A regulatory relic: After 60 years of research on cancer risk, the Delaney Clause continues to keep us in the past.

The Delaney Clause of the Federal Food, Drug, and Cosmetic Act became law in 1958 because of concerns that potentially harmful chemicals were finding their way into foods and causing cancer. It states, "[n]o additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal." The United States Food and Drug Administration (US FDA) and United States Environmental Protection Agency (US EPA, prior to implementation of the Food Quality Protection Act) were charged with implementing this clause. Over 60 years, advances in cancer research have elucidated how chemicals induce cancer. Significant advancements in analytical methodologies have allowed for accurate and progressively lower detection limits, resulting in detection of trace amounts. Based on current scientific knowledge, there is a need to revisit the Delaney Clause's utility. The lack of scientific merit to the Delaney Clause was very apparent when recently the US FDA had to revoke the food additive approvals of 6 synthetic flavoring substances because high dose testing in animals demonstrated a carcinogenic response. However, US FDA determined that these 6 synthetic flavoring substances do not pose a risk to public health under the conditions of intended use. The 7th substance, styrene, was de-listed because it is no longer used by industry. The scientific community is committed to improving public health by promoting relevant science in risk assessment and regulatory decision making, and this was discussed in scientific sessions at the American Association for the Advancement of Science (AAAS) 2020 Annual Meeting and the Society of Toxicology (SOT) 2019 Annual Meeting. Expert presentations included advances in cancer research since the 1950s; the role of the Delaney Clause in the current regulatory paradigm with a focus on synthetic food additives; and the impact of the clause on scientific advances and regulatory decision making. The sessions concluded with panel discussions on making the clause more relevant based on 21st-century science.

US EPA's regulatory pesticide evaluations need clearer guidelines for considering mammary gland tumors and other mammary gland effects.

Breast cancer risk from pesticides may be missed if effects on mammary gland are not assessed in toxicology studies required for registration. Using US EPA's registration documents, we identified pesticides that cause mammary tumors or alter development, and evaluated how those findings were considered in risk assessment. Of 28 pesticides that produced mammary tumors, EPA's risk assessment acknowledges those tumors for nine and dismisses the remaining cases. For five pesticides that alter mammary gland development, the implications for lactation and cancer risk are not assessed. Many of the mammary-active pesticides activate pathways related to endocrine disruption: altering steroid synthesis in H295R cells, activating nuclear receptors, or affecting xenobiotic metabolizing enzymes. Clearer guidelines based on breast cancer biology would strengthen assessment of mammary gland effects, including sensitive histology and hormone measures. Potential cancer risks from several common pesticides should be re-evaluated, including: malathion, triclopyr, atrazine, propylene oxide, and 3-iodo-2-propynyl butylcarbamate (IPBC).

Assessment of metal contamination and the associated human health risk from dustfall deposition: a study in a mid-sized town in India.

It is evident from the past studies that dust fallout is a severe concern due to its impact to urban air quality and public health. This study mainly examines the spatial and seasonal variation of dustfall at ambient levels and chemical characterization of its insoluble fraction for Kharagpur Town, India. Dustfall samples were collected monthly for 1 year (July 2014 to June 2015) from four sampling sites. The results showed that the maximum dustfall deposition is found during summer (March to June) and in the range of 2.01 ± 0.36 to 15.74 ± 3.83 ton km-2 month-1, and minimum deposition is during monsoon season (July to October) in the range of 0.42 ± 0.72 to 7.38 ± 5.8 ton km-2 month-1. Selected metals like Sc, V, Cr, Co, Ni, Zn, Y, Zr, Ce, Hf, and Pb were analyzed using the high-resolution inductively coupled mass spectrometer (HR-ICP-MS) technique, and the contamination level of heavy metals was assessed using the geoaccumulation index (Igeo) and enrichment factor (EF). To estimate the sources for the metallic contaminants, principal component analysis (PCA) was conducted. The US EPA health risk assessment model was applied to determine the hazard index and hazard quotient values. The results show the significant level of enrichment for Pb (EF = 41.79) and Cr (EF = 4.39). The Igeo values point out moderate contamination by Pb (Igeo = 2.01) and Cr (Igeo = 1.6) in Kharagpur Town. This study suggests that in the context of noncancer risk of heavy metals as determined by the hazard index (HI) and hazard quotient (HQ) values, ingestion is the main source of exposure to dust in adults and children followed by dermal contact. Considering the inhalation route, carcinogenic risk level of Cr, Co, and Ni for adults and children is lower than the EPA's safe limit (10-6 to 10-4), indicating that cancer risk of these metals due to exposure to dustfall in Kharagpur is negligible.

Viewing evidence of harm accompanying uses of glyphosate-based herbicides under US legal requirements.

Some epidemiological experts feel there is sufficient proof that glyphosate use adversely affects human health, and glyphosate has been labeled as probably carcinogenic by the International Agency for Research on Cancer. Federal law in the United States provides two major options under which health concerns about glyphosate use might be addressed. First, registrations of glyphosate-based herbicides (GBHs) need to be cancelled if the costs are greater that its benefits. Since the cancellation of GBH registrations in the United States would lead to higher maize and soybean prices that would adversely affect food security, further analyses are needed. Second, US law requires consideration of the human dietary risk from pesticide residues, and tolerances of allowable amounts of glyphosate residues allowed to remain in or on food items have been established. Social cost curves depicting three options for regulating GBHs show preferred strategies dependent upon the magnitude of adverse effects on human health and food insecurity. Measures to reduce harm to humans can be identified to ameliorate health damages to allow some uses of GBHs to continue, but only if the evidence supports the conclusion that "no harm will result from aggregate exposure to the pesticide chemical residue."

"Ain't Necessarily So!": The Brake Industry's Impact on Asbestos Regulation in the 1970s.

Canada is proposing a ban on asbestos, and the US Environmental Protection Agency has listed it among the first 10 materials it is investigating under the new Toxic Substances Control Act revisions. However, this effort is currently running up against enormous industry and political opposition. Here, we detail the activities in the early 1970s of the Friction Materials Standards Institute, an industry trade association, to stifle earlier attempts to regulate asbestos use in brake linings, one of the oldest and most obvious sources of asbestos exposure to mechanics, among others. (Am J Public Health. 2017: 1395-1399. doi: 10.2105/AJPH.2017.303901).

Gasoline toxicology: overview of regulatory and product stewardship programs.

Significant efforts have been made to characterize the toxicological properties of gasoline. There have been both mandatory and voluntary toxicology testing programs to generate hazard characterization data for gasoline, the refinery process streams used to blend gasoline, and individual chemical constituents found in gasoline. The Clean Air Act (CAA) (Clean Air Act, 2012: § 7401, et seq.) is the primary tool for the U.S. Environmental Protection Agency (EPA) to regulate gasoline and this supplement presents the results of the Section 211(b) Alternative Tier 2 studies required for CAA Fuel and Fuel Additive registration. Gasoline blending streams have also been evaluated by EPA under the voluntary High Production Volume (HPV) Challenge Program through which the petroleum industry provide data on over 80 refinery streams used in gasoline. Product stewardship efforts by companies and associations such as the American Petroleum Institute (API), Conservation of Clean Air and Water Europe (CONCAWE), and the Petroleum Product Stewardship Council (PPSC) have contributed a significant amount of hazard characterization data on gasoline and related substances. The hazard of gasoline and anticipated exposure to gasoline vapor has been well characterized for risk assessment purposes.

A review and critique of U.S. EPA's risk assessments for asbestos.

U.S. Environmental Protection Agency (EPA) recently conducted a risk assessment for exposure to Libby amphibole asbestos that is precedent-setting for two reasons. First, the Agency has not previously conducted a risk assessment for a specific type of asbestos fiber. Second, the risk assessment includes not only an inhalation unit risk (IUR) for the cancer endpoints, but also a reference concentration (RfC) for nonmalignant disease. In this paper, we review the procedures used by the Agency for both cancer and nonmalignant disease and discuss the strengths and limitations of these procedures. The estimate of the RfC uses the benchmark dose method applied to pleural plaques in a small subcohort of vermiculite workers in Marysville, Ohio. We show that these data are too sparse to inform the exposure-response relationship in the low-exposure region critical for estimation of an RfC, and that different models with very different exposure-response shapes fit the data equally well. Furthermore, pleural plaques do not represent a disease condition and do not appear to meet the EPA's definition of an adverse condition. The estimation of the IUR for cancer is based on a subcohort of Libby miners, discarding the vast majority of lung cancers and mesotheliomas in the entire cohort and ignoring important time-related factors in exposure and risk, including effect modification by age. We propose that an IUR based on an endpoint that combines lung cancer, mesothelioma, and nonmalignant respiratory disease (NMRD) in this cohort would protect against both malignant and nonmalignant disease. However, the IUR should be based on the entire cohort of Libby miners, and the analysis should properly account for temporal factors. We illustrate our discussion with our own independent analyses of the data used by the Agency.

Advancing human health risk assessment: integrating recent advisory committee recommendations.

Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose-response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose-response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches.

Animal use and lessons learned in the U.S. High Production Volume Chemicals Challenge Program.

BACKGROUND: Launched by the U.S. Environmental Protection Agency (EPA) in 1998, the High Production Volume (HPV) Challenge Program was developed to address the perceived gap in basic hazard information for the 2,800 chemicals produced or imported into the United States in quantities of ≥ 1 million pounds per year. Health and environmental effects data obtained from either existing information or through new vertebrate animal testing were voluntarily submitted by chemical companies (sponsors) to the U.S. EPA. Despite the potential for extensive animal testing, animal welfare guidelines were not provided until after the start of the program. OBJECTIVES: We evaluated compliance with the animal welfare principles that arose from an agreement reached between the U.S. EPA and animal protection organizations and tracked the HPV program's use of animals for testing. DISCUSSION: Under a worst-case scenario, the HPV program had the potential to consume 3.5 million animals in new testing. After application of animal-saving measures, approximately 127,000 were actually used. Categorization of chemicals based on similar structure-activity and application of read-across, along with use of existing test data, were the most effective means of reducing animal testing. However, animal-saving measures were inconsistently used by both sponsors and the U.S. EPA. CONCLUSIONS: Lessons learned from the HPV program can be applied to future programs to minimize animal testing and promote more human-relevant chemical risk assessment.

Potential air toxics hot spots in truck terminals and cabs.

INTRODUCTION: Hot spots are areas where concentrations of one or more air toxics--organic vapors or particulate matter (PM)--are expected to be elevated. The U.S. Environmental Protection Agency's (EPA*) screening values for air toxics were used in our definition of hot spots. According to the EPA, a screening value "is used to indicate a concentration of a chemical in the air to which a person could be continually exposed for a lifetime ... and which would be unlikely to result in a deleterious effect (either cancer or noncancer health effects)" (U.S. EPA 2006). Our characterization of volatile organic compounds (VOCs; namely 18 hydrocarbons, methyl tert-butyl ether [MTBE], acetone, and aldehydes) was added onto our ongoing National Cancer Institute-funded study of lung cancer and particulate pollutant concentrations (PM with an aerodynamic diameter < or = 2.5 microm [PM2.5], elemental carbon [EC], and organic carbon [OC]) and source apportionment of the U.S. trucking industry. We focused on three possible hot spots within the trucking terminals: upwind background areas affected by nearby industrial parks; downwind areas affected by upwind and terminal sources; and the loading docks and mechanic shops within terminal as well as the interior of cabs of trucks being driven on city, suburban, and rural streets and on highways. METHODS: In Phase 1 of our study, 15 truck terminals across the United States were each visited for five consecutive days. During these site visits, sorbent tubes were used to collect 12-hour integrated samples of hydrocarbons and aldehydes from upwind and downwind fence-line locations as well as inside truck cabs. Meteorologic data and extensive site information were collected with each sample. In Phase 2, repeat visits to six terminals were conducted to test the stability of concentrations across time and judge the representativeness of our previous measurements. During the repeat site visits, the sampling procedure was expanded to include real-time sampling for total hydrocarbon (HC) and PM2.5 at the terminal upwind and downwind sites and inside the truck cabs, two additional monitors in the yard for four-quadrant sampling to better characterize the influence of wind, and indoor sampling in the loading dock and mechanic shop work areas. RESULTS: Mean and median concentrations of VOCs across the sampling locations in and around the truck terminals showed significant variability in the upwind concentrations as well as in the intensity of exposures for drivers, loading-dock workers, and mechanics. The area of highest concentrations varied, although the lowest concentrations were always found in the upwind background samples. However, the downwind samples, which included the terminal's contribution, were on average only modestly higher than the upwind samples. In the truck terminal, the mechanic-shop-area concentrations were consistently elevated for many of the VOCs (including the xylenes, alkanes, and acetone) and particulates; the loading-dock concentrations had relatively high concentrations of 1,3-butadiene, formaldehyde, and acetaldehyde; and nonsmoking driver exposures were elevated for benzene, MTBE, styrene, and hexane. Also, the loading dock and yard background concentrations for EC and PM2.5 were highly correlated with many of the VOCs (50% of pairs tested with Spearman r > 0.5 and 75% with r > 0.4); in the mechanic shop VOCs were correlated with EC but not PM2.5 (r = 0.4-0.9 where significant); and for driver exposures VOC correlations with EC and PM2.5 were relatively low, with the exception of a few aromatics, primarily benzene (r = 0.4-0.5). A principal component analysis of background source characteristics across the terminal locations that had repeat site visits identified three different groupings of variables (the "components"). This analysis suggested that a strong primary factor for hydrocarbons (alkanes and aromatics) was the major contributor to VOC variability in the yard upwind measurement. Aldehydes and acetone, which loaded onto the second and third components, were responsible for a smaller contribution to VOC variability. A multi-layer exposure model was constructed using structural equation modeling techniques that significantly predicted the yard upwind concentrations of individual VOCs as a function of wind speed, road proximity, and regional location (R2 = 0.5-0.9). This predicted value for the yard background concentration was then used to calculate concentrations for the loading dock and mechanic shop. Finally, we conducted a detailed descriptive analysis of the real-time data collected in the yard and in truck cabs during the six repeat site visits, which included more than 50 12-hour sessions at each sampling location. The real-time yard monitoring results suggested that under some conditions there was a clear upwind-to-downwind trend indicating a terminal contribution, which was not apparent in the integrated sampling data alone. They also suggested a nonlinear relationship with wind speed: calm conditions (wind speed < 2 mph) were associated with erratic upwind-downwind differences, lower wind speeds (2 to 10 mph) favored transport with little dilution, and higher wind speeds (> 10 mph) favored dilution and dispersal (more so for VOCs than for PM). Finally, an analysis of the real-time data for driver exposures in trucks with a global positioning system (GPS) matched with geographic information system (GIS) data suggested a clear influence of traffic and industrial sources along a given route with peaks in driver exposures. These peaks were largely associated with traffic, major intersections, idling at the terminals, and pickup and delivery (P&D) periods. However, VOCs and PM2.5 had different exposure patterns: VOCs exposures increased when the vehicle was stopped, and PM2.5 exposures increased during travel in traffic. CONCLUSIONS: All three types of testing sites--upwind and downwind fence-line locations and inside truck cabs while in heavy traffic--met the established definition for a hot spot by having periods with concentrations of pollutants that exceeded the EPA's screening values. Most frequently, the pollutants with concentrations exceeding the screening values were formaldehyde, acetaldehyde, and EC (which serves as a marker for diesel particulate); less frequently they were 1,3-butadiene and benzene. In the case of the downwind location of a single truck terminal without an aggregation of other sources, high concentrations of VOCs and PM were infrequent. Using structural equation modeling, a model was developed that could identify combinations of conditions and factors likely to produce hot spots. Source apportionment analyses showed that EC came predominantly from diesel emissions. As expected from the sites studied, organic vapors associated with vehicle emissions (C6-C8 alkanes and aromatics) were the predominant components of VOCs, followed by formaldehyde and acetaldehyde. For driver exposures, high VOC values were associated with stopped vehicles, and high PM2.5 values were associated with conditions during driving.

Comparison of methods of estimation of lifetime cancer risk due to chronic exposure to transuranics.

The cancer risk due to chronic transuranic intakes is properly calculated using an integration over multiple years of intake of the annual effective dose rates arising each year following an intake multiplied by age-dependent risk functions for the year during which the dose is actually received. Approximate computations of risk involving sums of the products of committed effective dose and the age-dependent risk functions for each year of intake indicate the appropriateness of the committed effective dose as a surrogate quantity for risk when applied to different circumstances. The assumptions that all dose is received at the time of intake with committed effective dose and that risk is uniform over a range of ages both lead to a misuse of the available age-dependent risk functions and thus contribute to a divergence from the true risk associated with an intake over multiple years. Comparison of the correctly integrated risk functions with the approximations gives insights into how the current committed effective dose models used for regulatory purposes are not necessarily indicative of the risk for chronic intakes of radionuclides with long biological and radiological half-lives. A summary and comparison of such computations for transuranic intakes was prepared for the ingestion of water and the inhalation of different particle sizes by both males and females. Risk results for committed effective dose consistently overestimated risks by approximately 100% for all transuranics for ingestion models and approximately 75% for all transuranics for Type M inhalation models considering age-dependent risk models. For constant risk as a function of age, the committed effective dose integration underestimated the actual risk situation by nearly 60% for ingestion and 50% for Type M inhalation during the first 20 y.

Toxic tale: an 'enviro' learns why we need tighter controls on home pesticide use.

She had her house sprayed for fleas and then suffered a severe autoimmune reaction to the chemicals. Now she argues for tighter controls.

Human health and the environment can't wait for reform: current opportunities for the federal government and states to address chemical risks under the Toxic Substances Control Act.

Expressing its concern about growing rates of cancer and other diseases, coupled with the lack of data about the effect of the thousands of chemicals used in U.S. society, in 1976 Congress enacted the Toxic Substances Control Act (TSCA). Congress intended for TSCA to shed new light on chemical risks and provide the U.S. Environmental Protection Agency (EPA) with a set of tools to address those risks and protect human health and the environment. In the years since TSCA's passage, the procedural hurdles and the difficult-to-meet legal standards built into the statute, along with a court decision rejecting EPA's use of its authority to ban dangerous chemicals, have impeded EPA's ability to regulate chemical use and manufacture. This Comment argues that both the EPA and state governments have the authority to act now to address the risks posed by dangerous chemicals. By utilizing certain sections of the statute in new and aggressive ways, EPA can effectively address chemical risks. Further, this Comment argues that TSCA's preemption provision affords states leeway to continue to regulate the use of chemicals within their borders. Though reform of TSCA is necessary, EPA and states can effectively protect against chemical risks in the near-term by using the full extent of their authority under the current law.