination rate, was developed previously in rodents to describe the pharmacokinetics of TCDD and has been extrapolated to human exposure for this study. Optimizations were performed using data from a random selection of veterans from the Ranch Hand cohort and data from a human volunteer who was exposed to TCDD. Assessment of this PBPK model used additional data from the Ranch Hand cohort and a clinical report of two women exposed to TCDD. This PBPK model suggests that previous exposure assessments may have significantly underestimated peak blood concentrations, resulting in potential exposure misclassifications. Application of a PBPK model that incorporates an inducible elimination of TCDD may improve the exposure assessments in epidemiologic studies of TCDD.

Body Burden↗
PubMed2004

Physiologically based pharmacokinetic model for developmental exposures to TCDD in the rat.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent developmental toxicant in rodents, and these effects occur at exposures similar to background human body burdens. A physiologically based pharmacokinetic (PBPK) model can aid in quantitatively describing the relationship between exposure, dose, and response. The aim of this work was the development a PBPK model to describe the relationship between maternal TCDD exposure and fetal TCDD concentrations during critical windows of susceptibility in the rat. This PBPK model is a modification of an eight-compartment model that describes the adult female rat. The modified model reduces the compartments from eight to four maternal compartments (liver, fat, placenta and rest of the body). Activation of the placental compartment and a separate fetal compartment occurs during gestation. The systemic circulation connects the maternal compartments. The physiological and biochemical parameters were obtained from the literature. The model validation used experimental data from acute and subchronic exposures prior to and during gestation. The simulations predict the TCDD tissue concentrations of the maternal compartments within the standard deviation of the experimental data. The model overestimates the fetal concentrations by approximately a factor of two at low subchronic exposures, but does predict the fetal tissue concentrations within the range of the experimental data at the higher exposures. This model may provide a framework for the development of a human PBPK model to estimate fetal TCDD concentrations in human health risk assessments.

Animals↗
PubMed2004

Enhanced potential for oxidative stress in livers of senescent rats by the peroxisome proliferator-activated receptor alpha agonist perfluorooctanoic acid.

Aging sensitizes the liver to the hepatocarcinogenic effect of PPARalpha agonists via unknown mechanisms. This study was designed to investigate age-dependent, hepatic effects of the non-metabolizable PPARalpha agonist perfluorooctanoic acid (PFOA) on the delicate balance between activities of pathways involved in H(2)O(2) production and elimination. Male Fischer-344 rats, ranging in age from juvenile (4 weeks old), post puberty (10 weeks old), mature adulthood (20 weeks old), middle age (50 weeks old), to senescence (100 weeks old), were treated intragastrically with either 150mg PFOA/kg in 0.5ml corn oil, or with corn oil alone. Animals were sacrificed at predetermined time-points ranging from 0-28 days post PFOA or oil administration. Hepatic peroxisomal beta-oxidizing activities were significantly elevated (four- to six-fold) in all age groups by PFOA. While levels declined to near basal values within 3-7 days in 4 and 10, they remained elevated for an additional week in 20-, 50- and 100-week-old rats. However, catalase activity was significantly lower in senescent livers compared with all other groups. In conclusion, aging does not appear to hinder the capacity of the liver to produce excess H(2)O(2) through peroxisomal beta-oxidation upon exposure to PPAR agonists. However, the reduced ability of the senescent liver to recover from PFOA-induced potential increase in H(2)O(2) production, coupled with the apparent diminished capacity of this liver to decompose H(2)O(2), enhances the potential for hepatic oxidative damage in aged animals. This may explain the enhanced susceptibility of the senescent liver to the hepatocarcinogenic effect of PPAR agonists.

Aging↗
PubMed2004

Brominated flame retardants: cause for concern?

Brominated flame retardants (BFRs) have routinely been added to consumer products for several decades in a successful effort to reduce fire-related injury and property damage. Recently, concern for this emerging class of chemicals has risen because of the occurrence of several classes of BFRs in the environment and in human biota. The widespread production and use of BFRs; strong evidence of increasing contamination of the environment, wildlife, and people; and limited knowledge of potential effects heighten the importance of identifying emerging issues associated with the use of BFRs. In this article, we briefly review scientific issues associated with the use of tetrabromobisphenol A, hexabromocyclododecane, and three commercial mixtures of polybrominated diphenyl ethers and discuss data gaps. Overall, the toxicology database is very limited; the current literature is incomplete and often conflicting. Available data, however, raise concern over the use of certain classes of brominated flame retardants.

Databases, Factual↗
PubMed2003

Age-independent, gray matter-localized, brain-enhanced oxidative stress in male fischer 344 rats: brain levels of F(2)-isoprostanes and F(4)-neuroprostanes.

While studies showed that aging is accompanied by increased exposure of the brain to oxidative stress, others have not detected any age-correlated differences in levels of markers of oxidative stress. Use of conventional markers of oxidative damage in vivo, which may be formed ex vivo and/or eliminated by endogenous metabolism, may explain these conflicting results. Recently, F(2)-isoprostanes and F(4)-neuroprostanes, peroxidation products of arachidonic acid and docosahexaenoic acid, respectively, have been identified as sensitive and reliable markers of oxidative injury. Therefore, this study was designed to quantify brain levels of F(2)-isoprostanes and F(4)-neuroprostanes and their precursors in 4, 10, 50, and 100 week old male Fischer 344 rats. Data show that levels of F(2)-isoprostanes and F(4)-neuroprostanes were comparable in all animal age groups. However, levels of F(4)-neuroprostanes were approximately 20-fold higher than those of F(2)-isoprostanes in all age groups, despite the fact that brain levels of docosahexaenoic acid were only twice as high as those of arachidonic acid. Based on our findings, it is concluded that aging is not accompanied by enhanced brain susceptibility to oxidative stress. Furthermore, the metabolically active gray matter of the brain, where docosahexaenoic acid is abundant, appears more susceptible to oxidative stress than the white matter.

Age Distribution↗
PubMed2003

Health effects of polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs).

This article reviews the state of the science regarding the health effects of polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs). While thousands of articles have been published on the health effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs), little is know about the brominated and mixed chloro/bromo homologs. Available literature suggests that brominated compounds have similar toxicity profiles to their chlorinated homologs. However, further research investigating health effects will only be useful if exposure scenarios truly exist. Current exposure data is extremely limited, posing a major data gap in assessing potential risk of these chemicals. The rapid increase in the use of brominated flame retardants has raised the level of environmental concern regarding PBDDs/PBDFs as it is likely that human, as well as wildlife, exposure to brominated dioxins and furans will increase with their use.

Benzofurans↗
PubMed2003

Cancer and developmental exposure to endocrine disruptors.

Developing organisms have increased susceptibility to cancer if they are exposed to environmental toxicants during rapid growth and differentiation. Human studies have demonstrated clear increases in cancer after prenatal exposure to ionizing radiation, and there is suggestive evidence that brain tumors and leukemia are associated with parental exposures to chemicals. Animal experiments have demonstrated increased tumor formation induced by prenatal or neonatal exposure to a variety of chemicals, including direct-acting carcinogens and drugs. Recently, natural estrogens have been classified as known human carcinogens. Prenatal exposure to natural and synthetic estrogens is associated with increases in breast and vaginal tumors in humans as well as uterine tumors in animals. Synthetic halogenated chemicals increase liver tumors after early life-stage exposure. Recently, a prototypical endocrine-disrupting compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin, has been shown to be a developmental toxicant of the mammary gland in rodents. Dioxin alters multiple endocrine systems, and its effects on the developing breast involve delayed proliferation and differentiation of the mammary gland, as well as an elongation of the window of sensitivity to potential carcinogens. Implications of these new findings suggest that causes of endocrine-related cancers or susceptibility to cancer may be a result of developmental exposures rather than exposures existing at or near the time of tumor detection.

Adult↗
PubMed2003

Exposure assessment for endocrine disruptors: some considerations in the design of studies.

In studies designed to evaluate exposure-response relationships in children's development from conception through puberty, multiple factors that affect the generation of meaningful exposure metrics must be considered. These factors include multiple routes of exposure; the timing, frequency, and duration of exposure; need for qualitative and quantitative data; sample collection and storage protocols; and the selection and documentation of analytic methods. The methods for exposure data collection and analysis must be sufficiently robust to accommodate the a priori hypotheses to be tested, as well as hypotheses generated from the data. A number of issues that must be considered in study design are summarized here.

Adolescent↗
PubMed2002

A mixture of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and non-ortho polychlorinated biphenyls (PCBs) changed the lipid content of pregnant Long Evans rats.

Pregnant Long Evans rats received 1.0 microg/kg of dioxin toxic equivalents (TEQ) by oral gavage on the 15th gestational day (GD 15), using a dosing mixture that contained two polychlorinated dioxins, four polychlorinated furans and three non-ortho polychlorinated biphenyls (PCBs). Rats were sacrificed on GD 16, GD 21 and postnatal day 4 (PND 4). The lipid content of fetus, pup, placenta and maternal liver, serum and adipose tissue were determined. Treated GD 16 and GD 21 fetuses had identical lipid content to the control group, yet the lipid content of treated pups on PND 4 was 32% higher than that of the control group. On the other hand, the lipid content of placenta, liver, and serum from the treated dams was 44-50%, 24%, and 38% lower than that of the control group, respectively. Thus, a low-dose mixture of dioxin-like compounds can cause changes in lipid content. The lipid content of offspring was not affected until they were exposed via lactation.

Adipose Tissue↗