Evaluation of potential toxicity of smoke from controlled burns of furnished rooms - effect of flame retardancy.

It has been reported that incorporation of fire retardants into home furnishings and electronics increases the toxicity of smoke produced during combustion in house fires. Studies have been limited to exercises in analytical chemistry but the biological effects of emissions, particularly regarding chronic toxicity, have not been investigated. The combustion of furnishings with and without chemical flame retardants (FR) regarding (1) ignition resistance and fire progression, (2) chemical composition of smoke (analytical chemistry), and (3) toxicity was compared. Data demonstrated that flame retarded furnishings slowed the generation of toxic levels of acutely toxic gases. The potential chronic toxicity of smoke was assessed using the ToxTracker® assay. Smoke samples from rooms with less flame retarded furnishings exhibited a lesser response in this assay than smoke samples from rooms with flame retarded furnishings. Chemicals associated with activation of the aryl hydrocarbon receptor (AHR), namely benzo[b]fluoranthene, benzo[a]anthracene, benzo[a]pyrene, chrysene, and indeno[1,2,3-cd]pyrene, were not found in smoke from more flame retarded furnished rooms, but were present only in smoke from rooms with less flame retarded furnishings. In conclusion, smoke resulting from combustion of flame retarded furnishings did not increase indicators of potential chronic toxicity hazards relative to non-flame retarded furnishings.

Kinetics of metabolism of deltamethrin and cis- and trans-permethrin in vitro. Studies using rat and human liver microsomes, isolated rat hepatocytes and rat liver cytosol.

The kinetics of metabolism of deltamethrin (DLM) and cis- and trans-permethrin (CPM and TPM) was studied in male Sprague-Dawley rat and human liver microsomes. DLM metabolism kinetics was also studied in isolated rat hepatocytes, liver microsomes and cytosol. Apparent intrinsic clearance (CLint) values for the metabolism of DLM, CPM and TPM by cytochrome P450 (CYP) and carboxylesterase (CES) enzymes in rat and human liver microsomes decreased with increasing microsomal protein concentration. However, when apparent CLint values were corrected for nonspecific binding to allow calculation of unbound (i.e., corrected) CLint values, the unbound values did not vary greatly with microsomal protein concentration. Unbound CLint values for metabolism of 0.05-1 µM DLM in rat liver microsomes (CYP and CES enzymes) and cytosol (CES enzymes) were not significantly different from rates of DLM metabolism in isolated rat hepatocytes. This study demonstrates that the nonspecific binding of these highly lipophilic compounds needs to be taken into account in order to obtain accurate estimates of rates of in vitro metabolism of these pyrethroids. While DLM is rapidly metabolised in vitro, the hepatocyte membrane does not appear to represent a barrier to the absorption and hence subsequent hepatic metabolism of this pyrethroid.

Differential lymphatic versus portal vein uptake of the synthetic pyrethroids deltamethrin and cis-permethrin in rats.

The objective of this study was to obtain data on pathways of absorption of the synthetic pyrethroids deltamethrin (DLM) and cis-permethrin (CPM) following oral administration to rats. Adult male Sprague-Dawley rats with cannulated mesenteric lymph ducts and hepatic portal veins were given single doses of either 5 mg/kg DLM or 60 mg/kg CPM via the duodenum and lymph and portal blood samples collected for up to 300 min. The pyrethroid dosing vehicles (5 mL/kg body weight) were either corn oil or glycerol formal. Levels of DLM and CPM in lymph and portal blood samples were determined by high-performance liquid chromatography-mass spectrometry-mass spectrometry. Over the time period studied, levels of both DLM and CPM following administration in either corn oil or glycerol formal were greater in lymph than in portal blood. Lymphatic uptake of both DLM and CPM was enhanced following dosing in glycerol formal than in corn oil. The results of this study suggest that after oral administration to rats, these two pyrethroids are predominantly absorbed via the lymphatic system rather than via portal blood. The data obtained in this study thus support a recently developed physiologically-based pharmacokinetic (PBPK) model to evaluate age-related differences in pyrethroid pharmacokinetics in the rat, where it was assumed that absorption of pyrethroids was predominantly via lymphatic uptake.

Metabolism of bifenthrin, ß-cyfluthrin, λ-cyhalothrin, cyphenothrin and esfenvalerate by rat and human cytochrome P450 and carboxylesterase enzymes.

The metabolism of bifenthrin (BIF), ß-cyfluthrin (CYFL), λ-cyhalothrin (CYHA), cyphenothrin (CYPH) and esfenvalerate (ESF) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 90, 21 and 15 days and from adult humans. Pyrethroid metabolism was also studied with some human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. All five pyrethroids were metabolised by adult (90 day old) rat hepatic microsomal CYP and CES enzymes and by cytosolic CES enzymes. The pyrethroids were also metabolised by human liver microsomes and cytosol. Some species differences were observed. Pyrethroid metabolism by cytosolic CES enzymes contributes to the overall hepatic clearance of these compounds. CYFL, CYHA, CYPH and ESF were metabolised by rat plasma CES enzymes, whereas none of the pyrethroids were metabolised by human plasma. This study demonstrates that the ability of male rats to metabolise these pyrethroids by hepatic CYP and CES enzymes and plasma CES enzymes increases with age. In all instances, apparent intrinsic clearance values were lower in 15 than in 90 day old rats. All pyrethroids were metabolised by some of the human expressed CYP enzymes studied and apart from BIF were also metabolised by CES enzymes.

Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids.

The assessment of potentially sensitive populations is an important application of risk assessment. To address the concern for age-related sensitivity to pyrethroid insecticides, life-stage physiologically based pharmacokinetic (PBPK) modeling supported by in vitro to in vivo extrapolation was conducted to predict age-dependent changes in target tissue exposure to 8 pyrethroids. The purpose of this age-dependent dosimetry was to calculate a Data-derived Extrapolation Factor (DDEF) to address age-related pharmacokinetic differences for pyrethroids in humans. We developed a generic human PBPK model for pyrethroids based on our previously published rat model that was developed with in vivo rat data. The results demonstrated that the age-related differences in internal exposure to pyrethroids in the brain are largely determined by the differences in metabolic capacity and in physiology for pyrethroids between children and adults. The most important conclusion from our research is that, given an identical external exposure, the internal (target tissue) concentration is equal or lower in children than in adults in response to the same level of exposure to a pyrethroid. Our results show that, based on the use of the life-stage PBPK models with 8 pyrethroids, DDEF values are essentially close to 1, resulting in a DDEF for age-related pharmacokinetic differences of 1. For risk assessment purposes, this indicates that no additional adjustment factor is necessary to account for age-related pharmacokinetic differences for these pyrethroids.

Piperonyl butoxide: Mode of action analysis for mouse liver tumour formation and human relevance.

In a 79 week bioassay the pesticide synergist piperonyl butoxide (PBO) was shown to significantly increase the incidence of hepatocellular adenoma (but not hepatocellular carcinoma) in male CD-1 mice at dietary levels of 100 and 300 mg/kg/day PBO and in female mice at a dietary level of 300 mg/kg/day. As PBO is not a genotoxic agent, a series of investigative studies were undertaken to elucidate the mode of action (MOA) for PBO-induced mouse liver tumour formation. Male CD-1 mice were fed diets to provide intakes of 0 (control), 30, 100 and 300 mg/kg/day PBO and for purposes of comparison 500 ppm sodium phenobarbital (NaPB), a known constitutive androstane receptor (CAR) activator, for 7 and 14 days. Treatment with 100 and 300 mg/kg/day PBO and 500 ppm NaPB increased relative liver weight which was associated with hepatocyte hypertrophy, with hepatocyte replicative DNA synthesis (RDS) being increased after 7 days treatment. The treatment of CD-1 mice with 30-300 mg/kg/day PBO for 14 days resulted in significant dose-dependent increases in hepatic microsomal cytochrome P450 (CYP) content and 7-pentoxyresorufin O-depentylase (PROD) activity and in hepatic Cyp2b10 mRNA levels. In contrast, PBO produced a biphasic effect on markers of activation of the peroxisome proliferator-activated receptor alpha (PPARα), with small increases in microsomal lauric acid 12-hydroxylase activity and hepatic Cyp4a10 mRNA levels being observed in mice given 100 mg/kg/day with PBO, with either no increase or a significant inhibition being observed in mice given 300 mg/kg/day PBO. The hepatic effects of PBO in male CD-1 mice were generally similar to those produced by NaPB and were reversible after the cessation of treatment for 28 days. Studies were also performed in male C57BL/6J (wild type) mice and in hepatic CAR and pregnane X receptor (PXR) knockout mice (CAR KO/PXR KO mice), where in the CAR KO/PXR KO mice PBO had little effect on markers of CAR activation, but produced some increases in markers of PPARα activation. The treatment of male CD-1 mouse hepatocytes for 4 days with 5-50 µM PBO, 10-1000 µM NaPB and 25 ng/mL epidermal growth factor (EGF) resulted in significant increases in hepatocyte RDS. While treatment of hepatocytes from one male and one female human donor with 5-500 µM PBO and 10-1000 µM NaPB for 4 days had no effect on hepatocyte RDS, treatment with EGF resulted in significant increases in RDS in both human hepatocyte preparations. In summary, PBO is predominantly a hepatic CAR activator at carcinogenic dose levels in CD-1 mice, with activation of hepatic CAR resulting in a suppression of the effect of PBO on hepatic PPARα. A robust MOA for PBO-induced mouse liver tumour formation has been established, this MOA being similar to that previously identified for NaPB and some other rodent liver CAR activators. Based on the lack of effect of PBO on RDS in human hepatocytes, it is considered that the MOA for PBO-induced mouse liver tumour formation is qualitatively not plausible for humans.

An Evaluation of the Human Relevance of the Liver Tumors Observed in Female Mice Treated With Permethrin Based on Mode of Action.

In 2-year studies, the nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, we demonstrated that the mode of action (MOA) for mouse liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), resulting in a mitogenic effect. In the present study, the effects of permethrin and 2 major permethrin metabolites, namely 3-phenoxybenzoic acid and trans-dichlorochrysanthemic acid, on cytochrome P450 mRNA levels and cell proliferation (determined as replicative DNA synthesis) were evaluated in cultured CD-1 mouse, Wistar rat, and human hepatocytes. Permethrin and 3-phenoxybenzoic acid induced CYP4A mRNA levels in both mouse and human hepatocytes, with trans-dichlorochrysanthemic acid also increasing CYP4A mRNA levels in mouse hepatocytes. 3-Phenoxybenzoic acid induced CYP4A mRNA levels in rat hepatocytes, with trans-dichlorochrysanthemic acid increasing both CYP4A mRNA levels and replicative DNA synthesis. Permethrin, 3-phenoxybenzoic acid, and trans-dichlorochrysanthemic acid stimulated replicative DNA synthesis in mouse hepatocytes but not in human hepatocytes, demonstrating that human hepatocytes are refractory to the mitogenic effects of permethrin and these 2 metabolites. Thus, although some of the key (eg, PPARα activation) and associative (eg, CYP4A induction) events in the established MOA for permethrin-induced mouse liver tumor formation could occur in human hepatocytes at high doses of permethrin, 3-phenoxybenzoic acid, and/or trans-dichlorochrysanthemic acid, increased cell proliferation (an essential step in carcinogenesis by nongenotoxic PPARα activators) was not observed. These results provide additional evidence that the established MOA for permethrin-induced mouse liver tumor formation is not plausible for humans.

Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans.

To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.

Exploring the science, safety, and benefits of air care products: perspectives from the inaugural air care summit.

Seventy-one percent of US households purchase air care products. Air care products span a diverse range of forms, including scented aerosol sprays, pump sprays, diffusers, gels, candles, and plug-ins. These products are used to eliminate indoor malodors and to provide pleasant scent experiences. The use of air care products can lead to significant benefits as studies have shown that indoor malodor can cause adverse effects, negatively impacting quality of life, hygiene, and the monetary value of homes and cars, while disproportionately affecting lower income populations. Additionally, studies have also shown that scent can have positive benefits related to mood, stress reduction, and memory enhancement among others. Despite the positive benefits associated with air care products, negative consumer perceptions regarding the safety of air care products can be a barrier to their use. During the inaugural Air Care Summit, held on 18 May 2018 in the Washington, DC, metropolitan area, multidisciplinary experts including industry stakeholders, academics, and scientific and medical experts were invited to share and assess the existing data related to air care products, focusing on ingredient and product safety and the benefits of malodor removal and scent. At the Summit's completion, a panel of independent experts representing the fields of pulmonary medicine, medical and clinical toxicology, pediatric toxicology, basic science toxicology, occupational dermatology and experimental psychology convened to review the data presented, identify potential knowledge gaps, and suggest future research directions to further assess the safety and benefits of air care products.

Evaluation of Age-Related Pyrethroid Pharmacokinetic Differences in Rats: Physiologically-Based Pharmacokinetic Model Development Using In Vitro Data and In Vitro to In Vivo Extrapolation.

An in vitro to in vivo (IVIVE) extrapolation based-physiologically based pharmacokinetic (PBPK) modeling approach was demonstrated to understand age-related differences in kinetics and how they potentially affect age-related differences in acute neurotoxic effects of pyrethroids. To describe the age-dependent changes in pyrethroid kinetics, it was critical to incorporate age-dependent changes in metabolism into the model. As such, in vitro metabolism data were collected for 3 selected pyrethroids, deltamethrin (DLM), cis-permethrin, and trans-permethrin, using liver microsomes and cytosol, and plasma prepared from immature and adult rats. Resulting metabolism parameters, maximum rate of metabolism (Vmax) and Michaelis-Menten constant (Km), were biologically scaled to respective in vivo parameters for use in the age-specific PBPK model. Then, age-dependent changes in target tissue exposure, i.e., brain Cmax, to a given pyrethroid were simulated across ages using the model. The PBPK model recapitulated in vivo time-course plasma and brain concentrations of the 3 pyrethroids in immature and adult rats following oral administration of both low and high doses of these compounds. A single model structure developed for DLM was able to describe the kinetics of the other 2 pyrethroids when used with compound- and age-specific metabolism parameters, suggesting that one generic model for pyrethroids as a group can be used for early age-sensitivity evaluation if appropriate metabolic parameters are used. This study demonstrated the validity of applying IVIVE-based PBPK modeling to development of age-specific PBPK models for pyrethroids in support of pyrethroid risk assessment of potentially sensitive early age populations in humans.

Involvement of Peroxisome Proliferator-Activated Receptor-Alpha in Liver Tumor Production by Permethrin in the Female Mouse.

The nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, based on findings of a Pathology Working Group involving an expert panel of pathologists, it was concluded that permethrin increased liver tumors at 2500 and 5000 ppm in female mice, but no treatment-related tumorigenic response occurred in male mice at dose levels examined in the 2-year bioassay. To evaluate a possible mode of action (MOA) for the permethrin female CD-1 mouse hepatocellular tumors, a number of investigative studies were conducted. In time-course studies in female CD-1 mice, permethrin increased relative liver weight and enhanced hepatocyte proliferation within 1 week. Treatment with permethrin resulted in marked increases in CYP4A enzyme activities and mRNA levels, but only slightly increased CYP2B markers, suggesting that permethrin primarily activates the peroxisome proliferator-activated receptor alpha (PPARα) and to a much lesser extent the constitutive androstane receptor. The effects of permethrin on relative liver weight, hepatocyte proliferation and CYP4A enzyme activities and mRNA levels were dose-dependent and were reversible within 5 weeks after cessation of treatment. The hepatic effects of permethrin observed in wild-type female mice were markedly reduced in PPARα knockout female mice. These results demonstrate that the MOA for hepatocellular tumor formation by permethrin in female mice involves activation of PPARα resulting in a mitogenic effect. The MOA for permethrin-induced mouse liver tumor formation due to PPARα activation is considered to be not plausible for humans. This conclusion is strongly supported by available epidemiological data for permethrin.

Metabolism of deltamethrin and cis- and trans-permethrin by rat and human liver microsomes, liver cytosol and plasma preparations.

The metabolism of deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 15, 21 and 90 days and from adult humans. DLM and CPM were metabolised by rat hepatic microsomal cytochrome P450 (CYP) enzymes and to a lesser extent by microsomal and cytosolic carboxylesterase (CES) enzymes, whereas TPM was metabolised to a greater extent by CES enzymes. In human liver, DLM and TPM were mainly metabolised by CES enzymes, whereas CPM was metabolised by CYP and CES enzymes. The metabolism of pyrethroids by cytosolic CES enzymes contributes to the overall hepatic clearance of these compounds. DLM, CPM and TPM were metabolised by rat, but not human, plasma CES enzymes. This study demonstrates that the ability of male rats to metabolise DLM, CPM and TPM by hepatic CYP and CES enzymes and plasma CES enzymes increases with age. In all instances, apparent intrinsic clearance values were lower in 15 than in 90 day old rats. As pyrethroid-induced neurotoxicity is due to the parent compound, these results suggest that DLM, CPM and TPM may be more neurotoxic to juvenile than to adult rats.

Metabolism of deltamethrin and cis- and trans-permethrin by human expressed cytochrome P450 and carboxylesterase enzymes.

The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CLint) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5. None of the pyrethroids were metabolised by CYP2A6, CYP2E1, CYP3A7 or CYP4A11. DLM, CPM and TPM were metabolised by both human CES1 and CES2 enzymes. Apparent CLint values for pyrethroid metabolism by CYP and CES enzymes were scaled to per gram of adult human liver using abundance values for microsomal CYP enzymes and for CES enzymes in liver microsomes and cytosol. TPM had the highest and CPM the lowest apparent CLint values for total metabolism (CYP and CES enzymes) per gram of adult human liver. Due to their higher abundance, all three pyrethroids were extensively metabolised by CES enzymes in adult human liver, with CYP enzymes only accounting for 2%, 10% and 1% of total metabolism for DLM, CPM and TPM, respectively.

Safety assessment of the use of Bacillus-based cleaning products.

Non-pathogenic Bacillus species used in cleaning products produce the appropriate enzymes to degrade stains and soils. However, there is little scientific data regarding the human exposure by inhalation of Bacillus spores during or after use of microbial-based cleaning products. Herein, air samples were collected at various locations in a ventilated, carpeted, residential room to determine the air concentration of viable bacteria and spores during and after the application of microbial-based carpet cleaning products containing Bacillus spores. The influence of human activities and vacuuming was investigated. Bioaerosol levels associated with use and post-application activities of whole room carpet treatments were elevated during post-application activity, but quickly returned to the indoor background range. Use of trigger spray spot applications generated aerosolized spores in the immediate vicinity, however, their use pattern and the generation of mostly non-respirable particles suggest minimal risks for pulmonary exposure from their use. The aerosol counts associated with use of these microbial-based cleaners were below the recommendation for safe exposure levels to non-pathogenic and non-toxigenic microorganisms except during application of the spot cleaner. The data presented suggest that carpet cleaning products, containing non-pathogenic Bacillus spores present a low potential for inhalation exposure and consequently minimal risk of adverse effects.

An Evaluation of the Human Relevance of the Lung Tumors Observed in Female Mice Treated With Permethrin Based on Mode of Action.

Permethrin increased the incidence of bronchiolo-alveolar adenomas in female mice but not male mice or female or male rats. Studies were conducted to determine whether permethrin has mitogenic activity in Club cells in mouse lung as the basis for the mode of action (MOA) for the lung adenoma induction. Several short-term experiments focusing on time-course, dose-response, reversibility, sex difference, strain difference, and species difference were evaluated for Club cell proliferation and morphology. The findings demonstrated that permethrin slightly and continuously enhanced Club cell proliferation at tumor-associated dose levels in female mice, but did not increase proliferation in male mice or in female rats. Electron microscopic examination demonstrated that permethrin produced morphological alterations in Club cells prior to increasing the Club cell proliferation. There was no evidence of increased cell death. These alterations in Club cells were also observed with a close structural analog cypermethrin. Taken together, the present studies provide evidence that the MOA for induction of mouse lung adenomas by permethrin involves slight morphological effects on Club cells, sustained Club cell proliferation, and eventually hyperplasia and bronchiolo-alveolar adenoma in susceptible mice. The potential human carcinogenic hazard of permethrin based on the tumorigenic MOA for lung tumors in mice was evaluated using the International Programme on Chemical Safety Human Relevance Framework. As humans are quantitatively much less sensitive to agents that increase Club cell proliferation and tumor formation in mice, it is not likely permethrin will lead to an increase in susceptibility to lung tumor development in humans. Epidemiological data for permethrin strongly supports this conclusion.

Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages.

Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth. The median CYP2C8 expression was significantly greater among samples from subjects older than 35 postnatal days (n = 122) compared with fetal samples and those from very young infants (fetal to 35 days postnatal, n = 100) (0.00 vs. 13.38 pmol/mg microsomal protein; p < 0.0001). In contrast, the median CYP1A2 expression was significantly greater after 15 months postnatal age (n = 55) than in fetal and younger postnatal samples (fetal to 15 months postnatal, n = 167) (0.0167 vs. 2.354 pmol/mg microsomal protein; p < 0.0001). CYP2C8, but not CYP1A2, protein levels significantly correlated with those of CYP2C9, CYP2C19, and CYP3A4 (p < 0.001), consistent with CYP2C8 and CYP1A2 ontogeny probably being controlled by different mechanisms. This study provides key data for the physiologically based pharmacokinetic model-based prediction of age-dependent pyrethroid metabolism, which will be used for IVIVE to support pyrethroid risk assessment for early life stages.

Subchronic toxicology of tetrabromobisphenol A in rats.

Tetrabromobisphenol A (TBBPA) is used to protect a wide range of electrical and electronic equipment, consumer electronics and office and communication equipment from catching fire. TBBPA reacts covalently with other monomers becoming an integral part of the cross-linked molecular structure. This study was conducted to evaluate the subchronic toxicity of TBBPA administered by gavage daily for 13 weeks at 0, 100, 300, and 1000 mg/kg/day in male and female CD® rats. A 6-week post-treatment control and 1000 mg/kg/day recovery groups were included. TBBPA exerted no marked effect on the rate of mortality, clinical signs, body or organ weights, feed consumption, histopathology, urinalysis, ophthalmology, and neurological outcomes in a functional observation battery, motor activity, serum thyroid stimulating hormone, serum triiodothyronine, or other serum chemistries. Although differences were observed for bilirubin and alkaline phosphatase, the observed alterations were within the normal range and thus were neither biologically or toxicologically meaningful. The single thyroid-related parameter affected by TBBPA was a reduction in serum thyroxine levels, but the decrease was not of sufficient magnitude to induce other more sensitive indicators of thyroid perturbation. The No Observed Adverse Effect Level was at least 1000 mg/kg/day, the highest dose tested. Based on an upper bound aggregate exposure for adults estimated by the European Union, the margin of exposure is approximately 5000, suggesting that, for the endpoints examined in this study, exposure to TBBPA presents a reasonable certainty of no harm.