Tala R. Henry

The Toxicity Data Landscape for Environmental Chemicals

Objective Thousands of chemicals are in common use, but only a portion of them have undergone significant toxicologic evaluation, leading to the need to prioritize the remainder for targeted testing. To address this issue, the U.S. Environmental Protection Agency (EPA) and other organizations are developing chemical screening and prioritization programs. As part of these efforts, it is important to catalog, from widely dispersed sources, the toxicology information that is available. The main objective of this analysis is to define a list of environmental chemicals that are candidates for the U.S. EPA screening and prioritization process, and to catalog the available toxicology information. Data sources We are developing ACToR (Aggregated Computational Toxicology Resource), which combines information for hundreds of thousands of chemicals from > 200 public sources, including the U.S. EPA, National Institutes of Health, Food and Drug Administration, corresponding agencies in Canada, Europe, and Japan, and academic sources. Data extraction ACToR contains chemical structure information; physical–chemical properties; in vitro assay data; tabular in vivo data; summary toxicology calls (e.g., a statement that a chemical is considered to be a human carcinogen); and links to online toxicology summaries. Here, we use data from ACToR to assess the toxicity data landscape for environmental chemicals. Data synthesis We show results for a set of 9,912 environmental chemicals being considered for analysis as part of the U.S. EPA ToxCast screening and prioritization program. These include high-and medium-production-volume chemicals, pesticide active and inert ingredients, and drinking water contaminants. Conclusions Approximately two-thirds of these chemicals have at least limited toxicity summaries available. About one-quarter have been assessed in at least one highly curated toxicology evaluation database such as the U.S. EPA Toxicology Reference Database, U.S. EPA Integrated Risk Information System, and the National Toxicology Program.

Comparison of relative binding affinities of endocrine active compounds to fathead minnow and rainbow trout estrogen receptors

Twelve chemicals were tested for binding affinity to rainbow trout liver estrogen receptor (rbtER) and fathead minnow liver ER (fhmER). The chemicals included estradiol (E2), diethylstilbestrol (DES), ethinylestradiol (EE2), estrone (El), estriol, tamoxifen (TAM), genistein (GEN), p-nonylphenol (PNP), p-tert-octylphenol (PTOP), methoxychlor (MXC), testosterone, and methyltestosterone (MT). Relative binding affinity (RBA) was calculated for each chemical as a function of E2 binding to the receptor. The estrogens DES, EE2, and E1 bound with high affinity to both receptors, with respective RBAs of 583, 166, and 28% (fathead minnow) and 179, 89, and 5% (rainbow trout). Relative binding affinity of E3, TAM, and GEN for both fhmER and rbtER were moderate, with values between 0.3 and 5%. The alkylphenols had weak affinity for the ERs with RBAs for the fhmER of 0.1 and 0.01 for PNP and PTOP, respectively. Corresponding values for the rbtER are 0.027 and 0.009. Estradiol ([3H]E2) only partially was displaced from both the fhmER and the rbtER by MXC, T, and MT. Comparison of RBAs of the chemicals tested for fhmER and rbtER indicates that the rank order of RBAs essentially are the same for both species.

Integrated Approach to PBT and POP Prioritization and Risk Assessment

Abstract This article summarizes discussions at the SETAC Pellston Workshop on “Science-Based Guidance and Framework for the Evaluation and Identification of PBTs and POPs” and provides an overview of other articles from that workshop that are also published in this issue. Identification of persistent, bioaccumulative, and toxic substances (PBTs) and persistent organic pollutants (POPs) and evaluation of their impact are more complicated than those for other chemicals and remain a challenge. The main reason for this is that PBT substance and POP assessment is associated with higher uncertainty and generally requires more data. However, for some data-rich PBTs and POPs, that identification and assessment of impact are feasible has been clearly demonstrated. New scientific developments and techniques are able to significantly increase the certainty of the various elements of PBT and POP assessment, and the current scientific literature provides many successful and illustrative examples that can be used as methodologies to build on. Applying multiple approaches for assessment is advisable, because it will reduce uncertainty and may increase confidence and improve the quality of decision-making.

Polar Narcosis in Aquatic Organisms

The majority of industrial organic chemicals lack identifiable structural characteristics that result in specific biological activity. These nonpolar-nonelectrolytes are acutely toxic to aquatic organisms via a nonspecific mode of action termed narcosis. The toxicity of industrial chemicals eliciting nonpolar narcosis can be reliably predicted by log P (baseline toxicity models). Using single chemical and joint toxic action models, several research groups have reported classes of polar compounds (for example, esters, phenols, and anilines) that elicit a narcosis-like syndrome; however, they are more acutely toxic than what is predicted using baseline toxicity models. An assessment of rainbow trout (Salmo gairdneri) in vivo respiratory-cardiovascular responses during intoxication by polar narcotic phenol and aniline derivatives established a toxicity syndrome unique to that elicited by nonpolar narcotics. This finding further suggests a mode of action unique to polar narcotics and supports the use of structure-activity relationships specific for these compounds. The proposition that there may be multiple mechanisms or sites of narcotic action is compatible with recent studies concerning the cellular and molecular mechanisms of anesthetic action.

Meeting The Common Needs of a More Effective and Efficient Testing and Assessment Paradigm for Chemical Risk Management

Significant advances have been made in human health and ecological risk assessment over the last decade. Substantial challenges, however, remain in providing credible scientific information in a timely and efficient manner to support chemical risk assessment and management decisions. A major challenge confronting risk managers is the need for critical information to address risk uncertainties in large chemical inventories such as high- and medium-production-volume industrial chemicals or pesticide inert ingredients. From a strategic and tactical viewpoint, an integrated approach that relies on all existing knowledge and uses a range of methods, including those from emerging and novel technologies, is needed to advance progressive and focused testing strategies, as well as to advance the utility and predictability of the risk assessment by providing more relevant information. A hypothesis-based approach that draws on all relevant information is consistent with the vision articulated in the 2007 report by the National Research Council, Toxicity Testing in the 21st Century: A Vision and a Strategy. This article describes the current practices in evaluating chemical risks and ongoing efforts to enhance the quality and efficiency of risk assessment and risk management decisions within the Office of Prevention, Pesticides, and Toxic Substances at the U.S. Environmental Protection Agency.

Toward Identifying the Next Generation of Superfund and Hazardous Waste Site Contaminants

Background This commentary evolved from a workshop sponsored by the National Institute of Environmental Health Sciences titled “Superfund Contaminants: The Next Generation” held in Tucson, Arizona, in August 2009. All the authors were workshop participants. Objectives Our aim was to initiate a dynamic, adaptable process for identifying contaminants of emerging concern (CECs) that are likely to be found in future hazardous waste sites, and to identify the gaps in primary research that cause uncertainty in determining future hazardous waste site contaminants. Discussion Superfund-relevant CECs can be characterized by specific attributes: They are persistent, bioaccumulative, toxic, occur in large quantities, and have localized accumulation with a likelihood of exposure. Although still under development and incompletely applied, methods to quantify these attributes can assist in winnowing down the list of candidates from the universe of potential CECs. Unfortunately, significant research gaps exist in detection and quantification, environmental fate and transport, health and risk assessment, and site exploration and remediation for CECs. Addressing these gaps is prerequisite to a preventive approach to generating and managing hazardous waste sites. Conclusions A need exists for a carefully considered and orchestrated expansion of programmatic and research efforts to identify, evaluate, and manage CECs of hazardous waste site relevance, including developing an evolving list of priority CECs, intensifying the identification and monitoring of likely sites of present or future accumulation of CECs, and implementing efforts that focus on a holistic approach to prevention.

Effects-based chemical category approach for prioritization of low affinity estrogenic chemicals

Regulatory agencies are charged with addressing the endocrine disrupting potential of large numbers of chemicals for which there is often little or no data on which to make decisions. Prioritizing the chemicals of greatest concern for further screening for potential hazard to humans and wildlife is an initial step in the process. This paper presents the collection of in vitro data using assays optimized to detect low affinity estrogen receptor (ER) binding chemicals and the use of that data to build effects-based chemical categories following QSAR approaches and principles pioneered by Gilman Veith and colleagues for application to environmental regulatory challenges. Effects-based chemical categories were built using these QSAR principles focused on the types of chemicals in the specific regulatory domain of concern, i.e. non-steroidal industrial chemicals, and based upon a mechanistic hypothesis of how these non-steroidal chemicals of seemingly dissimilar structure to 17ß-estradiol (E2) could interact with the ER via two distinct binding types. Chemicals were also tested to solubility thereby minimizing false negatives and providing confidence in determination of chemicals as inactive. The high-quality data collected in this manner were used to build an ER expert system for chemical prioritization described in a companion article in this journal.

Comment on "More of EPA's SPARC online calculator--the need for high-quality predictions of chemical properties".

SPARC Online CalculatorsThe Need for High-Quality Predictions of Chemical Properties” We thank Arp et al. (1) for drawing attention to the need for reliable chemical property estimation software that can be downloaded or accessed free. Their comparison of the SPARC online calculator (SPARC Performs Automated Reasoning in Chemistry; http:// ibmlc2.chem.uga.edu/sparc/) (2) and the Estimation Programs Interface Suite v4.00 (EPI Suite; http:// www.epa.gov/opptintr/exposure/ pubs/episuite.htm) highlights SPARC’s utility for estimating certain parameters of interest in environmental assessment, and partitioning properties for a broad array of phases. Missing from their discussion is appreciation of the larger context in which EPI Suite exists, and of its primary intended role as a screening tool. As stated in its interface and Web site, EPI Suite is designed for quick evaluation of chemicals for exposure potential or prioritizing materials for future work. The U.S. EPA’s Office of Pollution Prevention and Toxics (OPPT) has developed or supported several such tools to help in evaluating (1) what happens to chemicals when they are used and released; (2) how workers, the general public, consumers, and the environment may be exposed; and (3) what adverse effects may result from such exposure. These tools are intended for scientists, engineers, risk assessors, and regulators familiar with chemical risk assessment principles. Their use enables assessors to consider health and safety issues when making chemical management decisions; compare product alternatives or substitute chemicals for potential risk; and identify pollution prevention and risk reduction opportunities. Other OPPT tools include OncoLogic (http://www.epa. gov/oppt/sf/pubs/oncologic.htm) for predicting carcinogenicity, ECOSAR (http://www.epa.gov/ oppt/newchems/tools/21ecosar. htm) for estimating aquatic toxicity, Analog Identification Methodology (AIM) (http://aim.epa.gov), and the PBT (Persistent, Bioaccumulative, Toxic) Profiler (http://www. pbtprofiler.net/). By providing a science-based, cost-effective way to screen new chemistries, OPPT’s tools and expertise have helped industry advance green chemistry and thereby inform substitution. This entire segment of the chemical enterprise is notably absent from Arp et al.’s list of users (“researchers, students, and citizen scientists”). To help users achieve their objectives, many of the features on Arp et al.’s (1) wish list for SPARC are already available in EPI Suite. For example, EPI Suite’s predictive methods are completely transparent in the extensive help files and have been described in numerous publications. With batch processing, available for 15 years, thousands of chemicals can be processed in seconds. EPI Suite estimates many parameters of interest to health and environmental scientists that are not found in SPARC, or in some cases, even in expensive commercial software. There are also useful features available only when certain programs are run individually. For example, KOWWIN and HENRYWIN (Henry’s Law constant) allow estimation starting from analog data, yielding more accurate predictions. The next version will include external links to web-based programs and data sources including SPARC; structure entry by drawing (via a 2D chemical structure editor); better estimation for organosilicon compounds; and more. These examples show that not only does EPI Suite continue to innovate, but also that the voices of users are being heard. We believe that the pollution prevention community and their needs should be more widely recognized. These strongly emphasize rapid, convenient, and transparent methods for chemical screening.