Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency

Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards

Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence-based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard

Choosing Wisely in Daily Practice: An Intervention Study on Antinuclear Antibody Testing by Rheumatologists

OBJECTIVE: To assess the effect of a simple intervention on antinuclear antibody (ANA) test overuse by rheumatologists. METHODS: This was an explorative, pragmatic, before-and-after, controlled implementation study among rheumatologists working at 3 rheumatology departments in secondary and tertiary care centers in The Netherlands. The intervention was given in all study centers separately and combined education with feedback. Six outcome measures describe the intervention effects: the ANA/new patient ratio (APR), difference with the target APR, percentage of positive ANA tests, percentage of repeated ANA testing, percentage of ANA-associated diseases, and APR variation between rheumatologists. Outcomes were compared between the pre- and postintervention period (both 12 months) using (multilevel) logistic regression or F testing. Results are reported together for centers 1 and 2, and separately for center 3, because ANA tests could not be linked to an individual rheumatologist in center 3. RESULTS: The APR decreased from 0.37 to 0.11 after the intervention in centers 1 and 2 (odds ratio [OR] 0.19, 95% confidence interval [95% CI] 0.17-0.22, P < 0.001) and from 0.45 to 0.30 in center 3 (OR 0.53, 95% CI 0.45-0.62, P < 0.001). The percentage of repeated ANA requests in all centers and the APR variation for centers 1 and 2 decreased significantly. Only in center 3 did the percentage of ANA-associated diseases increase significantly. CONCLUSION: A simple intervention resulted in a relevant and significant decrease in the numbers of ANA tests requested by rheumatologists, together with an improvement on 3 other outcome measures

Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity

AbstractThe Adverse Outcome Pathway (AOP) concept has recently been proposed to support a paradigm shift in regulatory toxicology testing and risk assessment. This concept is similar to the Mode of Action (MOA), in that it describes a sequence of measurable key events triggered by a molecular initiating event in which a stressor interacts with a biological target. The resulting cascade of key events includes molecular, cellular, structural and functional changes in biological systems, resulting in a measurable adverse outcome. Thereby, an AOP ideally provides information relevant to chemical structure-activity relationships as a basis for predicting effects of structurally similar compounds. AOPs could potentially also form the basis for qualitative and quantitative predictive modeling of the human adverse outcome resulting from molecular initiating or other key events for which higher-throughput testing methods are available or can be developed.A variety of cellular and molecular processes are known to be critical for normal function of the central (CNS) and peripheral nervous systems (PNS). Because of the biological and functional complexity of the CNS and PNS, it has been challenging to establish causative links and quantitative relationships between key events that comprise the pathways leading from chemical exposure to an adverse outcome in the nervous system. Following introduction of the principles of MOA and AOPs, examples of potential or putative adverse outcome pathways specific for developmental or adult neurotoxicity are summarized and aspects of their assessment considered. Their possible application in developing mechanistically informed Integrated Approaches to Testing and Assessment (IATA) is also discussed

The coalition for conservation genetics: Working across organizations to build capacity and achieve change in policy and practice

Abstract The Coalition for Conservation Genetics (CCG) brings together four eminent organizations with the shared goal of improving the integration of genetic information into conservation policy and practice. We provide a historical context of conservation genetics as a field and reflect on current barriers to conserving genetic diversity, highlighting the need for collaboration across traditional divides, international partnerships, and coordinated advocacy. We then introduce the CCG and illustrate through examples how a coalition approach can leverage complementary expertise and improve the organizational impact at multiple levels. The CCG has proven particularly successful at implementing large synthesis-type projects, training early-career scientists, and advising policy makers. Achievements to date highlight the potential for the CCG to make effective contributions to practical conservation policy and management that no one “parent” organization could achieve on its own. Finally, we reflect on the lessons learned through forming the CCG, and our vision for the future