Systematic update to the mammalian relative potency estimate database and development of best estimate toxic equivalency factors for dioxin-like compounds.

The World Health Organization (WHO) assesses potential health risks of dioxin-like compounds using Toxic Equivalency Factors (TEFs). This study systematically updated the relative potency (REP) database underlying the 2005 WHO TEFs and applied advanced methods for quantitative integration of study quality and dose-response. Data obtained from fifty-one publications more than doubled the size of the previous REP database (∼1300 datasets). REP quality and relevance for these data was assessed via application of a consensus-based weighting framework. Using Bayesian dose-response modeling, available data were modeled to produce standardized dose/concentration-response Hill curves. Study quality and REP data were synthesized via Bayesian meta-analysis to integrate dose/concentration-response data, author-calculated REPs and benchmark ratios. The output is a prediction of the most likely relationship between each congener and its reference as model-predicted TEF uncertainty distributions, or the 'best estimate TEF' (BE-TEF). The resulting weighted BE-TEFs were similar to the 2005 TEFs, though provide more information to inform selection of TEF values as well as to provide risk assessors and managers with information needed to quantitatively characterize uncertainty around TEF values. Collectively, these efforts produce an updated REP database and an objective, reproducible approach to support development of TEF values based on all available data.

Transcriptomic analyses of livers from mice exposed to 1,4-dioxane for up to 90 days to assess potential mode(s) of action underlying liver tumor development.

1,4-Dioxane is a volatile organic compound with industrial and commercial applications as a solvent and in the manufacture of other chemicals. 1,4-Dioxane has been demonstrated to induce liver tumors in chronic rodent bioassays conducted at very high doses. The available evidence for 1,4-dioxane-induced liver tumors in rodents aligns with a threshold-dependent mode of action (MOA), with the underlying mechanism being less clear in the mouse than in rats. To gain a better understanding of the underlying molecular mechanisms related to liver tumor development in mice orally exposed to 1,4-dioxane, transcriptomics analysis was conducted on liver tissue collected from a 90-day drinking water study in female B6D2F1/Crl mice (Lafranconi et al., 2020). Using tissue samples from female mice exposed to 1,4-dioxane in the drinking water at concentrations of 0, 40, 200, 600, 2,000 or 6,000 ppm for 7, 28, and 90 days, transcriptomic analyses demonstrate minimal treatment effects on global gene expression at concentrations below 600 ppm. At higher concentrations, genes involved in phase II metabolism and mitotic cell cycle checkpoints were significantly upregulated. There was an overall lack of enrichment of genes related to DNA damage response. The increase in mitotic signaling is most prevalent in the livers of mice exposed to 1,4-dioxane at the highest concentrations for 90 days. This finding aligns with phenotypic changes reported by Lafranconi et al. (2020) after 90-days of exposure to 6,000 ppm 1,4-dioxane in the same tissues. The transcriptomics analysis further supports overarching study findings demonstrating a non-mutagenic, threshold-based, mitogenic MOA for 1,4-dioxane-induced liver tumors.

A high dose mode of action for tetrabromobisphenol A-induced uterine adenocarcinomas in Wistar Han rats: A critical evaluation of key events in an adverse outcome pathway framework.

TBBPA is a non-genotoxic flame retardant used to improve fire safety in a wide variety of consumer products. Estimated human exposures to TBBPA are very low (<0.000084 mg/kg-day), relative to the doses (500 and 1000 mg/kg-day of TBBPA) administered in a recent bioassay that resulted in uterine tumors in Wistar Han rats following chronic exposure. As part of an effort to characterize the relevance of the uterine tumors to humans, data and biological knowledge relevant to the progression of events associated with TBBPA-induced uterine tumors in female rats were organized in an adverse outcome pathway (AOP) framework. Based on a review of possible MOAs for chemically induced uterine tumors and available TBBPA data sets, a plausible molecular initiating event (MIE) was the ability of TBBPA to bind to and inhibit estrogen sulfotransferases, the enzymes responsible for sulfation of estradiol. Subsequent key events in the AOP, including increased bioavailability of unconjugated estrogens in uterine tissue, would occur as a result of decreased sulfation, leading to a disruption in estrogen homeostasis, increased expression of estrogen responsive genes, cell proliferation, and hyperplasia. Available data support subsequent key events, including generation of reactive quinones from the metabolism of estrogens, followed by DNA damage that could contribute to the development of uterine tumors. Uncertainties associated with human relevance are highlighted by potential strain/species sensitivities to development of uterine tumors, as well as the characterization of a dose-dependent MIE. For the latter, it was determined that the TBBPA metabolic profile is altered at high doses (such as those used in the cancer bioassay), and thus an MIE that is only operative under repeated high dose, administration. The MIE and subsequent key events for the development of TBBPA-induced uterine tumors are not feasible in humans given differences in the kinetic and dynamic factors associated with high dose exposures in rats relative to human exposure levels to TBBPA.

Evaluation of impact of shale gas operations in the Barnett Shale region on volatile organic compounds in air and potential human health risks.

Shale gas exploration and production (E&P) has experienced substantial growth across the U.S. over the last decade. The Barnett Shale, in north-central Texas, contains one of the largest, most active onshore gas fields in North America, stretching across 5000 square miles and having an estimated 15,870 producing wells as of 2011. Given that these operations may occur in relatively close proximity to populated/urban areas, concerns have been expressed about potential impacts on human health. In response to these concerns, the Texas Commission on Environmental Quality established an extensive air monitoring network in the region. This network provides a unique data set for evaluating the potential impact of shale gas E&P activities on human health. As such, the objective of this study was to evaluate community-wide exposures to volatile organic compounds (VOCs) in the Barnett Shale region. In this current study, more than 4.6 million data points (representing data from seven monitors at six locations, up to 105 VOCs/monitor, and periods of record dating back to 2000) were evaluated. Measured air concentrations were compared to federal and state health-based air comparison values (HBACVs) to assess potential acute and chronic health effects. None of the measured VOC concentrations exceeded applicable acute HBACVs. Only one chemical (1,2-dibromoethane) exceeded its applicable chronic HBACV, but it is not known to be associated with shale gas production activities. Annual average concentrations were also evaluated in deterministic and probabilistic risk assessments and all risks/hazards were below levels of concern. The analyses demonstrate that, for the extensive number of VOCs measured, shale gas production activities have not resulted in community-wide exposures to those VOCs at levels that would pose a health concern. With the high density of active wells in this region, these findings may be useful for understanding potential health risks in other shale play regions.

Physiologically based pharmacokinetic model for humans orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in humans. Compartments were included for gastrointestinal lumen, oral mucosa, stomach, small intestinal tissue, blood, liver, kidney, bone, and a combined compartment for remaining tissues. As chronic exposure to high concentrations of Cr(VI) in drinking water cause small intestinal cancer in mice, the toxicokinetics of Cr(VI) in the upper gastrointestinal tract of rodents and humans are important for assessing internal tissue dose in risk assessment. Fasted human stomach fluid was collected and ex vivo Cr(VI) reduction studies were conducted and used to characterize reduction of Cr(VI) in human stomach fluid as a mixed second-order, pH-dependent process. For model development, toxicokinetic data for total chromium in human tissues and excreta were identified from the published literature. Overall, the PBPK model provides a good description of chromium toxicokinetics and is consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in typical humans (i.e., model predictions are within a factor of three for approximately 86% of available data). By accounting for key species differences, sources of saturable toxicokinetics, and sources of uncertainty and variation, the rodent and human PBPK models can provide a robust characterization of toxicokinetics in the target tissue of the small intestine allowing for improved health risk assessment of human populations exposed to environmentally-relevant concentrations.

Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in rats and mice following long-term oral exposure. Model compartments were included for GI lumen, oral mucosa, forestomach/stomach, small intestinal mucosa (duodenum, jejunum, ileum), blood, liver, kidney, bone, and a combined compartment for remaining tissues. Data from ex vivo Cr(VI) reduction studies were used to characterize reduction of Cr(VI) in fed rodent stomach fluid as a second-order, pH-dependent process. For model development, tissue time-course data for total chromium were collected from rats and mice exposed to Cr(VI) in drinking water for 90 days at six concentrations ranging from 0.1 to 180 mg Cr(VI)/L. These data were used to supplement the tissue time-course data collected in other studies with oral administration of Cr(III) and Cr(VI), including that from recent NTP chronic bioassays. Clear species differences were identified for chromium delivery to the target tissue (small intestines), with higher concentrations achieved in mice than in rats, consistent with small intestinal tumor formation, which was observed upon chronic exposures in mice but not in rats. Erythrocyte:plasma chromium ratios suggest that Cr(VI) entered portal circulation at drinking water concentrations equal to and greater than 60 mg/L in rodents. Species differences are described for distribution of chromium to the liver and kidney, with liver:kidney ratios higher in mice than in rats. Overall, the PBPK model provides a good description of chromium toxicokinetics, with model predictions for tissue chromium within a factor of 3 for greater than 80% of measurements evaluated. The tissue data and PBPK model predictions indicate a concentration gradient in the small intestines (duodenum > jejunum > ileum), which will be useful for assessing the tumor response gradient observed in mouse small intestines in terms of target tissue dose. The rodent PBPK model presented here, when used in conjunction with a human PBPK model for Cr(VI), should provide a more robust characterization of species differences in toxicokinetic factors for assessing the potential risks associated with low-dose exposures of Cr(VI) in human populations.

Reduction of a large fish tissue analyte database: identifying and assessing data specific to a remediation site for risk assessment application.

The Lower Passaic River (LPR) is one of the most heavily industrialized waterways in the US with both historical and continuing discharges of chemicals from point and non-point sources. Significant efforts have been initiated on behalf of public, private, and regulatory entities to restore this degraded urban river. Considerable attention has been devoted to characterizing environmental media with respect to human and ecological risk. As part of these efforts, a wealth of environmental data have been collected and analyzed for a variety of metals, pesticides, organic compounds, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins/furans (PCDD/Fs), and dioxin-like compounds. The objectives of the study described in this paper were two-fold: (1) to generate LPR-specific data for use in human health risk assessment by characterizing concentrations of contaminants in LPR fish tissue samples based on publicly available data using a methodical and transparent approach, and (2) using the resulting data, to calculate the contaminant concentrations in a "Representative Fish," which is a representation of proportional fish tissue concentrations calculated based upon consumption patterns of LPR anglers. The data reduction, processing, and analyses described provide a representative dataset for the conduct of a human health assessment associated with fish consumption from the LPR.

Assessment of human health risks posed by consumption of fish from the Lower Passaic River, New Jersey.

The Lower Passaic River (LPR) in New Jersey has been impacted by variety of human activities over the course of the last two centuries. In this risk assessment, we assessed potential human health risks associated with consumption of fish from the LPR, the human exposure pathway of greatest concern when addressing contaminated sediments. Our risk assessment incorporates fish consumption information gathered during a year-long, intercept-style creel angler survey and representative fish tissue concentrations for 156 chemicals of potential concern (COPCs) obtained from USEPA's public database (OurPassaic website: http://www.ourpassaic.org/projectsites/premis_public/index.cfm?fuseaction=contaminants). Due to the large number of COPCs investigated, this risk assessment was divided into two phases: (1) identification of COPCs that contribute to the majority of overall excess cancer risk and hazard estimates using deterministic and probabilistic methods, and (2) probabilistic characterization of risk using distributions of chemical concentration and cooking loss for those compounds identified in Phase 1. Phase 1 relied on point estimates of COPC concentrations and demonstrated that PCDD/Fs and PCBs (dioxin-like and non-dioxin-like) are the greatest contributors to cancer risk, while non-dioxin-like PCBs are the primary contributors to non-cancer hazard estimates. Total excess cancer risks for adult and child and receptors estimated in Phase 1 were within USEPA's acceptable excess cancer risk range, with the exception of RME child (3.0 x 10(-4) and 1.3 x 10(-4) for deterministic and probabilistic approaches, respectively). Phase 2 focused on PCDD, PCDF, and PCBs and used distributions of chemical concentrations in fish. The results showed that all excess cancer risk estimates were within the acceptable risk range, although non-cancer hazard estimates for PCBs slightly exceeded a Hazard Index of 1. This HHRA of LPR fish ingestion represents the most comprehensive evaluation conducted to date, and demonstrates that measured concentrations of COPCs are not likely to pose a health risk to people who currently consume fish from the LPR.

Assessment of potential human health risks posed by benzene in beverages.

A recent study by the U.S. Food and Drug Administration (FDA) indicated that some beverages contained benzene at levels above the federal drinking water standard of 5 parts per billion (ppb). In tests conducted by the FDA, Crystal Light Sunrise Classic Orange (CLSCO) was reported to contain benzene levels as high as 87.9 ppb. The purpose of the present study was to better characterize benzene concentrations in CLSCO and to quantify potential human health risks. Twenty-eight samples of CLSCO were obtained from retail stores in Houston, Tex., U.S.A. The mean benzene concentrations in 16 oz original and new formulation bottles were 90 and 0.18 ppb, respectively, while 64-oz bottles contained an average of 3.38 ppb. A variety of exposure scenarios were evaluated to determine potential health risks using both deterministic and probabilistic techniques. In the deterministic analyses, upper bound point estimate cancer risks ranged from 5.4E-6 to 8.7E-8, while hazard indices (HI) ranged from 0.28 to 0.00104. Probabilistic analyses were conducted to develop more realistic cancer risk estimates. In these analyses, the 50th and 95th percentile cancer risk estimates were 3.7E-6 and 8.0E-6, and the 50th and 95th percentile hazard indices were 0.19 and 0.42, respectively. In conclusion, all cancer risk estimates and noncancer hazards met the typical health risk benchmarks established by the U.S. regulatory agencies (1E-4 to 1E-6 for cancer and hazard indices less than 1.0).

Risk of gastrointestinal disease associated with exposure to pathogens in the sediments of the Lower Passaic River.

High levels of pathogenic microorganisms have been documented previously in waters of the Lower Passaic River in northern New Jersey. The purpose of this study was to characterize the microbial contamination of river sediments near combined sewer overflows (CSOs), a known source of pathogens. Concentrations of fecal coliform, total coliform, fecal Streptococcus, fecal Enterococcus, Pseudomonas aeruginosa, Staphylococcus aureus, Giardia lamblia, and Cryptosporidium parvum organisms were measured in 16 samples from three mudflat locations along the Lower Passaic River, as well as from an upstream location. Selected samples were also analyzed for antibiotic resistance. All of the samples contained high concentrations of total coliform, fecal coliform, fecal Streptococcus, and fecal Enterococcus organisms. Analysis of isolates of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli from several samples indicated that each strain was resistant to at least one antibiotic typically used in clinical settings. Eight of 16 samples contained Giardia, and one sample contained Cryptosporidium. With these sampling data, a quantitative microbial risk assessment was conducted to evaluate the probability of infection or illness resulting from incidental ingestion of contaminated sediments over a 1-year period. Three potential exposure scenarios were considered: visitor, recreator, and homeless person. Single-event risk was first evaluated for the three individual exposure scenarios; overall risk was then determined over a 1-year period using Monte Carlo techniques to characterize uncertainty. For fecal Streptococcus and Enterococcus, annualized risk estimates for gastrointestinal illness ranged from approximately 0.42 to 0.53 for recreators, 0.07 to 0.10 for visitors, and 0.62 to 0.72 for homeless individuals across the three sampling locations. Annualized risk of Giardia infection ranged from 0.14 to 0.64 for recreators, 0.01 to 0.1 for visitors, and 0.30 to 0.87 for homeless individuals, across all locations where detected. Cryptosporidium was detected at one location, and the corresponding annualized risk of infection was 0.32, 0.05, and 0.51 for recreators, visitors, and homeless individuals, respectively. This risk assessment suggests that pathogen-contaminated sediments near areas of CSO discharge in the Lower Passaic River could pose a health risk to individuals coming into contact with sediments in the mudflat areas.

Development of a metabolism factor for polycyclic aromatic hydrocarbons for use in multipathway risk assessments of hazardous waste combustion facilities.

As a state authorized to permit hazardous waste combustion facilities, the Texas Natural Resource Conservation Commission (TNRCC) has conducted several site-specific, multipathway risk assessments in support of permitting actions. These risk assessments were carried out in accordance with guidance provided in U.S. Environmental Protection Agency's Human Health Risk Assessment Protocol for Hazardous Waste Combustion Facilities, Peer Review Draft (HHRAP). This protocol uses a prospective, screening-level, risk assessment paradigm and incorporates conservative default assumptions. In conducting such risk assessments, staff of the Toxicology and Risk Assessment Section have found that modeled emissions of polycyclic aromatic hydrocarbons (PAHs) at concentrations near or below detectable levels can produce unacceptable risk in the "farmer" exposure scenario. In accordance with recommendations in HHRAP, the TNRCC followed a tiered approach, whereby additional site-specific information is incorporated in place of standard default assumptions in cases where the initial screening-level risk assessment yielded unacceptable risk or hazard. Sensitivity analyses indicated that one of the key parameters affecting the risk estimates for PAHs in the farmer exposure scenario was the way in which PAHs were modeled up through the food chain. Therefore, refinement of the model focused on the development of a PAH-specific metabolism factor, as described in the article.

Two approaches for assessing human safety of disperse blue 1.

Disperse Blue 1 is an anthraquinone dye used at low levels in semipermanent hair color formulations. Dietary administration of Disperse Blue 1 in a National Toxicology Program (NTP) carcinogenesis bioassay produced transitional- and squamous-cell tumors, leiomyomas, and leiomyosarcomas of the urinary bladders of male and female F344/N rats. The occurrence of tumors in the urinary bladder of rats was associated with urothelial hyperplasia and the presence of urinary calculi. Despite the occurrence of urinary bladder calculi and other nonneoplastic changes, there was no evidence of urinary bladder carcinogenesis in B6C3F1 mice fed Disperse Blue in the diet for up to 2 years. A study conducted in rats of the same strain by Burnett and Squire confirmed the occurrence of calculi and transitional-cell neoplasms in the rat bladder. However, no mesenchymal-cell tumors were detected at a comparable dietary level. Further, Burnett and Squire found evidence of reversibility of the proliferative changes in the rat urinary bladder following cessation of treatment at 6 months. Disperse Blue 1 has been tested in a variety of in vivo and in vitro genotoxicity assays and was negative in vivo but produced a weak and mixed pattern of genotoxic responses in vitro which may be attributable to a constituent of the commercial preparations. Evaluation of the available data for Disperse Blue 1 and comparison with the responses observed in the urinary bladders of rats administered other rodent bladder carcinogens considered to act through a secondary mechanism indicate that a threshold approach is appropriate for assessing risk. With this approach, an uncertainty factor of 1000 applied to the no-observed-adverse-effect level in the NTP bioassay yielded a safe exposure level of 45-56 micrograms/kg/day. In contrast, with a conventional quantitative risk assessment approach, the exposure level corresponding to an upper limit on lifetime risk of 10(-6) to 10(-5) was 0.39 to 3.9 micrograms/kg/day, respectively. The safe level of Disperse Blue 1 derived using the threshold approach is approximately 20 times greater than the maximum average daily applied dose of 2.7 micrograms/kg/day associated with its use in semipermanent hair color formulations, while the exposure associated with the 10(-5) risk level using the linearized multistage model in the conventional approach was determined to be 1.5 times greater. Because oral absorption is substantially more than dermal absorption, the actual margin of safety is most likely much greater than either of these comparisons suggests.(ABSTRACT TRUNCATED AT 400 WORDS)

Generally recognized as safe (GRAS) evaluation of 4-hexylresorcinol for use as a processing aid for prevention of melanosis in shrimp.

4-Hexylresorcinol (C12H18O2) is proposed for use as a processing aid for prevention of melanosis ("black spot") in shrimp and as an alternative to the currently approved sulfites. A safety evaluation was conducted to affirm, based upon scientific procedures, the generally recognized as safe ("GRAS") status of 4-hexylresorcinol for proposed use. The GRAS safety evaluation compiled, reviewed, and analyzed data on the following areas: chemical identity, analytical methodology, historical and proposed uses, functionality, and safety. The publicly available safety data on 4-hexylresorcinol cover a broad range of potential toxicity concerns including acute and subacute toxicity, subchronic toxicity, carcinogenicity, mutagenicity, and allergenicity. These studies, along with the aforementioned data, demonstrate that 4-hexylresorcinol presents no risk of toxicity at the levels proposed for treatment of shrimp, and the use of 4-hexylresorcinol as a processing aid to prevent melanosis in shrimp is GRAS.