Weight of evidence evaluation for chemical-induced immunotoxicity for PFOA and PFOS: findings from an independent panel of experts.

Immunotoxicity is the critical endpoint used by some regulatory agencies to establish toxicity values for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, the hypothesis that exposure to certain per- and polyfluoroalkyl substances (PFAS) causes immune dysregulation is subject to much debate. An independent, international expert panel was engaged utilizing methods to reduce bias and "groupthink". The panel concluded there is moderate evidence that PFOS and PFOA are immunotoxic, based primarily on evidence from animal data. However, species concordance and human relevance cannot be well established due to data limitations. The panel recommended additional testing that includes longer-term exposures, evaluates both genders, includes other species of animals, tests lower dose levels, assesses more complete measures of immune responses, and elucidates the mechanism of action. Panel members agreed that the Faroe Islands cohort data should not be used as the primary basis for deriving PFAS risk assessment values. The panel agreed that vaccine antibody titer is not useful as a stand-alone metric for risk assessment. Instead, PFOA and PFOS toxicity values should rely on multiple high-quality studies, which are currently not available for immune suppression. The panel concluded that the available PFAS immune epidemiology studies suffer from weaknesses in study design that preclude their use, whereas available animal toxicity studies provide comprehensive dataset to derive points of departure (PODs) for non-immune endpoints. The panel recommends accounting for potential PFAS immunotoxicity by applying a database uncertainty factor to POD values derived from animal studies for other more robustly supported critical effects.

Derivation of subacute guidance values for chemical contaminants of drinking water quality standard in Japan.

The concentration of chemicals in drinking water may transiently and accidently exceed the Drinking Water Quality Standard (DWQS). If the level of a contaminant is not expected to cause adverse effects for a limited period of exposure, immediate suspension of the water supply may not be necessary. Assessments should be conducted using subacute guidance values (SGVs). In this study, we assessed 26 chemicals for the DWQS to establish the SGVs. Principally, a key study was selected from subacute studies to derive a Subacute Reference Dose (saRfD). The SGV was calculated from the saRfD for adults (drinking water intakes: 40 mL/kg/day) and children (drinking water intakes: 150 mL/kg/day). No allocation factor was applied to derive the SGV. We established the SGV for 20 chemicals, which were 2-38 times higher than the corresponding DWQS. However, SGVs for six chemicals were the same as the corresponding DWQS. Therefore, immediate action will be required for these six accidental contaminants. Our established SGVs are useful for assessing accidental contamination.

Cannabidiol safety considerations: Development of a potential acceptable daily intake value and recommended upper intake limits for dietary supplement use.

Consumer use of hemp-derived products continues to rise, underscoring the need to establish evidence-based safety guidance. The present study sought to develop recommendations for oral upper intake limits of cannabidiol (CBD) isolate. Sufficiently robust and reliable data for this purpose were identified from published human clinical trials and guideline-compliant toxicity studies in animal models. Based on the metrics used in this assessment, a potential Acceptable Daily Intake (ADI) value of 0.43 mg/kg-bw/d (e.g., 30 mg/d for 70-kg adult) was determined for the general population based on liver effects in human studies. This value applies to the most sensitive subpopulations, including children, over a lifetime of exposure and from all sources, including food. For dietary supplements with adequate product labeling intended for use by healthy adults only, a potential Upper Intake Limit (UL) of 70 mg/d was determined based on reproductive effects in animals. For healthy adults, except those trying to conceive, or currently pregnant or lactating, a conservative dietary supplement UL of 100 mg/d was identified based on liver effects; however, as the target population excludes individuals at risk for liver injury, an alternative dietary supplement UL of 160 mg/d for this population can also be considered.

Recommended Reference Values for Risk Assessment of Oral Exposure to Copper.

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) database, the authoritative source of U.S. risk assessment toxicity factors, currently lacks an oral reference dose (RfD) for copper. In the absence of such a value, various health-based reference values for copper are available for use in risk assessment. We summarize the scientific bases and differences in assumptions among key reference values for ingested copper to guide selection of appropriate values for risk assessment. A comprehensive review of the scientific literature best supports the oral RfD of 0.04 mg/kg body weight/day derived by EPA from their Drinking Water Action Level. This value is based on acute gastrointestinal effects but is further supported by broader analysis of copper deficiency and toxicity.

Integration of Toxicogenomics and Physiologically Based Pharmacokinetic Modeling in Human Health Risk Assessment of Perfluorooctane Sulfonate.

Toxicogenomics and physiologically based pharmacokinetic (PBPK) models are useful approaches in chemical risk assessment, but the methodology to incorporate toxicogenomic data into a PBPK model to inform risk assessment remains to be developed. This study aimed to develop a probabilistic human health risk assessment approach by integrating toxicogenomic dose-response data and PBPK modeling using perfluorooctane sulfonate (PFOS) as a case study. Based on the available human in vitro and mouse in vivo toxicogenomic data, we identified the differentially expressed genes (DEGs) at each exposure paradigm/duration. Kyoto Encyclopedia of Genes and Genomes and disease ontology enrichment analyses were conducted on the DEGs to identify significantly enriched pathways and diseases. The dose-response data of DEGs were analyzed using the Bayesian benchmark dose (BMD) method. Using a previously published PBPK model, the gene BMDs were converted to human equivalent doses (HEDs), which were summarized to pathway and disease HEDs and then extrapolated to reference doses (RfDs) by considering an uncertainty factor of 30 for mouse in vivo data and 10 for human in vitro data. The results suggested that the median RfDs at different exposure paradigms were similar to the 2016 U.S. Environmental Protection Agency's recommended RfD, while the RfDs for the most sensitive pathways and diseases were closer to the recent European Food Safety Authority's guidance values. In conclusion, genomic dose-response data and PBPK modeling can be integrated to become a useful alternative approach in risk assessment of environmental chemicals. This approach considers multiple endpoints, provides toxicity mechanistic insights, and does not rely on apical toxicity endpoints.

Cadmium exposures and deteriorations of cognitive abilities: estimation of a reference dose for mixture risk assessments based on a systematic review and confidence rating.

To support a mixture risk assessment with a focus on developmental neurotoxicity we evaluated the strength of evidence for associations of cadmium exposures with declines in IQ by conducting a systematic review and confidence rating. We searched peer-reviewed studies published in English between 2012 and July 2021 and identified 15 eligible studies (11 prospective cohort studies, and 4 cross-sectional studies). Of the 10 studies that observed associations of cadmium exposure with child IQ declines, two achieved an overall "High (H)" confidence rating, five a "Medium to High (M/H)", one a "Medium (M)" and two a "Low (L)" confidence rating. Five studies did not detect significant associations between cadmium exposure and reduced cognitive ability; of these, two received a "High (H)" confidence rating, two an overall rating of "Medium to High (M/H)" and one a "Medium (M)" rating. The null findings reported by the "High (H)" and Medium to High (M/H)" studies could partly be explained by low exposures to cadmium or confounding with high levels of lead. By using a one-compartment toxicokinetic model in a reverse dosimetry approach, we estimated that a daily intake of 0.2 µg/kg body weight/day corresponds to urinary cadmium levels no longer associated with cognitive declines observed in a "High (H)"-confidence study. This estimate is 1.8-fold lower than the current health-based guidance value (HBGV) for kidney toxicity of 0.36 µg/kg bodyweight/day established by the European Food Safety Authority (EFSA). Our value does not have the normative character associated with health-based guidance values and is intended only as a reasonable estimate for the purpose of mixture risk assessments. However, with cadmium exposures in Europe between 0.28 (middle bound) and up to 0.52 µg/kg bodyweight/day (95th percentile), our review suggests that pregnant women and children are poorly protected against neurodevelopmental effects. This warrants a revision of the current HBGV.

Systematic review of associations of polychlorinated biphenyl (PCB) exposure with declining semen quality in support of the derivation of reference doses for mixture risk assessments.

BACKGROUND: Mixture risk assessments require reference doses for common health endpoints of all the chemicals to be considered together. In support of a mixture risk assessment for male reproductive health, we conducted a systematic review of the literature on associations between exposures to Polychlorinated Biphenyls (PCBs) and declines in semen quality. PCBs can act as Aryl-hydrocarbon Receptor (AhR)-agonists and Androgen Receptor (AR)-antagonists, both mechanisms which can affect sperm parameters. PCBs and other AR-antagonists can produce additive combination effects. Based on these observations our objective was to systematically gather data from animal and human studies to derive a reference dose for declines in semen quality for individual PCB. METHODS: We systematically reviewed and evaluated the evidence in human epidemiological and experimental animal studies on associations between PCBs and deteriorations in semen quality. Human data and findings from animal studies with PCB mixtures were considered as supporting evidence. Information for individual congeners from animal studies was required for inclusion in mixture risk assessment. Using a robust confidence rating approach, we identified suitable studies to derive reference doses for individual PCB congeners. RESULTS: Evaluation of human epidemiological studies revealed several reports of adverse effects on sperm parameters linked to PCB exposures, although some studies reported improved semen quality. Our review of experimental animal studies found that treatments with PCBs affected semen quality, in most cases adversely. We found robust evidence that PCB-118 and -169 were linked to declines in semen quality. Evidence for adverse effects of PCB-126, -132, -149, and -153 was moderate, whereas for PCB-77 it was slight and for PCB-180 indeterminate. Using widely accepted risk assessment procedures, we estimated reference dose values of 0.0029 µg/kg/day for PCB-118 and 0.00533 µg/kg/day for PCB-169. In addition, we derived values for PCB-126: 0.000073 µg/kg/day, PCB-132: 0.0228 µg/kg/day, PCB-149: 0.656 µg/kg/day, and PCB-153: 0.0058 µg/kg/day. CONCLUSIONS: We found robust evidence for links between PCB exposure and deteriorations in semen quality, and derived reference doses for a set of congeners. We intend to use these values in combination with congener-specific exposure data in a mixture risk assessment for declines in semen quality, involving several other antiandrogenic chemicals.

A broader view on deriving a reference dose for THC traces in foods.

An Acute Reference Dose (ARfD) of 1 µg of delta-9-tetrahydrocannabinol (THC) per kilogram (kg) of body weight (bw) per day was recommended by the European Food Safety Authority (EFSA) for its assessment of possible acute health risks from the intake of industrial hemp food products. The scientific basis for this opinion, such as their choice of a Point of Departure for identification of the Lowest Observed Adverse Effect Level (LOAEL) for THC on the central nervous system, and the seeming absence of an experimental No Observed Adverse Effect Level (NOAEL), is critically reviewed. Moreover, the risk assessment for an ARfD derivation for THC is then reconsidered. In contrast to the EFSA Scientific Opinion of 2015, a higher LOAEL is presently identified from pharmacokinetic and pharmacodynamic studies, and forensic data, in representative cohorts of healthy humans after oral administrations of low THC doses. A NOAEL for THC is derived through this combination of results, demonstrating a threshold for impairment of psychomotor function only after intake of an oral THC bolus beyond 2.5 mg for the average healthy adult. This 2.5 mg dose produces mean THC blood serum levels of <2 ng/mL, as well as do two doses when taken daily within a time interval of ≥6 h. The forensic threshold of THC that is correlated with the impairment of psychomotor function is known to be between 2 and 5 ng/mL in blood serum for adults. For an appropriately spaced intake of 2 × 2.5 mg THC per day, an adult can therefore be regarded as being at the NOAEL. Applying a default uncertainty factor of 10 for intraspecies variability to a NOAEL of 2 × 2.5 mg (over ≥6 hours) for THC, yields a "daily dose of no concern" or a "tolerable upper intake level" of 0.50 mg, corresponding to 7 µg/kg bw. Starting with a NOAEL of only 2.5 mg, consumed as a single bolus, the lowest possible daily ARfD of THC would therefore be 0.25 mg, or 3.5 µg/kg bw for healthy adults, as the absolutely most conservative estimate. Other justifiable estimates have ranged up to 14 µg/kg bw per day.

Using existing knowledge for the risk evaluation of crop protection products in order to guide exposure driven data generation strategies and minimise unnecessary animal testing.

Traditionally, human health risk assessment focuses on defining the hazard through mammalian toxicity studies followed by exposure estimation. We have explored ways of predicting exposure based primarily on the use scenario and comparing the exposure to reference dose values derived by various regulatory agencies (US EPA, JMPR, and EU Commission) in order to identify mammalian toxicity studies that are relevant to human health risk assessment. Human dietary exposure was based on existing residue data for substances with comparable use on the same or similar crops. Human occupational exposures were based on the use scenarios and application methods. To provide a point of comparison for the exposure predictions, data were collated for acute, chronic and occupational reference dose values derived by various regulatory agencies (US EPA, JMPR, and EU Commission). The exposure predictions and range of hazard endpoints were compared using the ILSI HESI Risk21 risk matrix plots in order to visualise and contextualise the level of potential concern for the exposure prediction. In addition, an approach is proposed to categorise the likelihood of acceptability of risk based on where the exposure sits relative to the distribution of reference dose values. The approaches proposed in this study allow for exposure prediction based on the Good Agricultural Practice (GAP) in conjunction with the use of existing hazard data for crop protection products in order to make an initial determination on acceptability of risk and to identify key studies that are required for human health risk assessment and also opportunities for study waivers.

Role of epidemiology in risk assessment: a case study of five ortho-phthalates.

BACKGROUND: The association between environmental chemical exposures and chronic diseases is of increasing concern. Chemical risk assessment relies heavily on pre-market toxicity testing to identify safe levels of exposure, often known as reference doses (RfD), expected to be protective of human health. Although some RfDs have been reassessed in light of new hazard information, it is not a common practice. Continuous surveillance of animal and human data, both in terms of exposures and associated health outcomes, could provide valuable information to risk assessors and regulators. Using ortho-phthalates as case study, we asked whether RfDs deduced from male reproductive toxicity studies and set by traditional regulatory toxicology approaches sufficiently protect the population for other health outcomes. METHODS: We searched for epidemiological studies on benzyl butyl phthalate (BBP), diisobutyl phthalate (DIBP), dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP), and bis(2-ethylhexyl) phthalate (DEHP). Data were extracted from studies where any of the five chemicals or their metabolites were measured and showed a statistically significant association with a health outcome; 38 studies met the criteria. We estimated intake for each phthalate from urinary metabolite concentration and compared estimated intake ranges associated with health endpoints to each phthalate's RfD. RESULT: For DBP, DIBP, and BBP, the estimated intake ranges significantly associated with health endpoints were all below their individual RfDs. For DEHP, the intake range included associations at levels both below and above its RfD. For DCHP, no relevant studies could be identified. The significantly affected endpoints revealed by our analysis include metabolic, neurodevelopmental and behavioral disorders, obesity, and changes in hormone levels. Most of these conditions are not routinely evaluated in animal testing employed in regulatory toxicology. CONCLUSION: We conclude that for DBP, DIBP, BBP, and DEHP current RfDs estimated based on male reproductive toxicity may not be sufficiently protective of other health effects. Thus, a new approach is needed where post-market exposures, epidemiological and clinical data are systematically reviewed to ensure adequate health protection.

The dietary risk index system: a tool to track pesticide dietary risks.

BACKGROUND: For years the United States Department of Agriculture's Pesticide Data Program and the United Kingdom's Food Standards Agency have published annual or quarterly data on pesticide residues in foods. Both programs report residues in conventionally grown, organic, and imported foods. The US program has tested about 288,000 food samples since 1992, primarily fruits and vegetables consumed by children. Since 1999 the UK has tested about 72,000 samples of a wider range of foods. These data are vital inputs in tracking trends in pesticide dietary risks. METHODS: The Dietary Risk Index (DRI) system facilitates detailed analyses of US and UK pesticide residue data, trends, and chronic risk distributions. The DRI value for a pesticide is the dietary intake of that pesticide from a single serving of food divided by the pesticide's acceptable daily intake as set by the US Environmental Protection Agency. It can be calculated based on average annual residue concentrations, and on residue levels in individual samples of food. DRI values can be aggregated over multiple pesticides in single foods, and over individual pesticides in multiple foods. RESULTS: The DRI system provides insights into the levels, trends, and distribution of pesticide dietary risk across most widely consumed foods. By drawing on both US Pesticide Data Program and UK-Food Standards Agency residue data, the DRI is capable of assessing pesticide risks in a significant portion of the global food supply. Substantial reductions in pesticide dietary risks occurred in the early 2000s, primarily from replacement of organophosphate insecticides with seemingly lower-risk neonicotinoids. However, there remain several areas of concern and opportunities to reduce risks. Both herbicide and fungicide dietary risks are rising. Organically grown produce poses risks far lower than corresponding, conventionally grown produce. Risk differences are inconsistent between domestic and imported foods. CONCLUSIONS: The surest ways to markedly reduce pesticide dietary risks are to shift relatively high-risk fruits and vegetables to organic production. For other foods, reducing reliance on pesticides overall, and especially high-risk pesticides, will incrementally lower risks. The DRI system can help focus such efforts and track progress in reducing pesticide dietary risk.

An analysis of the setting of the acute reference dose (ARfD) for pesticides in Europe.

To protect human health, acute reference values have been established for pesticides which have the potential to cause a toxic effect after acute human exposure. These values are used to identify exposure levels below which there is no appreciable risk. Comprehensive reference documents, including OECD criteria, are available to aid identification of relevant toxicological endpoints. Within Europe, there is a concern that the identification process is inconsistent and unnecessarily conservative such that safe products with no established human health risk are being restricted. For this reason, the basis for the setting of an acute reference dose (ARfD) has been investigated for 130 pesticides to better understand how the toxicological endpoints are selected. The investigation has shown that most ARfDs are derived from repeat dose studies and that there is an over-representation of prenatal developmental toxicity studies. There is clear evidence that ARfDs derived from rabbit developmental toxicity studies are set over conservatively with regard to acute maternal effects and often inappropriately. To facilitate an improved system, refinements to the existing process are recommended, the use of maternal data in the rabbit as the basis for deriving an ARfD is critically evaluated and a new, more pragmatic approach to ARfD derivation is proposed.

Assessment of veterinary drug residues in food: Considerations when dealing with sub-optimal data.

The use of veterinary drugs in food-producing animals may lead to residues in animal-derived foodstuffs, potentially posing a risk to human safety. While the process of veterinary drug residue risk assessment continues to evolve as new data emerges, a recurring challenge is when sub-optimal or incomplete data are provided with the expectation of supporting a robust risk assessment. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) is comprised of international experts who routinely deal with such data challenges when performing veterinary drug residue evaluations. Recent developments in veterinary drug residue risk assessment are described, including specific consequences of sub-optimal data during the risk assessment process. When feasible, practical solutions to such challenges are also highlighted. Case examples from recent JECFA veterinary drug evaluations are provided to clearly quantify and illustrate the concepts described. The information provided is intended to facilitate the generation of improved quality data, enabling more timely and robust veterinary drug residue risk assessments.

The derivation of a Reference Dose (RfD) for perfluorooctane sulfonate (PFOS) based on immune suppression.

Exposure to perfluorooctane sulfonate (PFOS) is ubiquitous in populations and environments worldwide. Its long half-life in humans, indefinite persistence in the environment, and awareness of its widespread presence in drinking water make the human health assessment of PFOS a priority. While developmental, endocrine, and hepatic effects, and increased serum cholesterol are among the outcomes resulting from PFOS exposure, immunosuppression has also consistently emerged as an adverse effect. An in-depth review of the relevant scientific literature on the toxicology of PFOS has identified immunosuppression as a sensitive endpoint for PFOS toxicity. Here, we focus specifically on that endpoint and provide a detailed derivation of a Reference Dose (RfD) of 1.8 × 10-6 mg/kg/day for chronic human exposure to PFOS. This RfD is based on decreased plaque-forming cell (PFC) response in mice, an endpoint that reflects suppression of the immune response to a foreign antigen. We additionally identify two endpoints in the epidemiology literature, decreased vaccine response and increased incidence of childhood infections, that are associated with PFOS exposure and that are consistent with and support the decreased PFC response endpoint from animal studies. We provide a weight of evidence analysis integrating the evidence from animal and epidemiology endpoints. Finally, we compare this RfD to the PFOS RfD derived by the United States Environmental Protection Agency (USEPA) Office of Water based on a developmental endpoint. Based on this comparison, and given our assessment, the USEPA RfD does not provide sufficient protection against the adverse health effects of PFOS. The RfD derived herein is intended to be public health protective and appropriately minimizes PFOS exposure based on available evidence.

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

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

Derivation of a chronic reference dose for perfluorohexane sulfonate (PFHxS) for reproductive toxicity in mice.

Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid that was used as an industrial surfactant, but is now found as an environmental contaminant worldwide. In addition to its use as an industrial surfactant, it is a legacy contaminant from the use of aqueous film-forming foams. Despite its widespread occurrence in the environment and evidence of biological activity associated with PFHxS and similar perfluoroalkyl sulfonic acids in rodents, there is no oral toxicity value currently available from the IRIS Database. To derive an oral reference dose (RfD) for PFHxS, available toxicity studies were reviewed using a weight-of-evidence approach. A 42-day mouse reproductive study was chosen as the critical study for the derivation of the oral RfD. Benchmark dose modeling was utilized to derive a point of departure (POD) for a reduction in litter size. A 95% lower confidence limit on the benchmark dose (BMDL) of 13,900 ng/mL (serum PFHxS) was modeled for a reduction in litter size. An oral RfD for PFHxS of 4.0 ng/kg/d was calculated by conversion of the BMDL to a human equivalent oral dose using a human half-life adjusted dosimetric conversion factor and the application of a total uncertainty factor of 300. Additional research is needed to better characterize the toxicity associated with oral exposure to PFHxS and refine the development of toxicity values.

Application of qualitative and quantitative uncertainty assessment tools in developing ranges of plausible toxicity values for 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Increasing interest in characterizing risk assessment uncertainty is highlighted by recent recommendations from the National Academy of Sciences. In this paper we demonstrate the utility of applying qualitative and quantitative methods for assessing uncertainty to enhance risk-based decision-making for 2,3,7,8-tetrachlorodibenzo-p-dioxin. The approach involved deconstructing the reference dose (RfD) via evaluation of the different assumptions, options, models and methods associated with derivation of the value, culminating in the development of a plausible range of potential values based on such areas of uncertainty. The results demonstrate that overall RfD uncertainty was high based on limitations in the process for selection (e.g., compliance with inclusion criteria related to internal validity of the co-critical studies, consistency with other studies), external validity (e.g., generalizing findings of acute, high-dose exposure scenarios to the general population), and selection and classification of the point of departure using data from the individual studies (e.g., lack of statistical and clinical significance). Building on sensitivity analyses conducted by the US Environmental Protection Agency in 2012, the resulting estimates of RfD values that account for the uncertainties ranged from ~1.5 to 179 pg/kg/day. It is anticipated that the range of RfDs presented herein, along with the characterization of uncertainties, will improve risk assessments of dioxins and provide important information to risk managers, because reliance on a single toxicity value limits the information needed for making decisions and gives a false sense of precision and accuracy.

Development of an oral reference dose for the perfluorinated compound GenX.

Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long-chain poly-fluoroalkyl substances, which tend to have long clearance half-lives and are environmentally persistent. Unlike poly-fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non-cancer oral reference dose (RfD) for GenX based on available repeated dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark dose models and Bayesian benchmark dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2-year bioassay in rats (0.01-0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for GenX.

Polybrominated diphenyl ethers (PBDEs) in dust in typical indoor public places in Hangzhou: Levels and an assessment of human exposure.

Polybrominated diphenyl ethers (PBDEs) are organic pollutants (POPs) with the characteristics of environmental persistence, long-distance transmission in nature, biological accumulation and toxic effects on human health. To investigate the level of contamination due to PBDEs in typical indoor public places in Hangzhou, dust samples were collected from ten supermarkets, three electronic markets and five different areas throughout one commodity market. Based on sample pretreatment and GC-ECD instrumental analysis, the contamination characteristics, sources and the influencing factors of 14 PBDE congeners were analyzed. The results revealed that the mean of ∑14PBDEs in dust in the supermarkets and electronic markets was 546.13 ng/g and 1140.05 ng/g, respectively, while in the commodity market the mean was 1005.42 ng/g and varied in the five different areas as follows: shoe areas (1367.22 ng/g) > parking lot (1001.05 ng/g) > waiting halls (970.31 ng/g) > packet areas (933.23 ng/g) > curtain areas (755.28 ng/g). The high levels of PBDE were attributed to the quantity of electrical appliances in the supermarkets (r = 0.708*, p < 0.05) and the electronic markets (r = 0.799**, p < 0.05) through Spearman correlation coefficient analysis. BDE-209 was the dominant congener, accounting for 53.72% in supermarkets and 64.25% in electronic markets. The calculated inhalation exposure revealed that the exposure level of PBDEs varied in supermarkets, electronic markets and commodity markets, with values of 0.476 ng/day/kg, 0.993 ng/day/kg and 0.876 ng/day/kg, respectively. Moreover, BDE-209's contribution to the total intake of PBDEs was the highest, with a value of 0.072-0.970 ng/day/kg, while the value of BDE-183 was the lowest, with a value of 0-0.020 ng/day/kg. The exposure level of PBDEs in the studied indoor public places was lower than the reference dose of EPA.