2 research outputs found
Quantitative Structure–Activity Relationship Models for Ready Biodegradability of Chemicals
The
European REACH regulation requires information on ready biodegradation,
which is a screening test to assess the biodegradability of chemicals.
At the same time REACH encourages the use of alternatives to animal
testing which includes predictions from quantitative structure–activity
relationship (QSAR) models. The aim of this study was to build QSAR
models to predict ready biodegradation of chemicals by using different
modeling methods and types of molecular descriptors. Particular attention
was given to data screening and validation procedures in order to
build predictive models. Experimental values of 1055 chemicals were
collected from the webpage of the National Institute of Technology
and Evaluation of Japan (NITE): 837 and 218 molecules were used for
calibration and testing purposes, respectively. In addition, models
were further evaluated using an external validation set consisting
of 670 molecules. Classification models were produced in order to
discriminate biodegradable and nonbiodegradable chemicals by means
of different mathematical methods: <i>k</i> nearest neighbors,
partial least squares discriminant analysis, and support vector machines,
as well as their consensus models. The proposed models and the derived
consensus analysis demonstrated good classification performances with
respect to already published QSAR models on biodegradation. Relationships
between the molecular descriptors selected in each QSAR model and
biodegradability were evaluated
<i>In Vitro</i> and <i>in Silico</i> Derived Relative Effect Potencies of Ah-Receptor-Mediated Effects by PCDD/Fs and PCBs in Rat, Mouse, and Guinea Pig CALUX Cell Lines
For
a better understanding of species-specific relative effect potencies
(REPs), responses of dioxin-like compounds (DLCs) were assessed. REPs
were calculated using chemical-activated luciferase gene expression
assays (CALUX) derived from guinea pig, rat, and mouse cell lines.
Almost all 20 congeners tested in the rodent cell lines were partial
agonists and less efficacious than 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin (TCDD). For this reason, REPs were calculated for
each congener using concentrations at which 20% of the maximal TCDD
response was reached (REP<sub>20TCDD</sub>). REP<sub>20TCDD</sub> values
obtained for PCDD/Fs were comparable with their toxic equivalency
factors assigned by the World Health Organization (WHO-TEF), while
those for PCBs were in general lower than the WHO-TEF values. Moreover,
the guinea pig cell line was the most sensitive as indicated by the
20% effect concentrations of TCDD of 1.5, 5.6, and 11.0 pM for guinea
pig, rat, and mouse cells, respectively. A similar response pattern
was observed using multivariate statistical analysis between the three
CALUX assays and the WHO-TEFs. The mouse assay showed minor deviation
due to higher relative induction potential for 2,3,7,8-tetrachlorodibenzofuran
and 2,3,4,6,7,8-hexachlorodibenzofuran and lower for 1,2,3,4,6,7,8-heptachlorodibenzofuran
and 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). 2,3,7,8-Tetrachlorodibenzofuran
was more than two times more potent in the mouse assay as compared
with that of rat and guinea pig cells, while measured REP<sub>20TCDD</sub> for PCB126 was lower in mouse cells (0.05) as compared with that
of the guinea pig (0.2) and rat (0.07). In order to provide REP<sub>20TCDD</sub> values for all WHO-TEF assigned compounds, quantitative
structure–activity relationship (QSAR) models were developed.
The QSAR models showed that specific electronic properties and molecular
surface characteristics play important roles in the AhR-mediated response. <i>In silico</i> derived REP<sub>20TCDD</sub> values were generally
consistent with the WHO-TEFs with a few exceptions. The QSAR models
indicated that, e.g., 1,2,3,7,8-pentachlorodibenzofuran and 1,2,3,7,8,9-hexachlorodibenzofuran
were more potent than given by their assigned WHO-TEF values, and
the non-<i>ortho</i> PCB 81 was predicted, based on the
guinea-pig model, to be 1 order of magnitude above its WHO-TEF value.
By combining <i>in vitro</i> and <i>in silico</i> approaches, REPs were established for all WHO-TEF assigned compounds
(except OCDD), which will provide future guidance in testing AhR-mediated
responses of DLCs and to increase our understanding of species variation
in AhR-mediated effects