Application of probabilistic methods to address variability and uncertainty in estimating risks for non-cancer health effects.

Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this "bright line" approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose. We identify and review existing approaches for conducting probabilistic non-cancer risk assessments. Using perchloroethylene (PCE), a priority chemical for the U.S. Environmental Protection Agency under the Toxic Substances Control Act, we calculate risk-specific doses for the effects on cognitive deficits using probabilistic risk assessment approaches. Our probabilistic risk assessment shows that chronic exposure to 0.004 ppm PCE is associated with approximately 1-in-1,000 risk for a 5% reduced performance on the Wechsler Memory Scale Visual Reproduction subtest with 95% confidence. This exposure level associated with a 1-in-1000 risk for non-cancer neurocognitive deficits is lower than the current RfC for PCE of 0.0059 ppm, which is based on standard point of departure and uncertainty factor approaches for the same neurotoxic effects in occupationally exposed adults. We found that the population-level risk of cognitive deficit (indicating central nervous system dysfunction) is estimated to be greater than the cancer risk level of 1-in-100,000 at a similar chronic exposure level. The extension of toxicological endpoints to more clinically relevant endpoints, along with consideration of magnitude and severity of effect, will help in the selection of acceptable risk targets for non-cancer effects. We find that probabilistic approaches can 1) provide greater context to existing RfDs and RfCs by describing the probability of effect across a range of exposure levels including the RfD/RfC in a diverse population for a given magnitude of effect and confidence level, 2) relate effects of chemical exposures to clinical disease risk so that the resulting risk assessments can better inform decision-makers and benefit-cost analysis, and 3) better reflect the underlying biology and uncertainties of population risks.

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Comparison of Recreational Fish Consumption Advisories Across the USA.

PURPOSE OF REVIEW: Our comparative analysis sought to understand the factors which drive differences in fish consumption advisories across the USA - including exposure scenarios (acute and chronic health risk, non-cancer and cancer health endpoints), toxicity values (reference dose, cancer slope factor, acute tolerance level), and meal size and bodyweight assumptions. RECENT FINDINGS: Fish consumption provides essential nutrients but also results in exposure to contaminants such as PCBs and methylmercury. To protect consumers from the risks of fish contaminants, fish consumption advisories are established, most often by state jurisdictions, to estimate the amount of a certain fish species a person could consume throughout their lifetime without harm. However, inconsistencies in advisories across the USA confuse consumers and undermine the public health goals of fish advisory programs. To date, no rigorous comparison of state and national fish consumption advisories has been reported. Our work identifies discrepancies in key assumptions used to derive risk-based advisories between US states, reflecting differences in the interpretation of toxicity science. We also address the implications for these differences by reviewing advisories issued by contiguous states bordering two waterbodies: Lake Michigan and the Lower Mississippi River. Our findings highlight the importance of regional collaboration when issuing advisories, so that consumers of self-caught fish are equipped with clear knowledge to make decisions to protect their health.

The association of cadmium and lead exposures with red cell distribution width.

Elevated red blood cell distribution width (RDW), traditionally an indicator of anemia, has now been recognized as a risk marker for cardiovascular disease incidence and mortality. Experimental and acute exposure studies suggest that cadmium and lead individually affect red blood cell production; however, associations between environmental exposures and RDW have not been explored. We evaluated relationships of environmental cadmium and lead exposures to RDW. We used data from 24,607 participants aged ≥20 years in the National Health and Nutrition Examination Survey (2003-2016) with information on blood concentrations of cadmium and lead, RDW and socio-demographic factors. In models adjusted for age, sex, race/ethnicity, education, poverty income ratio, BMI, alcohol consumption, smoking status and serum cotinine, RDW was increasingly elevated across progressively higher quartiles of blood cadmium concentration. A doubling of cadmium concentration was associated with 0.16 higher RDW (95% CI: 0.14, 0.18) and a doubling of lead concentration with 0.04 higher RDW (95% CI: 0.01, 0.06). Also, higher cadmium and lead concentrations were associated with increased odds of high RDW (RDW>14.8%). The associations were more pronounced in women and those with low-to-normal mean corpuscular volume (MCV) and held even after controlling for iron, folate or vitamin B12 deficiencies. In analysis including both metals, cadmium remained associated with RDW, whereas the corresponding association for lead was substantially attenuated. In this general population sample, blood cadmium and lead exposures were positively associated with RDW. The associations may indicate hemolytic or erythropoietic mechanisms by which exposure increases mortality risk.

Human health risks due to airborne polychlorinated biphenyls are highest in New Bedford Harbor communities living closest to the harbor.

In response to concerns raised by communities surrounding the New Bedford Harbor Superfund site, we completed a field and modeling study that concluded the harbor is the primary source of polychlorinated biphenyls (PCBs) in air around the harbor. The follow-up question from residents was whether the PCBs measured in air pose a risk to their health. The US Environmental Protection Agency focuses their site-specific, risk-based decisions for site clean-up on cancers. We focused our assessment on the non-cancer effects on the thyroid based on the congener specific patterns and concentrations of PCBs measured in air near and distant to the harbor. Human and animal studies of PCB-induced effects on the thyroid provide evidence to support our analysis. Drawing from the published toxicological data, we used a Margin of Exposure (MOE) approach to derive a human-equivalent concentration in air associated with human health effects on the thyroid. Based on the MOEs calculated herein, evaluation of the MOE indicates that changes in thyroid hormone levels are possible among people living adjacent to the Harbor. Changes in thyroid hormone levels are more likely among people who live near the harbor compared to residents living in areas distant from the harbor. This risk assessment documents potential health risks associated with proximity to a marine Superfund Site using site-specific ambient air PCB congener data.

High-throughput in Vitro Data To Inform Prioritization of Ambient Water Monitoring and Testing for Endocrine Active Chemicals.

The presence of industrial chemicals, consumer product chemicals, and pharmaceuticals is well documented in waters in the U.S. and globally. Most of these chemicals lack health-protective guidelines and many have been shown to have endocrine bioactivity. There is currently no systematic or national prioritization for monitoring waters for chemicals with endocrine disrupting activity. We propose ambient water bioactivity concentrations (AWBCs) generated from high throughput data as a health-based screen for endocrine bioactivity of chemicals in water. The U.S. EPA ToxCast program has screened over 1800 chemicals for estrogen receptor (ER) and androgen receptor (AR) pathway bioactivity. AWBCs are calculated for 110 ER and 212 AR bioactive chemicals using high throughput ToxCast data from in vitro screening assays and predictive pathway models, high-throughput toxicokinetic data, and data-driven assumptions about consumption of water. Chemical-specific AWBCs are compared with measured water concentrations in data sets from the greater Denver area, Minnesota lakes, and Oregon waters, demonstrating a framework for identifying endocrine bioactive chemicals. This approach can be used to screen potential cumulative endocrine activity in drinking water and to inform prioritization of future monitoring, chemical testing and pollution prevention efforts.

A comparison between monitoring and dispersion modeling approaches to assess the impact of aviation on concentrations of black carbon and nitrogen oxides at Los Angeles International Airport.

Aircraft activity and airport operations can increase combustion-related air pollutant concentrations, but it is difficult to distinguish aviation emissions from traffic and other local sources. Emission inventories are uncertain and dispersion models may not capture aircraft plume complexity; ambient monitoring data require detailed statistical analyses to extract aviation signals. The goal of this study is to compare two modeling approaches including monitoring-based regression models and the EDMS/AERMOD dispersion model, informing improvements and allowing quantitation of aviation impacts on air quality through multi-pollutant sensitivity and multi-monitor fate/transport analyses. Aggregate concentration comparisons are similar, though diurnal patterns show potential weaknesses in near-field dispersion, treatment of overnight conditions, and emission inventory accuracy.

Sewer Gas: An Indoor Air Source of PCE to Consider During Vapor Intrusion Investigations.

The United States Environmental Protection Agency (USEPA) is finalizing its vapor intrusion guidelines. One of the important issues related to vapor intrusion is background concentrations of volatile organic chemicals (VOCs) in indoor air, typically attributed to consumer products and building materials. Background concentrations can exist even in the absence of vapor intrusion and are an important consideration when conducting site assessments. In addition, the development of accurate conceptual models that depict pathways for vapor entry into buildings is important during vapor intrusion site assessments. Sewer gas, either as a contributor to background concentrations or as part of the site conceptual model, is not routinely evaluated during vapor intrusion site assessments. The research described herein identifies an instance where vapors emanating directly from a sanitary sewer pipe within a residence were determined to be a source of tetrachloroethylene (PCE) detected in indoor air. Concentrations of PCE in the bathroom range from 2.1 to 190 ug/m3 and exceed typical indoor air concentrations by orders of magnitude resulting in human health risk classified as an "Imminent Hazard" condition. The results suggest that infiltration of sewer gas resulted in PCE concentrations in indoor air that were nearly two-orders of magnitude higher as compared to when infiltration of sewer gas was not known to be occurring. This previously understudied pathway whereby sewers serve as sources of PCE (and potentially other VOC) vapors is highlighted. Implications for vapor intrusion investigations are also discussed.

Predictors of tris(1,3-dichloro-2-propyl) phosphate metabolite in the urine of office workers.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a flame retardant widely used in furniture containing polyurethane foam. It is a carcinogen, endocrine disruptor, and potentially neurotoxic. Our objectives were to characterize exposure of adult office workers (n=29) to TDCPP by measuring its primary metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), in their urine; measuring TDCPP in dust from their homes; offices and vehicles; and assessing possible predictors of exposure. We identified TDCPP in 99% of dust (GM=4.43µg/g) and BDCPP in 100% of urine samples (GM=408pg/mL). Concentrations of TDCPP were significantly higher in dust from vehicles (GM=12.5µg/g) and offices (GM=6.06µg/g) than in dust from the main living area (GM=4.21µg/g) or bedrooms (GM=1.40µg/g) of worker homes. Urinary BDCPP concentrations among participants who worked in a new office building were 26% of those who worked in older buildings (p=0.01). We found some evidence of a positive trend between urinary BDCPP and TDCPP in office dust that was not observed in the other microenvironments and may be related to the timing of urine sample collection during the afternoon of a workday. Overall our findings suggest that exposure to TDCPP in the work environment is one of the contributors to the personal exposure for office workers. Further research is needed to confirm specific exposure sources (e.g., polyurethane foam), determine the importance of exposure in other microenvironments such as homes and vehicles, and address the inhalation and dermal exposure pathways.

Methodological limitations may prevent the observation of non-Hodgkin's lymphoma in bioassays of polychlorinated biphenyls.

Epidemiological studies increasingly indicate that polychlorinated biphenyls (PCBs) contribute to the risk of non-Hodgkin's lymphoma (NHL). In rodent bioassays, PCBs have long been demonstrated to be liver carcinogens, and excess tumors in the thyroid, lung, and other organs have been observed in more recent studies. Leukemias and lymphomas now classified as NHL were observed in one bioassay in which a concurrent infection was also reported. Clinical and epidemiological studies show immunosuppression and inflammation are strong risk factors for NHL, and both epidemiology and toxicology studies show that PCBs are immunosuppressive and cause inflammation. We reviewed published carcinogenesis bioassays conducted using commercial PCB products, individual congeners, and congener mixtures, with a focus on bioassay protocols and immune-related observations. Based on a mode-of-action framework for PCBs, we suggest that an immune challenge in conjunction with PCB exposure may be necessary for the observation of NHL. We conclude that the lack of concordance between human epidemiology and animal bioassays with respect to NHL may simply be the result of the bioassay methodology used, and not a difference in underlying biology. The lack of concordance should not be construed as evidence that PCBs do not contribute to the risk of NHL.