Identification and characterization of calcium binding protein, spermatid-associated 1 (CABS1)# in selected human tissues and fluids.

Calcium binding protein, spermatid associated 1 (CABS1) is a protein most widely studied in spermatogenesis. However, mRNA for CABS1 has been found in numerous tissues, albeit with little information about the protein. Previously, we identified CABS1 mRNA and protein in human salivary glands and provided evidence that in humans CABS1 contains a heptapeptide near its carboxyl terminus that has anti-inflammatory activities. Moreover, levels of an immunoreactive form of CABS1 were elevated in psychological stress. To more fully characterize human CABS1 we developed additional polyclonal and monoclonal antibodies to different sections of the protein and used these antibodies to characterize CABS1 in an overexpression cell lysate, human salivary glands, saliva, serum and testes using western blot, immunohistochemistry and bioinformatics approaches exploiting the Gene Expression Omnibus (GEO) database. CABS1 appears to have multiple molecular weight forms, consistent with its recognition as a structurally disordered protein, a protein with structural plasticity. Interestingly, in human testes, its cellular distribution differs from that in rodents and pigs, and includes Leydig cells, primary spermatogonia, Sertoli cells and developing spermatocytes and spermatids, Geodata suggests that CABS1 is much more widely distributed than previously recognized, including in the urogenital, gastrointestinal and respiratory tracts, as well as in the nervous system, immune system and other tissues. Much remains to be learned about this intriguing protein.

A critical review of the application of polymer of low concern regulatory criteria to fluoropolymers II: Fluoroplastics and fluoroelastomers.

Fluoropolymers are a distinct class of per- and polyfluoroalkyl substances (PFAS), high molecular weight (MW) polymers with fluorine attached to their carbon-only backbone. Fluoropolymers possess a unique combination of properties and unmatched functional performance critical to the products and manufacturing processes they enable and are irreplaceable in many uses. Fluoropolymers have documented safety profiles; are thermally, biologically, and chemically stable, negligibly soluble in water, nonmobile, nonbioavailable, nonbioaccumulative, and nontoxic. Although fluoropolymers fit the PFAS structural definition, they have very different physical, chemical, environmental, and toxicological properties when compared with other PFAS. This study describes the composition, uses, performance properties, and functionalities of 14 fluoropolymers, including fluoroplastics and fluoroelastomers, and presents data to demonstrate that they satisfy the widely accepted polymer hazard assessment criteria to be considered polymers of low concern (PLC). The PLC criteria include physicochemical properties, such as molecular weight, which determine bioavailability and warn of potential hazard. Fluoropolymers are insoluble (e.g., water, octanol) solids too large to migrate into the cell membrane making them nonbioavailable, and therefore, of low concern from a human and environmental health standpoint. Further, the study results demonstrate that fluoropolymers are a distinct and different group of PFAS and should not be grouped with other PFAS for hazard assessment or regulatory purposes. When combined with an earlier publication by Henry et al., this study demonstrates that commercial fluoropolymers are available from the seven participating companies that meet the criteria to be considered PLC, which represent approximately 96% of the global commercial fluoropolymer market. Integr Environ Assess Manag 2023;19:326-354. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Identification and classification of commercially relevant per- and poly-fluoroalkyl substances (PFAS).

Per- and poly-fluoroalkyl substances (PFAS) are a universe of fluorinated organic substances with very different physical, chemical, and biological properties including polymers and non-polymers; solids, liquids, and gases. Commercial PFAS-based products have been used in a wide variety of industrial and consumer applications because they have unique performance properties of significant socioeconomic value. The PFAS definition has evolved and expanded over the years. Numerous lists of PFAS, some with thousands of entries, have been compiled, but none have clearly identified which of the substances are commercially relevant. This study is the first to use a bona-fide "bottom up" approach to identify how many of the 4730 PFAS substances listed in a 2018 OECD/UNEP Report are directly connected to commercial products based on input from three major global producers. This study provides new and valuable insight into the 2018 OECD/UNEP Report list of PFAS substances. The results show that 256, less than 6%, of the 4730 PFAS substances presented in the 2018 OECD/UNEP Report are commercially relevant globally. This study suggests that grouping and categorizing PFAS using fundamental classification criteria based on composition and structure can be used to identify appropriate groups of PFAS substances for risk assessment, thereby dispelling assertions that there are too many PFAS chemistries to conduct proper regulatory risk assessments for the commercially relevant substances. Integr Environ Assess Manag 2021;17:1045-1055. © 2021 The Chemours Company, Beach Edge Consulting, LLC, AGC Chemicals Americas Inc., Daikin America Inc. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Estimating Environmental Hazard and Risks from Exposure to Per- and Polyfluoroalkyl Substances (PFASs): Outcome of a SETAC Focused Topic Meeting.

Per- and polyfluoroalkyl substances (PFAS) are a group of highly fluorinated synthetic chemicals that were originally developed for uses as surfactants and surface protectors. Increasingly, specific substances of this class are being found in environmental media (e.g., surface water, soils, sediments, food sources), and concerns regarding exposure to humans and environmental receptors have been described by the public, legislators, and the general population. Data suggest that some PFAS (such as certain of the long-chain ones) bioaccumulate and have long biological half-lives, particularly in humans. Toxicity data in various organisms are variable as are their toxicokinetics. A Society of Environmental Toxicology and Chemistry (SETAC) Focused Topic Meeting and workshop entitled Environmental Risk Assessment of PFAS convened during 12 to 15 August, 2019 in Durham, North Carolina (USA) and brought together experts from around the globe to highlight recent advances in research pertinent to evaluating environmental and human health risks from exposures. The objectives of the Focused Topic Meeting and workshop were: 1) to review new and emerging information on PFAS chemical classification and grouping, environmental chemistry, detection technology, fate and transport, exposure potential, human health toxicity, and ecological toxicity; and 2) to harness the expertise of attendees to discuss and formulate a roadmap to prioritize the study of specific PFAS with the goal of developing a risk assessment approach that considers mechanistic (including computational) data for extrapolating exposure and data across different species/scenarios and compounds within environmental exposure pathways. We present the key issues that were discussed. Environ Toxicol Chem 2021;40:543-549. © 2020 SETAC.

Structural and posttranslational analysis of human calcium-binding protein, spermatid-associated 1.

Recently, we detected a novel biomarker in human saliva called calcium-binding protein, spermatid-associated 1 (CABS1). CABS1 protein had previously been described only in testis, and little was known of its characteristics other than it was considered a structurally disordered protein. Levels of human CABS1 (hCABS1) in saliva correlate with stress, whereas smaller sized forms of hCABS1 in saliva are associated with resilience to stress. Interestingly, hCABS1 also has an anti-inflammatory peptide sequence near its carboxyl terminus, similar to that of a rat prohormone, submandibular rat 1. We performed phylogenetic and sequence analysis of hCABS1. We found that from 72 CABS1 sequences currently annotated in the National Center for Biotechnology Information protein database, only 14 contain the anti-inflammatory domain "TxIFELL," all of which are primates. We performed structural unfoldability analysis using PONDER and FoldIndex and discovered three domains that are highly disordered. Predictions of three-dimensional structure of hCABS1 using RaptorX, IonCom, and I-TASSER software agreed with these findings. Predicted neutrophil elastase cleavage density also correlated with hCABS1 regions of high structural disorder. Ligand binding prediction identified Ca2+ , Mg2+ , Zn2+ , leucine, and thiamine pyrophosphate, a pattern observed in enzymes associated with energy metabolism and mitochondrial localization. These new observations on hCABS1 raise intriguing questions about the interconnection between the autonomic nervous system, stress, and the immune system. However, the precise molecular mechanisms involved in the complex biology of hCABS1 remain unclear. We provide a detailed in silico analysis of relevant aspects of the structure and function of hCABS1 and postulate extracellular and intracellular roles.

A critical review of the application of polymer of low concern and regulatory criteria to fluoropolymers.

Per- and polyfluoroalkyl substances (PFAS) are a group of fluorinated substances that are in the focus of researchers and regulators due to widespread presence in the environment and biota, including humans, of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Fluoropolymers, high molecular weight polymers, have unique properties that constitute a distinct class within the PFAS group. Fluoropolymers have thermal, chemical, photochemical, hydrolytic, oxidative, and biological stability. They have negligible residual monomer and oligomer content and low to no leachables. Fluoropolymers are practically insoluble in water and not subject to long-range transport. With a molecular weight well over 100 000 Da, fluoropolymers cannot cross the cell membrane. Fluoropolymers are not bioavailable or bioaccumulative, as evidenced by toxicology studies on polytetrafluoroethylene (PTFE): acute and subchronic systemic toxicity, irritation, sensitization, local toxicity on implantation, cytotoxicity, in vitro and in vivo genotoxicity, hemolysis, complement activation, and thrombogenicity. Clinical studies of patients receiving permanently implanted PTFE cardiovascular medical devices demonstrate no chronic toxicity or carcinogenicity and no reproductive, developmental, or endocrine toxicity. This paper brings together fluoropolymer toxicity data, human clinical data, and physical, chemical, thermal, and biological data for review and assessment to show that fluoropolymers satisfy widely accepted assessment criteria to be considered as "polymers of low concern" (PLC). This review concludes that fluoropolymers are distinctly different from other polymeric and nonpolymeric PFAS and should be separated from them for hazard assessment or regulatory purposes. Grouping fluoropolymers with all classes of PFAS for "read across" or structure-activity relationship assessment is not scientifically appropriate. Integr Environ Assess Manag 2018;14:316-334. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Quantitative Lateral Flow Assays for Salivary Biomarker Assessment: A Review.

Saliva is an emerging biofluid with a significant number of applications in use across research and clinical settings. The present paper explores the reasons why saliva has grown in popularity in recent years, balancing both the potential strengths and weaknesses of this biofluid. Focusing on reasons why saliva is different from other common biological fluids such as blood, urine, or tears, we review how saliva is easily obtained, with minimal risk to the donor, and reduced costs for collection, transportation, and analysis. We then move on to a brief review of the history and progress in rapid salivary testing, again reviewing the strengths and weaknesses of rapid immunoassays (e.g., lateral flow immunoassay) compared to more traditional immunoassays. We consider the potential for saliva as an alternative biofluid in a setting where rapid results are important. We focus the review on salivary tests for small molecule biomarkers using cortisol as an example. Such salivary tests can be applied readily in a variety of settings and for specific measurement purposes, providing researchers and clinicians with opportunities to assess biomarkers in real time with lower transportation, collection, and analysis costs, faster turnaround time, and minimal training requirements. We conclude with a note of cautious optimism that the field will soon gain the ability to collect and analyze salivary specimens at any location and return viable results within minutes.

Choice of knee cartilage thickness change metric for different treatment goals in efficacy studies.

INTRODUCTION: In knee osteoarthritis, local increase and decrease in cartilage thickness has been observed over short time intervals. Hence, averaging cartilage change across large regions may not capture the complexity of structural alterations in disease progression. This study aims to examine the relative performance of different metrics of cartilage thickness change for different clinical studies scenarios. MATERIALS AND METHODS: Metrics for assessing cartilage thickness change were characterized by conventional measures of change versus absolute values (the magnitude) of change, and by different methods of summarizing change over (sub-) regions. Sample sizes for these metrics were derived for 6-24-month observation periods, and for different treatment efficacies. Treatment effects were derived from an observational trial with 6-, 12-, and 24-month follow-up, ranging from slowing cartilage loss to stimulating cartilage growth. RESULTS: Projected sample sizes ranged from 10 to >10,000 patients/arm (median = 164), depending on metric choice, treatment efficacy, and observation period. The smallest sample sizes for metrics using magnitude of change typically were half the size of those using conventional measures of change. Extreme values, e.g., minimum change or average of last four-ordered values of absolute change, required smaller sample sizes than metrics averaging over one or more regions. CONCLUSIONS: Metrics using extreme magnitudes of change were most efficient in detecting differences between treatment and placebo, i.e., involved the smallest sample sizes across different DMOAD study lengths and treatment efficacies. Ancillary metrics can be used to clarify whether differences between treatment and placebo indicate structural benefit when needed.

Location-independent analysis of structural progression of osteoarthritis-Taking it all apart, and putting the puzzle back together makes the difference.

OBJECTIVE: The metric accepted by regulatory bodies for determining structural progression in clinical trials of knee osteoarthritis (OA) remains change in radiographic joint space width in the medial femorotibial compartment. However, magnetic resonance imaging has revealed that cartilage loss is spatially heterogeneous, and that it is enigmatic which knee will lose cartilage at which location. Whereas previous reviews have focused on imaging in general, the purpose of this particular perspective is to highlight availability and applications of location-independent analysis methodology in measuring structural progression in epidemiological and interventional clinical trials, and to highlight its specific advantages over existing methodologies. METHODS: Narrative review/perspective based on a Pubmed search of original articles from 2009 to current. RESULTS: Ordering longitudinal change in subregion cartilage thickness by magnitude and direction, and averaging such ordered values or sums of negative and positive changes across knees is shown to be superior in detecting risk factors and interventional effects on structural progression of knee OA. Further, the methodology permits exploration of cartilage loss and gain simultaneously, phenomena that are missed when measurements are confined to cartilage volume or thickness loss in plates or compartments. CONCLUSIONS: Given spatial heterogeneity of cartilage loss in knee OA, location-independent analysis by MRI may provide opportunity for a paradigm shift. The authors recommend use of a location-independent metrices as the structural endpoints in epidemiological and intervention trials, particularly when examining anabolic and catabolic drug effects. Location-independent methods may be translated to analysis of cartilage composition and other articular tissues.

Biotransformation potential of 6:2 fluorotelomer sulfonate (6:2 FTSA) in aerobic and anaerobic sediment.

Aqueous film-forming foam (AFFF) products are used in industrial and military firefighting around the globe. These products contain fluoroalkylthioamido sulfonates, fluoroalkylthiobetaine, and other related substances as the major ingredients, which can be biotransformed in the environment to form 6:2 fluorotelomer sulfonate (6:2 FTSA, F(CF2)6CH2CH2SO3-) as one of the major initial biotransformation products. Limited information is available on 6:2 FTSA aerobic biotransformation in activated sludge and pure microbial culture. This is the first study to report 6:2 FTSA biotransformation in aerobic and anaerobic sediment. 6:2 FTSA was rapidly biotransformed in aerobic river sediment with a half-life less than 5 d. Major stable transformation products observed after 90 d included 5:3 Acid [F(CF2)5CH2CH2COOH), 16 mol%), PFPeA [F(CF2)4COOH, 21 mol%] and PFHxA (F(CF2)5COOH, 20 mol%). 6:2 fluorotelomer alcohol [6:2 FTOH, F(CF2)6CH2CH2OH] was readily biotransfomed whereas 6:2 FTSA biotransformation did not occur in anaerobic sediment over 100 d, indicating that the enzymatic desulfonation step limited 6:2 FTSA biotransformation in anaerobic sediment. These results suggest that 6:2 FTSA related products, after release to the aerobic environment, is likely to biodegrade forming 5:3 Acid, PFPeA and PFHxA. This study also indicates that 6:2 FTSA formed from its aforementioned precursors may be persistent in the anaerobic environment after their potential release. This work provides insight to understanding the fate and environmental loading of AFFF-related products and their major transformation products in the environment.

Aquatic hazard, bioaccumulation and screening risk assessment for ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate.

The fluoropolymer manufacturing industry is moving to alternative polymerization processing aid technologies with more favorable toxicological and environmental profiles as part of a commitment to curtail the use of long-chain perfluoroalkyl acids (PFAAs). To facilitate the environmental product stewardship assessment and premanufacture notification (PMN) process for a candidate replacement chemical, we conducted acute and chronic aquatic toxicity tests to evaluate the toxicity of ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (C6HF11O3.H3N) or the acid form of the substance to the cladoceran, Daphnia magna, the green alga, Pseudokirchneriella subcapitata, and a number of freshwater fish species including the rainbow trout, Oncorhynchus mykiss, In addition, testing with the common carp, Cyprinus carpio, was conducted to determine the bioconcentration potential of the acid form of the compound. Based on the relevant criteria in current regulatory frameworks, the results of the aquatic toxicity and bioconcentration studies indicate the substance is of low concern for aquatic hazard and bioconcentration in aquatic organisms. Evaluation of environmental monitoring data in conjunction with the predicted no effect concentration (PNEC) based on the available data suggest low risk to aquatic organisms.

Absorption, distribution, metabolism, excretion, and kinetics of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid ammonium salt following a single dose in rat, mouse, and cynomolgus monkey.

Ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate has been developed as a processing aid used in the manufacture of fluoropolymers. The absorption, distribution, elimination, and distribution (ADME) and kinetic behavior of this substance has been evaluated in rats, mice, and cynomolgus monkeys by oral and intravenous routes of exposure and studied in both plasma and urine. The test substance is rapidly and completely absorbed in both rats and mice and both in vivo and in vitro experiments indicate that it is not metabolized. The test substance is rapidly eliminated exclusively in the urine in both rats and mice, with rats eliminating it more quickly than mice (approximately 5h elimination half-life in rats, 20 h half-life in mice). Pharmacokinetic analysis in monkeys, rats, and mice indicate rapid, biphasic elimination characterized by a very fast alpha phase and a slower beta phase. The beta phase does not contribute to potential accumulation after multiple dosing in rats or monkeys. Comparative pharmacokinetics in rats, mice, and monkeys indicates that the rat is more similar to the monkey and is therefore a more appropriate rodent model for pharmacokinetics in primates.

Aquatic hazard, bioaccumulation and screening risk assessment for 6:2 fluorotelomer sulfonate.

This study assessed the aquatic toxicity and bioaccumulation potential of 6:2 fluorotelomer sulfonate (6:2 FTSA). Acute and chronic aquatic hazard endpoints indicate 6:2 FTSA is not classified for aquatic hazard according to GHS or European CLP legislation. The aqueous bioconcentration factors for 6:2 FTSA were <40 and the dietary assimilation efficiency, growth corrected half-life and dietary biomagnification factor (BMF) were 0.435, 23.1d and 0.295, respectively. These data indicate that 6:2 FTSA is not bioaccumulative in aquatic organisms. Comparison of PNECs with the reported surface water concentrations (non-spill situations) suggests low risk to aquatic organisms from 6:2 FTSA. Future studies are needed to elucidate the biotic and abiotic fate of commercial AFFF surfactants in the environment.

Salivary cortisol results obtainable within minutes of sample collection correspond with traditional immunoassays.

PURPOSE: Cortisol is frequently assayed as a stress-responsive biomarker which changes over the course of minutes to meet the demands of a person's social context. Salivary cortisol is often used as a noninvasive sampling method that possesses important health implications. A critical barrier to psychobiological research that involves salivary cortisol is a time delay of days to months before cortisol results are obtained via immunoassay, long after the person is no longer proximate to the social context in which they provided the sample. The present study was designed to address this critical barrier through creation of a lateral flow test (LFT) cortisol device capable of measuring salivary cortisol within minutes of sample collection. The LFT is frequently used within commercial point-of-care settings to obtain rapid answers to the presence/absence of a biomarker. The present study extends the LFT into the research domain by presenting performance characteristics of a quantitative LFT that measures salivary cortisol within 20 minutes of sample collection. METHODS: Saliva samples from 29 adults (15 men) were obtained in the morning and afternoon by using Passive Drool and then the Super·SAL Extra Collection Device (hereafter Super·SAL) and later assayed with LFT and a commercially available enzyme immunoassay. FINDINGS: Results indicate the LFT correlated well with these collection methods (R = 0.872 with Super · SAL, R = 0.739 with Passive Drool, P < 0.0001) and at comparable levels to correspondence of Super · SAL with Passive Drool (R = 0.798, P < 0.0001) which were measured with the same assay. IMPLICATIONS: These results open an exciting new possibility to integrate this technologic advance into stress research, including knowing and potentially changing the person's social context in a time-sensitive manner. Methodological improvements such as this have the possibility of refining conceptual models of stress reactivity and regulation.

RNAPro•SAL: a device for rapid and standardized collection of saliva RNA and proteins.

The stabilization and processing of salivary transcriptome and proteome biomarkers is a critical challenge due to the ubiquitous nature of nucleases and proteases as well as the inherent instability of these biomarkers. Furthermore, extension of salivary transcriptome and proteome analysis to point-of-care and remote sites requires the availability of self-administered ambient temperature collection and storage tools. To address these challenges, a self-contained whole saliva collection and extraction system, RNAPro•SAL, has been developed that provides rapid ambient temperature collection along with concurrent processing and stabilization of extracellular RNA (exRNA) and proteins. The system was compared to the University of California, Los Angeles (UCLA) standard clinical collection process (standard operating procedure, SOP). Both systems measured total RNA and protein, and exRNA IL-8, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ß-actin and ribosomal protein S9 (RPS9) by qPCR. Proteome analysis was measured by EIA analysis of interleukin-8 (IL-8), and ß-actin, as well as total protein. Over 97% of viable cells were removed by both methods. The system compared favorably to the labor-intensive clinical SOP, which requires low-temperature collection and isolation, yielding samples with similar protein and exRNA recovery and stability.

Inhalation and oral toxicokinetics of 6:2 FTOH and its metabolites in mammals.

The toxicokinetics of 6:2 fluorotelomer alcohol (6:2 FTOH) and its terminal perfluorinated and polyfluorinated metabolites (PFBA, PFHxA, PFHpA and 5:3 Acid) have been calculated from laboratory studies of rats and from a biomonitoring study of humans. In vitro studies with mouse, rat and human hepatocytes indicate qualitatively similar metabolic pathways of 6:2 FTOH. In a one-day inhalation study of 6:2 FTOH in rats, PFBA, PFHxA, PFHpA and 5:3 Acid were determined to be the major metabolites in plasma with calculated elimination half-lives of 1.3-15.4h and metabolic yields up to 2.7 mol%. In five-day and 23-day inhalation studies and a 90-day oral study of 6:2 FTOH, the plasma or serum concentration profile of 5:3 Acid was several-fold higher than concentrations observed in the single day study, resulting in an estimated elimination half-life of 20-30 d. In contrast, the concentrations of PFBA, PFHxA and PFHpA showed little or no concentration increase with repeated exposure. Elimination half-lives of PFHxA, PFHpA and 5:3 Acid in humans were estimated from a study of professional ski wax technicians who were occupationally exposed to aerosolized and volatilized components of fluorinated glide wax. The resulting human elimination half-life values of PFHxA, PFHpA and 5:3 Acid were 32, 70 and 43 d, respectively. Based on a one compartment toxicokinetic model, current environmental air concentrations of 6:2 FTOH are estimated to result in plasma concentrations of PFHxA, PFHpA and 5:3 Acid that are less than or equal to typical LOQ values, in agreement with extant biomonitoring results.

Oral repeated-dose systemic and reproductive toxicity of 6:2 fluorotelomer alcohol in mice.

6:2 fluorotelomer alcohol (6:2 FTOH) was evaluated for potential systemic repeated-dose and reproductive toxicity in mice. 6:2 FTOH was administered by oral gavage to CD-1 mice as a suspension in 0.5% aqueous methylcellulose with 0.1% Tween-80 at dosages of 1, 5, 25, or 100 mg/kg/day. The no-observed-adverse-effect level (NOAEL) for systemic toxicity was 25 mg/kg/day (males) and 5 mg/kg/day (females), based on effects at higher doses on mortality, clinical observations, body weight, nutritional parameters, hematology (red and white blood cell), clinical chemistry (liver-related), liver weights, and histopathology (liver, teeth, reproductive tract, and mammary gland). However, 6:2 FTOH was not a selective reproductive toxicant. The NOAEL for reproductive toxicity was >100 mg/kg/day; no effects on reproductive outcome were observed at any dosage. The NOAEL for viability and growth of the offspring was 25 mg/kg/day, based on clinical signs of delayed maturation in pups, and reductions in pup survival and pup body weight during lactation at 100 mg/kg/day. While the severity of the effects was generally greater in mice than previously reported in CD rats, the overall NOAELs were identical in both species, 5 mg/kg/day for systemic toxicity and 25 mg/kg/day for offspring viability/growth. 6:2 FTOH was not a selective reproductive toxicant in either species; no effects on reproductive outcome occurred at any dose level, and any effects observed in offspring occurred at dose levels that induced mortality and severe toxicity in maternal animals.

6:2 Fluorotelomer iodide in vitro metabolism by rat liver microsomes: comparison with [1,2-(14)C] 6:2 fluorotelomer alcohol.

6:2 Fluorotelomer iodide [6:2 FTI, F(CF2)6CH2CH2I] is the industrial raw material used to manufacture 6:2 fluorotelomer alcohol [6:2 FTOH, F(CF2)6CH2CH2OH] and 6:2 FTOH-based products. During its manufacture and industrial use, workers may be exposed to via oral, dermal or inhalation of 6:2 FTI. Therefore it is useful to understand how 6:2 FTI may be metabolized and into what transformation products. 6:2 FTI in vitro rat liver microsomal metabolism was explored for the first time to compare its biotransformation potential with that of [1,2-(14)C] 6:2 FTOH [F(CF2)6(14)CH2(14)CH2OH]. 6:2 FTI and 6:2 FTOH metabolite yields were determined in closed-bottle systems using Sprague Dawley and Wistar Han rat microsomes after incubation at 37 °C for up to 6h with NADPH (reduced form of nicotinamide adenine dinucleotide phosphate)-addition and NADPH-regenerating systems, respectively. 5:3 acid [F(CF2)5CH2CH2COOH] was the most abundant metabolite for 6:2 FTI (3.3-6.3 mol%) and 6:2 FTOH (9-12 mol%). Perfluorobutanoic acid (PFBA), perfluoropentanoic acid (PFPeA), and perfluorohexanoic acid (PFHxA) in sum accounted for 1.3-2.2 mol% from 6:2 FTI and 2.7-4.4 mol% from 6:2 FTOH biotransformation. Perfluoroheptanoic acid (PFHpA) accounted for 0.14-0.36 mol% from 6:2 FTI but only 0.01-0.06 mol% from 6:2 FTOH biotransformation. These results suggest that mammalian systems exposed to 6:2 FTI or 6:2 FTOH would form 5:3 acid, PFBA, PFPeA, PFHxA as the primary stable metabolites, whereas more PFHpA would be expected from 6:2 FTI biotransformation.

Global emission inventories for C4-C14 perfluoroalkyl carboxylic acid (PFCA) homologues from 1951 to 2030, Part I: production and emissions from quantifiable sources.

We quantify global emissions of C4-C14 perfluoroalkyl carboxylic acid (PFCA) homologues during the life-cycle of products based on perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctane sulfonyl fluoride (POSF), and fluorotelomer compounds. We estimate emissions of 2610-21400 tonnes of C4-C14 PFCAs in the period from 1951 to 2015, and project 20-6420 tonnes to be emitted from 2016 to 2030. The global annual emissions steadily increased in the period 1951-2002, followed by a decrease and then another increase in the period 2002-2012. Releases from fluoropolymer production contributed most to historical PFCA emissions (e.g. 55-83% in 1951-2002). Since 2002, there has been a geographical shift of industrial sources (particularly fluoropolymer production sites) from North America, Europe and Japan to emerging Asian economies, especially China. Sources differ between PFCA homologues, sometimes considerably, and the relative contributions of each source change over time. For example, whereas 98-100% of historical (1951-2002) PFOA emissions are attributed to direct releases during the life-cycle of products containing PFOA as ingredients or impurities, a much higher historical contribution from PFCA precursor degradation is estimated for some other homologues (e.g. 9-78% for PFDA). We address the uncertainties of the PFCA emissions by defining a lower and a higher emission scenario, which differ by approximately a factor of eight.