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.

Charting a Path Forward: Assessing the Science of Chemical Risk Evaluations under the Toxic Substances Control Act in the Context of Recent National Academies Recommendations.

BACKGROUND: In 2016, Congress enacted the Frank R. Lautenberg Chemical Safety for the 21st Century Act ("the Lautenberg Act"), which made major revisions to the main U.S. chemical safety law, the 1976 Toxic Substances Control Act (TSCA). Among other reforms, the Lautenberg Act mandates that the U.S. Environmental Protection Agency (U.S. EPA) conduct comprehensive risk evaluations of chemicals in commerce. The U.S. EPA recently finalized the first set of such chemical risk evaluations. OBJECTIVES: We examine the first 10 TSCA risk evaluations in relation to risk science recommendations from the National Academies to determine consistency with these recommendations and to identify opportunities to improve future TSCA risk evaluations by further implementing these key approaches and methods. DISCUSSION: Our review of the first set of TSCA risk evaluations identified substantial deviations from best practices in risk assessment, including overly narrow problem formulations and scopes; insufficient characterization of uncertainty in the evidence; inadequate consideration of population variability; lack of consideration of background exposures, combined exposures, and cumulative risk; divergent approaches to dose-response assessment for carcinogens and noncarcinogens; and a flawed approach to systematic review. We believe these deviations result in underestimation of population exposures and health risks. We are hopeful that the agency can use these insights and have provided suggestions to produce chemical risk evaluations aligned with the intent and requirements of the Lautenberg Act and the best available science to better protect health and the environment-including the health of those most vulnerable to chemical exposures. https://doi.org/10.1289/EHP9649.

The effect of the Environmental Protection Agency maximum contaminant level on arsenic exposure in the USA from 2003 to 2014: an analysis of the National Health and Nutrition Examination Survey (NHANES).

Background: The current US Environmental Protection Agency (EPA) maximum contaminant level (MCL) for arsenic in public water systems (10 µg/L) took effect in 2006. Arsenic is not federally regulated in private wells. The impact of the 2006 MCL on arsenic exposure in the US, as confirmed through biomarkers, is presently unknown. We evaluated national trends in water arsenic exposure in the US, hypothesizing that urinary arsenic levels would decrease over time among participants using public water systems but not among those using well water. We further estimated the expected number of avoided lung, bladder, and skin cancer cases. Methods: We evaluated 14,127 participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2014 with urinary dimethylarsinate (DMA) and total arsenic available. To isolate water exposure, we expanded a residual-based method to remove tobacco and dietary contributions of arsenic. We applied EPA risk assessment approaches to estimate the expected annual number of avoided cancer cases comparing arsenic exposure in 2013-2014 vs. 2003-2004. Findings: Among public water users, fully adjusted geometric means (GMs) of DMA decreased from 3.01 µg/L in 2003-2004 to 2.49 µg/L in 2013-2014 (17% reduction; 95% confidence interval 10%, 24%; p-trend<0.01); no change was observed among well water users (p-trend= 0.35). Assuming these estimated exposure reductions will remain similar across a lifetime, we estimate a reduction of 200 to 900 lung and bladder cancer cases per year depending on the approach used. Interpretation: The decline in urinary arsenic among public water but not private well users in NHANES 2003-2014 indicates that the implementation of the current MCL has reduced arsenic exposure in the US population. Our study supports prior work showing that well water users are inadequately protected against drinking water arsenic, and confirms the critical role of federal drinking water regulations in reducing toxic exposures and protecting human health. Funding: This work was supported by the National Institute of Environmental Health Sciences (1R01ES025216, R01ES021367, 5P30ES009089 and P42ES010349). A. E. Nigra was supported by 5T32ES007322.

Mitigating dietary arsenic exposure: Current status in the United States and recommendations for an improved path forward.

Inorganic arsenic (iAs) is a well-characterized carcinogen, and recent epidemiologic studies have linked chronic exposures to non-cancer health outcomes, including cardiovascular disease, diabetes, skin lesions and respiratory disorders. Greater vulnerability has been demonstrated with early life exposure for health effects including lung and bladder cancer, immunotoxicity and neurodevelopment. Despite its well-known toxicity, there are important gaps in the regulatory oversight of iAs in food and in risk communication. This paper focuses on the US regulatory framework in relation to iAs in food and beverages. The state of existing regulatory agency toxicological assessments, monitoring efforts, standard setting, intervention policies and risk communication are explored. Regarding the approach for standard setting, risk-based evaluations of iAs in particular foods can be informative but are insufficient to create a numeric criterion, given current uncertainties in iAs toxicology and the degree to which traditional risk targets can be exceeded by dietary exposures. We describe a process for prioritizing dietary exposures for different lifestages and recommend a relative source contribution-based approach to setting criteria for arsenic in prioritized foods. Intervention strategies begin with an appropriately set criterion and a monitoring program that documents the degree to which this target is met for a particular food. This approach will promote improvements in food production to lower iAs contamination for those foods which initially do not meet the criterion. Risk communication improvements are recommended to ensure that the public has reliable information regarding sources and alternative dietary choices. A key recommendation is the consideration of meal frequency advice similar to what is currently done for contaminants in fish. Recent action level determinations by FDA for apple juice and infant rice cereal are evaluated and used as illustrations of how our recommended approach can further the goal of exposure mitigation from key sources of dietary iAs in the US.

Nitarsone, Inorganic Arsenic, and Other Arsenic Species in Turkey Meat: Exposure and Risk Assessment Based on a 2014 U.S. Market Basket Sample.

BACKGROUND: Use of nitarsone, an arsenic-based poultry drug, may result in dietary exposures to inorganic arsenic (iAs) and other arsenic species. Nitarsone was withdrawn from the U.S. market in 2015, but its use in other countries may continue. OBJECTIVES: We characterized the impact of nitarsone use on arsenic species in turkey meat and arsenic exposures among turkey consumers, and we estimated cancer risk increases from consuming turkey treated with nitarsone before its 2015 U.S. withdrawal. METHODS: Turkey from three cities was analyzed for total arsenic, iAs, methylarsonate (MA), dimethylarsinate, and nitarsone, which were compared across label type and month of purchase. Turkey consumption was estimated from NHANES data to estimate daily arsenic exposures for adults and children 4-30 months of age and cancer risks among adult consumers. RESULTS: Turkey meat from conventional producers not prohibiting nitarsone use showed increased mean levels of iAs (0.64 µg/kg) and MA (5.27 µg/kg) compared with antibiotic-free and organic meat (0.39 µg/kg and 1.54 µg/kg, respectively) and meat from conventional producers prohibiting nitarsone use (0.33 µg/kg and 0.28 µg/kg, respectively). Samples with measurable nitarsone had the highest mean iAs and MA (0.92 µg/kg and 10.96 µg/kg, respectively). Nitarsone was higher in October samples than in March samples, possibly resulting from increased summer use. Based on mean iAs concentrations in samples from conventional producers with no known policy versus policies prohibiting nitarsone, estimated lifetime daily consumption by an 80-kg adult, and a recently proposed cancer slope factor, we estimated that use of nitarsone by all turkey producers would result in 3.1 additional cases of bladder or lung cancer per 1,000,000 consumers. CONCLUSIONS: Nitarsone use can expose turkey consumers to iAs and MA. The results of our study support the U.S. Food and Drug Administration's removal of nitarsone from the U.S. market and further support its removal from the global marketplace. Citation: Nachman KE, Love DC, Baron PA, Nigra AE, Murko M, Raber G, Francesconi KA, Navas-Acien A. 2017. Nitarsone, inorganic arsenic, and other arsenic species in turkey meat: exposure and risk assessment based on a 2014 U.S. market basket sample. Environ Health Perspect 125:363-369; http://dx.doi.org/10.1289/EHP225.

Arsenic and arsenic species in shellfish and finfish from the western Arabian Gulf and consumer health risk assessment.

This study reports the levels of total arsenic and arsenic species in marine biota such as clams (Meretrix meretrix; N=21) and pearl oyster (Pinctada radiata; N=5) collected from nine costal sites in Jan 2014, and cuttlefish (Sepia pharaonis; N=8), shrimp (Penaeus semisulcatus; N=1), and seven commercially important finfish species (N=23) collected during Apr-May 2013 from seven offshore sites in the western Arabian Gulf. Total As and As species such as dimethylarsinic acid (DMA), arsenobetaine (AB), trimethylarsine oxide (TMAO), arsenocholine (AC), tetramethylarsonium ion (Tetra), arsenosugar-glycerol (As-Gly) and inorganic As (iAs) were determined by using ICPMS and HPLC/ICPMS. In bivalves, the total As concentrations ranged from 16 to 118mg/kg dry mass; the toxic iAs fraction contributed on average less than 0.8% of the total As, while the nontoxic AB fraction formed around 58%. Total As concentrations for the remaining seafood (cuttlefish, shrimp and finfish) ranged from 11 to 134mg/kg dry mass and the iAs and AB fractions contributed on average 0.03% and 81% respectively of the total As. There was no significant relationship between the tissue concentrations of total As and iAs in the samples. There was also no significant relationship between As levels in seafood and geographical location or salinity of the waters from which samples were collected. Based on our results, we recommend introducing a maximum permissible level of arsenic in seafood from the Gulf based on iAs content rather than based on total As. Our analyses of cancer risks and non-cancer hazards identified non-negligible risks and the potential for hazards; the greatest risks were identified for expatriate consumers of bivalves and high-end consumers of seafood. Despite this, many uncertainties remain that would be best addressed by further analyses.

Hazard Ranking Methodology for Assessing Health Impacts of Unconventional Natural Gas Development and Production: The Maryland Case Study.

The recent growth of unconventional natural gas development and production (UNGDP) has outpaced research on the potential health impacts associated with the process. The Maryland Marcellus Shale Public Health Study was conducted to inform the Maryland Marcellus Shale Safe Drilling Initiative Advisory Commission, State legislators and the Governor about potential public health impacts associated with UNGDP so they could make an informed decision that considers the health and well-being of Marylanders. In this paper, we describe an impact assessment and hazard ranking methodology we used to assess the potential public health impacts for eight hazards associated with the UNGDP process. The hazard ranking included seven metrics: 1) presence of vulnerable populations (e.g. children under the age of 5, individuals over the age of 65, surface owners), 2) duration of exposure, 3) frequency of exposure, 4) likelihood of health effects, 5) magnitude/severity of health effects, 6) geographic extent, and 7) effectiveness of setbacks. Overall public health concern was determined by a color-coded ranking system (low, moderately high, and high) that was generated based on the overall sum of the scores for each hazard. We provide three illustrative examples of applying our methodology for air quality and health care infrastructure which were ranked as high concern and for water quality which was ranked moderately high concern. The hazard ranking was a valuable tool that allowed us to systematically evaluate each of the hazards and provide recommendations to minimize the hazards.

Hydrocarbon Release During Fuel Storage and Transfer at Gas Stations: Environmental and Health Effects.

At gas stations, fuel is stored and transferred between tanker trucks, storage tanks, and vehicle tanks. During both storage and transfer, a small fraction of unburned fuel is typically released to the environment unless pollution prevention technology is used. While the fraction may be small, the cumulative release can be substantial because of the large quantities of fuel sold. The cumulative release of unburned fuel is a public health concern because gas stations are widely distributed in residential areas and because fuel contains toxic and carcinogenic chemicals. We review the pathways through which gasoline is chronically released to atmospheric, aqueous, and subsurface environments, and how these releases may adversely affect human health. Adoption of suitable pollution prevention technology should not only be based on equipment and maintenance cost but also on energy- and health care-saving benefits.

Hormone Use in Food Animal Production: Assessing Potential Dietary Exposures and Breast Cancer Risk.

In recent years, increasing attention has been paid to the role of hormones in breast cancer etiology, following reports that heightened levels of endogenous hormones and exposure to exogenous hormones and other endocrine-disrupting chemicals through food and the environment are associated with increased breast cancer risk. Seven hormone drugs (testosterone propionate, trenbolone acetate, estradiol, zeranol, progesterone, melengestrol acetate, and bovine somatotropin) are approved by the U.S. Food and Drug Administration for use in food animals. There is concern that these drugs or their biologically active metabolites may accumulate in edible tissues, potentially increasing the risk of exposure for consumers. To date, the potential for human exposure to residues of these compounds in animal products, as well as the risks that may result from this exposure, is poorly understood. In this paper, we discuss the existing scientific evidence examining the toxicological significance of exposure to hormones used in food animal production in relation to breast cancer risk. Through a discussion of U.S. federal regulatory programs and the primary literature, we interpret the state of surveillance for residues of hormone drugs in animal products and discuss trends in meat consumption in relation to the potential for hormone exposure. Given the lack of chronic bioassays of oral toxicity of the seven hormone compounds in the public literature and the limitations of existing residue surveillance programs, it is not currently possible to provide a quantitative characterization of risks that result from the use of hormonal drugs in food animal production, complicating our understanding of the role of dietary hormone exposure in the population burden of breast cancer.

Caramel color in soft drinks and exposure to 4-methylimidazole: a quantitative risk assessment.

Caramel color is added to many widely-consumed beverages as a colorant. Consumers of these beverages can be exposed to 4-methylimidazole (4-MEI), a potential carcinogen formed during its manufacture. California's Proposition 65 law requires that beverages containing 4-MEI concentrations corresponding to exposures that pose excess cancer risks > 1 case per 100,000 exposed persons (29 µg 4-MEI/day) carry warning labels. Using ultrahigh-performance liquid chromatography-tandem mass spectrometry, we assessed 4-MEI concentrations in 12 beverages purchased in California and a geographically distant metropolitan area (New York) in which warning labels are not required. In addition, we characterized beverage consumption by age and race/ethnicity (using weighted means calculated from logistic regressions) and assessed 4-MEI exposure and resulting cancer risks and US population cancer burdens attributable to beverage consumption. Data on beverage consumption were obtained from the National Health and Nutrition Examination Survey, dose-response data for 4-MEI were obtained from the California Environmental Protection Agency Office of Environmental Health Hazards Assessment, and data on population characteristics were obtained from the U.S. Census Bureau. Of the 12 beverages, Malta Goya had the highest 4-MEI concentration (915.8 to 963.3µg/L), lifetime average daily dose (LADD - 8.04x10-3 mg/kgBW-day), lifetime excess cancer risk (1.93x10-4) and burden (5,011 cancer cases in the U.S. population over 70 years); Coca-Cola had the lowest value of each (4-MEI: 9.5 to 11.7µg/L; LADD: 1.01x10-4 mg/kgBW-day; risk: 1.92x10-6; and burden: 76 cases). 4-MEI concentrations varied considerably by soda and state/area of purchase, but were generally consistent across lots of the same beverage purchased in the same state/area. Routine consumption of certain beverages can result in 4-MEI exposures > 29 µg/day. State regulatory standards appear to have been effective in reducing exposure to carcinogens in some beverages. Federal regulation of 4-MEI in caramel color may be appropriate.

Roxarsone, inorganic arsenic, and other arsenic species in chicken: a U.S.-based market basket sample.

BACKGROUND: Inorganic arsenic (iAs) causes cancer and possibly other adverse health outcomes. Arsenic-based drugs are permitted in poultry production; however, the contribution of chicken consumption to iAs intake is unknown. OBJECTIVES: We sought to characterize the arsenic species profile in chicken meat and estimate bladder and lung cancer risk associated with consuming chicken produced with arsenic-based drugs. METHODS: Conventional, antibiotic-free, and organic chicken samples were collected from grocery stores in 10 U.S. metropolitan areas from December 2010 through June 2011. We tested 116 raw and 142 cooked chicken samples for total arsenic, and we determined arsenic species in 65 raw and 78 cooked samples that contained total arsenic at ≥ 10 µg/kg dry weight. RESULTS: The geometric mean (GM) of total arsenic in cooked chicken meat samples was 3.0 µg/kg (95% CI: 2.5, 3.6). Among the 78 cooked samples that were speciated, iAs concentrations were higher in conventional samples (GM = 1.8 µg/kg; 95% CI: 1.4, 2.3) than in antibiotic-free (GM = 0.7 µg/kg; 95% CI: 0.5, 1.0) or organic (GM = 0.6 µg/kg; 95% CI: 0.5, 0.8) samples. Roxarsone was detected in 20 of 40 conventional samples, 1 of 13 antibiotic-free samples, and none of the 25 organic samples. iAs concentrations in roxarsone-positive samples (GM = 2.3 µg/kg; 95% CI: 1.7, 3.1) were significantly higher than those in roxarsone-negative samples (GM = 0.8 µg/kg; 95% CI: 0.7, 1.0). Cooking increased iAs and decreased roxarsone concentrations. We estimated that consumers of conventional chicken would ingest an additional 0.11 µg/day iAs (in an 82-g serving) compared with consumers of organic chicken. Assuming lifetime exposure and a proposed cancer slope factor of 25.7 per milligram per kilogram of body weight per day, this increase in arsenic exposure could result in 3.7 additional lifetime bladder and lung cancer cases per 100,000 exposed persons. CONCLUSIONS: Conventional chicken meat had higher iAs concentrations than did conventional antibiotic-free and organic chicken meat samples. Cessation of arsenical drug use could reduce exposure and the burden of arsenic-related disease in chicken consumers.

A comparative study of allowable pesticide residue levels on produce in the United States.

BACKGROUND: The U.S. imports a substantial and increasing portion of its fruits and vegetables. The U.S. Food and Drug Administration currently inspects less than one percent of import shipments. While countries exporting to the U.S. are expected to comply with U.S. tolerances, including allowable pesticide residue levels, there is a low rate of import inspections and few other incentives for compliance. METHODS: This analysis estimates the quantity of excess pesticide residue that could enter the U.S. if exporters followed originating country requirements but not U.S. pesticide tolerances, for the top 20 imported produce items based on quantities imported and U.S. consumption levels. Pesticide health effects data are also shown. RESULTS: The model estimates that for the identified items, 120 439 kg of pesticides in excess of U.S. tolerances could potentially be imported to the U.S., in cases where U.S. regulations are more protective than those of originating countries. This figure is in addition to residues allowed on domestic produce. In the modeling, the top produce item, market, and pesticide of concern were oranges, Chile, and Zeta-Cypermethrin. Pesticides in this review are associated with health effects on 13 body systems, and some are associated with carcinogenic effects. CONCLUSIONS: There is a critical information gap regarding pesticide residues on produce imported to the U.S. Without a more thorough sampling program, it is not possible accurately to characterize risks introduced by produce importation. The scenario presented herein relies on assumptions, and should be considered illustrative. The analysis highlights the need for additional investigation and resources for monitoring, enforcement, and other interventions, to improve import food safety and reduce pesticide exposures in originating countries.