George M. Gray

Transforming Environmental Health Protection

We propose a shift from primarily in vivo animal studies to in vitro assays, in vivo assays with lower organisms, and computational modeling for toxicity assessments.

Weight of the Evidence Evaluation of Low-Dose Reproductive and Developmental Effects of Bisphenol A

ABSTRACT A panel convened by the Harvard Center for Risk Analysis (HCRA) evaluated the weight of evidence for potential developmental and reproductive toxicity of bisphenol A (BPA, CASRN 80-05-7) in animals at doses well below the Lowest Observed Adverse Effect Level (LOAEL) of 50 mg/kg-day previously identified by the U.S. Environmental Protection Agency (US EPA) and even US EPAs reference dose (RfD) of 0.05 mg/kg-day. The effects are hypothesized to occur through an endocrine-modulating mode of action, specifically through estrogen receptors. The panel focused on potential male reproductive effects but also examined other endpoints possibly associated with hormone-like effects. The review considered studies published through April 2002. A formal deliberation framework focused on consistency, generalizability, and biological plausibility. The panel found no consistent affirmative evidence of low-dose BPA effects for any endpoint. Inconsistent responses across rodent species and strains made generalizability of low-dose BPA effects questionable. Lack of adverse effects in two multiple-generation reproductive and developmental studies casts doubt on suggestions of significant physiological or functional impairment. The panel was concerned about generalization of non-oral administration results to oral exposures. Differences in the pattern of BPA responses compared to estradiol or diethylstilbestrol (DES) cast doubt on estrogenicity as a low-dose mechanism of action for BPA. Finally, there is indirect evidence that humans may be less sensitive to possible estrogenic effects from BPA exposure due to pharmacodynamic factors. The panel recommended replication of existing studies under carefully controlled conditions and further study of BPAs pharmacokinetics and pharmacodynamics. The study was funded by a grant from the American Plastics Council.

Legislating Acceptable Cancer Risk from Exposure to Toxic Chemicals

Introduction ................................................... 270 I. Quantitative Risk Assessment ............................. 277 A. Hazard Identification ................................. 279 B. Dose-Response Evaluation ............................ 285 C. Exposure Assessment ................................. 290 D. Risk Characterization ......... .................. 293 II. Narrative Statutes and Risk Assessment at EPA ........... 295 A. The Delaney Clause: A Bright Line of Zero Risk ...... 297 B. Health-Based Statutes: The Clean Air Act ............. 300 C. Risk-Benefit Balancing: TSCA and FIFRA ............ 304 D. Technology-Based Statutes: The Safe Drinking Water and Clean Water Acts ................................ 309 E. Hybrid Narrative Statutes ............................ 313 1. The Resource Conservation and Recovery Act ..... 314 2. Superfund ........................................ 317 F. Use of Risk Assessment at EPA: A Summary ......... 320 III. Legislating Bright Lines ................................... 322 A. The Clean Air Act Amendments of 1990 .............. 323 B. Recent Legislative Proposals .......................... 327 IV. Statutory Bright Lines: A Host of Possibilities ............. 329 A. Bright Lines in Priority Setting ....................... 329

Workshop report: Strategies for setting occupational exposure limits for engineered nanomaterials

Occupational exposure limits (OELs) are important tools for managing worker exposures to chemicals; however, hazard data for many engineered nanomaterials (ENMs) are insufficient for deriving OELs by traditional methods. Technical challenges and questions about how best to measure worker exposures to ENMs also pose barriers to implementing OELs. New varieties of ENMs are being developed and introduced into commerce at a rapid pace, further compounding the issue of OEL development for ENMs. A Workshop on Strategies for Setting Occupational Exposure Limits for Engineered Nanomaterials, held in September 2012, provided an opportunity for occupational health experts from various stakeholder groups to discuss possible alternative approaches for setting OELs for ENMs and issues related to their implementation. This report summarizes the workshop proceedings and findings, identifies areas for additional research, and suggests potential avenues for further progress on this important topic.

US Environmental Protection Agency Uses Operations Research to Reduce Contamination Risks in Drinking Water

The US Environmental Protection Agency (EPA) is the lead federal agency for the security of drinking water in the United States. The agency is responsible for providing information and technical assistance to the more than 50,000 water utilities across the country. The distributed physical layout of drinking-water utilities makes them inherently vulnerable to contamination incidents caused by terrorists. To counter this threat, the EPA is using operations research to design, test, and deploy contamination warning systems (CWSs) that rapidly detect the presence of contaminants in drinking water. We developed a software tool to optimize the design process, published a decision-making process to assist utilities in applying the tool, pilot-tested the tool on nine large water utilities, and provided training and technical assistance to a larger group of utilities. We formed a collaborative team of industry, academia, and government to critique our approach and share CWS deployment experiences. Our work has demonstrated that a CWS is a cost-effective, timely, and capable method of detecting a broad range of contaminants. Widespread application of these new systems will significantly reduce the risks associated with catastrophic contamination incidents: the median estimated fatalities reduction for the nine utilities already studied is 48 percent; the corresponding economic-impact reduction is over

Policy: Rethink chemical risk assessments

19 billion. Because of this operations research program, online monitoring programs, such as a CWS, are now the accepted technology for reducing contamination risks in drinking water.

An Approach to Integrating Occupational Safety and Health into Life Cycle Assessment: Development and Application of Work Environment Characterization Factors

The US Environmental Protection Agency needs to speed up its risk analyses and address uncertainty, say George M. Gray and Joshua T. Cohen.

Food safety: Risk assessment methodology and decision-making criteria

Integrating occupational safety and health (OSH) into life cycle assessment (LCA) may provide decision makers with insights and opportunities to prevent burden shifting of human health impacts between the nonwork environment and the work environment. We propose an integration approach that uses industry‐level work environment characterization factors (WE‐CFs) to convert industry activity into damage to human health attributable to the work environment, assessed as disability‐adjusted life years (DALYs). WE‐CFs are ratios of work‐related fatal and nonfatal injuries and illnesses occurring in the U.S. worker population to the amount of physical output from U.S. industries; they represent workplace hazards and exposures and are compatible with the life cycle inventory (LCI) structure common to process‐based LCA. A proof of concept demonstrates application of the WE‐CFs in an LCA of municipal solid waste landfill and incineration systems. Results from the proof of concept indicate that estimates of DALYs attributable to the work environment are comparable in magnitude to DALYs attributable to environmental emissions. Construction and infrastructure‐related work processes contributed the most to the work environment DALYs. A sensitivity analysis revealed that uncertainty in the physical output from industries had the most effect on the WE‐CFs. The results encourage implementation of WE‐CFs in future LCA studies, additional refinement of LCI processes to accurately capture industry outputs, and inclusion of infrastructure‐related processes in LCAs that evaluate OSH impacts.

Principles for Conduct of Pest Risk Analyses: Report of an Expert Workshop

As our scientific technology grows, risk assessment methods become more complex and, therefore, open to greater scientific debate. Risk assessment has always been a part of the regulatory notification and approval process for foods. However, the methodologies applied to risk assessment and decision-making have become diverse, dependent on a number of features, including the areas of the world in which one operates, the need to use cumulative risk assessment for pesticides and otheringredients or alternative risk assessment considerations for evaluating nontraditional or bioengineered foods. Diverse institutional structures within a single federal regulatory authority may tend to lead to diversity in risk outcomes that creates policy decisions that complicate and confuse the risk management process. On top of this challenge, decisions become more complicated by the need to examine beneficial factors of foods rather than the adverse effects of foods and food additives. Foods are a complex mixture ofingredients. Regulatory groups recognize the need to use new approaches for evaluating the safety and risks associated with foods and food additives, and to do so in a timely manner. The United States Food and Drug Administration (US FDA) in its need to ensure standards of “reasonable certainty of no harm” continues to explore alternative means to be responsive to petitioners as well as continue to examine scientifically validated means, e.g., quantitative structure-activity relationship (QSAR), and computer-assisted programs, within the approval process to assist in the evaluation of risks. Another means to improve the risk management process would include the cumulative risk assessment of pesticides that will, no doubt, be the beginning of more intensive efforts to understand cumulative exposures and the inherent risks from multiple pathways of exposure. The passage of the Food Quality Protection Act (FQPA) resulted in developing additional risk assessment methodologies and approaches to assess the potential for multiple exposures and risks. Addressing the international criteria used in decision-making related to foods safety assessment has resulted in acceptable intake values for foodingredients for carcinogens and noncarcinogens that, in general, tend to be more stringent in the United States compared to Europe. Clearly, the need for harmonization of risk assessment criteria and the impact of the decision process on regulatory approvals and safety assessment is a future need for the continued assurances of food safety. The topics presented in this paper are based on a symposium held in November 2002 at the annual meeting of the American College of Toxicology.

Improving Weight of Evidence Approaches to Chemical Evaluations

The North American Free Trade Agreement (NAFTA) and the General Agreement on Tariffs and Trade (GATT) have focused attention on risk assessment of potential insect, weed, and animal pests and diseases of livestock. These risks have traditionally been addressed through quarantine protocols ranging from limits on the geographical areas from which a product may originate, postharvest disinfestation procedures like fumigation, and inspections at points of export and import, to outright bans. To ensure that plant and animal protection measures are not used as nontariff trade barriers, GATT and NAFTA require pest risk analysis (PRA) to support quarantine decisions. The increased emphasis on PRA has spurred multiple efforts at the national and international level to design frameworks for the conduct of these analyses. As approaches to pest risk analysis proliferate, and the importance of the analyses grows, concerns have arisen about the scientific and technical conduct of pest risk analysis. In January of 1997, the Harvard Center for Risk Analysis (HCRA) held an invitation-only workshop in Washington, D.C. to bring experts in risk analysis and pest characterization together to develop general principles for pest risk analysis. Workshop participants examined current frameworks for PRA, discussed strengths and weaknesses of the approaches, and formulated principles, based on years of experience with risk analysis in other setting and knowledge of the issues specific to analysis of pests. The principles developed highlight the both the similarities of pest risk analysis to other forms of risk analysis, and its unique attributes.