204 research outputs found
Suitability of skin integrity tests for dermal absorption studies in vitro
AbstractSkin absorption testing in vitro is a regulatory accepted alternative method (OECD Guideline 428). Different tests can be applied to evaluate the integrity of the skin samples. Here, we compared the pre- or post-run integrity tests (transepidermal electrical resistance, TEER; transepidermal water loss, TEWL; absorption of the reference compounds water, TWF, or methylene blue, BLUE) and additionally focused on co-absorption of a 3H-labeled internal reference standard (ISTD) as integrity parameter. The results were correlated to absorption profiles of various test compounds. Limit values of 2kΩ, 10gmâ2hâ1 and 4.5â10â3cmhâ1 for the standard methods TEER, TEWL and TWF, respectively, allowed distinguishing between impaired and intact human skin samples in general. Single skin samples did, however, not, poorly and even inversely correlate with the test-compound absorption. In contrast, results with ISTD (e.g. 3H-testosterone) were highly correlated to the absorption of 14C-labeled test compounds. Importantly, ISTD did not influence analytics or absorption of test compounds. Therefore, ISTD, especially when adjusted to the physico-chemical properties of test compounds, is a promising concept to assess the integrity of skin samples during the whole course of absorption experiments. However, a historical control dataset is yet necessary for a potential routine application
Multidifferential study of identified charged hadron distributions in -tagged jets in proton-proton collisions at 13 TeV
Jet fragmentation functions are measured for the first time in proton-proton
collisions for charged pions, kaons, and protons within jets recoiling against
a boson. The charged-hadron distributions are studied longitudinally and
transversely to the jet direction for jets with transverse momentum 20 GeV and in the pseudorapidity range . The
data sample was collected with the LHCb experiment at a center-of-mass energy
of 13 TeV, corresponding to an integrated luminosity of 1.64 fb. Triple
differential distributions as a function of the hadron longitudinal momentum
fraction, hadron transverse momentum, and jet transverse momentum are also
measured for the first time. This helps constrain transverse-momentum-dependent
fragmentation functions. Differences in the shapes and magnitudes of the
measured distributions for the different hadron species provide insights into
the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb
public pages
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
Mechanisms of the Improved Biological Response with Silicate Substitution in Hydroxy Apatite
Hydroxyapatite (HA) is a bioactive calcium phosphate based ceramic commonly used. as a bone graft substitute. The bioactivity of this material has been reported to be enhanced through site specific substitution of 0.8wt% silicate for phosphate into the HA lattice (SiHA). The aim of this thesis was to explore the possible mechanisms behind this bioactivity enhancement. Two hypothesises were proposed whereby bioactivity may be enhanced by either (1) an 'indirect effect', where alterations in the ion concentrations in the fluid surrounding the graft materials influenced osteoblast development or metabolism and/or (2) by a 'direct effect', where differences in the material physiochemistry influenced protein adsorption, which in subsequently promotes osteoblast attachment and consequently development or metabolism. In order to probe these two hypotheses a broad area of activity was undertaken, including production of morphologically matched HA and. SiHA, analysis of surface physiochemistry and chemical interactions under cell culture conditions in addition to analysis of material-protein interactions, cell attachment, metabolism and development. . Whilst the morphological parameters of the microporous HA and SiHA were matched, differences in the physiochemical properties were noted, such' as the increase in surface free energy from 29.43±6.39mJ/m2 (HA) to 56.67±1.07mJ/m2 (SiHA). Exposure of HA and SiHA to cell culture . medium led to a depletion of 10.8% and 27.1 % phosphate ions in medium respectively. Moreover, exposure to SiHA resulted in a significant increase in pH and release of up to 0.22mM silicon in the medium. Serum proteins were identified to influence the ionic interactions between the apatite and medium. However, these significant changes in ion composition were not seen to impact on the development of osteoblast-like cells. Impro\red bioactivity through the 'indirect effect' of ionic interactions between SiHA and the surrounding medium was therefore not established. Analysis of serum protein adsorption demonstrated that within 24 hours, 50±5.2J.lg and 35.9±4.0J.lg total protein was adsorbed to SiHA and HA specimens respectively. Further to the determination of ...EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Modelle zur Bestimmung der perkutanen Absorption â Experimentelle Einflussparameter und in silico PrĂ€diktionen
Dermal absorption â the uptake of compounds via the skin â is a relevant
parameter for risk assessment of chemicals, cosmetics and plant protection
products. Besides in vivo tests, in vitro determination is accepted by many
regulatory agencies â if experiments are conducted in accordance to OECD
Guideline 428 and Guidance document 28. However, the named documents provide a
framework whereupon variability regarding performance and results may be
observed in different laboratories. A way to minimize variability is to
understand the influence of experimental conditions and higher standardization
of the system. Regarding the latter, the Guideline requests an integrity test
which should ensure the exclusive use of undamaged skin preparations. Proposed
tests are TEWL (transepidermal water loss), TEER (transepidermal electrical
resistance), application of a reference compound like water (TWF,
transepidermal water flux) or the integrated use of an internal standard
(ISTD). However, contradictory opinions concerning applicability, experimental
performances and limit values have been reported. To evaluate the suitability
of different tests and review the present limit values, absorption results of
four 14C-labeled test compounds (MCPA (2-methyl-4-chlorophenoxyacetic acid),
MCPA-EHE (MCPA 2-ethylhexylester), testosterone and caffeine) were compared
with results of five integrity tests: TEWL, TWF, TEER in advance, ISTD (3H-
mannitol, 3H-caffeine, or 3H-testosterone) concurrently and BLUE
(transepidermal methylene blue absorption) at the end of the run. The standard
methods TEWL, TWF and TEER were assessed to be appropriate tools for rough
differentiation between intact and impaired skin samples in advance of
experiments, when using limit values 10 g/(mÂČ*h), 4.5*10-3 cm/h and 2 kOhm,
respectively. However, only the absorption characteristics of a parallelly
applied ISTD were highly correlated with absorption results of the 14C-labeled
test compound (e.g. RÂČ 0.86 for maxKp (maximum permeability coefficient) 14C-
MCPA and 3H-testosterone). Further advantages of the ISTD approach are the
possibility to rate the barrier function over the entire experimental period
and to distinguish substance-specific wash-in effects from barrier-disruption
related effects. The independence of 3H-ISTD and 14C-test compound analytics
as well as the independence of their absorption characteristics were shown in
the current work. An obstacle for routine application is the need of
historical datasets for various ISTDs â representative for various
physicochemical properties â applied under various experimental conditions.
Regarding investigation of possible influential experimental parameters, the
use of flow-through and static study design was compared. Therefore, 14C-MCPA
and 3H-testosterone were applied on dermatomed rat skin semi-occlusively with
water as the receptor fluid. In accordance with the literature, similar
absorption results were obtained with the two experimental designs, e.g. maxKp
values for 14C-MCPA of 21.4 ± 10.4*10-5cm/h under static and 22.8
±18.4*10-5cm/h under flow-through conditions. Repeated application of a
formulation containing the pesticide MCPA over three days in advance to the
application of the corresponding radio-labeled formulation on rat skin led to
a significant increase of the absorption (AD 75 ± 24 %) compared to the
standard experiments with a single application of 14C-MCPA (14 ± 3 %). This
effect was only partly due to the formulation, but also due to mechanical and
chemical stress during washing procedures between the applications. It was
observed that the skin became less resistant to mechanical treatment with
increasing time. Therefore, the study design with repeated dosing in vitro was
assessed as not feasible for routine applications. Furthermore, absorption
characteristics of dermatomed (DMS) and full-thickness (FTS) skin samples
derived from the same human donor were compared under identical experimental
conditions. Absorption results for four 14C-labeled (MCPA-EHE, MCPA,
testosterone and caffeine) and two 3H-labeled (testosterone and mannitol)
penetrants under finite dose conditions were in the same order of magnitude
for both preparation types (e.g. 3H-testosterone, absorbed dose (AD) 22.1 ±
7.1 % for DMS and 25.6 ± 9.2 % for FTS). However, DMS was assessed to be more
suitable for routine studies due to Kp values closer to the steady state
situation. Since the availability of human skin is limited, rat skin,
StrataTestÂź (a commercially available reconstructed human skin) and skin-PAMPA
(an abiotic stratum corneum membrane) were assessed for their suitability to
determine dermal absorption. Therefore, experiments were conducted with 14C-
labeled and unlabeled model compounds (testosterone, caffeine and MCPA) under
similar experimental conditions. In accordance with the literature, rat skin
was assessed to be an appropriate alternative to human skin due to absorption
results in the same order of magnitude and fulfilling the regulatory principle
of âworst caseâ for purposes of risk assessment (e.g. for pesticides). Skin-
PAMPA was highly over-predictive in comparison to human skin ((max)Kp 3- to
53-fold). If focusing on aqueous solutions skin-PAMPA was less over-predictive
((max)Kp 3- to 8-fold) and the results were correlated to human skin results
(R2 0.89). However, further tests are needed to assess its usability for other
vehicles â which would be crucial for its application as screening tool during
pesticide development. In contrast, formulations could be applied on the cell-
based construct StrataTestÂź. However, the system was highly over-predictive in
comparison to human skin (maxKp 5- to 49-fold, AD 3- to 4-fold), not
correlated to human in vitro experiments and therefore assessed as
inappropriate to determine dermal absorption. Besides the absorption, also
xenobiotic-metabolizing enzyme activities were investigated for StrataTestÂź
using subcellular fractions. Remarkable esterase and NAT 1 activities were
detected in S9 fraction (3.6 ± 0.1 and 7.2 ±1.6 nmol/(min*mg), respectively).
But lacking UGT 1 and ADH activity and providing low AlDH and FMO 1/3
activities (3.1 ± 0.8 and 0.5 ± 0.1 nmol/(min*mg), respectively) â measured in
microsomes or cytosol â StrataTestÂź was closer to a keratinocyte cell line
than to the metabolic properties of excised human skin, reconstructed human
epidermis (EpiDermTM) or other full-thickness skin constructs (EpiDermTMFT and
PhenionŸFT). Additionally, cryoconserved human skin (-20°C, up to 1 year) was
examined for preserved esterase activity. Using S9 fraction and model
substrates MCPA-EHE and fluorescein diacetate resulted in activities of 0.67 ±
0.26 nmol/(mg*min) and 0.7 ± 0.6 nmol/(min*mg), respectively. Furthermore,
model compound MCPA-EHE was partially cleaved to MCPA during dermal absorption
experiments in vitro. It was concluded, that a change of absorption
characteristic due to metabolic hydrolysis and changed physicochemical
properties is covered qualitatively when using cryoconserved human skin.
However, considering the hints of enzyme degradation during storage, a
considerably lower extent is likely. Finally, in silico prediction models for
dermal absorption with special focus on mixture-related effects were
developed. Data from more than 342 dermal absorption experiments in vitro were
used, which comprised 56 test compounds in more than 100 formulations. A model
based on one substance-specific Abraham descriptor (Rf2, solute excess molar
refractivity), a mixture-specific factor (TPSA, topological polar surface
area) and a species indicator (SpI) was assessed to be appropriate to estimate
the magnitude of permeation of compound-mixture combinations and therefore to
be a suitable screening tool for early stages of development (e.g. for
pesticides). More precise predictions were possible with the substance-based
approach where substance-related information were bundled in class variables
and combined with mixture factors (molinspLogHBAcc, logarithmic number of
hydrogen bond acceptors, Adme1/Pow, inverse octanol/water partition
coefficient, Adme1/RotB, inverse number of rotatable bonds). This model allows
reliable interpolations for included test substances to novel formulations.
Taken together, the current work supplements current knowledge about the in
vitro methodology as well as the in silico predictions for dermal absorption.
However, further improvements are needed to enhance the reproducibility of the
former and allow the routine application of the latter.Die dermale Resorption â die Aufnahme von Stoffen ĂŒber die Haut â ist ein
relevanter Parameter fĂŒr die Risikobewertung von Chemikalien, Kosmetika und
Pflanzenschutzmitteln. Neben in vivo Versuchen werden fĂŒr die Bewertung
Ergebnisse aus in vitro Tests in der EU regulatorisch anerkannt, sofern die
Experimente entsprechend der OECD Guideline 428 und dem Guidance document 28
durchgefĂŒhrt wurden. Allerdings definieren die Dokumente nur ein GrundgerĂŒst
der Methode, weshalb die DurchfĂŒhrung und auch die Ergebnisse verschiedener
Labore unterschiedlich ausfallen können. Eine Möglichkeit die experimentelle
VariabilitÀt zu minimieren, ist den Einfluss variabler Testbedingungen zu
verstehen und die Standardisierung des Testsystems voranzutreiben. Ein
ValiditĂ€tskriterium nach OECD Guideline ist z. B. die DurchfĂŒhrung eines
IntegritÀtstest, der den exklusiven Einsatz intakter Hautproben gewÀhrleisten
soll. Zu den vorgeschlagenen Methoden zÀhlen TEWL (transepidermaler
Wasserverlust), TEER (transepidermaler elektrischer Widerstand), die
Applikation einer Referenzsubstanz wie z. B. Wasser (TWF, transepidermaler
Wasserfluss) oder der Einsatz eines internen Standards (ISTD). Allerdings wird
die Anwendung einzelner Methoden kontrovers diskutiert und fĂŒr andere fehlt
ein gemeinsamer Konsens hinsichtlich der DurchfĂŒhrung und der anzuwendenden
Grenzwerte. Um die ZweckmĂ€Ăigkeit der verschiedenen Methoden und die aktuellen
Grenzwerte zu beurteilen, wurden in der vorliegenden Arbeit die Ergebnisse von
Resorptionsuntersuchungen von vier 14C-markierten Testsubstanzen (MCPA
(2-Methyl-4-chlorphenoxyessigsÀure), MCPA-EHE (MCPA-2-ethylhexylester),
Testosteron, und Coffein) mit den Ergebnissen von fĂŒnf IntegritĂ€tstests
verglichen: TEWL, TWF, TEER, jeweils im Vorfeld, ISTD (3H-Mannitol, 3H-
Coffein, oder 3H-Testosteron) zusammen mit der Testsubstanz und BLUE
(transepidermale Resorption von Methylenblau) am Ende des Versuches. Die
Standardmethoden TEWL, TWF und TEER erwiesen sich als geeignet zur
Vorselektion von intakten Hautproben bei Einhaltung folgender Grenzwerte: 10
g/(mÂČ*h), 4.5*10-3 cm/h und 2 kOhm. Indessen war die Korrelation zu den
Resorptionsergebnissen der 14C-markierten Testsubsubstanz gering. Im Gegensatz
dazu, bestand eine Korrelation zwischen den Ergebnisse des ISTD und den
Ergebnissen der Testsubstanz (z. B. RÂČ 0.86 fĂŒr maxKp (maximaler
PermeabilitÀtskoeffizient) von 14C-MCPA und 3H-Testosteron). Weitere Vorteile
des IntegritĂ€tstests ISTD sind die Bewertung der Hautbarriere ĂŒber die gesamte
Expositionszeit hinweg und die Unterscheidung von substanzspezifischen âwash-
inâ Effekten von Effekten, die auf eine gestörte Hautbarriere zurĂŒckzufĂŒhren
sind. Weiterhin wurde in der vorliegenden Arbeit gezeigt, dass sich die 14C-
markierte Testsubstanz und der 3H-markierte ISTD nicht gegenseitig
hinsichtlich Analytik oder Resorptionsverhalten beeinflussen. FĂŒr eine
Routineanwendung des IntegritÀtstests ISTD fehlen allerdings noch historischen
Daten. Es wird empfohlen, Daten fĂŒr mehrere ISTDs â reprĂ€sentativ fĂŒr
verschiedene physikalisch-chemische Eigenschaften â unter verschiedenen
experimentellen Bedingungen als historischen Vergleichsdatensatz zu
generieren. BezĂŒglich experimenteller Einflussfaktoren auf die dermale
Resorption in vitro, wurden in der vorliegenden Arbeit Ergebnisse von
statischen und âDurchflussâ-Experimenten verglichen. Dazu wurde 14C-MCPA und
3H-Testosteron semi-okklusiv auf Rattenhaut appliziert. In Ăbereinstimmung mit
der Literatur wurden fĂŒr beide Systeme Ă€hnliche Ergebnisse erzielt (z. B. ein
maxKp (14C-MCPA) von 21.4 ± 10.4*10-5cm/h im statischen und von 22.8
±18.4*10-5cm/h im Durchflusssystem). Wiederholte Applikation einer MCPA-
Formulierung ĂŒber drei Tage auf Rattenhaut, fĂŒhrte zu einer verstĂ€rkten
Resorption der anschlieĂend applizierten 14C-MCPA Dosis (AD 75 ± 24 %) im
Vergleich zur Applikation einer Einzeldosis 14C-MCPA (14 ± 3 %). Dieser Effekt
war auf die Formulierung, aber auch auf den mechanischen und chemischen Stress
durch die Waschungen zwischen den Applikationen zurĂŒckzufĂŒhren. Die Hautproben
waren mit voranschreitender Zeit weniger resistent gegenĂŒber solchen
EinflĂŒssen. Insgesamt erwies sich dieser in vitro Ansatz zur routinemĂ€Ăigen
Untersuchung des Einflusses einer wiederholten Applikation als nicht geeignet.
Weiterhin wurde der Einfluss der HautprÀparation auf die Resorption in vitro
untersucht. Dazu wurde unter identischen experimentellen Bedingungen,
dermatomisierte Haut (DMS) und Vollhaut (FTS) vom selben humanen Spender
eingesetzt. Vier 14C-markierte (MCPA-EHE, MCPA, Testosteron und Coffein) und
zwei 3H-markierte (Testosteron und Mannitol) Testsubstanzen wurden als finite
Dosen appliziert. Die Resorptionsergebnisse lagen fĂŒr beide
HautprĂ€parationsarten im gleichen GröĂenbereich (z. B. absorbierte Dosis (AD,
3H-Testosteron) 22.1 ± 7.1 % fĂŒr DMS und 25.6 ± 9.2 % fĂŒr FTS). Insgesamt
wurden beide PrĂ€parationsarten fĂŒr Routinestudien als geeignet bewertet.
Allerdings ist DMS FTS vorzuziehen, da die erzielten maxKp-Werte mit DMS nÀher
am âsteady stateâ lagen als die maxKp-Werte, die mit FTS generiert wurden. Da
die VerfĂŒgbarkeit von Humanhaut fĂŒr Forschungszwecke begrenzt ist, wurde die
Eignung von RattenhautprÀparaten, StrataTestŸ (ein kommerziell erhÀltliches
Humanhautkonstrukt) und skin-PAMPA (eine synthetische Stratum-corneum-Membran)
hinsichtlich einer Anwendung zur Bestimmung dermaler Resorption ĂŒberprĂŒft.
Dazu wurden Experimente mit 14C-markierten und nicht markierten
Modellsubstanzen (Testosteron, Coffein und MCPA) unter vergleichbaren
experimentellen Bedingungen durchgefĂŒhrt. In Ăbereinstimmung mit der
Literatur, wurde Rattenhaut als geeignete Alternative zur Humanhaut bewertet,
da deren Einsatz zu Resorptionen in der gleichen GröĂenordnung fĂŒhrte und
gleichzeitig das regulatorische Prinzip des âworst caseâ fĂŒr Risikobewertungen
von z. B. Pflanzenschutzmitteln erfĂŒllte. Skin-PAMPA erwies sich als
ĂŒberprĂ€diktiv ((max)Kp 3- bis 53-fach höher im Vergleich zu den Ergebnissen
mit Humanhaut in vitro). Wurde der Effekt der Mischung mit berĂŒcksichtigt und
nur die Daten fĂŒr wĂ€ssrige Lösungen miteinander verglichen, so lagen die
Resorptionsergebnisse mit skin-PAMPA nÀher an den Referenzwerten ((max)Kp 3-
bis 8-fach höher im Vergleich zu den Ergebnissen mit Humanhaut in vitro) und
es ergab sich eine Korrelation von R2 0.89. Ob skin-PAMPA auch fĂŒr andere
Vehikel als Wasser geeignet ist â was fĂŒr die Untersuchung von
Pflanzenschutzmittelformulierungen unablĂ€ssig wĂ€re â muss noch gezeigt werden.
Im Gegensatz dazu, können verschiedenste Formulierungen auf StrataTestŸ
appliziert werden. Allerdings waren die Resorptionsergebnisse mit diesem
Konstrukt im Vergleich zur Humanhaut ĂŒberprĂ€diktiv (maxKp 5- bis 49-fach, AD
2- bis 4fach), zeigten keine Korrelation zu den Humanhautdaten und wurden
deshalb zur Bestimmung dermaler Resorption als nicht geeignet bewertet. Neben
der Barrierefunktion von StrataTestŸ wurden auch AktivitÀten von
fremdstoffmetabolisierenden Enzymen charakterisiert. Mit hohen Esterase- und
NAT 1- AktivitÀten (3.6 ± 0.1 and 7.2 ±1.6 nmol/(min*mg)) in S9 Fraktion,
geringen AlDH- und FMO 1/3- AktivitÀten (3.1 ± 0.8 and 0.5 ± 0.1 nmol/(min*mg)
und der Abwesenheit von UGT 1- und ADH- AktivitĂ€t â gemessen in
Zytosolfraktion oder mikrosomaler Fraktion â, entspricht das Profil des
Konstrukts mehr dem Profil einer Keratinozyten-Zelllinie als dem exzidierter
Humanhaut oder anderen humanen Epidermis- (EpiDermTM) oder Vollhautkonstrukten
(EpiDermTMFT and PhenionÂźFT) aus der Literatur. Weiterhin wurde die
EsteraseaktivitÀt in gefrorenen Humanhautproben untersucht. Bei Einsatz von S9
Fraktion und Modellsubstrat MCPA-EHE und Fluoresceindiacetat wurden
AktivitÀten von 0.67 ± 0.26 nmol/(mg*min) und 0.7 ± 0.6 nmol/(min*mg)
gemessen. Eine partielle Spaltung von MCPA-EHE zu MCPA wurde auch wÀhrend
dermaler Resorptionsexperimente in vitro beobachtet. BerĂŒcksichtigt man die
Hinweise auf Abbau des Enzyms wĂ€hrend der Lagerung, kann man schlieĂen, dass
teilweise â aber nicht quantitativ â hydrolaseabhĂ€ngige VerĂ€nderungen der
physikalisch-chemischen Eigenschaften und damit mögliche Ănderungen der
Resorptionscharakteristika bei Verwendung solcher HautstĂŒcke in dermalen
Resorptionsstudien in vitro mit erfasst werden. SchlieĂlich wurde ein in
silico Modell fĂŒr dermale Resorption unter spezieller BerĂŒcksichtigung von
Mischungseffekten entwickelt. Dazu wurden Daten von mehr als 342 in vitro
Experimenten mit 56 Substanzen in mehr als 100 Formulierungen verwendet. Ein
Modell basierend auf einem substanzspezifischen Abraham Deskriptor (Rf2,
âsolute excess molar refractivityâ), einem mischungs-spezifischen Faktor
(TPSA, âtopological polar surface areaâ) und einem Speziesindikator (SpI)
erwies sich als geeignet, die GröĂenordnung der Resorption einer Substanz-
Mischungs-Kombination vorherzusagen. Damit stellt dieses Modell ein geeignetes
Werkzeug fĂŒr die frĂŒhen Entwicklungsphasen von z. B. Pflanzenschutzmitteln
dar. PrÀzisere Vorhersagen waren mit dem substanzbasierten Modell möglich. In
diesem Modell wurden substanzbezogene Informationen in Klassenvariablen
gebĂŒndelt und mit Mischungsfaktoren (molinspLogHBAcc, Logarithmus der Anzahl
an WasserstoffbrĂŒckenbindungsakzeptoren, Adme1/Pow, inverser
Verteilungskoeffizient Oktanol/Wasser, Adme1/RotB, inverse Anzahl an
rotierbaren Bindungen) kombiniert. Dieses Modell erlaubt die Interpolation zu
neuen Formulierungen fĂŒr integrierte Substanzen. Insgesamt ergĂ€nzt die
vorliegende Arbeit aktuelle Kenntnisse hinsichtlich Einflussparameter der in
vitro Methode zur Bestimmung der HautpermeabilitÀt und der Eignung
verschiedener HautintegritÀtstests aber auch die Forschung zur Entwicklung von
validen in silico PrÀdiktionsmodellen. Allerdings sind weitere Untersuchungen
zu empfehlen, um die Reproduzierbarkeit der Methode weiter zu erhöhen und die
Routineapplikation der PrÀdiktionsmodelle zu ermöglichen
Elektronischer Transport in EinzelmolekĂŒlmessungen photoschaltbarer MolekĂŒle in Lösungsmittelumgebung
publishe
Computer models versus reality: How well do in silico models currently predict the sensitization potential of a substance
Industrial chemicals need to be assessed for their potential to cause skin sensitization. The European chemical and cosmetic legislations have generated increased availability of reliable experimental data on skin sensitization potentials but also a greater demand for non-animal testing methods. In this study, animal data on 55 non-sensitizing and 45 sensitizing chemicals was reviewed and used to test the performance of computer (in silico) models for the prediction of skin sensitization. Statistical models (Vega, Case Ultra, TOPKAT), mechanistic models (Toxtree, OECD (Q)SAR toolbox v3.1, DEREK) and a hybrid model (TIMES-SS) were evaluated. Substances were selected which were not expected to be found in the model training sets. This study also explored other aspects, such as ease of use and data interpretation, and applicability for regulatory purposes.JRC.I.5-Systems Toxicolog
Applicability of in silico models for the prediction of the sensitization potential of industrial chemicals
Quantitative Analyses of Key Odorants and Their Precursors Reveal Differences in the Aroma of Gluten-Free Rice Bread and Wheat Bread
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