Alan Poole

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam.

Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×10(6) (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10(-7)) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers.

Guidance on the selection of cohorts for the extended one-generation reproduction toxicity study (OECD test guideline 443).

The extended one-generation reproduction toxicity study (EOGRTS; OECD test guideline 433) is a new and technically complex design to evaluate the putative effects of chemicals on fertility and development, including effects upon the developing nervous and immune systems. In addition to offering a more comprehensive assessment of developmental toxicity, the EOGRTS offers important improvements in animal welfare through reduction and refinement in a modular study design. The challenge to the practitioner is to know how the modular aspects of the study should be triggered on the basis of prior knowledge of a particular chemical, or on earlier findings in the EOGRTS itself, requirements of specific regulatory frameworks notwithstanding. The purpose of this document is to offer guidance on science-based triggers for these extended evaluations.

Framework for the quality assurance of ’omics technologies considering GLP requirements

ABSTRACT ‘Omics technologies are gaining importance to support regulatory toxicity studies. Prerequisites for performing ‘omics studies considering GLP principles were discussed at the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Workshop Applying ‘omics technologies in Chemical Risk Assessment. A GLP environment comprises a standard operating procedure system, proper pre‐planning and documentation, and inspections of independent quality assurance staff. To prevent uncontrolled data changes, the raw data obtained in the respective ‘omics data recording systems have to be specifically defined. Further requirements include transparent and reproducible data processing steps, and safe data storage and archiving procedures. The software for data recording and processing should be validated, and data changes should be traceable or disabled. GLP‐compliant quality assurance of ‘omics technologies appears feasible for many GLP requirements. However, challenges include (i) defining, storing, and archiving the raw data; (ii) transparent descriptions of data processing steps; (iii) software validation; and (iv) ensuring complete reproducibility of final results with respect to raw data. Nevertheless, ‘omics studies can be supported by quality measures (e.g., GLP principles) to ensure quality control, reproducibility and traceability of experiments. This enables regulators to use ‘omics data in a fit‐for‐purpose context, which enhances their applicability for risk assessment. HighlightsFramework for GLP principles in ‘omics technologies.Applying ‘omics technologies in Chemical Risk Assessment.Definition of raw data in omics technologies.Challenges: archiving, data processing, software validation.

Building a developmental toxicity ontology.

BACKGROUND As more information is generated about modes of action for developmental toxicity and more data are generated using high-throughput and high-content technologies, it is becoming necessary to organize that information. This report discussed the need for a systematic representation of knowledge about developmental toxicity (i.e., an ontology) and proposes a method to build one based on knowledge of developmental biology and mode of action/ adverse outcome pathways in developmental toxicity. METHODS This report is the result of a consensus working group developing a plan to create an ontology for developmental toxicity that spans multiple levels of biological organization. RESULTS This report provide a description of some of the challenges in building a developmental toxicity ontology and outlines a proposed methodology to meet those challenges. As the ontology is built on currently available web-based resources, a review of these resources is provided. Case studies on one of the most well-understood morphogens and developmental toxicants, retinoic acid, are presented as examples of how such an ontology might be developed. DISCUSSION This report outlines an approach to construct a developmental toxicity ontology. Such an ontology will facilitate computer-based prediction of substances likely to induce human developmental toxicity.

Diiodomethyl-p-tolylsulfone: Evaluation of the mode of action for reproductive toxicity

The mode of action (MOA) underpinning the reproductive toxicity of diiodomethyl-p-tolylsulfone (DIMPTS) is excess systemic iodine levels, resulting in hypothyroidism. This MOA evaluation also addresses the potential for toxicity and adverse health outcomes during critical windows of development for different tissues. The data indicate that testicular development in the neonate represents the tissue and life-stage that are most sensitive to iodine toxicity. Life-stage specific dosimetry appears to be a major determinant of this sensitivity, with the neonate being exposed to higher levels of iodine than the fetus during the period of testicular development, in particular Sertoli cell maturation and differentiation. While no reports could be found in the literature linking excess iodine exposure in humans to testicular toxicity, there is evidence that neonates born to mothers with excessive iodine intake do exhibit signs of transient hypothyroidism. Although there are major physiological and temporal differences in testicular development and Sertoli cell replication between the rat and human, it is not inconceivable that continuous long term exposures to excess iodine first from maternal milk and then in the diet through to the onset of puberty could affect testicular development. However, exposures to iodinated substances - such as DIMPTS - contribute less than 1% of the required daily iodine intake for normal fetal and neonatal development and, consequently, continuous exposure to excess iodine during the pre-pubertal period is unlikely. As exposures to DIMPTS are both very low and sporadic in nature it is not likely that they represent any risk to health at any life-stage.