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QSAR models for reproductive toxicity and endocrine disruption in regulatory use--a preliminary investigation.

Jensen GE, Niemelä JR, Wedebye EB, Nikolov NG - SAR QSAR Environ Res (2008)

Bottom Line: A structure set of 57,014 European Inventory of Existing Chemical Substances (EINECS) chemicals was screened.A total of 5240 EINECS chemicals, corresponding to 9.2%, were predicted as reproductive toxicants by one or more of the models.The chemicals were also screened in three models for endocrine disruption.

View Article: PubMed Central - PubMed

Affiliation: National Food Institute, Department of Toxicology and Risk Assessment, Technical University of Denmark, Søborg, Denmark. gunje@food.dtu.dk

ABSTRACT
A special challenge in the new European Union chemicals legislation, Registration, Evaluation and Authorisation of Chemicals, will be the toxicological evaluation of chemicals for reproductive toxicity. Use of valid quantitative structure-activity relationships (QSARs) is a possibility under the new legislation. This article focuses on a screening exercise by use of our own and commercial QSAR models for identification of possible reproductive toxicants. Three QSAR models were used for reproductive toxicity for the endpoints teratogenic risk to humans (based on animal tests, clinical data and epidemiological human studies), dominant lethal effect in rodents (in vivo) and Drosophila melanogaster sex-linked recessive lethal effect. A structure set of 57,014 European Inventory of Existing Chemical Substances (EINECS) chemicals was screened. A total of 5240 EINECS chemicals, corresponding to 9.2%, were predicted as reproductive toxicants by one or more of the models. The chemicals predicted positive for reproductive toxicity will be submitted to the Danish Environmental Protection Agency as scientific input for a future updated advisory classification list with advisory classifications for concern for humans owing to possible developmental toxic effects: Xn (Harmful) and R63 (Possible risk of harm to the unborn child). The chemicals were also screened in three models for endocrine disruption.

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Algorithm for reproductive toxicity screening.
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fig1: Algorithm for reproductive toxicity screening.

Mentions: The models for teratogenic risk, rodent dominant lethal effect and D. melanogaster SLRL were included in the algorithm and applied in the screening of the EINECS structure set of 57,014 chemicals. Chemicals were considered predicted positive for reproductive toxicity if a positive prediction was obtained in any of the models within the applicability domain (Figure 1). A total of 5240 chemicals were predicted positive by this procedure, corresponding to 9.2% of the 57,014 EINECS chemicals. Of these, 2331 (44% of the 5240) were identified by the teratogenic risk model and the rest were identified on the basis of the genotoxicity models exclusively. Table 4 lists the numbers of chemicals predicted positive by the individual models. A number of chemicals were identified by both the teratogenic risk model and one or both of the genotoxicity models (Table 5). Out of the 2,331 chemicals predicted positive by the teratogenic risk model, 349 chemicals (15%) were also predicted positive by one or both of the genotoxicity models. For these chemicals the predicted reproductive toxicity effect may be due to mutation in germ cells or mutation may be an active mechanism prior to the teratogenic effect. In many cases, a toxicological threshold is assumed to exist for reproductive toxicity. With mutagenic chemicals this may not be the case, and they may therefore be of even greater concern.


QSAR models for reproductive toxicity and endocrine disruption in regulatory use--a preliminary investigation.

Jensen GE, Niemelä JR, Wedebye EB, Nikolov NG - SAR QSAR Environ Res (2008)

Algorithm for reproductive toxicity screening.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2607135&req=5

fig1: Algorithm for reproductive toxicity screening.
Mentions: The models for teratogenic risk, rodent dominant lethal effect and D. melanogaster SLRL were included in the algorithm and applied in the screening of the EINECS structure set of 57,014 chemicals. Chemicals were considered predicted positive for reproductive toxicity if a positive prediction was obtained in any of the models within the applicability domain (Figure 1). A total of 5240 chemicals were predicted positive by this procedure, corresponding to 9.2% of the 57,014 EINECS chemicals. Of these, 2331 (44% of the 5240) were identified by the teratogenic risk model and the rest were identified on the basis of the genotoxicity models exclusively. Table 4 lists the numbers of chemicals predicted positive by the individual models. A number of chemicals were identified by both the teratogenic risk model and one or both of the genotoxicity models (Table 5). Out of the 2,331 chemicals predicted positive by the teratogenic risk model, 349 chemicals (15%) were also predicted positive by one or both of the genotoxicity models. For these chemicals the predicted reproductive toxicity effect may be due to mutation in germ cells or mutation may be an active mechanism prior to the teratogenic effect. In many cases, a toxicological threshold is assumed to exist for reproductive toxicity. With mutagenic chemicals this may not be the case, and they may therefore be of even greater concern.

Bottom Line: A structure set of 57,014 European Inventory of Existing Chemical Substances (EINECS) chemicals was screened.A total of 5240 EINECS chemicals, corresponding to 9.2%, were predicted as reproductive toxicants by one or more of the models.The chemicals were also screened in three models for endocrine disruption.

View Article: PubMed Central - PubMed

Affiliation: National Food Institute, Department of Toxicology and Risk Assessment, Technical University of Denmark, Søborg, Denmark. gunje@food.dtu.dk

ABSTRACT
A special challenge in the new European Union chemicals legislation, Registration, Evaluation and Authorisation of Chemicals, will be the toxicological evaluation of chemicals for reproductive toxicity. Use of valid quantitative structure-activity relationships (QSARs) is a possibility under the new legislation. This article focuses on a screening exercise by use of our own and commercial QSAR models for identification of possible reproductive toxicants. Three QSAR models were used for reproductive toxicity for the endpoints teratogenic risk to humans (based on animal tests, clinical data and epidemiological human studies), dominant lethal effect in rodents (in vivo) and Drosophila melanogaster sex-linked recessive lethal effect. A structure set of 57,014 European Inventory of Existing Chemical Substances (EINECS) chemicals was screened. A total of 5240 EINECS chemicals, corresponding to 9.2%, were predicted as reproductive toxicants by one or more of the models. The chemicals predicted positive for reproductive toxicity will be submitted to the Danish Environmental Protection Agency as scientific input for a future updated advisory classification list with advisory classifications for concern for humans owing to possible developmental toxic effects: Xn (Harmful) and R63 (Possible risk of harm to the unborn child). The chemicals were also screened in three models for endocrine disruption.

Show MeSH
Related in: MedlinePlus