Perfluorohexanoic acid toxicity, part II: Application of human health toxicity value for risk characterization.

Perfluorohexanoic acid (PFHxA) is a short-chain, six-carbon PFAA and is a primary impurity, degradant, and metabolite associated with the short-chain fluorotelomer-based chemistry used in the United States, Europe and Japan today. With the shift towards short-chain PFAA chemistry, uncertainties remain regarding human health risks associated with current exposure levels. Here, we present a critical review and assessment of data relevant to human health risk assessment to today's short-chain PFAA chemistry. Human biomonitoring surveys indicate that PFHxA is infrequently detected in the environment as well as in human serum and urine; however, human health concerns may persist in locations where PFHxA is detected. In a companion paper (Luz et al., 2019) we comprehensively evaluate the available toxicity data for PFHxA, and derive a chronic human health-based reference dose (RfD) for PFHxA of 0.25 mg/kg-day based on benchmark dose modeling of renal papillary necrosis in chronically exposed female rats. In this paper, we apply this RfD in human health-based screening levels calculations, and derive a drinking water lifetime health advisory of 1400 µg/L and a residential groundwater screening level for children of 4000 µg/L. Compared to environmental concentration data, even sites with more elevated concentrations of PFHxA in the environment are at least an order of magnitude lower than these screening levels. Available PFHxA human serum and urine biomonitoring data, used as a biomarker for general population exposure, demonstrates that the general human population exposures to PFHxA are low. Previous estimates of daily intake rates for infants exposed to PFHxA through breast milk, formula, and baby foods (Lorenzo et al., 2016) combined with the most conservative PFHxA peer-reviewed toxicity value (Luz et al., 2019) demonstrate that the margin of safety for PFHxA is high. Therefore, PFHxA and related fluorotelomer precursors currently appear to present negligible human health risk to the general population and are not likely to drive or substantially contribute to risk at sites contaminated with PFAS mixtures. PFHxA may also represent a suitable marker for the safety of fluorotelomer replacement chemistry used today.

Perfluorohexanoic acid toxicity, part I: Development of a chronic human health toxicity value for use in risk assessment.

Perfluorohexanoic acid (PFHxA) is a short-chain, six-carbon perfluoroalkyl acid (PFAA) and is a primary impurity, degradant, and metabolite associated with the short-chain fluorotelomer-based chemistry used globally today. The transition to short-chain fluorotelomer-based products as a cornerstone in replacement fluorochemistry has raised questions regarding potential human health risks associated with exposure to fluorotelomer-based substances and therefore, PFHxA. Here, we present a critical review of data relevant to such a risk assessment, including epidemiological studies and in vivo and in vitro toxicity studies that examined PFHxA acute, subchronic, and chronic toxicity. Key findings from toxicokinetic and mode-of-action studies are also evaluated. Sufficient data exist to conclude that PFHxA is not carcinogenic, is not a selective reproductive or developmental toxicant, and does not disrupt endocrine activity. Collectively, effects caused by PFHxA exposure are largely limited to potential kidney effects, are mild and/or reversible, and occur at much higher doses than observed for perfluorooctanoic acid (PFOA). A chronic human-health-based oral reference dose (RfD) for PFHxA of 0.25 mg/kg-day was calculated using benchmark dose modeling of renal papillary necrosis from a chronic rat bioassay. This RfD is four orders of magnitude greater than the chronic oral RfD calculated by the U.S. Environmental Protection Agency for PFOA. The PFHxA RfD can be used to inform public health decisions related to PFHxA and fluorotelomer precursors for which PFHxA is a terminal degradant. These findings clearly demonstrate that PFHxA is less hazardous to human health than PFOA. The analyses presented support site-specific risk assessments as well as product stewardship initiatives for current and future short-chain fluorotelomer-based products.

Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.

Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH.

An analysis of the use of the relative source contribution term in derivation of drinking water standards using perfluorooctanoic acid as an example.

The relative source contribution (RSC) term has long been used by the US Environmental Protection Agency (USEPA) and state regulatory agencies in setting criteria in water. The RSC reflects the proportion of the total daily intake of a chemical that can be derived from water when all other sources of exposure (e.g., food, air) are considered. This term is applied by the USEPA and state regulatory agencies when deriving ambient water quality criteria, maximum contaminant level goals, and drinking water health advisories for noncarcinogenic and threshold carcinogenic compounds. The value assigned to the RSC term affects the calculated criteria directly, with the allowable concentration in water decreasing with a decreasing RSC. A default RSC value of 20%-applied by regulatory entities in the USA for more than 40 years-assumes that 80% of an individual's exposure to a chemical's reference dose is from nonwater sources. Although the RSC is a chemical-specific parameter, there are few instances where a value other than the default of 20% has been approved and used. In 2000, USEPA outlined the process for developing chemical-specific RSC values, yet primary use of the default RSC value has continued since then. This article reviews USEPA's methodology for deriving chemical-specific RSC values and provides a case example using perfluorooctanoic acid (PFOA) to explore how the USEPA and state regulatory agencies are applying USEPA's guidance. The case study highlights inconsistent derivation of the RSC term, rooted in limitations in the current methodology. We suggest additional clarification of and more thoughtful use of the available data that may not meet USEPA's current adequacy requirements. We also recommend that the USEPA discuss recommendations for using biomonitoring data to set RSCs. Integr Environ Assess Manag 2023;19:605-612. © 2022 SETAC.

Ecological risk assessment in the context of global climate change.

Changes to sources, stressors, habitats, and geographic ranges; toxicological effects; end points; and uncertainty estimation require significant changes in the implementation of ecological risk assessment (ERA). Because of the lack of analog systems and circumstances in historically studied sites, there is a likelihood of type III error. As a first step, the authors propose a decision key to aid managers and risk assessors in determining when and to what extent climate change should be incorporated. Next, when global climate change is an important factor, the authors recommend seven critical changes to ERA. First, develop conceptual cause-effect diagrams that consider relevant management decisions as well as appropriate spatial and temporal scales to include both direct and indirect effects of climate change and the stressor of management interest. Second, develop assessment end points that are expressed as ecosystem services. Third, evaluate multiple stressors and nonlinear responses-include the chemicals and the stressors related to climate change. Fourth, estimate how climate change will affect or modify management options as the impacts become manifest. Fifth, consider the direction and rate of change relative to management objectives, recognizing that both positive and negative outcomes can occur. Sixth, determine the major drivers of uncertainty, estimating and bounding stochastic uncertainty spatially, temporally, and progressively. Seventh, plan for adaptive management to account for changing environmental conditions and consequent changes to ecosystem services. Good communication is essential for making risk-related information understandable and useful for managers and stakeholders to implement a successful risk-assessment and decision-making process.

Development of a preliminary relative risk model for evaluating regional ecological conditions in the Delaware River Estuary, USA.

Effective environmental management and restoration of urbanized systems such as the Delaware River Estuary requires a holistic understanding of the relative importance of various stressor-related impacts throughout the watershed, both historical and ongoing. To that end, it is important to involve as many stakeholders as possible in the management process and to develop a system for sharing of scientific data and information, as well as effective technical tools for evaluating and disseminating the data needed to make management decisions. In this study, we describe a preliminary assessment that was undertaken to evaluate the relative risks for the variety of stressors currently operating within the Delaware Estuary using a relative risk model (RRM) framework. This model was constructed using existing data and information on the ecological conditions and stressors in the main-stem Delaware River below the head of tide at Trenton, New Jersey, USA. A large database was developed with pertinent data from a variety of library, scientific, and regulatory sources. Data were compiled, reviewed, and characterized before development of the Estuary-specific RRM. Our primary goals and objectives in developing this preliminary RRM for the Estuary were to 1) determine if the RRM framework can be adapted to a large complex estuarine system such as the Delaware River, 2) identify the issues associated with adapting the model framework to the various management issues and regional areas/habitats of the River, 3) help identify data needs and potential refinements that might be needed to more specifically quantify relative stressor risks in various areas and habitats of the Estuary to better inform future management goals/actions by Stakeholders. The key conclusions of our preliminary assessment are 1) a diverse suite of stressors is likely affecting the ecological conditions of the Delaware Estuary, 2) chemical (toxicants/contaminants) and physical (sedimentation, habitat loss) stressors were found to be on par with regards to their ranking, and 3) the RRM, in its current form, made it difficult to effectively balance the inequality in the sizes of the study subareas considered in the assessment. Management objectives and related research activities should focus on collecting the necessary data and information to further refine the RRM and assess the relative impacts of these stressors at various scales in the Estuary. By having such a framework and tool available, we believe that stakeholders within the Delaware River watershed will be able to make more informed and risk-based management decisions regarding restoration options for the Estuary.

Effective coordination and cooperation between ecological risk assessments and natural resource damage assessments: a new synthesis.

Although ecological risk assessments (ERAs) and natural resource damage assessments (NRDAs) are performed under different statutory and regulatory authorities, primarily the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA), as currently practiced, the activities typically overlap. ERAs performed as part of the response process (typically by the US Environmental Protection Agency [USEPA]) should be closely coordinated with the natural resource trustees' (trustees') NRDAs. Trustees should actively participate in the early stages of the remedial investigation (RI) and work with USEPA, including the potentially responsible parties (PRPs), when appropriate, to coordinate NRDA data needs with those of the RI. Close coordination can present opportunities to avoid inefficiencies, such as unnecessary resampling or duplicate data gathering, and provide the opportunity to fulfill both process requirements with a few well-designed investigations. Early identification of opportunities for practical combined assessment can save money and time as the restoration process proceeds and facilitate a cooperative resolution of the entire site's CERCLA liability. The Society of Environmental Toxicology and Chemistry (SETAC) convened an invited workshop (August 2008) to address coordination between ERA and NRDA efforts. This paper presents the findings and conclusions of the Framework Work Group, which considered technical issues common to each process, while mindful of the current legal and policy landscape, and developed recommendations for future practice.