Single Oral Exposure Research Articles

SD랫드에서 다이아지논의 경구노출에 의한 급성 혈액독성

SD랫드에서 다이아지논의 경구노출에 의한 급성 혈액독성

Blood pharmacokinetic of 17 common pesticides in mixture following a single oral exposure in rats: implications for human biomonitoring and exposure assessment.

Human biomonitoring provides information about chemicals measured in biological matrices, but their interpretation remains uncertain because of pharmacokinetic (PK) interactions. This study examined the PKs in blood from Long-Evans rats after a single oral dose of 0.4mg/kg bw of each pesticide via a mixture of the 17 pesticides most frequently measured in humans. These pesticides are β-endosulfan; β-hexachlorocyclohexane [β-HCH]; γ-hexachlorocyclohexane [γ-HCH]; carbofuran; chlorpyrifos; cyhalothrin; cypermethrin; diazinon; dieldrin; diflufenican; fipronil; oxadiazon; pentachlorophenol [PCP]; permethrin; 1,1-dichloro-2,2bis(4-chlorophenyl)ethylene [p,p'-DDE]; 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane [p,p'-DDT]; and trifluralin. We collected blood at 10 min to 48-h timepoints in addition to one sample before gavage (for a control). We used GS-MS/MS to measure the pesticide (parents and major metabolites) concentrations in plasma, determined the PK parameters from 20 sampling timepoints, and analyzed the food, litter, and cardboard in the rats' environment for pesticides. We detected many parents and metabolites pesticides in plasma control (e.g., diethyl phosphate [DEP]; PCP; 3-phenoxybenzoic acid [3-PBA]; 3,5,6-trichloro-2-pyridinol [TCPy], suggesting pre-exposure contamination. The PK values post-exposure showed that the AUC0-∞ and Cmax were highest for TCPy and PCP; β-endosulfan, permethrin, and trifluralin presented the lowest values. Terminal T1/2 and MRT for γ-HCH and β-HCH ranged from 74.5h to 117.1h; carbofuran phenol presented the shortest values with 4.3h and 4.8h. These results present the first PK values obtained through a realistic pattern applied to a mixture of 17 pesticides to assess exposure. This study also highlights the issues of background exposure and the need to work with a relevant mixture found in human matrices.

Environmental cadmium exposure and pancreatic cancer: Evidence from case control, animal and in vitro studies

Although profoundly studied, etiology of pancreatic cancer (PC) is still rather scarce. Some of established risk factors of PC are connected to an increased cadmium (Cd) body burden. Hence, the aim of this study was to investigate the role of this environmental pollutant in PC development by conducting human observational, experimental and in vitro studies.The case-control study included 31 patients with a histologically based diagnosis of exocrine PC subjected to radical surgical intervention as cases and 29 accidental fatalities or subjects who died of a nonmalignant illness as controls. Animal study included two treated groups of Wistar rats (15 and 30 mg Cd/kg b.w) and untreated control group, sacrificed 24 h after single oral exposure. In in vitro study pancreas hTERT-HPNE and AsPC-1 cells were exposed to different Cd concentrations corresponding to levels measured in human cancerous pancreatic tissue.Cd content in cancer tissue significantly differed from the content in healthy controls. Odds ratio levels for PC development were 2.79 (95% CI 0.91–8.50) and 3.44 (95% CI 1.19–9.95) in the third and fourth quartiles of Cd distribution, respectively. Animal study confirmed Cd deposition in pancreatic tissue. In vitro studies revealed that Cd produces disturbances in intrinsic pathway of apoptotic activity and the elevation in oxidative stress in pancreatic cells.This study presents three different lines of evidence pointing towards Cd as an agent responsible for the development of PC.

Simultaneously Improving Mechanical, Formulation, and In Vivo Performance of Naproxen by Co-Crystallization

Naproxen (NAP), an anti-inflammatory drug belonging to class II of Biopharmaceutic Classification System, has low aqueous solubility and dissolution rate which limit its oral bioavailability. The focus of this investigation was to assess the impact of co-crystallization in improving the physico-mechanical and in vivo performance of NAP. NAP was co-crystallized using nicotinamide as a co-former employing liquid-assisted grinding method and characterized by intrinsic dissolution rate, DSC, and PXRD. Prepared co-crystal exhibited improved physicochemical and mechanical properties. Mechanical behavior of NAP and developed co-crystal was analyzed by drawing tabletability curves. Over the entire range of used compaction pressure, NAP showed poor tensile strength (< 2MPa) which resulted in lamination and capping in some tablets. In contrast, tensile strength of co-crystal gradually increased with pressure and was ~ 1.80 times that of NAP at 5000psi. Intrinsic dissolution profile of co-crystal showed a more than five and twofold faster dissolution than NAP in 0.1M HCl and phosphate buffer pH 7.4 at 37°C. In addition, formulation of co-crystal powder into tablets by direct compression demonstrated enhanced dissolution profiles (~ 43% in 0.1M HCl and ~ 92% in phosphate buffer pH 7.4) in comparison to a marketed product, Neoprox (~ 25 and ~ 80%) after 60min. In a single dose oral exposure study conducted in sheep, co-crystal showed more than 1.5-fold increase in AUC and Cmax. In conclusion, co-crystals of NAP illustrated better tabletability, in vitro and in vivo performance.

Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane.

We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. Conformational analysis suggested that trans-3″-substituted trioxolanes would exhibit Fe(II) reactivity and antiparasitic activity similar to that achieved with canonical cis-4″ substitution. The chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria model. As predicted, the trans-3″ analogues exhibited in vitro antiplasmodial activity remarkably similar to that of their cis-4″ comparators. In contrast, efficacy in the Plasmodium berghei mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3″ analogues (e.g., 12i) outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials.

The tissue distribution, metabolism and hepatotoxicity of benzoylurea pesticides in male Eremias argus after a single oral administration

Benzoylurea pesticides (BPUs) are widely used to control the locust, but the toxicokinetics and hepatotoxicity of BPUs in lizards have not been investigated. In this study, the tissue distribution, metabolism and liver toxicity of diflubenzuron and flufenoxuron were assessed in the Eremias argus following a single oral exposure. Diflubenzuron preferred to accumulate in the fat and brain (>1.0 mg kg−1) and was rapidly eliminate in other tissues. In the liver, 4-chloroaniline was one of diflubenzuron metabolites, although with a concentration less than 0.05% of the accumulated diflubenzuron. No significant difference was observed in the liver histopathology between the control and diflubenzuron exposure group. The expressions of Cyp1a and Ahr gene which control the cell apoptosis were also equal to the control level. After flufenoxuron exposure, biomodal phenomenon was observed in the liver, skin, brain, gonad, kidney, heart and blood circulation was an important route for the flufenoxuron penetration. The concentrations of flufenoxuron in all tissues were greater than 1.0 mg kg−1 at 168 h. The excretion of flufenoxuron in the faeces was 1.5 fold higher than diflubenzuron. The hepatocytes in the flufenoxuron treated group showed vacuolation of cytoplasm and decreased nucleus. In addition, the Cyp1a and Ahr genes were significantly up-regulated in the flufenoxuron exposure group. These results suggested that the higher hepatotoxicity of flufenoxuron may be attributed to the higher residual level in the lizard tissues and the Cyp1a and Ahr genes can serve as biomarkers to assess the liver toxicity.

Drug discovery: Chemical diversity targets malaria.

A molecule selected from a library of compounds that have structures similar to natural products targets several stages of the malarial parasite's life cycle, offering single-dose treatment of the disease in mouse models. See Article p.344 Antimalarial drugs have thus far been mainly derived from natural products and synthetic 'drug-like' compounds. This study describes the discovery, following screens against libraries of compounds reminiscent of natural products, of promising small molecules that are highly active against the malaria parasite. Of particular interest is a series of bicyclic azetidines that inhibit a novel malaria target, phenylalanine tRNA–ligase. The bicyclic azetidines can cure mice from all life stages of the Plasmodium parasite with a single low-dose in different mouse infection assays, including a humanized mouse model of malaria liver-stage disease. These compounds have the potential to cure and prevent transmission of the disease in a single oral exposure.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rats

Several studies have shown that acute fluoride (F(-)) exposure impairs cardiac function, but the molecular mechanism is not clear. In order to study this, male Wistar rats were treated with single oral doses of 45 and 90mg/kg F(-) for 24h. A significant accumulation of F(-) was found in the serum and myocardium of experimental rats. F(-) treatment causes myocardial necrosis as evident from increased levels of myocardial troponin I, creatine kinase, lactate dehydrogenase and aspartate transaminase. In addition, F(-) induces myocardial oxidative stress via increased reactive oxygen species, lipid peroxidation, protein carbonyl content and nitrate levels along with decreased in the levels of enzymatic (superoxide dismutase 2, catalase, glutathione peroxidase and glutathione s transferase pi class) and non-enzymatic (reduced glutathione) antioxidants. Notably, F(-) triggers myocardial apoptosis through altered Bax/Bcl2 ratio and increased cytochrome c, caspase 3p20 and terminal deoxynucleotidyl transferase dUTP nick end labeled positive cells. An increased cardiac expression of Nox4 and p38α MAPK in F(-) treated rats indicates the oxidative and apoptotic damage. Moreover, ultra-structural changes, histopathological and luxol fast blue staining demonstrates the degree of myocardial damage at subcellular level. Taken together, these findings reveal that acute F(-) exposure causes cardiac impairment by altering the expression of oxidative stress, apoptosis and necrotic markers.

Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles

Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm − 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies – each with different TiO2 particulate-types, demonstrated an absence of adverse toxicological effects. Apart from reporting the findings of these three studies, this publication also focuses on additional critical issues associated with particle and nanotoxicology studies. First, describing the detailed methodology requirements and rigor upon which the standardized OECD 408 guideline subchronic oral toxicity studies are conducted. Moreover, an attempt is made to reconcile the complex issue of particle size distribution as it relates to measurements of nanoscale and pigment-grade TiO2 particles. Clearly this has been a confusing issue and often misrepresented in the media and the scientific literature. It is clear that the particle-size distribution for pigment-grade TiO2, contains a small (“tail”) component of nanoscale particles (i.e., 21% by particle number and <1% by weight in the test material used in the 90-day study). However, this robust particle characterization finding should not be confused with mislabeling the test materials as exclusively in the nanoscale range. Moreover, based upon the findings presented herein, there appears to be no significant oral toxicity impact contributed by the nanoscale component of the TiO2 Test Material sample in the 90-day study. Finally, it seems reasonable to conclude that the study findings should be considered for read-across purposes to food-grade TiO2 particles (e.g., E171), as the physicochemical characteristics are quite similar.

Oral antigen exposure in newborn piglets circumvents induction of oral tolerance in response to intraperitoneal vaccination in later life.

BackgroundWe previously determined that newborn piglets orally gavaged with Ovalbumin (OVA) responded to systemic OVA re-exposure with tolerance; if adjuvants were included in oral vaccine, piglets responded with antibody-mediated immunity (Vet Immunol Immunopathol 161(3–4):211–21, 2014). Here, we will investigate whether newborn piglets gavaged with a vaccine comprised of OVA plus unmethylated CpG oligodeoxynucleotides (CpG; soluble component; OVA/CpG) combined with OVA plus CpG encapsulated within polyphosphazene microparticles (MP; particulate component) responded with systemic and mucosal immunity. To monitor the response to systemic antigen re-exposure, piglets were i.p.-immunized with OVA plus Incomplete Freund’s Adjuvant (IFA) one month later.ResultsNewborn piglets (n = 5/group) were gavaged with a combined soluble and particulate vaccine consisting of OVA (0.5-0.05 mg) plus 50 μg CpG and 0.5 mg OVA plus 50 μg CpG encapsulated within a polyphosphazene MP (0.5 mg) referred to as OVA/CpG + MP. Control piglets were gavaged with saline alone. Piglets were i.p. immunized with 10 mg OVA (or saline) in IFA at four weeks of age and then euthanized at eight weeks of age. We observed significantly higher titres of serum anti-OVA immunoglobulin (Ig) IgM, IgA, IgG, IgG1, IgG2 and IgG in piglets immunized with 0.05 mg OVA/CpG + MP relative to saline control animals. Thus, a single oral exposure at birth to a combined soluble and particulate OVA vaccine including adjuvants can circumvent induction of oral tolerance which impacts response to i.p. vaccination in later life. Further, piglets gavaged with 0.05 mg OVA/CpG + MP generated significant anti-OVA IgG and IgG1 titres in lung compared to saline control piglets but results were comparable to titres measured in parenteral control piglets. Peripheral blood mononuclear cells (PBMCs) ex vivo-stimulated with OVA showed markedly decreased production of IL-10 cytokine after 72 hours relative to animal-matched cells incubated with media alone. No production of IFN-γ was observed from any groups.ConclusionNewborn piglets gavaged with low dose soluble and particulate OVA plus CpG ODN and polyphosphazene adjuvants produced antigen-specific antibodies in serum and lung after systemic re-exposure in later life. These data indicate circumvention of oral tolerance but not induction of oral immunity.

Relative Potency for Altered Humoral Immunity Induced by Polybrominated and Polychlorinated Dioxins/Furans in Female B6C3F1/N Mice

The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment.

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use "if somewhat protective" was ∼75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C(max) 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK-PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.

Acute Oral Ethanol Exposure Triggers Asthma In Cockroach Allergen–Sensitized Mice

Asthma may be triggered by multiple mediators, including allergen-IgE cross-linking and non-IgE mechanisms. Several clinical studies have shown acute ethanol consumption exacerbates asthma, yet no animal model exists to study this process. We developed a model of ethanol-triggered asthma in allergen-sensitized mice to evaluate the mechanisms of ethanol inducing asthma-like responses. Outbred mice were exposed to cockroach allergens on Days 0 and 14; and on Day 21, mice received ethanol by oral gavage. Tracer studies confirmed alcohol aspiration did not occur. Within 30 minutes, alcohol induced degranulation of over 74% of mast cells, and multiple parameters of asthma-like pulmonary inflammation were triggered. Ethanol-gavaged mice had a fivefold increased production of eotaxin-2 (534 pg/mL) and a sevenfold increase in bronchoalveolar eosinophils (70,080 cells). Ethanol induced a 10-fold increase in IL-13, from 84 pg/mL in sensitized mice to 845 pg/mL in ethanol-gavaged sensitized mice. In cockroach allergen-sensitized mice, ethanol triggered asthma-like changes in respiratory physiology and a significant fivefold increase in airway mucin production. Importantly, none of these asthmatic exacerbations were observed in normal mice gavaged with ethanol. Cromolyn sodium effectively stabilized mast cells, yet increased mucin production and bronchoalveolar eosinophil recruitment. Together, these data show a single oral alcohol exposure will trigger asthma-like pulmonary inflammation in allergen-sensitized mice, providing a novel asthma model.

Absorption and Excretion of 14C-Perfluorooctanoic Acid (PFOA) in Angus Cattle (Bos taurus)

Perfluoroalkyl substances (PFASs), such as perfluorooctanoic acid (PFOA), are environmentally persistent industrial chemicals often found in biosolids. Application of these biosolids to pastures raises concern about the accumulation of PFOA in the edible tissues of food animals. Because data on the absorption, distribution, metabolism, and excretion (ADME) of PFOA in cattle were unavailable, a study was conducted to determine pharmacokinetic parameters following a single oral exposure (1 mg/kg body weight of (14)C-PFOA) in four Lowline Angus steers. Radiocarbon was quantified in blood, urine, and feces for 28 days and in tissues at the time of slaughter (28 days) by liquid scintillation counting (LSC) or by combustion analysis with LSC with confirmation by liquid chromatography-tandem mass spectrometry (LC-MS/MS). (14)C-PFOA was completely absorbed and excreted (100.7 ± 3.3% recovery) in the urine within 9 days of dosing. The plasma elimination half-life was 19.2 ± 3.3 h. No (14)C-PFOA-derived radioactivity was detected in edible tissues. Although PFOA was rapidly absorbed, it was also rapidly excreted by steers and did not persist in edible tissues, suggesting meat from cattle exposed to an acute dose of PFOA is unlikely to be a major source of exposure to humans.

Mutagenicity of ipriflavone in vivo and in vitro

Ipriflavone (7-isopropoxy-isoflavone) is a semisynthetic isoflavone derivative from daidzein and prescribed to prevent and treat osteoporosis in postmenopausal women. In the present study, ipriflavone was investigated with regard to their cytotoxic and mutagenic effects using the micronucleus assay (MN) in vivo on cells of bone marrow and peripheral blood of Swiss albino mice and the micronucleus test with the cytokinesis-blocked micronucleus assay (CBMN assay) on human peripheral blood lymphocytes. The studies were performed in mice with three dosages of the drug, 1.71, 8.57 and 42.85mg/kgbw in single oral exposure, and for two dosages, 5 and 10μg/mL in the CBMN assay. Ipriflavone, in the dosages tested, did not differ from controls neither in the induction of MN nor induced cytotoxicity to cells in the in vivo test. However, in the CBMN assay, the concentration of 10μg/mL induced a statistically significant increase in MN formation and decreased cell proliferation, demonstrating to be mutagenic and cytotoxic at this concentration.

Accumulation Dynamics of Chlordanes and Their Enantiomers in Cockerels (Gallus gallus) after Oral Exposure

After a single oral exposure of technical chlordane, levels of cis-chlordane (CC), trans-chlordane (TC), heptachlor (HEP), heptachlorepoxide (HEPX), and oxychlordane (OXY) were determined in gastrointestinal residues, droppings, and various tissues of cockerels at times of 60, 120, 160, 200, 300, 500, 1000, and 2000 min. Over 98% of CC and TC were found to be bioaccessible; only 1.1% of CC and TC were directly excreted through droppings without further biotransformation. According to the single-compartment toxicokinetic modeling, CC and TC shared similar absorption rates in the whole body while TC showed a slightly more rapid elimination rate, with a half-life of 13.4 h for CC and 12.5 h for TC. The metabolites HEPX and OXY appeared quickly in tissues 60 min after exposure and were mainly accumulated in fat and liver tissues. Concentrations of CC, TC, and HEP in cockerel tissues roughly followed the order as fat > intestine > skin > liver> brain > muscle > blood. Levels of CC, TC, and HEP in various tissues showed significant correlation with the lipid contents of the tissues (p < 0.05) for samples beginning 500 min after exposure. A multicompartment toxicokinetic model was developed to characterize the accumulation dynamics of CC and TC in the various tissues. All tissues of cockerels enantioselectively accumulated (-)-CC and (+)-TC, and fat, skin, and liver tissues showed a relatively stronger capacity of enantioenrichment. The enantiomer fractions (EFs) of droppings remained nearly racemic at first but gradually decreased to less than 0.5 for CC and increased to more than 0.5 for TC, which could rule out enantioselective absorption and excretion of CC and TC in cockerels. The one-compartment toxicokinetic model was applied to the individual enantiomers of CC and TC. Different elimination rates but similar absorption rates were observed between the enantiomers for both CC and TC.

Cytochrome P450-specific human PBPK/PD models for the organophosphorus pesticides: Chlorpyrifos and parathion

Organophosphorus pesticides (OPs) remain a potential concern to human health because of their continuing use worldwide. Phosphororthioate OPs like chlorpyrifos and parathion are directly activated and detoxified by various cytochrome P450s (CYPs), with the primary CYPs involved being CYP2B6 and CYP2C19. The goal of the current study was to convert a previously reported human pharmacokinetic and pharmacodynamic (PBPK/PD) model for chlorpyrifos, that used chlorpyrifos metabolism parameters from rat liver, into a human CYP based/age-specific model using recombinant human CYP kinetic parameters ( V max, K m), hepatic CYP content and plasma binding measurements to estimate new values for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition and to use the model as a template for the development of a comparable parathion PBPK/PD model. The human CYP based/age-specific PBPK/PD models were used to simulate single oral exposures of adults (19 year old) and infants (1 year) to chlorpyrifos (10,000, 1000 and 100 μg/kg) or parathion (100, 25 and 5 μg/kg). Model simulations showed that there is an age dependency in the amount of blood cholinesterase inhibition observed, however additional age-dependent data are needed to further optimize age-specific human PBPK/PD modeling for these OP compounds. PBPK/PD model simulations estimated that a 4-fold increase or decrease in relative CYP2B6 and CYP2C19 content would produce a 9–22% inhibition in blood AChE activity following exposure of an adult to chlorpyrifos (1000 μg/kg). Similar model simulation produced an 18–22% inhibition in blood AChE activity following exposure of an adult to parathion (25 μg/kg). Individuals with greater CYP2B6 content and lower CYP2C19 content were predicted to be most sensitive to both OPs. Changes in hepatic CYP2B6 and CYP2C19 content had more of an influence on cholinesterase inhibition for exposures to chlorpyrifos than parathion, which agrees with previously reported literature that these CYPs are more reaction biased for desulfurization (activation) and dearylation (detoxification) of chlorpyrifos compared to parathion. The data presented here illustrate how PBPK/PD models with human enzyme-specific parameters can assist ongoing risk assessment efforts and aid in the identification of sensitive individuals and populations.

Toxicokinetics of the Flame Retardant Hexabromocyclododecane Alpha: Effect of Dose, Timing, Route, Repeated Exposure, and Metabolism

Alpha-hexabromocyclododecane (α-HBCD) is an emerging persistent organic pollutant present in the hexabromocyclododecane (HBCD) commercial mixture. HBCD is used as an additive flame retardant in a wide variety of household consumer products. Three main stereoisomers, alpha (α), beta (β), and gamma (γ), comprise roughly 10, 10, and 80% of the mixture, respectively. Despite its small contribution to HBCD global production and usage, α-HBCD is the major stereoisomer found in wildlife and human tissues including breast milk and blood in North America, European Union, and Asia. No mammalian or human data are currently available regarding the toxicokinetics of α-HBCD. This study was conducted in an effort to fully characterize the absorption, distribution, metabolism, and elimination of α-HBCD following a single and repeated exposure with respect to dose, time, and route of administration in female C57BL/6 mice. Results indicate that ∼90% of the administered dose (3 mg/kg) was absorbed after oral exposure. Disposition was (1) dictated by lipophilicity, as adipose, liver, muscle, and skin were major depots and (2) was dose dependent with nonlinear accumulation at higher doses. Elimination, both whole-body and from individual tissues, was biphasic. α-HBCD-derived radioactivity was excreted in the feces as parent and metabolites, whereas urine only contained metabolites. Presence of polar metabolites in the blood and urine were a major factor in determining the rapid initial whole-body half-life after a single oral exposure. Initial half-lives were ∼1-3 days and much longer terminal half-lives of 17 days were observed, suggesting the potential for α-HBCD bioaccumulation. A 10-day repeated study supports α-HBCD bioaccumulation potential. Stereoisomerization previously observed after exposure to γ-HBCD was not seen after exposure of α-HBCD. The toxicokinetic behavior reported here has important implications for the extrapolation of toxicological studies of the commercial HBCD mixture to the assessment of risk of α-HBCD which is the major stereoisomer found in wildlife and people.

Acute Testis Toxicity of Bisphenol A Diglycidyl Ether in Sprague-Dawley Rats

Bisphenol A diglycidyl ether (BADGE) is a liquid compound obtained by condensation of two molecules of epichlorohydrin with one molecule of bisphenol A. General and reproductive toxicity with BADGE has been reported higher than 1000 mg/kg/day. This study was performed to show the effects of acute exposure to BADGE below 1000 mg/kg/day on the testis in adult male rats. BADGE was administered by gastric lavage in a single dose of 500, 750, 1000, and 2000 mg/kg/day in 8-week old male SPF Sprague-Dawley rats. The right testis was processed for light microscopic analysis. The left testis was homogenized and spermatids were counted to determine the daily sperm production and daily abnormal sperm production. The sperm count, sperm motility, and incidence of abnormal sperm were estimated in the epididymis. In testicular sections, the seminiferous tubules were observed for qualitative changes. The progression of spermatogenesis was arbitrarily classified as full-matured, maturing, and immature. The specimen slide was observed at 3 points and 10 seminiferous tubules were evaluated at each point. The male rats exposed to single oral dose of BADGE at 750, 1000, and 2000 mg/kg/day were significantly increased the number of immature and maturing sperm on the testis. There were no significant differences with respect to sperm head count, sperm motility, and sperm abnormality in the BADGE treatment groups. These results suggest that single oral exposure of BADGE 750 mg/kg/day can affect adult male testis development.