Mapping marine benthic biological traits to facilitate future sustainable development.

Escalating societal demands placed on the seabed mean there has never been such a pressing need to align our understanding of the relationship between the physical impact of anthropogenic activities (e.g., installation of wind turbines, demersal fishing) and the structure and function of the seabed assemblages. However, spatial differences in benthic assemblages based on empirical data are currently not adequately incorporated into decision-making processes regarding future licensable activities or wider marine spatial planning frameworks. This study demonstrates that, through harnessing a Big Data approach, large-scale, continuous coverage maps revealing differences in biological traits expressions of benthic assemblages can be produced. We present independent maps based on a suite of response traits (depicting differences in responses to natural or anthropogenically induced change) and effects traits (reflecting different functional potential), although maps derived using single traits or combinations of a range of traits are possible. Models predicting variations in response traits expression provide greater confidence than those predicting effects traits. We discuss how such maps may be used to assist in the decision-making process for the licensing of anthropogenic activities and as part of marine spatial planning approaches. The confidence in such maps to reflect spatial variations in marine benthic trait expression may, in the future, inherently be improved through (1) the inclusion of more empirical macrofaunal assemblage field data; (2) an improved knowledge of marine benthic taxa trait expression; and (3) a greater understanding of the traits responsible for determining a taxon's response to an anthropogenic pressure and a taxon's functional potential.

Perioperative Anticoagulation in Patients with Cancer.

PURPOSE OF REVIEW: There is a paucity of evidence for managing perioperative anticoagulation in patients with cancer. This review aims to provide clinicians who provide care for patients with cancer an overview of the available information and strategies needed to provide optimal care in a perioperative setting. RECENT FINDINGS: There is new evidence available around the management of perioperative anticoagulation in patients with cancer. The new literature and guidance were analyzed and summarized in this review. Management of perioperative anticoagulation in individuals with cancer is a challenging clinical dilemma. The approach to managing anticoagulation requires clinicians to review both disease and treatment specific patient factors that can contribute to both thrombotic and bleed risks. A thorough patient-specific assessment is essential in ensuring patients with cancer receive appropriate care in the perioperative setting.

Dose Uptake of Platinum- and Ruthenium-based Compound Exposure in Zebrafish by Inductively Coupled Plasma Mass Spectrometry with Broader Applications.

Metals and metal-based compounds comprise multifarious pharmaco-active and toxicological xenobiotics. From heavy metal toxicity to chemotherapeutics, the toxicokinetics of these compounds have both historical and modern-day relevance. Zebrafish have become an attractive model organism in elucidating pharmaco- and toxicokinetics in environmental exposure and clinical translation studies. Although zebrafish studies have the benefit of being higher-throughput than rodent models, there are several significant constraints to the model. One such limitation is inherent in the waterborne dosing regimen. Water concentrations from these studies cannot be extrapolated to provide reliable internal dosages. Direct measurements of the metal-based compounds allow for a better correlation with compound-related molecular and biological responses. To overcome this limitation for metals and metal-based compounds, a technique was developed to digest zebrafish larval tissue after exposure and quantify metal concentrations within tissue samples by inductively coupled plasma mass spectrometry (ICPMS). ICPMS methods were used to determine the metal concentrations of platinum (Pt) from cisplatin and ruthenium (Ru) from several novel Ru-based chemotherapeutics in zebrafish tissue. Additionally, this protocol distinguished concentrations of Pt that were sequestered in the chorion of the larval compared with the zebrafish tissue. These results indicate that this method can be applied to quantitate the metal dose present in larval tissues. Further, this method may be adjusted to identify specific metals or metal-based compounds in a broad range of exposure and dosing studies.

Anticancer Activity and In Vitro to In Vivo Mechanistic Recapitulation of Novel Ruthenium-Based Metallodrugs in the Zebrafish Model.

Ruthenium is popular as a metal core for chemotherapeutics, due to versatile molecular coordination. Because new metallodrugs are synthesized at high rates, our studies included assays in zebrafish to expedite the initial evaluation as anticancer agents. Here we evaluated novel metallodrugs (PMC79 and LCR134), and cisplatin, a widely used platinum-based chemotherapeutic. We hypothesized that this model could characterize anticancer properties and recapitulate previous in vitro results in vivo. Our findings suggest anticancer properties of PMC79 and LCR134 were similar with less toxicity than cisplatin. Exposures from 24 to 72 h at or below the LOAELs of PMC79 and LCR134 (3.9 µM and 13.5 µm, respectively), impaired blood vessel development and tailfin regeneration. Blood vessel examination through live imaging of larvae revealed distinct regional antiangiogenic impacts. The significant decrease in gene expression of the VEGF-HIF pathway and beta-actin could explain the morphological effects observed in the whole organism following exposure. Tailfin amputation in larvae exposed to PMC79 or LCR134 inhibited tissue regrowth and cell division, but did not impact normal cell proliferation unlike cisplatin. This suggests Ru drugs may be more selective in targeting cancerous cells than cisplatin. Additionally, in vitro mechanisms were confirmed. PMC79 disrupted cytoskeleton formation in larvae and P-glycoprotein transporters in vivo was inhibited at low doses which could limit off-target effects of chemotherapeutics. Our results demonstrate the value for using the zebrafish in metallodrug research to evaluate mechanisms and off-target effects. In light of the findings reported in this article, future investigation of PMC79 and LCR134 are warranted in higher vertebrate models.

Integration of α, ß and γ components of macroinvertebrate taxonomic and functional diversity to measure of impacts of commercial sand dredging.

Effects of commercial sand mining on aquatic diversity are of increasing global concern, especially in parts of some developing countries. However, understanding of this activity on the diversity of macroinvertebrates remains focused on the α component of species diversity, rather than community functioning. Thus, there remains much uncertainty regarding how each component of taxonomic (TD) and functional (FD) diversity respond to the activity both in freshwater and marine environments. Here, we assessed the effect of sand dredging on α, ß and γ components of TD and FD during different dredging periods based on the response of macroinvertebrate communities over 4 years in the second largest freshwater lake in China. After three years of active dredging, substantial reductions in each component (α, ß and γ) of TD and FD were observed within the dredged area. Moreover, after one year of natural recovery, a distinct restoration was observed with an obvious return in multiple facets of TD and FD indices. No such changes were observed within the adjacent and reference areas. Decreases in the multiple components of TD and FD within the dredged area were most likely associated with the direct extraction of substrate and associated benthic fauna and indirect variations of the water and sediment environment (e.g., increases in water depth and decreases in %Clay). Furthermore, dispersal processes and mass effects mainly contributed to the maintenance of TD and FD during the dredged and recovery stages. In addition, the fast recovery of TD and FD was also related to the simple taxonomic structure and highly connected nature of the study area. Our results suggest that a more precise experimental design (BACI) should be pursued to avoid potentially confounding effects (e.g., natural disturbance) because the sensitivity of diversity indices depends upon different experimental designs. Moreover, measurement of the impacts of sand dredging on macroinvertebrate diversity can be undertaken within a rigorous framework for better understanding the patterns and processes of each component of TD and FD under the sand dredging disturbance.

What's hot and what's not: Making sense of biodiversity 'hotspots'.

Conserving biogeographic regions with especially high biodiversity, known as biodiversity 'hotspots', is intuitive because finite resources can be focussed towards manageable units. Yet, biodiversity, environmental conditions and their relationship are more complex with multidimensional properties. Assessments which ignore this risk failing to detect change, identify its direction or gauge the scale of appropriate intervention. Conflicting concepts which assume assemblages as either sharply delineated communities or loosely collected species have also hampered progress in the way we assess and conserve biodiversity. We focus on the marine benthos where delineating manageable areas for conservation is an attractive prospect because it holds most marine species and constitutes the largest single ecosystem on earth by area. Using two large UK marine benthic faunal datasets, we present a spatially gridded data sampling design to account for survey effects which would otherwise be the principal drivers of diversity estimates. We then assess γ-diversity (regional richness) with diversity partitioned between α (local richness) and ß (dissimilarity), and their change in relation to covariates to test whether defining and conserving biodiversity hotspots is an effective conservation strategy in light of the prevailing forces structuring those assemblages. α-, ß- and γ-diversity hotspots were largely inconsistent with each metric relating uniquely to the covariates, and loosely collected species generally prevailed with relatively few distinct assemblages. Hotspots could therefore be an unreliable means to direct conservation efforts if based on only a component part of diversity. When assessed alongside environmental gradients, α-, ß- and γ-diversity provide a multidimensional but still intuitive perspective of biodiversity change that can direct conservation towards key drivers and the appropriate scale for intervention. Our study also highlights possible temporal declines in species richness over 30 years and thus the need for future integrated monitoring to reveal the causal drivers of biodiversity change.

Cisplatin alkylating activity in zebrafish causes resistance to chorionic degradation and inhibition of osteogenesis.

Zebrafish have gained popularity as a model organism due to their rapid, external, and transparent development, high fecundity, and gene homology with higher vertebrate models and humans. Specifically, drug discovery has had high success in the implementation of zebrafish in studies for target discovery, efficacy, and toxicity. However, a major limitation of the zebrafish model is a dependence on waterborne exposure in order to maintain high throughput capabilities. Dose delivery can be impeded by a matrix of N-linked glycoproteins and other polypeptides called the chorion. This acelluar barrier is protective of the developing embryo, and thus new approaches for assessment have involved their removal. In these studies, we explored the chorionic interference of a well-characterized alkylating chemotherapeutic, cisplatin, known to accumulate in the chorion of zebrafish and cause delayed hatching. Our results indicated that increased exposure of cisplatin due to dechorionation did not alter morphological endpoints, although retained confinement reduced total body length and yolk utilization. Additionally, inhibition of osteogenesis visualized with Alizarian Red staining, was observable in dechorionated and non-dechorionated treatment groups. The chorions of cisplatin-treated embryos showed resistance to degradation unless treated with a pronase solution. This may be may be due to cisplatin covalently crosslinking which reinforces the structure. As such, the chorion may play an advantageous role in studies to determine alkylating activity of novel compounds. Furthermore, the expression of zebrafish hatching enzyme was not affected by cisplatin exposure. These studies demonstrate that not only was recapitulation of mechanistic activity supported in zebrafish, but highly relevant off-target toxicities observed in higher vertebrates were identified in zebrafish, regardless of chorionation. Experimental design in drug discovery should consider preliminary studies without dechorionation in order to determine dose impediment or off-target adducting.

Degraded functional structure of macroinvertebrates caused by commercial sand dredging practices in a flood plain lake.

In parts of developing countries, the over-exploitation of sands from inland waters has led to serious environmental concerns. However, understanding of the impacts of commercial sand dredging on inland water ecosystem functions remains limited. Herein, we assess the effects of this activity on the functional structure of the macroinvertebrate community and its recovery processes based on a 4-year survey, in the South Dongting Lake in China. Our result showed a simplified macroinvertebrate functional structures within the dredged area, as evidenced by a loss of certain trait categories (e.g., oval and conical body form) and a significant reduction in trait values due to the direct removal of macroinvertebrates and indirect alternations to physical environmental conditions (e.g., water depth and %Medium sand). Moreover, clear increases were observed in certain trait categories (e.g., small body size and swimmer) resulting from the dredging-related disturbance (e.g., increased turbidity) within the adjacent area. Furthermore, one year after the cessation of dredging, a marked recovery in the taxonomic and functional structure of macroinvertebrate assemblages was observed with most lost trait categories returning and an increase in the trait values of eight categories (e.g., body size 1.00-3.00 cm and oval body form) within the dredged and adjacent area. In addition, dispersal processes and sediment composition were the main driver for the structuring of the macroinvertebrate taxonomic and functional assemblages during the dredging stages, whilst water environmental conditions dominated the taxonomic structure and dispersal processes determined the functional structure during the recovery stage. Implications of our results for monitoring and management of this activity in inland waters are discussed.

Supporting people in mental health crisis in 21st-century Britain.

Recent years have seen a surge in interest in mental healthcare and some reduction in stigma. Partly as a result of this, alongside a growing population and higher levels of societal distress, many more people are presenting with mental health needs, often in crisis. Systems that date back to the beginning of the National Health Service still form the basis for much care, and the current system is complex, hard to navigate and often fails people. Law enforcement services are increasingly being drawn into providing mental healthcare in the community, which most believe is inappropriate. We propose that it is now time for a fundamental root and branch review of mental health emergency care, taking into account the views of patients and the international evidence base, to 'reset' the balance and commission services that are humane and responsive - services that are fit for the 21st century.

The testing of people with any risk factor for hepatitis C in community pharmacies is cost-effective.

New antiviral drugs with high efficacy mean the hepatitis C virus (HCV) can now be eliminated. To achieve this, it is necessary to identify undiagnosed cases of HCV. However, the costs of testing should be considered when judging the overall cost-effectiveness of treatment. This study describes the cost-effectiveness of a community pharmacy testing service in a population of people at risk of HCV living on the Isle of Wight (United Kingdom). Dry blood spot testing was conducted in anyone with a known risk factor for HCV in 20 community pharmacies. The outcomes and costs were entered into a Markov model. Cost and health utilities from the model were used to calculate an incremental cost-effectiveness ratio (ICER). In 24 months, 186 tests were conducted, 13 were positive for HCV RNA and six of these (46%) received treatment during the follow-up period. All achieved a sustained virological response at 3 months. The overall cost of the testing and treatment intervention was £242 183, and the ICER for the service was £3689 per quality-adjusted life year (QALY) gained. If screening had been restricted to just people with a history of injecting drug use (PWID) the ICER would have been £4865 per QALY gained. The service was effective at identifying people with HCV infection, and despite the additional cost of targeted testing, its cost-effectiveness was below the commonly accepted thresholds. In this setting, restricting targeted testing to PWID would not improve the cost-effectiveness.

Ruthenium-Cyclopentadienyl Bipyridine-Biotin Based Compounds: Synthesis and Biological Effect.

Prospective anticancer metallodrugs should consider target-specific components in their design in order to overcome the limitations of the current chemotherapeutics. The inclusion of vitamins, which receptors are overexpressed in many cancer cell lines, has proven to be a valid strategy. Therefore, in this paper we report the synthesis and characterization of a set of new compounds [Ru(η5-C5H5)(P(C6H4R)3)(4,4'-R'-2,2'-bpy)]+ (R = F and R' = H, 3; R = F and R' = biotin, 4; R = OCH3 and R' = H, 5; R = OCH3 and R' = biotin, 6), inspired by the exceptional good results recently obtained for the analogue bearing a triphenylphosphane ligand. The precursors for these syntheses were also described following modified literature procedures, [Ru(η5-C5H5)(P(C6H4R)3)2Cl], where R is -F (1) or -OCH3 (2). The structure of all compounds is fully supported by spectroscopic and analytical techniques and by X-ray diffraction studies for compounds 2, 3, and 5. All cationic compounds are cytotoxic in the two breast cancer cell lines tested, MCF7 and MDA-MB-231, and much better than cisplatin under the same experimental conditions. The cytotoxicity of the biotinylated compounds seems to be related with the Ru uptake by the cells expressing biotin receptors, indicating a potential mediated uptake. Indeed, a biotin-avidin study confirmed that the attachment of biotin to the organometallic fragment still allows biotin recognition by the protein. Therefore, the biotinylated compounds might be potent anticancer drugs as they show cytotoxic effect in breast cancer cells at low dose dependent on the compounds' uptake, induce cell death by apoptosis and inhibit the colony formation of cancer cells causing also less severe side effects in zebrafish.

A novel screening method for transition metal-based anticancer compounds using zebrafish embryo-larval assay and inductively coupled plasma-mass spectrometry analysis.

As novel metallodrugs continue to emerge, they are evaluated using models, including zebrafish, that offer unique sublethal endpoints. Testing metal-based anticancer compounds with high-throughput zebrafish toxicological assays requires analytical methods with the sensitivity to detect these sublethal tissue doses in very small sample masses (e.g., egg mass 100 µg). A robust bioanalytical model, zebrafish embryos coupled with inductively coupled plasma-mass spectrometry (ICPMS) for measurement of delivered dose, creates a very effective means for screening metal-based chemotherapeutic agents. In this study, we used ICPMS quantitation with the zebrafish embryo assays to detect metal equivalents at multiple response endpoints for two compounds, the chemotherapeutic agent cisplatin and ruthenium (Ru)-based prospective metallodrug, PMC79. We hypothesized that cisplatin and PMC79 have different mechanisms for inducing apoptosis and result in similar lesions but different potencies following water-borne exposure. An ICPMS method was developed to detect the metal in waterborne solution and tissue (detection limit: 5 parts per trillion for Ru or platinum [Pt]). The Ru-based compound was more potent (LC50 : 7.8 µm) than cisplatin (LC50 : 158 µm) and induced disparate lesions. Lethality from cisplatin exposure exhibited a threshold (values >15 mg/L) while no threshold was observed for delayed hatching (lowest observed adverse effect level 3.75 mg/L cisplatin; 8.7 Pt (ng)/organism). The Ru organometallic did not have a threshold for lethality. Cisplatin-induced delayed hatching was investigated further by larval-Pt distribution and preferentially distributed to the chorion. We propose that zebrafish embryo-larval assays coupled with ICPMS serve as a powerful platform to evaluate relative potency and toxic effects of metallodrug candidates.

Subtle morphometric, behavioral and gene expression effects in larval zebrafish exposed to PFHxA, PFHxS and 6:2 FTOH.

Recent studies of perfluoroalkylated substances (PFASs) have focused on the toxicity of long chain PFASs, such as PFOS or PFOA, which have been demonstrated to cause an array of developmental and behavioral effects. However, less is known about low molecular weight PFASs and alternatives. This study examined the morphometric and behavioral effects in zebrafish following developmental exposures of C6 PFASs: perfluorohexanoic acid, PFHxA, perfluorohexane sulfonate, PFHxS, and 6:2 fluorotelomer alcohol, 6:2 FTOH. Embryos were exposed to 0.02-20 µM concentrations of these compounds from the high stage (˜3 h post fertilization, hpf) until 120 hpf. Morphometric and gene expression endpoints were examined at 120 hpf. Genes selected for analysis were previously shown to be altered in zebrafish developmentally exposed to PFOS and PFOA. Additionally, exposed larvae were transferred to clean water and reared until 14 days post fertilization, dpf, when behavioral assays were completed and morphometric endpoints examined. While PFHxA was found to be the most acutely toxic at 120 hpf, few morphometric effects were observed. Gene expression was the most sensitive endpoint with significant increased tgfb1a, bdnf, and ap1s1 expression observed with PFHxA exposure. PFHxS exposure produced morphometric effects in the larvae, specifically increased length and yolk sac area at 2 and 20 µM. This phenotype persisted to the 14 dpf time point, where these larvae additionally displayed decreased distance traveled and crosses through the center of the arena of the behavioral assay. Exposure to 6:2 FTOH caused no morphometric effects at 120 hpf, and this compound was the least acutely toxic. However, expression of both tgfb1a and bdnf were increased by greater than 2 fold change at this time point. Effects also persisted to 14 dpf where a significant increase in distance traveled and velocity were observed in the behavioral assay. This study demonstrates effects on behavioral, morphometric and gene expression endpoints with developmental PFHxA, PFHxS, and 6:2 FTOH exposures in zebrafish.

Fulvestrant for Untreated Hormone-Receptor Positive Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Clinical and cost-effectiveness evidence on fulvestrant for untreated hormone-receptor positive locally advanced or metastatic breast cancer was submitted to the single technology appraisal process of the National Institute for Health and Care Excellence by the manufacturer of fulvestrant. The Southampton Health Technology Assessments Centre was commissioned by the National Institute for Health and Care Excellence as an independent Evidence Review Group to critique the company's submitted evidence. Fulvestrant was compared directly with anastrozole in two randomised controlled trials and was compared indirectly by means of a network meta-analysis with anastrozole, letrozole and tamoxifen. This article summarises the Evidence Review Group's review of the company's submission and summarises the guidance the National Institute for Health and Care Excellence Appraisal Committee issued in January 2018. The Evidence Review Group had several concerns, the most important of which related to the degree to which fulvestrant might confer a benefit in overall survival. This was because mature data were not available from the key phase III trial FALCON. The economic model was sensitive to changes in overall survival and the Evidence Review Group considered the incremental cost-effectiveness ratio was uncertain and likely to increase once mature results from FALCON become available. The National Institute for Health and Care Excellence Appraisal Committee concluded that fulvestrant could not be recommended for treating locally advanced or metastatic estrogen-receptor-positive breast cancer in postmenopausal women who have not received previous endocrine therapy.

Unprecedented inhibition of P-gp activity by a novel ruthenium-cyclopentadienyl compound bearing a bipyridine-biotin ligand.

Two new ruthenium complexes, [Ru(η5-Cp)(PPh3)(2,2'-bipy-4,4'-R)]+ with R = -CH2OH (Ru1) or dibiotin ester (Ru2) were synthesized and fully characterized. Both compounds were tested against two types of breast cancer cells (MCF7 and MDA-MB-231), showing better cytotoxicity than cisplatin in the same experimental conditions. Since multidrug resistance (MDR) is one of the main problems in cancer chemotherapy, we have assessed the potential of these compounds to overcome resistance to treatments. Ru2 showed exceptional selectivity as P-gp inhibitor, while Ru1 is possibly a substrate. In vivo studies in zebrafish showed that Ru2 is well tolerated up to 1.17 mg/L, presenting a LC50 of 5.73 mg/L at 5 days post fertilization.

Responses of macroinvertebrates and local environment to short-term commercial sand dredging practices in a flood-plain lake.

In parts of the developing world, the expansion of industrial sand mining activities has led to serious environmental concerns. However, current understanding of the effects of this activity on an inland water ecosystem remains limited. Herein, we choose the "most affected" lake in China (Dongting Lake), to assess short-term (1year) effects of sand dredging on key environmental parameters and on the structure of the macroinvertebrate assemblage. Within the dredged area we observed increases in water depth (on average 2.17m), turbidity and changes in sediment composition (e.g., increase in % medium sand, and a decrease in % clay). In addition, dredging was associated with a 50 % reduction in taxa richness, Simpson and Shannon-Wiener indices, and a 72 and 99 % reduction in abundance and biomass, respectively. Indirect effects were also observed in the zone surrounding the extraction sites (ca. 500m), most likely as a result of the dredging processes (e.g., sediment screening and overspill) and water flow. No such effects were observed at a nearby reference site. The direct removal of sediment and indirect alteration of physical conditions (e.g., water depth, turbidity and sediment composition) appear to be the most likely cause of variations in the benthic community. Implications of our findings for the planning, management and monitoring of sand dredging in inland waters are discussed.

Reslizumab for Treating Asthma with Elevated Blood Eosinophils Inadequately Controlled by Inhaled Corticosteroids: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process, the manufacturer of reslizumab (Teva) submitted evidence for its clinical and cost effectiveness for the treatment of eosinophilic asthma inadequately controlled by inhaled corticosteroids. NICE commissioned Southampton Health Technology Assessments Centre (SHTAC) as an independent Evidence Review Group (ERG) to provide a critique of the manufacturer's submitted evidence. Reslizumab is compared with best standard of care and omalizumab, for a small 'overlap' population of patients who have both eosinophilic and IgE-mediated severe asthma. This paper provides a summary of the ERG's review of the manufacturer's submission, and summarises the NICE Appraisal Committee's subsequent guidance (issued in August 2017). The ERG considered that there were limitations in the approach proposed by the manufacturer for the exacerbation rate and the utility for severe exacerbation. The company amended their initial analysis, following comments from the ERG and the NICE committee, whereby the incremental cost effectiveness ratio was £29,870 per QALY gained for reslizumab compared with best standard care. The NICE Appraisal Committee (AC) concluded that reslizumab was recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if (1) the blood eosinophil count has been recorded as 400 cells per microlitre or more and (2) the patient has had three or more asthma exacerbations in the past 12 months, and (3) the company provides reslizumab with the discount agreed in the patient access scheme.

Key scientific issues in developing drinking water guidelines for perfluoroalkyl acids: Contaminants of emerging concern.

Perfluoroalkyl acids (PFAAs), a group of synthetic organic chemicals with industrial and commercial uses, are of current concern because of increasing awareness of their presence in drinking water and their potential to cause adverse health effects. PFAAs are distinctive among persistent, bioaccumulative, and toxic (PBT) contaminants because they are water soluble and do not break down in the environment. This commentary discusses scientific and risk assessment issues that impact the development of drinking water guidelines for PFAAs, including choice of toxicological endpoints, uncertainty factors, and exposure assumptions used as their basis. In experimental animals, PFAAs cause toxicity to the liver, the immune, endocrine, and male reproductive systems, and the developing fetus and neonate. Low-dose effects include persistent delays in mammary gland development (perfluorooctanoic acid; PFOA) and suppression of immune response (perfluorooctane sulfonate; PFOS). In humans, even general population level exposures to some PFAAs are associated with health effects such as increased serum lipids and liver enzymes, decreased vaccine response, and decreased birth weight. Ongoing exposures to even relatively low drinking water concentrations of long-chain PFAAs substantially increase human body burdens, which remain elevated for many years after exposure ends. Notably, infants are a sensitive subpopulation for PFAA's developmental effects and receive higher exposures than adults from the same drinking water source. This information, as well as emerging data from future studies, should be considered in the development of health-protective and scientifically sound guidelines for PFAAs in drinking water.