Reports

Stressors that exhibit immunosuppression might act by different mechanisms, i.e. alter the number of cells involved in the immune response, the ability of the cells to produce cytokines, chemokines, antibodies or growth factors, the composition of the subpopulations of cells present at the site of the response, or the function of the cells. This Adverse Outcome Pathway (AOP) describes how impairment of the signaling receptor IL-1R1 in T cells can lead to impaired T cell activation and antibody production, leading to increased susceptibility to infection. The AOP focuses on the blocking of binding of IL-1 to IL-1R1, leading to the Inhibition of Nuclear factor kappa B (NF-kB). This AOP is referred to as AOP 277 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki).

The present Adverse Outcome Pathway (AOP) describes the linkage between lung cancer initiated from the Deposition of Energy (DoE) into a cell by a prototypic stressor such as radon gas. The multiple ionization events from DoE can directly break DNA double strands and initiate the activation of repair machinery through non-homologous end joining, an efficient, but error-prone process. When double strand breaks occur in DNA regions that transcribe critical genes, mutations generated by faulty repair may alter the function of these genes or cause chromosomal aberrations. These events alter the functions of many gene products and affect cell growth, cycling, and apoptosis. Cell proliferation is then promoted by escaping the regulatory control and forming hyperplasia in lung epithelial cells, leading eventually to lung cancer. Although the weight of evidence for this AOP is strong, uncertainties remain on dose-effect relationships across KEs, particularly for DoE delivered at low doses and dose-rates.

The cardiovascular system is the first functional organ system to develop in the vertebrate embryo, reflecting its critical role during normal development and pregnancy. This Adverse Outcome Pathway focuses on the regulation and disruption of vasculogenesis-angiogenesis during embryonic development via disruption of the Vascular Endothelial Growth Factor (VEGF) signaling pathway. This pathway is a critical regulatory system for assembly of embryonic blood vessels. Genetic studies have shown that perturbing the VEGF signaling system can invoke varying degrees of adverse consequences, ranging from congenital angiodysplasia to fetal malformations and embryolethality. This AOP is referred to as AOP 43 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki).

Endocrine disrupting chemicals (EDCs) are contaminants of emerging environmental and health concern that have been detected in freshwater, wastewater and drinking water. They interfere with the endocrine system in humans and wildlife, and produce adverse effects such as developmental, reproductive, neurological and immune effects. Their presence in water raises concerns for the integrity of ecosystems and biodiversity. Addressing the challenges of EDCs in water is particularly complex due to their ability to trigger adverse effects at very low concentrations, their potency in mixtures with other chemicals, and the vast range of sources and entryways of this group of chemicals into the environment. This report presents new water quality monitoring methods, such as bioassays and non-targeted analysis, that are well equipped to capture the impacts of EDCs in water. These new methods supplement the traditional substance-by-substance chemical analysis of water quality. The report also outlines policy instruments to manage the chemicals’ lifecycle from source to end-of-pipe. It proposes tools and regulations that respond to the negative effects of endocrine disruption, even if the culprit chemical is still unknown. The analysis draws on case studies from OECD countries to provide practical examples and concrete policy actions.

Volume 10 of the Series contains the consensus document on the 'Environmental Considerations for Risk/Safety Assessment for the Release of Transgenic Plants' developed by the OECD Working Party on the Harmonisation of Regulatory Oversight in Biotechnology. Transgenic plant varieties are subject to official risk/safety assessment, science-based and case-by-case, before their potential release into the environment. The document contains general information on environmental risk/safety assessment, its key concepts, structure and planning. Annexes describe seven examples of environmental considerations routinely examined by assessors and taken from experience gained during such assessment: Invasiveness and weediness; Vertical gene flow; Organisms (animals); Soil functions; Plant health; Crop management practices; and Biodiversity (protected species and habitats/ecosystems). The purpose of this document is not to elaborate new terminology or to describe how to undertake an actual risk/safety assessment, but rather to outline an approach and provide illustrative examples for helping assessors in planning and structuring an environmental risk/safety assessment. This document should be of interest to regulators and safety assessors, as well as to plant breeders and the wider scientific community. More information, including other tools for environmental risk/safety assessment such as OECD consensus documents on the biology of crop species, are found at BioTrack Online.

This Adverse Outcome Pathway (AOP) describes the linkage between oxidative DNA damage and irreversible genomic damage (chromosomal aberrations and mutations). DNA damage is considered an important contributor to the adverse health effects of many environmental toxicants and this AOP may thus be of widespread use to the regulatory community. Although increase in oxidative DNA damage is the molecular initiating event for this AOP, there are numerous upstream key events that can also lead to DNA oxidation. Thus, this AOP may be expanded upstream, and could be incorporated into a variety of AOP networks. Furthermore, the AOP points to critical research gaps required to establish the quantitative associations and modulating factors that connect KEs across the AOP, and highlights the utility of novel test methods in understanding and evaluating the implications of oxidative DNA damage. This AOP is referred to as AOP 296 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki).

This method provides information on health hazard likely to arise from exposure to test substance (liquids, solids and aerosols) by application on the eye. This Test Guideline is intended preferably for use with albino rabbit. The test substance is applied in a single dose in the conjunctival sac of one eye of each animal. The other eye, which remains untreated, serves as a control. The initial test uses an animal; the dose level depends on the test substance nature. A confirmatory test should be made if a corrosive effect is not observed in the initial test, the irritant or negative response should be confirmed using up to two additional animals. It is recommended that it be conducted in a sequential manner in one animal at a time, rather than exposing the two additional animals simultaneously. The duration of the observation period should be sufficient to evaluate fully the magnitude and reversibility of the effects observed. The eyes should be examined at 1, 24, 48, and 72 hours after test substance application. The ocular irritation scores should be evaluated in conjunction with the nature and severity of lesions, and their reversibility or lack of reversibility. Use of topical anesthetics and systemic analgesics to avoid or minimize pain and distress in ocular safety testing procedures is described.

This Test Guideline describes in vitro assays, which use Androgen Receptor TransActivation (ARTA) to detect Androgen Receptor Agonists and Antagonists. The ARTA assay methods are mechanistically and functionally similar test methods that provide information on the transcription and translation of a reporter gene following the binding of a chemical to the androgen receptor and subsequent transactivation. The cell lines used in these assays express AR and have been stably transfected with an AR-responsive luciferase reporter gene, and are used to identify chemicals that activate (i.e. act as agonist) or inhibit (i.e. act as antagonists) AR-dependent transcription. Some chemicals may, in a cell type-dependent manner, display both agonist and antagonist activity and are known as selective AR modulators. The AR is activated following ligand binding, after which the receptor-ligand complex binds to specific DNA responsive elements and transactivates the receptor gene, resulting in an increase cellular expression of the luciferase enzyme. The enzyme then transforms the substrate to a bioluminescent product that can be quantitatively measured with a luminometer. This Test Guideline includes ARTA assays using the AR-EcoScreenTM cell line, the AR-CALUX® cell line, and 22Rv1/MMTV_GR-KO cell line.

This Test guideline describes studies on phototransformation in water to determine the potential effects of solar irradiation on chemicals in surface water, considering direct photolysis only. It is designed as a tiered approach. The Tier 1 is based on a theoretical screen. The rate of decline of a test chemical in a direct photolysis study is generally assumed to follow pseudo first-order kinetics. If the maximum possible losses is estimated to be superior or equal to 50% of the initial concentration over a 30-day period, an experimental study is proceeded in Tier 2. The direct photolysis rate constants for test chemicals in the laboratory is determined using preferably a filtered xenon arc lamp capable of simulating natural sunlight in the 290 to 800 nm, or sunlight irradiation, and extrapolated to natural water. If estimated losses are superior or equal to 20%, the transformation pathway and the identities, concentrations, and rate of formation and decline of major transformation products are identified. An optional task is the additional determination of the quantum yield for various types of water bodies, seasons, and latitudes of interest. The test chemical should be directly dissolved in the aqueous media saturated in air at a concentration which should not exceed half its solubility. For linear and non-linear regressions on the test chemical data in definitive or upper tier tests, the minimum number of samples collected should be 5 and 7 respectively. The exact number of samples and the timing of their collection is determined by a preliminary range-finding. Replicates (at least 2) of each experimental determination of kinetic parameters are recommended to determine variability and reduce uncertainty in their determination.

The in vitro micronucleus test is a genotoxicity test for the detection of micronuclei in the cytoplasm of interphase cells. Micronuclei may originate from acentric chromosome fragments (i.e. lacking a centromere), or whole chromosomes that are unable to migrate to the poles during the anaphase stage of cell division. The assay detects the activity of clastogenic and aneugenic test substances in cells that have undergone cell division during or after exposure to the test substance. This Test Guideline allows the use of protocols with and without the actin polymerisation inhibitor cytochalasin B. Cytochalasin B allows for the identification and selective analysis of micronucleus frequency in cells that have completed one mitosis, because such cells are binucleate. This Test Guideline also allows the use of protocols without cytokinesis block provided there is evidence that the cell population analysed has undergone mitosis.