Structure-based grouping of chemicals for targeted testing and read-across is an efficient way to reduce resources and animal usage. For substances of unknown or variable composition, complex ...reaction products, or biological materials (UVCBs), structure-based grouping is virtually impossible. Biology-based approaches such as metabolomics could provide a solution. Here, 15 steam-cracked distillates, registered in the EU through the Lower Olefins Aromatics Reach Consortium (LOA), as well as six of the major substance constituents, were tested in a 14-day rat oral gavage study, in line with the fundamental elements of the OECD 407 guideline, in combination with plasma metabolomics. Beyond signs of clinical toxicity, reduced body weight (gain), and food consumption, pathological investigations demonstrated the liver, thyroid, kidneys (males only), and hematological system to be the target organs. These targets were confirmed by metabolome pattern recognition, with no additional targets being identified. While classical toxicological parameters did not allow for a clear distinction between the substances, univariate and multivariate statistical analysis of the respective metabolomes allowed for the identification of several subclusters of biologically most similar substances. These groups were partly associated with the dominant (> 50%) constituents of these UVCBs, i.e., indene and dicyclopentadiene. Despite minor differences in clustering results based on the two statistical analyses, a proposal can be made for the grouping of these UVCBs. Both analyses correctly clustered the chemically most similar compounds, increasing the confidence that this biological approach may provide a solution for the grouping of UVCBs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•The potential systemic toxicity and mutagenicity of Oligopin®, a French Maritime Pine Bark extract, was evaluated.•Oligopin® was nongenotoxic in both bacterial and human cell assays.•Oligopin® was ...not acutely toxic and 90 days of oral administration to rats was well tolerated with a NOAEL of 1000 mg/kg/day.•The lack of adverse systemic effects in the 90 day study is concordant with findings from human clinical trials.•The NOAEL from the 90-day study suggests that Oligopin® is less systemically toxic than other FMPBE evaluated in subchronic studies.
The potential systemic toxicity of Oligopin®, a French Maritime Pine Bark extract (FMPBE) rich in procyanidolic oligomers, was evaluated in an acute oral limit test and a 90-day repeated dose oral toxicity study with Sprague Dawley rats. The potential mutagenicity was assessed in a bacterial reverse mutation assay and in vitro mammalian chromosome aberration assay with human lymphocytes. The results indicate that Oligopin® was nongenotoxic in both bacterial and human cell assays, was not acutely toxic via oral administration at up to 2000 mg/kg and was well tolerated following 90 days of oral administration to SD rats, with a no observed adverse effect level of 1000 mg/kg/day. The lack of significant adverse systemic effects in the 90 day study is concordant with findings from several human clinical trials. The acute toxicity and mutagenicity data are consistent with data reported by AFSSA in a summary of FMPBE safety, in which a NOAEL of 100 mg/kg/day was established. In contrast, the NOAEL derived from the 90-day study with Oligopin® was 1000 mg/kg/day, suggesting that it is less systemically toxic than other FMPBE previously evaluated in subchronic studies, and comparable to proanthocyanidins extracted from grape seeds, which are widely used as nutritional supplement ingredients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The target asymmetry
T
, recoil asymmetry
P
, and beam-target double polarization observable
H
were determined in exclusive
π
0
and
η
photoproduction off quasi-free protons and, for the first time, ...off quasi-free neutrons. The experiment was performed at the electron stretcher accelerator ELSA in Bonn, Germany, with the Crystal Barrel/TAPS detector setup, using a linearly polarized photon beam and a transversely polarized deuterated butanol target. Effects from the Fermi motion of the nucleons within deuterium were removed by a full kinematic reconstruction of the final state invariant mass. A comparison of the data obtained on the proton and on the neutron provides new insight into the isospin structure of the electromagnetic excitation of the nucleon. Earlier measurements of polarization observables in the
γ
p
→
π
0
p
and
γ
p
→
η
p
reactions are confirmed. The data obtained on the neutron are of particular relevance for clarifying the origin of the narrow structure in the
η
n
system at
W
=
1.68
GeV
. A comparison with recent partial wave analyses favors the interpretation of this structure as arising from interference of the
S
11
(
1535
)
and
S
11
(
1650
)
resonances within the
S
11
-partial wave.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although most primary hepatocellular cancers (HCCs) are attributable to chronic viral hepatitis and largely preventable, such cancers remain a leading cause of cancer-related mortality wherever ...chronic hepatitis B is endemic.
Many HCCs could be prevented by increasing awareness and knowledge of hepatitis B, optimizing the monitoring of chronic hepatitis B and using antiviral treatments - but there are gaps in the implementation of such strategies.
The "B Positive" programme, based in Sydney, Australia, is designed to improve hepatitis-B-related health outcomes among immigrants from countries with endemic hepatitis B. The programme offers information about disease screening, vaccination and treatment options, as well as optimized access to care.
The B Positive programme has been informed by economic modelling. The programme offers culturally tailored education on chronic hepatitis B to target communities and their health practitioners and regular follow-up through a population-based registry of cases.
As the costs of screening for chronic hepatitis B and follow-up are relatively low and less than one in every four cases may require antiviral drugs, optimizing access to treatment seems an appropriate and cost-effective management option. The identification and accurate staging of cases and the judicious use of antiviral medications are predicated upon an informed and educated health workforce. As establishing community trust is a lengthy process, delaying the implementation of programmes against chronic hepatitis B until antiviral drugs become cheaper is unwarranted.
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CEKLJ, DOBA, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Although viewed with scepticism by the medical and scientific community, complementary and alternative medicine (CAM) is being used by about 50% of Australians.
Integrative medicine is a holistic ...approach to cancer care, with some CAM of proven effectiveness being used as adjuvants to conventional medical treatments. However, there is little evidence of a systematic process of evaluation or dialogue between mainstream cancer medicine and CAM providers in Australia. Collaboration, guidance and support for relevant research in this area are needed.
The key elements of a process of furthering integrative medicine include improving knowledge about CAM; addressing uncertainties about CAM efficacy and safety; improving communication about CAM between medical practitioners and patients, and between medical practitioners and CAM practitioners; introducing regulatory frameworks and credentialing of CAM practitioners; and addressing ethical issues.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A 14-day rat study with plasma metabolomics was conducted to evaluate the toxicity of Benzene. Wistar rats were orally administered Benzene daily at doses of 0, 300 and 1000 mg/kg bw. The study ...identified liver and kidneys as target organs of Benzene toxicity and found reductions in total white blood cells, absolute lymphocyte and eosinophil cell counts, and increased relative monocyte counts suggesting bone marrow as a target organ. The study also confirmed liver as a target organ using metabolomics, which showed indications of a stress reaction in rats and changes in metabolites suggestive of a metabolic disorder. The metabolomics investigations did not find any other toxicologically relevant modes of action, and the observed metabolite changes were not associated with markers for mitochondrial dysfunction. The study concludes that integration of omics technologies, such as metabolomics, in regulatory toxicity studies is possible, confirms existing knowledge and adds additional information that can be used for mechanistic understanding of observed toxicity.
•Target organs after 14-day exposure to benzene are liver, kidney, bone marrow.•Metabolomics and toxicity parameters sufficient to identify subchronic toxicity.•Metabolomics indicates stress reaction and metabolic disorder in rats.•“smart” in vivo studies are a NAM that can reduce the need for subchronic in vivo testing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dicyclopentadiene (DCPD) was investigated in a 14-day oral rat toxicity study based on the OECD 407 guideline in combination with plasma metabolomics. Wistar rats received the compound daily via ...gavage at dose levels of 0, 50 and 150 mg/kg bw. The high dose induced transient clinical signs of toxicity and, in males only, reduced body weight gain. High dose liver changes were characterized by altered clinical chemistry parameters in both sexes and pathological changes in females. In high dose males an accumulation of alpha-2 u-globulin in the kidney was noted. Comparing the DCPD metabolome with previously established specific metabolome patterns in the MetaMap® Tox data base suggested that the high dose would result in liver enzyme induction leading to increased breakdown of thyroid hormones for males and females. An indication for liver toxicity in males was also noted. Metabolomics also suggested an effect on the functionality of the adrenals in high dose males, which together with published data, is suggestive of a stress related effect in this organ. The results of the present 14-day combined toxicity and metabolome investigations were qualitatively in line with literature data from subchronic oral studies in rats with DCPD. Importantly no other types of organ toxicity, or hormone dysregulation beyond the ones associated with liver enzyme induction and stress were indicated, again in line with results of published 90-day studies. It is therefore suggested that short term “smart” studies, combining classical toxicity with ‘omics technologies, could be a 2 R (refine and reduce) new approach method allowing for the reduction of in vivo toxicity testing.
•Dicyclopentadiene 14-day toxicity in rats target organs: liver and kidney.•Metabolomics correctly predicts subchronic DCPD toxicity.•“smart” in vivo studies are a NAM that can reduce the need for subchronic in vivo testing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aims Crohn's disease is associated with reductions in bone mineral density and an increased risk of fracture. Measurement of bone turnover markers suggest that in children this is due to reduced bone ...formation. This study aimed to investigate the influence of resting and activated leucocytes and their secreted products on the growth of osteoblast-like Saos2 cells in vitro. Methods Osteoblast-like Saos2 cells were cultured with resting or polyclonally activated populations of peripheral blood mononuclear cells (PBMCs) or isolated CD4+ T cells for 4 days. Cells were activated using anti-CD3/anti-CD28 monoclonal antibody-coated beads. The use of transwell inserts, which physically separate the different cell populations, determined the comparative influence of cell-cell contact and secreted factors on the observed effects. Results The culture of Saos2 cells with resting PBMCs and CD4+ T cells increased their proliferation, whereas activated cells inhibited the proliferation of Saos2 cells. These effects were still present with the use of transwell inserts, although final cell numbers were overall slightly higher. Differences were not of statistical significance, but there was a clear dose-response effect. Supernatants from activated CD4+ T cells (50% v/v) significantly reduced the number of Saos2 cells at day 5 (492349 vs 224325; p=0.01). The effect of the PBMC supernatant at day 5 was only marginally greater than that of the CD4+ T cells (263824 vs 224325; not significant). All data are derived from three independent experiments. Conclusions These results are consistent with a hypothesis that activated immune cells and/or their products are at least partially responsible for the reduced osteoblast activity that is seen in paediatric Crohn's disease. Furthermore, CD4+ T cells are mediators of inflammation in inflammatory bowel disease and these experiments demonstrate that these cells are primarily responsible for the effects seen.
To reduce the number of animals and studies needed to fulfill the information requirements as required by Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (EC no. ...1907/2006), a read-across approach was used to support approximately 30 higher olefins. This study aimed to assess the absorption potential of higher olefins through the gut wall as the experimentally determined bioavailability which would strengthen the read-across hypothesis and justification, reducing the need for toxicity studies on all of the higher olefins. The absorption potential of a series of higher olefins (carbon range from 6 to 28, with five configurations of the double bond) was determined in the in vitro everted rat small intestinal sac model and subsequently ranked. In addition, in silico approaches were applied to predict the reactivity, lipophilicity, and permeability of higher olefins. In the in vitro model, everted sacs were incubated in “fed-state simulated small intestinal fluid” saturated with individual higher olefins. The sac contents were then collected, extracted, and analyzed for olefin content using gas chromatography with a flame ionization detector. The C6 to C10 molecules were readily absorbed into the intestinal sacs. Marked inter-compound differences were observed, with the amount of absorption generally decreasing with the increase in carbon number. Higher olefins with ≥C14 carbons were either not absorbed or very poorly absorbed. In the reactivity simulation study, the reactivity is well described by the position of the double bond rather than the number of carbon atoms. In the lipophilicity and permeability analysis, both parameter descriptors depend mainly on the number of carbon atoms and less on the position of the double bond. In conclusion, these new approach methodologies provide supporting information on any trends or breakpoints in intestinal uptake and a hazard matrix based on carbon number and position of the double bond. This matrix will further assist in the selection of substances for inclusion in the mammalian toxicity testing programme.
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IJS, KILJ, NUK, PNG, UL, UM
Echinacea is a widely used herbal remedy for the treatment of colds and other infections. However, almost nothing is known about the disposition and pharmacokinetics of any of its components, ...particularly the alkamides and caffeic acid conjugates which are thought to be the active phytochemicals. In this investigation, we have examined serial plasma samples from 9 healthy volunteers who ingested echinacea tablets manufactured from ethanolic liquid extracts of
Echinacea angustifolia and
Echinacea purpurea immediately after a standard high fat breakfast. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkamides were rapidly absorbed and were measurable in plasma 20 min after tablet ingestion and remained detectable for up to 12 h. Concentration–time curves for 2,4-diene and 2-ene alkamides were determined. The maximal concentrations for the sum of alkamides in human plasma were reached within 2.3 h post ingestion and averaged 336
±
131 ng eq/mL plasma. No obvious differences were observed in the pharmacokinetics of individual or total alkamides in 2 additional fasted subjects who took the same dose of the echinacea preparation. This single dose study provides evidence that alkamides are orally available and that their pharmacokinetics are in agreement with the one dose three times daily regimen already recommended for echinacea.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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