Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Assessment of drug interaction potential between the HCV direct-acting antiviral agents elbasvir/grazoprevir and the HIV integrase inhibitors raltegravir and dolutegravir.

BACKGROUND: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. OBJECTIVES: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. METHODS: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. RESULTS: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. CONCLUSIONS: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Assessment of the Blood-Brain Barrier Permeability of Potential Neuroprotective Aurones in Parallel Artificial Membrane Permeability Assay and Porcine Brain Endothelial Cell Models.

Previously, several aurone derivatives were identified with promising neuroprotective activities. In developing these compounds to target the central nervous system (CNS), an assessment of their blood-brain barrier (BBB) permeability was performed using in vitro BBB models: parallel artificial membrane permeability assay-BBB which measures passive permeability and primary porcine brain endothelial cell model which enables determination of the involvement of active transport mechanism. Parallel artificial membrane permeability assay-BBB identified most compounds with high passive permeability, with 3 aurones having exceptional Pe values highlighting the importance of basic amine moieties and optimal lipophilicity for good passive permeability. Bidirectional permeability assays with porcine brain endothelial cell showed a significant net influx permeation of the aurones indicating a facilitated uptake mechanism in contrast to donepezil, a CNS drug included in the evaluation which only displayed passive permeation. From pH-dependent permeability assay coupled with data analysis using pCEL-X software, intrinsic transcellular permeability (Po) of a representative aurone 4-3 was determined, considering factors such as the aqueous boundary layer that may hinder accurate in vitro to in vivo correlation. The Po value determined supported the in vivo feasibility of the aurone as a CNS-active compound.

Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%.

Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator.

The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug-related material at steady state, an authentic standard was synthesized and used for comparison of steady-state exposures in humans and the 3-month safety studies in rats and dogs at the no-observed-adverse-effect level. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total maximal plasma concentration (∼7.7× and 1.8×) and area under the plasma concentration-time curve (AUC; 3.6× and 0.8× AUC) relative to the 100- and 300-mg doses, respectively, in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC50 = 0.17 µM; M1: EC50 = 4.69 µM). Furthermore, M1 did not inhibit major human P450 enzymes (IC50 > 30 µM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319.

A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology.

AIMS: ATI-2042 (budiodarone) is a chemical analogue of amiodarone with a half life of 7 h. It is electrophysiologically similar to amiodarone, but may not have metabolic and interaction side effects. The sophisticated electrocardiograph logs of advanced DDDRP pacemakers were used to monitor the efficacy of ATI-2042. The aim of this study was to determine the preliminary efficacy and safety of ATI-2042 in patients with paroxsymal atrial fibrillation (PAF) and pacemakers. METHODS AND RESULTS: Six women with AF burden (AFB) between 1 and 50% underwent six sequential 2-week study periods. Patients received 200 mg bid of ATI-2042 during Period 2 (p2), 400 mg bid during p3, 600 mg bid during p4, 800 mg bid during p5, and no drug during baseline and washout (p1 and p6). Pacemaker data for the primary outcome measure AFB were downloaded during each period. Mean AFB decreased between baseline and all doses: AFB at baseline (SD) was 20.3 +/- 14.6% and mean AFB at 200 mg bid was 5.2 +/- 4.2%, at 400 mg bid 5.2 +/- 5.2%, at 600 mg bid 2.8 +/- 3.4%, and at 800 mg bid 1.5 +/- 0.5%. The mean reductions in AFB at all doses of ATI-2042 were statistically significant (P < 0.005). Atrial fibrillation burden increased in washout. Atrial fibrillation episodes tended to increase with ATI-2042, but this was offset by substantial decreases in episode duration. ATI-2042 was generally well tolerated. CONCLUSION: ATI-2042 effectively reduced AFB over all doses studied by reducing mean episode duration. A large-scale study will be required to confirm this effect.

Nondestructive scat sampling in assessment of mink (Mustela vison) exposed to polychlorinated dibenzofurans (PCDFs).

The mink (Mustela vison) is often utilized as a sentinel species for ecological assessments at sites where contaminants of concern include dioxins and dioxin-like compounds. Utilizing mink scat as a nondestructive tool to determine internal exposure to dioxin-like compounds may allow for rapid, accurate estimates of exposure without the need to capture mink or their prey. To determine the relationships between concentrations of polychlorinated dibenzofurans (PCDFs) in tissues (liver and adipose) and those in scat, mink were fed PCDFs in scat during a controlled laboratory study for 180 days. Mink were fed a control diet, diets with three doses of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) or 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TCDF), and a diet with an environmentally relevant mixture of the two congeners. Concentrations of PCDFs in liver and adipose were measured after 0, 90, and 180 days of exposure. Concentrations of the two PCDF congeners in mink scat were determined after 2, 23, 45, 90, and 180 days of exposure. Concentrations of both PCDF congeners in scat were significantly correlated with those in liver and adipose tissue (r(2) = 0.94-0.97, p < 0.01). This indicates that measurements of concentrations of both PCDFs in scat can be used to predict concentrations of PCDFs in liver and adipose. Assimilation and elimination characteristics of 2,3,4,7,8-PeCDF or 2,3,7,8,-TCDF and a mixture of the two congeners by mink could be predicted from concentrations of these congeners in scat. Overall, concentrations of PCDFs in mink scat can be used as a rapid and inexpensive nondestructive method to predict concentrations of PCDFs in mink when certain assumptions are met.

An adaptable internal dose model for risk assessment of dietary and soil dioxin exposures in young children.

An adaptable model is presented for assessing the blood lipid concentrations of polychlorodibenzodioxins and polychlorodibenzofurans (PCDD/Fs) from dietary (breast milk, formula, milk, and other foods) and soil pathway exposures (soil ingestion and dermal contact) utilizing age-specific exposure and intake estimates for young children. The approach includes a simple one-compartment (adipose volume) toxicokinetic model that incorporates empirical data on age-dependent half-lives and bioavailability of PCDD/F congeners, child body size and intake rates, and recent data on breast milk and food dioxin levels. Users can enter site-specific soil concentration data on 2,3,7,8-chlorinated PCDD/F congeners for specific assessment of body burden changes from soil pathways in combination with background dietary exposures from birth through age 7 years. The model produces a profile of the estimated PCDD/F concentration in blood lipid (in World Health Organization 1998 dioxin toxic equivalents) versus time for a child from birth through age 7 years. The peak and time-weighted average (TWA) internal dose (defined as blood lipid dioxin toxic equivalents) for a variety of specific child exposure assumptions can then be compared to safe internal dose benchmarks for risk assessment purposes, similar to an approach taken by United States Environmental Protection Agency for assessing child lead exposures. We conclude that this adaptable toxicokinetic model can provide a more comprehensive assessment of potential health risks of PCDD/Fs to children because it integrates recent empirical findings on PCDD/F kinetics in humans and allows users to assess contributions from varied dietary and site-specific environmental exposure assumptions.

Depletion of selected polychlorinated biphenyl, dibenzodioxin, and dibenzofuran congeners in farmed rainbow trout (Oncorhynchus mykiss): a hint for safer fish farming.

Farmed fish can be exposed to persistent organic contaminants--such as polychlorinated biphenyls (PCBs), dibenzodioxins (PCDDs), and dibenzofurans (PCDFs)--via feed, this eventually resulting in accumulation levels of health concern. To study the correlation between feed contamination, chemical accumulation in fish muscle (fillet), and chemical depletion, an all-vegetal base (or blank) feed was prepared and fortified with a commercial PCB mixture (Aroclor 1254) and six PCDD and PCDF congeners (namely, 2,3,7,8-T(4)CDD, 2,3,7,8-T(4)CDF, 1,2,3,7,8-P(5)CDD, 1,2,3,7,8-P(5)CDF, O(8)CDD, and O(8)CDF) to reproduce realistic low, medium, and high contamination levels. After a 1-month exposure, trout (Oncorhynchus mykiss) were fed with the blank feed and sacrificed every 0.5 months over a 3-month period from exposure end; fillet specimens were sampled at each time. In all groups, the average fish weight increased linearly through the observation period. The chemical diminishing patterns observed were due to the combined effect of clearance and growth dilution: for 10 PCB and four PCDD and PCDF congeners, patterns were described with an empirical one-compartment (fish muscle) model. The canonical pseudo-first-order kinetic equation used was also modified into the form C=[C(0)exp(-k(C)t)] (m(W)t+1)(-1) to distinguish between the contributions to depletion from clearance, exp(-k(C)t), and growth dilution, (m(W)t+1)(-1). Most mean clearance half-life (HL(C)) estimates appear to be greater than 4 months, in a number of cases reaching magnitudes well over 10 months or even negative, thus clearly indicating a non-negligible contribution from a second compartment. Based on means and their 95% confidence intervals, the depletion HL(D) estimates of the 14 selected congeners seem to be comprised between 1.2-3.4 and 1.0-5.0 months, respectively: these values, accounting for both clearance and growth dilution, provide an indication of the relevance of a blank feed as a management option to reduce the overall PCB, PCDD, and PCDF content in farmed trout. Due to a lack of bioaccumulation, O(8)CDD and O(8)CDF yielded no results for evaluation, whereas for many PCB congeners results were insufficient for empirical modelling.

Assessment of PCBs and PCDD/Fs along the Chinese Bohai Sea coastline using mollusks as bioindicators.

Mollusk samples such as bivalves and gastropods were collected from eight sampling sites along Bohai Sea coastline from northeastern China. The samples were analyzed for polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) by high-resolution gas chromatography/high-resolution mass spectrometry (HRGC-HRMS) to elucidate bioaccumulation of persistent organic pollutants in benthon. Residue levels of sigmaPCBs and sigmaPCDD/Fs were in the ranges of 66.1 to 583.6 ng/g and 0.9 to 15317 pg/g on a lipid-weight basis, respectively, The pollution source was identified using principal component analysis (PCA) in some coastal areas. It indicated that the typical pollution sources were characterized by PCB3, which was one Chinese technical product of PCBs. PCA also revealed the similarity patterns of PCBs between identical species collected from the different sites. The higher gastropod PCB concentrations were related to a former capacitor factory and the paint factories in some coastal areas, but this was not the case with the bivalves. The results of this study suggest that some gastropod species may be a potential bioindicator or "sentinel" organism for marine PCBs monitoring.

Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease salivary flow using pooled population pharmacokinetic-pharmacodynamic data.

AIMS: To describe the population pharmacokinetic-pharmacodynamic relationship between darifenacin (UK-88,525) and its hydroxylated metabolite (UK-148,993), and the reduction in salivary flow (SF, a M3-mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. METHODS: A total of 262 individuals were pooled from 11 Phase 1 studies and one Phase 2 study. A comparison was made between a series of pharmacodynamic models (direct-effect, indirect-effect, link and binding model) using NONMEM. RESULTS: The binding model yielded the best description of the decrease in SF by fully accounting for the time course of the pharmacodynamic effect. An internal validation exercise demonstrated the robustness of this model. Covariate analysis identified a circadian rhythm in SF. This model, with confidence intervals (CI) determined by likelihood profiling, indicated that the relative potency of the metabolite to darifenacin to reduce SF was 11.1% (95% CI 3.8, 19.6). This implied that the metabolite was ninefold less potent than darifenacin in vivo. Accounting for the unbound fraction of darifenacin (2%) and its metabolite (13%), the in vivo protein binding-corrected relative potency was estimated to be 2.1%, indicating that the metabolite was 50-fold less potent than the parent drug. The model supported the assumption that no other metabolites contributing to the impairment of the SF were formed during first-pass, and that the development of sensitization or tolerance was not evident over time. The validation process indicated that the i.v.-oral crossover study was necessary for the estimation of the relative potency. CONCLUSIONS: Population modelling of darifenacin and its hydroxylated metabolite yielded individual pharmacokinetic predictions that could be used to assess the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. The metabolite had a negligible effect on SF.

Assessment of oral bioavailability enhancing approaches for SB-247083 using flow-through cell dissolution testing as one of the screens.

SB-247083 is a potent, nonpeptidic, orally active, ETA-selective, endothelin receptor antagonist. The diacid form and three salts (monoarginine, diarginine and disodium) of SB-247083 were evaluated during the pre-clinical phase of development. The developability attributes (i.e. hygroscopicity, thermal behavior, aqueous solubility, and drug-excipient compatibility) of these compounds were evaluated. In addition to these attributes, the flow-through cell (FTC) dissolution testing (using USP Apparatus 4) was used as a screening technique to evaluate several SB-247083 formulations of the diacid and its salts. FTC dissolution testing offers two distinct advantages over the more traditional static-condition dissolution testing: (1) maintenance of sink conditions; and (2) the ability to change the dissolution medium during a dissolution run. The former advantage is especially important for poorly aqueous soluble drugs having associated dissolution-rate-limitations, and the latter advantage allows one to more closely simulate the pH gradient associated with transit through the GI tract. Based on the comparative dissolution data, three formulations were chosen for oral dosing in dogs. The reasonable correlation found between the FTC dissolution results and the oral bioavailability data demonstrate that FTC dissolution testing can be a valuable tool for aiding in salt (solid-state form) and formulation selection in the early stages of development of drug candidates.

Assessment of human exposure to PCDDs, PCDFs and Co-PCBs using hair as a human pollution indicator sample I: Development of analytical method for human hair and evaluation for exposure assessment.

Dioxins including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and co-planar polychlorinated biphenyls (Co-PCBs) are highly toxic. Even at environmental pollution levels, they cause hormonal damage in women, and they have been shown to induce immunosuppression and genital function damage in humans. In this study, a new method using isotope dilution was established to detect PCDDs, PCDFs and Co-PCBs in human hair. This method, comprised of washing and cutting of hair, alkaline decomposition, hexane extraction, multilayer silica gel column chromatography, high performance liquid chromatography with a porous graphite carbon column and analysis by high resolution gas chromatography/high resolution mass spectrometry, enabled us to analyze PCDDs, PCDFs and Co-PCBs at trace levels of less than pg/g with good reproducibility. In addition, there was a correlation between some isomers in human hair and blood collected from identical donors. Human hair analysis is useful to evaluate human risk assessment including that due to environmental pollution.

Risk assessment of dioxin contamination in human food.

Dioxins are highly toxic by-products of incineration processes and of production of chloro-organic chemicals. Accidental poisonings have occurred repeatedly. The main human exposure is via the dietary route. Species comparisons of toxic effects on the basis of ingested doses are not possible because of the highly differing toxicokinetics between humans and experimental animals. On the basis of internal doses or body burdens acute toxic and tumorigenic responses are observed at similar levels in humans and rats. PCB/PCDD/F contamination at levels which have been reported of marketed chicken meat and eggs in 1999 in Belgium may have increased body burdens by approximately 10%. However, it is estimated that a several hundred-fold higher uptake would be necessary to reach body burdens leading to overt toxicity in normal human subjects.

Health risk assessment for inuit newborns exposed to dioxin-like compounds through breast feeding.

Inuit people living in the Arctic receive an unusually high dose of dioxin-like compounds through their traditional diet, which comprises large amounts of fatty tissues from various sea mammal species. During breast feeding, the mother transfers part of their body burden to its newborn. We estimated the impact of breast feeding on the body burden of Inuit from birth to age 75 years. Simulations performed with a toxicokinetic model revealed that breast feeding strongly influences body burden during childhood but not after age 20 years. Liver and adipose tissue concentrations expected in Inuit are well below those which induced severe adverse health effects in laboratory animals, e.g. cancer and reproduction. However, these concentrations approach levels generating subtle effects on reproductive systems.

Approach to risk assessment of chlorinated dioxins from Yusho PCB poisoning.

A Japanese was estimated to ingest 3 and 11 pg/kg/day of TEQ from PCDD/PCDFs and coplanar PCBs respectively through foods. A Japanese baby was calculated to consume 100-530 pg/kg/day level of TEQ through breast milk feeding, more than 60% being attributed to TEQ of coplanar PCBs. These intakes of TEQ were compared to the average (154 ng/kg/day) and minimum (28 ng/kg/day) intakes of Yusho, a PCB posioning occurred in Japan in 1968. There are three or four orders of magnitude difference between the daily TEQ intakes of general population and Yusho patients. However, the TEQ intakes by breast milk-fed babies of general population are at least 53 times less than the minimum intake of Yusho patients.

Use of toxic equivalency factors for risk assessment for dioxins and related compounds.

TCDD is the most toxic member of a class of polyhalogenated aromatic hydrocarbons that are structurally related, have a similar mechanism of action, and cause the same spectrum of responses. Because of the need to assess the risk from complex mixtures of these chemicals, the international community has adopted an interim approach that assigns relative potency factors to this family of chemicals, based on a comparison with the potency of TCDD. Each chemical that fits the criteria for this class is assigned a toxic equivalency factor, TEF, which is some fraction of that of TCDD. The total toxic equivalency of a mixture, TEQ, is the sum of the weighted potency of each compound in the mixture. Although there may be some variability between different responses in the determination of a TEF value for a compound, endpoint-specific TEFs are usually very similar. There may also be some species differences in TEFs. Again, if pharmacokinetic factors are taken into account, they are usually relatively minor. TEFs based on intake values may also exhibit some differences when compared to those based on target tissue concentrations. Using scientific judgment and a broad data base, interim TEF values have been recommended for PCDDs, PCDFs, and dioxin-like PCBs. Using such values, the TEF approach has been successful at predicting the toxicity of real world mixtures. Ongoing studies from our laboratory have validated the approach for synthetic mixtures that approximate congener ratios found in food samples. Whether non-additive interactions occur with nondioxin-like compounds found in environmentally relevant concentrations remain to be determined.

Polybrominated dibenzo-p-dioxins and dibenzofurans: literature review and health assessment.

Polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs) occur as trace (ppb) contaminants in brominated flame retardants and are produced during combustion of these chemicals. They are also formed when organics are incinerated in the presence of bromine, e.g., in municipal and industrial incinerators and in internal-combustion engines. Combustion of organics in the presence of both bromine and chlorine results in the formation of mixed (i.e., bromo, bromo/chloro and chloro) halogenated dibenzo-p-dioxins and dibenzofurans (HDDs and HDFs). There are 4600 potential mixed congeners. The biological effects of PBDDs and PBDFs are similar, if not identical, to those of PCDDs and PCDFs. Both groups of compounds induce hepatic aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-o-deethylase (EROD) in rats and cause wasting and thymic atrophy in rats and guinea pigs. Tetrabrominated dinenzo-p-dioxin (TBDD) and dibenzofuran (TBDF) are reproductive toxins in mice and produce skin lesions in the rabbit-ear acnegenic test. The brominated compounds appear to bind to the same cytosolic receptors believed to mediate the toxicities of the chlorinated analogs. When compared on a molar-concentration basis, the brominated compounds are equipotent to the chlorinated analogs. TBDD is absorbed after oral, dermal, or intratracheal administration in rats, stored in the liver and adipose tissue, and eliminated in the feces through biliary excretion. The biological half-lives of the brominated compounds appear to be somewhat shorter than those of the corresponding chlorinated species. The brominated compounds, like their chlorinated congeners, have the potential to cause dermal, hepatic, and gastrointestinal toxicities in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparing the results of a Monte Carlo analysis with EPA's reasonable maximum exposed individual (RMEI): a case study of a former wood treatment site.

In the United States, there are about 250 former sites that treated wood with preservatives that are now in need of some degree of remediation. The soil at many of these sites is contaminated with creosote, polycyclic aromatic hydrocarbons (PAHs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs). This paper compares the results of the current USEPA point estimate (deterministic) approach for predicting the health risks associated with exposure to PCDDs/PCDFs in soil with the results of a probabilistic approach which uses a Monte Carlo analysis. At many of these wood treatment sites the hazard posed by the PAHs, and especially pentachlorophenol, can be much greater than that due to PCDD and PCDFs; however, because at this site the health risk associated with PAHs was deemed negligible by ATSDR, only PCDDs/PCDFs were evaluated. Octachlorodibenzo-p-dioxin (OCDD) and octachlorodibenzofuran (OCDF) congeners were evaluated independently from the other congeners due to their prevalence in the environment and the availability of congener-specific data. The results of the reevaluation of the rodent bioassay data for 2,3,7,8-TCDD were considered in the probability distribution for the cancer potency factor. The authors' analyses indicate that when assessing exposure to soil via inhalation, ingestion, and dermal contact, the current regulatory approach used to estimate the reasonable maximally exposed individual (RMEI) (USEPA, Risk Assessment Guidance for Superfund, Vol. 1, Part A, 1989) can predict risks which are 10- to 100-fold greater than the 95th percentile risk predicted by a Monte Carlo analysis.