Use of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting.

The HESI-coordinated RISK21 roadmap and matrix are tools that provide a transparent method to compare exposure and toxicity information and assess whether additional refinement is required to obtain the necessary precision level for a decision regarding safety. A case study of the use of a pyrethroid, "pseudomethrin," in bed netting to control malaria is presented to demonstrate the application of the roadmap and matrix. The evaluation began with a problem formulation step.

Risk assessment in the 21st century: roadmap and matrix.

Abstract The RISK21 integrated evaluation strategy is a problem formulation-based exposure-driven risk assessment roadmap that takes advantage of existing information to graphically represent the intersection of exposure and toxicity data on a highly visual matrix. This paper describes in detail the process for using the roadmap and matrix. The purpose of this methodology is to optimize the use of prior information and testing resources (animals, time, facilities, and personnel) to efficiently and transparently reach a risk and/or safety determination.

A 21st century roadmap for human health risk assessment.

The Health and Environmental Sciences Institute (HESI)-coordinated Risk Assessment in the 21st Century (RISK21) project was initiated to develop a scientific, transparent, and efficient approach to the evolving world of human health risk assessment, and involved over 120 participants from 12 countries, 15 government institutions, 20 universities, 2 non-governmental organizations, and 12 corporations. This paper provides a brief overview of the tiered RISK21 framework called the roadmap and risk visualization matrix, and articulates the core principles derived by RISK21 participants that guided its development. Subsequent papers describe the roadmap and matrix in greater detail.

Identification of transcription factors and coactivators affected by dibutylphthalate interactions in fetal rat testes.

Previous analysis of in utero dibutylphthalate (DBP)-exposed fetal rat testes indicated that DBP's antiandrogenic effects were mediated, in part, by indirect inhibition of steroidogenic factor 1 (SF1), suggesting that peroxisome proliferator-activated receptor alpha (PPARα) might be involved through coactivator (CREB-binding protein [CBP]) sequestration. To test this hypothesis, we have performed chromatin immunoprecipitation (ChIP) microarray analysis to assess the DNA binding of PPARα, SF1, CBP, and RNA polymerase II in DBP-induced testicular maldevelopment target genes. Pathway analysis of expression array data in fetal rat testes examined at gestational day (GD) 15, 17, or 19 indicated that lipid metabolism genes regulated by SF1 and PPARα, respectively, were overrepresented, and the time dependency of changes to PPARα-regulated lipid metabolism genes correlated with DBP-mediated repression of SF1-regulated steroidogenesis genes.

Use and validation of HT/HC assays to support 21st century toxicity evaluations.

Advances in high throughput and high content (HT/HC) methods such as those used in the fields of toxicogenomics, bioinformatics, and computational toxicology have the potential to improve both the efficiency and effectiveness of toxicity evaluations and risk assessments. However, prior to use, scientific confidence in these methods should be formally established. Traditional validation approaches that define relevance, reliability, sensitivity and specificity may not be readily applicable.

Twenty-first century approaches to toxicity testing, biomonitoring, and risk assessment: perspectives from the global chemical industry.

The International Council of Chemical Associations' Long-Range Research Initiative (ICCA-LRI) sponsored a workshop, titled Twenty-First Century Approaches to Toxicity Testing, Biomonitoring, and Risk Assessment, on 16 and 17 June 2008 in Amsterdam, The Netherlands. The workshop focused on interpretation of data from the new technologies for toxicity testing and biomonitoring, and on understanding the relevance of the new data for assessment of human health risks. Workshop participants articulated their concerns that scientific approaches for interpreting and understanding the emerging data in a biologically relevant context lag behind the rapid advancements in the new technologies.

ECETOC workshop on the biological significance of DNA adducts: summary of follow-up from an expert panel meeting.

This workshop on the biological significance of DNA adducts included presentations of research results in the following areas: endogenous versus exogenous adduct levels; in vitro dose-response data on adducts and mutagenesis from alkylating agents; methyltransferases and alkyl transferase-like proteins in repair of O(6)-alkylguanine adducts; mathematical modeling of threshold dose-response in mutagenesis and carcinogenesis; and the use of genomics to characterize the relationships between adducts, gene expression, and downstream adverse effects. Presentations by regulatory scientists and other authorities addressed the role of adduct and mutation data in risk characterization. Consensus statements were developed and included the following: DNA adducts should be considered as biomarkers of exposure, which may play a key role in establishing a mode of action (MOA) for cancer.

TIMES-SS--a mechanistic evaluation of an external validation study using reaction chemistry principles.

The TImes MEtabolism Simulator platform used for predicting skin sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a consortium comprised of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic three-dimensional quantitative structure-activity relationships. Here, we describe an external validation exercise that was recently carried out.

Making sense of human biomonitoring data: findings and recommendations of a workshop.

The ability to measure chemicals in humans (often termed biomonitoring) is far outpacing the ability to interpret reliably these data for public health purposes, creating a major knowledge gap. Until this gap is filled, the great promise of routinely using biomonitoring data to support decisions to protect public health cannot be realized. Research is needed to link biomonitoring data quantitatively to the potential for adverse health risks, either through association with health outcomes or using information on the concentration and duration of exposure, which can then be linked to health guidelines.

TIMES-SS--a promising tool for the assessment of skin sensitization hazard. A characterization with respect to the OECD validation principles for (Q)SARs and an external evaluation for predictivity.

The TImes MEtabolism Simulator platform used for predicting Skin Sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a Consortium comprising industry and regulators. The model was developed with the aim of minimizing animal testing and to be scientifically valid in accordance with the OECD principles for (Q)SAR validation. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic 3D QSARs.

Skin sensitization: modeling based on skin metabolism simulation and formation of protein conjugates.

A quantitative structure-activity relationship (QSAR) system for estimating skin sensitization potency has been developed that incorporates skin metabolism and considers the potential of parent chemicals and/or their activated metabolites to react with skin proteins. A training set of diverse chemicals was compiled and their skin sensitization potency assigned to one of three classes. These three classes were, significant, weak, or nonsensitizing.