Paul A. Locke

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing - t4 report

Systemic toxicity testing forms the cornerstone for the safety evaluation of substances. Pressures to move from traditional animal models to novel technologies arise from various concerns, including: the need to evaluate large numbers of previously untested chemicals and new products (such as nanoparticles or cell therapies), the limited predictivity of traditional tests for human health effects, duration and costs of current approaches, and animal welfare considerations. The latter holds especially true in the context of the scheduled 2013 marketing ban on cosmetic ingredients tested for systemic toxicity. Based on a major analysis of the status of alternative methods (Adler et al., 2011) and its independent review (Hartung et al., 2011), the present report proposes a roadmap for how to overcome the acknowledged scientific gaps for the full replacement of systemic toxicity testing using animals. Five whitepapers were commissioned addressing toxicokinetics, skin sensitization, repeated-dose toxicity, carcinogenicity, and reproductive toxicity testing. An expert workshop of 35 participants from Europe and the US discussed and refined these whitepapers, which were subsequently compiled to form the present report. By prioritizing the many options to move the field forward, the expert group hopes to advance regulatory science.

Meeting report: alternatives for developmental neurotoxicity testing.

Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13–15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children’s health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders.

In vitro and other alternative approaches to developmental neurotoxicity testing (DNT).

To address the growing need for scientifically valid and humane alternatives to developmental neurotoxicity testing (DNT), we propose that basic research scientists in developmental neurobiology be brought together with mechanistic toxicologists and policy analysts to develop the science and policy for DNT alternatives that are based on evolutionarily conserved mechanisms of neurodevelopment. In this article we briefly review in vitro and other alternative models and present our rationale for proposing that resources be focused on adapting alternative simple organism systems for DNT. We recognize that alternatives to DNT will not completely replace a DNT paradigm that involves in vivo testing in mammals. However, we believe that alternatives will be of great value in prioritizing chemicals and in identifying mechanisms of developmental neurotoxicity, which in turn will be useful in refining and reducing in vivo mammalian tests for exposures most likely to be hazardous to the developing human nervous system.

Diagnostic radiation exposure in pediatric trauma patients.

BACKGROUND The amount of imaging studies performed for disease diagnosis has been rapidly increasing. We examined the amount of radiation exposure that pediatric trauma patients receive because they are an at-risk population. Our hypothesis was that pediatric trauma patients are exposed to high levels of radiation during a single hospital visit. METHODS Retrospective review of children who presented to Johns Hopkins Pediatric Trauma Center from July 1, 2004, to June 30, 2005. Radiographic studies were recorded for each patient and doses were calculated to give a total effective dose of radiation. All radiographic studies that each child received during evaluation, including any associated hospital admission, were included. RESULTS A total of 945 children were evaluated during the study year. A total of 719 children were included in the analysis. Mean age was 7.8 (±4.6) years. Four thousand six hundred three radiographic studies were performed; 1,457 were computed tomography (CT) studies (31.7%). Average radiation dose was 12.8 (±12) mSv. We found that while CT accounted for only 31.7% of the radiologic studies performed, it accounted for 91% of the total radiation dose. Mean dose for admitted children was 17.9 (±13.8) mSv. Mean dose for discharged children was 8.4 (±7.8) mSv (p<0.0001). Burn injuries had the lowest radiation dose [1.2 (±2.6) mSv], whereas motor vehicle collision victims had the highest dose [18.8 (±14.7) mSv]. CONCLUSION When the use of radiologic imaging is considered essential, cumulative radiation exposure can be high. In young children with relatively long life spans, the benefit of each imaging study and the cumulative radiation dose should be weighed against the long-term risks of increased exposure.

Predictors of Indoor Radon Concentrations in Pennsylvania, 1989–2013

Background Radon is the second-leading cause of lung cancer worldwide. Most indoor exposure occurs by diffusion of soil gas. Radon is also found in well water, natural gas, and ambient air. Pennsylvania has high indoor radon concentrations; buildings are often tested during real estate transactions, with results reported to the Department of Environmental Protection (PADEP). Objectives We evaluated predictors of indoor radon concentrations. Methods Using first-floor and basement indoor radon results reported to the PADEP between 1987 and 2013, we evaluated associations of radon concentrations (natural log transformed) with geology, water source, building characteristics, season, weather, community socioeconomic status, community type, and unconventional natural gas development measures based on drilled and producing wells. Results Primary analysis included 866,735 first measurements by building, with the large majority from homes. The geologic rock layer on which the building sat was strongly associated with radon concentration (e.g., Axemann Formation, median = 365 Bq/m3, IQR = 167–679 vs. Stockton Formation, median = 93 Bq/m3, IQR = 52–178). In adjusted analysis, buildings using well water had 21% higher concentrations (β = 0.191, 95% CI: 0.184, 0.198). Buildings in cities (vs. townships) had lower concentrations (β = –0.323, 95% CI: –0.333, –0.314). When we included multiple tests per building, concentrations declined with repeated measurements over time. Between 2005 and 2013, 7,469 unconventional wells were drilled in Pennsylvania. Basement radon concentrations fluctuated between 1987 and 2003, but began an upward trend from 2004 to 2012 in all county categories (p < 0.001), with higher levels in counties having ≥ 100 drilled wells versus counties with none, and with highest levels in the Reading Prong. Conclusions Geologic unit, well water, community, weather, and unconventional natural gas development were associated with indoor radon concentrations. Future studies should include direct environmental measurement of radon, as well as building features unavailable for this analysis. Citation Casey JA, Ogburn EL, Rasmussen SG, Irving JK, Pollak J, Locke PA, Schwartz BS. 2015. Predictors of indoor radon concentrations in Pennsylvania, 1989–2013. Environ Health Perspect 123:1130–1137; http://dx.doi.org/10.1289/ehp.1409014

Implementing the National Academy's Vision and Strategy for Toxicity Testing: Opportunities and Challenges Under the U.S. Toxic Substances Control Act

In 2007, the U.S. National Academy of Sciences, National Research Council (NRC), issued the report Toxicity Testing in the 21st Century: A Vision and a Strategy. This report, which was commissioned by the U.S. Environmental Protection Agency (EPA), called for the U.S. EPA to develop a new approach for how this agency evaluates the toxicity of compounds. The report recommended that the agency move from its current testing system, which is based largely on traditional toxicology, to a testing system that is based primarily on human cell lines and in vitro systems. Successful implementation of the reports vision and strategy will require that scientists, lawyers, and policymakers work together to bridge the gap among disciplines. An important step in building this bridge requires an analysis of the U.S. legal system that frames toxicity testing. If the U.S. laws, regulations, and policies erect barriers that would prevent or impede the U.S. EPA adoption of the NRC vision and strategy, it is important to identify these challenges. At the same time, if existing laws, regulations, and policies are fertile ground for these recommendations, opportunities should be documented. This article discusses and evaluates the challenges and opportunities that arise under key provisions of one major U.S. toxics law, the Toxics Substances Control Act (TSCA).

Low-Dose Radiation Knowledge Worth the Cost

The past two U.S. science funding news articles have highlighted budget cuts proposed for the Department of Energys Office of Science (“Attack on climate studies would shutter entire DOE biology program” and “A strong defense of science—and a stiff upper lip,” News & Analysis, J. Mervis, 18 March, pp. [1378][1] and [1379][2]). Notably, the proposal would also substantially reduce funding of the Low-Dose Research Program that is dedicated to understanding the relationship between biological responses and health consequences of low-dose radiation. Ironically, the news since these announcements has been punctuated by radiation leaks from failures at Japans nuclear power plants, congressional hearings on radiation from airport screening, discussion of radiation risks from CT scans in children, and reports of high radiation doses mistakenly administered in otherwise benign radiological diagnostics. The public is reasonably concerned that radiation exposures pose a health risk, but remains confused about the degree and nature of this risk. Given the important questions remaining about radiation exposure, hazards, and protection, it would be false economy to cut the current yearly allocation of

Communication of radiation benefits and risks in decision making: some lessons learned.

18 million from the Office of Biological and Environmental Research budget of

Introduction: Global Laws, Regulations, and Standards for Animals in Research

588 million. The program is a crucial component of the federal radiation research portfolio. Whereas high-dose effects are well studied, new systems biology and genetic approaches are just beginning to provide insight into the low-dose range. As recent events have shown, lack of knowledge is far more expensive than this relatively modest dollar investment. Reducing resources to understand the effects of radiation exposure to humans will inevitably fuel unwarranted public stress and worry. Sustained funding of this successful effort has paid, and will continue to pay, a substantial societal benefit that expands knowledge of low-dose radiation effects and informs public policy. 1. The views expressed are those of the signatories and not necessarily of their institutions [1]: /lookup/doi/10.1126/science.331.6023.1378 [2]: /lookup/doi/10.1126/science.331.6023.1379

Implementing Toxicity Testing in the 21st Century: Challenges and Opportunities

This paper is focused on summarizing the “lessons learned” from discussions at the 2010 NCRP Annual Meeting on effective communications on the subject of radiation benefits and risks in public exposures. Five main lessons learned are discussed in regard to effective methods of public communication: the use of new social media communication tools such as Facebook and Twitter, emergency situations that require rapid societal and personal messaging, medical radiological procedures where benefits must be described in comparison to long-term health risks of radiation exposures, and information that should be provided to stakeholders in situations such as environmental radionuclide contamination to which members of the public may be exposed. It is concluded that effective communications in which radiation benefits are contrasted with health risks of exposure are an important aspect of making and implementing decisions on employing radiation health protection procedures.