Introduction to benchmark dose methods and U.S. EPA's benchmark dose software (BMDS) version 2.1.1.

Traditionally, the No-Observed-Adverse-Effect-Level (NOAEL) approach has been used to determine the point of departure (POD) from animal toxicology data for use in human health risk assessments. However, this approach is subject to substantial limitations that have been well defined, such as strict dependence on the dose selection, dose spacing, and sample size of the study from which the critical effect has been identified. Also, the NOAEL approach fails to take into consideration the shape of the dose-response curve and other related information. The benchmark dose (BMD) method, originally proposed as an alternative to the NOAEL methodology in the 1980s, addresses many of the limitations of the NOAEL method. It is less dependent on dose selection and spacing, and it takes into account the shape of the dose-response curve. In addition, the estimation of a BMD 95% lower bound confidence limit (BMDL) results in a POD that appropriately accounts for study quality (i.e., sample size). With the recent advent of user-friendly BMD software programs, including the U.S. Environmental Protection Agency's (U.S. EPA) Benchmark Dose Software (BMDS), BMD has become the method of choice for many health organizations world-wide. This paper discusses the BMD methods and corresponding software (i.e., BMDS version 2.1.1) that have been developed by the U.S. EPA, and includes a comparison with recently released European Food Safety Authority (EFSA) BMD guidance.

Commentary: An open appeal to the EPA for Superfund ERA reform.

The ecological risk assessment guidance of virtually all federal and state agencies, private companies, and other interests can be traced to that of the essential design of the U.S. Environmental Protection Agency (EPA). The EPA ecological risk assessment paradigm has remained unchanged for all intents and purposes since its inception 30 years ago, this despite criticism expressed repeatedly by some, for many years. Despite the discipline's name, a core paradigm shortcoming is its inability to express risk, the probability of a receptor-of-concern at a contaminated site developing a toxicological endpoint (e.g., reproductive impairment). Further, common site context and biological realities (e.g., site sizes; home ranges of receptors-of concern) allow for the supported challenges that risk assessments aren't needed altogether, and instances of ecological damage at sites being unknown. This commentary is an open appeal to the EPA to replace the paradigm it has set forth, dispensing with failed processes (e.g., endeavoring to assess risk potential at 75 year-old sites; endeavoring to assess risk potential to wide-ranging species at one-acre properties). The commentary invites the EPA to respond, not with counter-arguments, but rather with explanations for the Agency's resistance to acknowledging problems with its guidance, followed by the Agency commitment to sorely needed ERA reform.

Generalized Read-Across (GenRA): A workflow implemented into the EPA CompTox Chemicals Dashboard.

Generalized Read-Across (GenRA) is a data driven approach which makes read-across predictions on the basis of a similarity weighted activity of source analogues (nearest neighbors). GenRA has been described in more detail in the literature (Shah et al., 2016; Helman et al., 2018). Here we present its implementation within the EPA's CompTox Chemicals Dashboard to provide public access to a GenRA module structured as a read-across workflow. GenRA assists researchers in identifying source analogues, evaluating their validity and making predictions of in vivo toxicity effects for a target substance. Predictions are presented as binary outcomes reflecting presence or absence of toxicity together with quantitative measures of uncertainty. The approach allows users to identify analogues in different ways, quickly assess the availability of relevant in vivo data for those analogues and visualize these in a data matrix to evaluate the consistency and concordance of the available experimental data for those analogues before making a GenRA prediction. Predictions can be exported into a tab-separated value (TSV) or Excel file for additional review and analysis (e.g., doses of analogues associated with production of toxic effects).  GenRA offers a new capability of making reproducible read-across predictions in an easy-to use-interface.

Databases applicable to quantitative hazard/risk assessment--towards a predictive systems toxicology.

The Workshop on The Power of Aggregated Toxicity Data addressed the requirement for distributed databases to support quantitative hazard and risk assessment. The authors have conceived and constructed with federal support several databases that have been used in hazard identification and risk assessment. The first of these databases, the EPA Gene-Tox Database was developed for the EPA Office of Toxic Substances by the Oak Ridge National Laboratory, and is currently hosted by the National Library of Medicine. This public resource is based on the collaborative evaluation, by government, academia, and industry, of short-term tests for the detection of mutagens and presumptive carcinogens. The two-phased evaluation process resulted in more than 50 peer-reviewed publications on test system performance and a qualitative database on thousands of chemicals. Subsequently, the graphic and quantitative EPA/IARC Genetic Activity Profile (GAP) Database was developed in collaboration with the International Agency for Research on Cancer (IARC). A chemical database driven by consideration of the lowest effective dose, GAP has served IARC for many years in support of hazard classification of potential human carcinogens. The Toxicological Activity Profile (TAP) prototype database was patterned after GAP and utilized acute, subchronic, and chronic data from the Office of Air Quality Planning and Standards. TAP demonstrated the flexibility of the GAP format for air toxics, water pollutants and other environmental agents. The GAP format was also applied to developmental toxicants and was modified to represent quantitative results from the rodent carcinogen bioassay. More recently, the authors have constructed: 1) the NIEHS Genetic Alterations in Cancer (GAC) Database which quantifies specific mutations found in cancers induced by environmental agents, and 2) the NIEHS Chemical Effects in Biological Systems (CEBS) Knowledgebase that integrates genomic and other biological data including dose-response studies in toxicology and pathology. Each of the public databases has been discussed in prior publications. They will be briefly described in the present report from the perspective of aggregating datasets to augment the data and information contained within them.

Human health risk assessment database, "the NHSRC toxicity value database": supporting the risk assessment process at US EPA's National Homeland Security Research Center.

The toxicity value database of the United States Environmental Protection Agency's (EPA) National Homeland Security Research Center has been in development since 2004. The toxicity value database includes a compilation of agent property, toxicity, dose-response, and health effects data for 96 agents: 84 chemical and radiological agents and 12 biotoxins. The database is populated with multiple toxicity benchmark values and agent property information from secondary sources, with web links to the secondary sources, where available. A selected set of primary literature citations and associated dose-response data are also included. The toxicity value database offers a powerful means to quickly and efficiently gather pertinent toxicity and dose-response data for a number of agents that are of concern to the nation's security. This database, in conjunction with other tools, will play an important role in understanding human health risks, and will provide a means for risk assessors and managers to make quick and informed decisions on the potential health risks and determine appropriate responses (e.g., cleanup) to agent release. A final, stand alone MS ACESSS working version of the toxicity value database was completed in November, 2007.

The Air Toxics Health Effects Database (ATHED).

The Air Toxics Health Effects Database (ATHED) is currently used by the EPA's Office of Air Quality Planning and Standards (OAQPS) to support risk assessments for the Residual Risk Program. An assessment of the residual risk is required to be performed at a specified time (typically 8 years) following the promulgation of a technology-based Maximum Achievable Control Technologies (MACT) standard. The goal of the Residual Risk Program is to assure that the risk that remains after MACT standards are implemented (i.e., the "residual risk") is acceptable, and if not, to propose additional regulations to mitigate those risks. ATHED maintains all available reference values for each chemical as separate data records, and includes values for all exposure durations (acute, short-term, subchronic and chronic). These values are used as benchmarks to determine acceptable exposure levels to the hazardous air pollutants (HAPs) listed in Section 112 of the Clean Air Act. ATHED also provides useful background information on the uncertainty and/or modifying factors that were applied in the derivation of each reference value, as well as the point of departure and the critical study/studies. To facilitate comparisons across durations for a specific chemical, ATHED data can be graphically presented.

ACToR--Aggregated Computational Toxicology Resource.

ACToR (Aggregated Computational Toxicology Resource) is a database and set of software applications that bring into one central location many types and sources of data on environmental chemicals. Currently, the ACToR chemical database contains information on chemical structure, in vitro bioassays and in vivo toxicology assays derived from more than 150 sources including the U.S. Environmental Protection Agency (EPA), Centers for Disease Control (CDC), U.S. Food and Drug Administration (FDA), National Institutes of Health (NIH), state agencies, corresponding government agencies in Canada, Europe and Japan, universities, the World Health Organization (WHO) and non-governmental organizations (NGOs). At the EPA National Center for Computational Toxicology, ACToR helps manage large data sets being used in a high-throughput environmental chemical screening and prioritization program called ToxCast.

U.S. EPA health assessment for diesel engine exhaust: a review.

In 2002 the U.S. Environmental Protection Agency (EPA) released a Health assessment Document for Diesel Engine Exhaust. The objective of this assessment was to examine the possible health hazards associated with exposure to diesel engine exhaust (DE). The assessment concludes that long-term inhalation exposure is likely to pose a lung cancer hazard to humans as inferred from epidemiologic and certain animal studies. Estimation of cancer potency from available epidemiology studies was not attempted because of the absence of a confident cancer dose-response and animal studies were not judged appropriate for cancer potency estimation. A noncancer chronic human health hazard is inferred from rodent studies which show dose-dependent inflammation and histopathology in the rat lung. For these noncancer effects a safe exposure concentration for humans was estimated. Short-term exposures were noted to cause irritation and inflammatory symptoms of a transient nature, these being highly variable across an exposed population. The assessment also indicates that there is emerging evidence for the exacerbation of existing allergies and asthma symptoms; however, as of 2002 the data were inadequate for quantitative dose-response analysis. The assessment conclusions are based on studies that used exposures from engines built prior to the mid 1990s. More recent engines without high-efficiency particle traps would be expected to have exhaust emissions with similar characteristics. With additional cancer epidemiology studies expected in 2007-2008, and a growing body of evidence for allergenicity and cardiovascular effects, future health assessments will have an expanded health effects data base to evaluate.

Cross-species coherence in effects and modes of action in support of causality determinations in the U.S. Environmental Protection Agency's Integrated Science Assessment for Lead.

The peer-reviewed literature on the health and ecological effects of lead (Pb) indicates common effects and underlying modes of action across multiple organisms for several endpoints. Based on such observations, the United States (U.S.) Environmental Protection Agency (EPA) applied a cross-species approach in the 2013 Integrated Science Assessment (ISA) for Lead for evaluating the causality of relationships between Pb exposure and specific endpoints that are shared by humans, laboratory animals, and ecological receptors (i.e., hematological effects, reproductive and developmental effects, and nervous system effects). Other effects of Pb (i.e., cardiovascular, renal, and inflammatory responses) are less commonly assessed in aquatic and terrestrial wildlife limiting the application of cross-species comparisons. Determinations of causality in ISAs are guided by a framework for classifying the weight of evidence across scientific disciplines and across related effects by considering aspects such as biological plausibility and coherence. As illustrated for effects of Pb where evidence across species exists, the integration of coherent effects and common underlying modes of action can serve as a means to substantiate conclusions regarding the causal nature of the health and ecological effects of environmental toxicants.

Pesticide exports from U.S. ports, 1997-2000.

U.S. Customs records reveal that 3.2 billion pounds of pesticide products were exported in 1997-2000, an average rate of 45 tons per hour. Nearly 65 million pounds of the exported pesticides were either forbidden or severely restricted in the United States; however, no banned pesticide export was recorded for the year 2000. 2.2 million pounds of pesticides regulated under a treaty on persistent organic pollutants (POPs) were exported between 1997 and 1999, with no such export in 2000. Exports of pesticides subject to the prior informed consent (PIC) treaty decreased 97% from the 1997 total of nearly 3 million pounds. Thus, international efforts to reduce the trade in hazardous pesticides may be bearing fruit. However, they are balanced by high rates of export of pesticides designated "extremely hazardous" by the WHO (89 million pounds), pesticides associated with cancer (170 million pounds), and pesticides associated with endocrine disrupting effects (368 million pounds), mostly to developing countries. These findings point in two directions: first, progress is possible, and second, the focus of international efforts should be expanded. From public health and environmental protection perspectives, exports of hazardous pesticides remain unacceptably high.

Lawmakers demand answers from EPA.

Washington, Oct. 6--Early this afternoon, lawmakers demanded answers from Environmental Protection Agency (EPA) Administrator Carol Browner. In a letter sent earlier today to Browner, House Science Committee Chairman F. James Sensenbrenner, Jr. (R-WI) demanded to know why her testimony and that of one of her deputies, Ramulo Diaz, at Wednesday"s Science Committee hearing conflicted with actions taken yesterday by the agency.

The Tox21 robotic platform for the assessment of environmental chemicals--from vision to reality.

Since its establishment in 2008, the US Tox21 inter-agency collaboration has made great progress in developing and evaluating cellular models for the evaluation of environmental chemicals as a proof of principle. Currently, the program has entered its production phase (Tox21 Phase II) focusing initially on the areas of modulation of nuclear receptors and stress response pathways. During Tox21 Phase II, the set of chemicals to be tested has been expanded to nearly 10,000 (10K) compounds and a fully automated screening platform has been implemented. The Tox21 robotic system combined with informatics efforts is capable of screening and profiling the collection of 10K environmental chemicals in triplicate in a week. In this article, we describe the Tox21 screening process, compound library preparation, data processing, and robotic system validation.