Ten-Year Analysis of Complications Related to Simple Basilar Skull Fractures in Children Presenting to a Trauma Center.

OBJECTIVES: Head trauma is a common presenting complaint among children requiring urgent medical attention, accounting for more than 600,000 emergency department (ED) visits annually, 4% to 30% of which identify skull fractures among the patient's injuries. Previous literature shows that children with basilar skull fractures (BSFs) are usually admitted for observation. We studied whether children with an isolated BSF have complications precluding them from safe discharge home from the ED. METHODS: We performed a retrospective review of ED patients aged 0 to 18 years given a simple BSF diagnosis (defined by nondisplaced fracture, with normal neurologic examination, Glasgow Coma Score of 15, no intracranial hemorrhage, no pneumocephalus) during a 10-year period to identify complications associated with their injury. Complications were defined as death, vascular injury, delayed intracranial hemorrhage, sinus thrombosis, or meningitis. We also considered hospital length of stay (LOS) longer than 24 hours or any return visit within 3 weeks of the original injury. RESULTS: Of the 174 patients included in the analysis, there were no deaths, cases of meningitis, vascular injury, nor delayed bleeding events. Thirty (17.2%) patients required a hospital LOS longer than 24 hours and 9 (5.2%) returned to the hospital within 3 weeks of discharge. Of those with LOS longer than 24 hours, 22 (12.6%) patients needed subspecialty consultation or intravenous fluids, 3 (1.7%) had cerebrospinal fluid leak, and 2 (1.2%) had a concern for facial nerve abnormality. On the return visits, only 1 (0.6%) patient required readmission for intravenous fluids because of nausea and vomiting. CONCLUSIONS: Our findings suggest that patients with uncomplicated BSFs can be safely discharged from the ED if the patient has reliable follow-up, is tolerating oral fluids, has no evidence of cerebrospinal fluid leak, and has been evaluated by appropriate subspecialists before discharge.

Sledding Accidents at a Level 1 Pediatric Trauma Center Between 2006 and 2016.

BACKGROUND: Sledding is not a risk-free winter sport. According to the US Consumer Product Safety Commission, there were an estimated 13,954 sledding accidents requiring medical care in 2010. However, specific information concerning pediatric injuries related to sledding is not well defined. OBJECTIVES: This study aimed to identify the most common types of injuries associated with sledding accidents and demographic factors related to risk of injury in pediatric patients, and to compare injuries associated with 2 different age groups and sexes. METHODS: This is a retrospective descriptive study of pediatric patients (<18 years of age) presenting to a regional level I pediatric trauma center secondary to a sledding injury between 2006 and 2016. Demographic information including sex, age, mechanism of injury, and injury severity score was captured and analyzed using descriptive statistics. RESULTS: There were 209 patients identified for 10 years. There were no mortalities. There were 85 patients with primary head injury, of which 82 (96.5%) were hospitalized and 33 (38.8%) required an intensive care unit (ICU) stay. Seventy-five patients primarily suffered from extremity injuries, of which 56 (74.6%) had lower extremity fractures requiring operative intervention. There was no difference in ICU or length of stay between younger children (0-11 years) and adolescents (12-18 years) or between male and female patients. CONCLUSIONS: Childhood sledding can result in a variety of significant injuries requiring surgical intervention and hospitalization. Children pulled on sleds behind motorized vehicles are at higher risk for more severe injuries resulting in a higher rate of ICU admission.

Measuring problem prescription opioid use among patients receiving long-term opioid analgesic treatment: development and evaluation of an algorithm for use in EHR and claims data.

Objective: Opioid surveillance in response to the opioid epidemic will benefit from scalable, automated algorithms for identifying patients with clinically documented signs of problem prescription opioid use. Existing algorithms lack accuracy. We sought to develop a high-sensitivity, high-specificity classification algorithm based on widely available structured health data to identify patients receiving chronic extended-release/long-acting (ER/LA) therapy with evidence of problem use to support subsequent epidemiologic investigations. Methods: Outpatient medical records of a probability sample of 2,000 Kaiser Permanente Washington patients receiving ≥60 days' supply of ER/LA opioids in a 90-day period from 1 January 2006 to 30 June 2015 were manually reviewed to determine the presence of clinically documented signs of problem use and used as a reference standard for algorithm development. Using 1,400 patients as training data, we constructed candidate predictors from demographic, enrollment, encounter, diagnosis, procedure, and medication data extracted from medical claims records or the equivalent from electronic health record (EHR) systems, and we used adaptive least absolute shrinkage and selection operator (LASSO) regression to develop a model. We evaluated this model in a comparable 600-patient validation set. We compared this model to ICD-9 diagnostic codes for opioid abuse, dependence, and poisoning. This study was registered with ClinicalTrials.gov as study NCT02667262 on 28 January 2016. Results: We operationalized 1,126 potential predictors characterizing patient demographics, procedures, diagnoses, timing, dose, and location of medication dispensing. The final model incorporating 53 predictors had a sensitivity of 0.582 at positive predictive value (PPV) of 0.572. ICD-9 codes for opioid abuse, dependence, and poisoning had a sensitivity of 0.390 at PPV of 0.599 in the same cohort. Conclusions: Scalable methods using widely available structured EHR/claims data to accurately identify problem opioid use among patients receiving long-term ER/LA therapy were unsuccessful. This approach may be useful for identifying patients needing clinical evaluation.

Feasibility of lung cancer RNA acquisition from a single transbronchial or transthoracic needle pass (FASTT trial).

INTRODUCTION: RNA isolation from tumor tissue is used for biomarker analyses and validation. Limited diagnostic material from small volume biopsies combined with an increasing demand for standard histologic, molecular characterization, and next generation sequencing applications often leads to limited material for research. We sought to evaluate small volume sampling of lung cancer tissue collected from a single needle pass during a diagnostic procedure and determine if it can provide RNA of acceptable quantity and quality. METHODS: We enrolled 140 patients with probable primary bronchogenic carcinoma and collected RNA from a dedicated FNA aspiration. Total RNA (ηg), RNA integrity number (RIN), and %Mass in base pairs were evaluated from each patient sample. A customized nanoString nCounter® 95-gene panel was used to profile the expression patterns of feature NSCLC genes. We compared gene expression patterns that distinguish lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) in our cohort with a corresponding Cancer Genome Atlas (TCGA) NSCLC datasets. RESULTS: Of the 149 patients consented. RNA-extraction was performed in 101 eligible patients. A satisfactory total RNA mass and RIN was quantified for all samples with a similar distribution among cellular subtypes. Mean %-Mass over 300 base pairs was noted for all specimens and 96% of samples met criteria to perform genetic evaluation with our commercialized gene expression assay. The FNA-derived transcriptomic results showed excellent consistency with the TCGA counterparts, and the differential expression pattern of LUAD vs LUSC subtypes were highly similar. DISCUSSION: In this study, RNA retrieval from a single-pass FNA regardless of procedural approach showed equivalence and suitability for gene expression assessments. RNA extraction from small volume samples has the potential to provide valuable material for genetic profiling.

Intradermal delivery of vaccine nanoparticles using hollow microneedle array generates enhanced and balanced immune response.

Hollow microneedles can help overcome the skin permeation barrier imposed by the stratum corneum and facilitate transcutaneous delivery of nanoparticle delivery systems. In the present study, we investigated the use of the hollow microneedle array for intradermal delivery of polymeric nanoparticles (NPs) in rats. Compared to intravenous and subcutaneous routes of administration, intradermal delivery of polymeric NPs via a hollow microneedle array resulted in a unique pharmacokinetic profile, characterized by an early burst transit through the draining lymph nodes and a relatively limited overall systemic exposure. Based on high local lymphatic concentrations achieved, we investigated the use of this modality for vaccine delivery. A model antigen ovalbumin (OVA) and TLR agonists imiquimod and monophosphoryl Lipid A encapsulated in poly(d,l-lactide-co-glycolide) (PLGA) NPs were used as the vaccine formulation. Compared to soluble OVA-based vaccine, OVA loaded NPs demonstrated faster antibody affinity maturation kinetics. Moreover, antigen loaded NPs delivered via a hollow microneedle array elicited a significantly higher IgG2a antibody response and higher number of interferon (IFN)-γ secreting lymphocytes, both markers of Th1 response, in comparison to antigen loaded NPs delivered by intramuscular injection and soluble antigen delivered through hollow microneedle array. Overall, our results show that hollow microneedle mediated intradermal delivery of polymeric NPs is a promising approach to improve the effectiveness of vaccine formulations.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

Adjuvants to prolong the local anesthetic effects of coated microneedle products.

The objective of this study was to identify an adjuvant for anesthetics coated on microneedles to provide rapid onset and prolonged analgesic action with minimal skin tissue reaction. Aqueous lidocaine or prilocaine formulations with or without clonidine or the related analogs, guanfacine and apraclonidine, were dip-coated onto polymeric microneedles. The amount of lidocaine or prilocaine coated onto the microneedles was assessed by high performance liquid chromatography (HPLC). Delivery efficiency and dermal pharmacokinetics associated with lidocaine or prilocaine delivered via the microneedles were characterized in vivo using domestic swine. Skin punch biopsies were collected and analyzed to determine the anesthetic concentrations in the skin using HPLC-mass spectrometry (LC-MS). Addition of clonidine to the formulations decreased the systemic absorption rate of the anesthetics from the patch application site without impacting the coating performance or the rapid onset of anesthesia. Formulations with 0.3 wt.% clonidine, identified as the optimal dose for lidocaine-delivery via microneedles, maintained the lidocaine skin concentration above the estimated therapeutic level (100 ng/mg) for 1 h without causing any skin irritation or color change. The other two clonidine analogs, guanfacine and apraclonidine, also led to delayed systemic absorption of lidocaine from the skin, indicating utility in providing prolonged analgesia.

Development of lidocaine-coated microneedle product for rapid, safe, and prolonged local analgesic action.

PURPOSE: To demonstrate rapid (~1 min) lidocaine delivery using 3M's solid microstructured transdermal system (sMTS) for prolonged, local analgesic action. METHODS: Polymeric microneedles were fabricated via injection molding and then dip-coated using an aqueous lidocaine formulation. The amount of lidocaine coated onto the microneedles was determined by high performance liquid chromatography (HPLC). To assess drug delivery and dermal pharmacokinetics, lidocaine-coated microneedles were inserted into domestic swine. Skin punch biopsies were collected and analyzed to determine lidocaine concentration in skin using HPLC-mass spectrometry (LC-MS). Commercial lidocaine/prilocaine EMLA (Eutectic Mixture of Local Anesthetic) cream was used as comparative control. RESULTS: Lidocaine dissolves rapidly off the microneedles and into skin such that the 1-min wear time achieves or exceeds lidocaine tissue levels needed to cause analgesia. This therapeutic threshold (100 ng/mg) was estimated by measuring the total amount of lidocaine and prilocaine in skin following a 1 h EMLA application. When co-formulated with 0.03 wt% vasoconstrictor-epinephrine, the concentration of lidocaine in tissue was maintained above 100 ng/mg for approximately 90 min. CONCLUSIONS: 3M's sMTS can be used to provide rapid delivery of lidocaine for local analgesia up to 90 min.

Enhanced delivery of topically-applied formulations following skin pre-treatment with a hand-applied, plastic microneedle array.

The purpose of this work is to characterize microchannels created by polymeric microneedles, applied by hand, and to demonstrate enhanced delivery of topically applied formulations of lidocaine hydrochloride and methylprednisolone sodium succinate (MPSS). 3M's Microstructured Transdermal System (MTS) arrays were applied to domestic swine to demonstrate reliability of penetration, depth of penetration and durability of the structures to repeat application and high force. Tissue levels of lidocaine and MPSS following topical application with and without microneedle pretreatment were determined by HPLC-MS analysis following digestion of biopsies. Almost all microneedles penetrate the stratum corneum upon hand force application. The depth of penetration varies from <100µm to nearly 150µm depending on the application force and the firmness of the underlying tissue. The arrays show excellent durability to repeated in-vivo application, with less than 5% of the structures evidencing even minimal tip bending after 16 applications. Under extreme force against a rigid surface, the microneedles bend but do not break. A lidocaine hydrochloride formulation applied topically in-vivo showed ~340% increase in local tissue levels when the MTS arrays were used to twice pre-treat the skin prior to applying the drug. Local delivery of a topically applied formulation of MPSS was over one order of magnitude higher when the application site was twice pre-treated with the MTS array. 3M's MTS array (marketed as 3M(TM) Microchannel Skin System) provides repeatable and robust penetration of the stratum corneum and epidermis and enhances delivery of some formulations such as lidocaine hydrochloride.

Rapid intradermal delivery of liquid formulations using a hollow microstructured array.

PURPOSE: The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application. METHODS: 3M's hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability. RESULTS: Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations. CONCLUSIONS: 3M's hMTS can provide rapid, intradermal delivery of 300-1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery.

Use of focused abdominal sonography for trauma at pediatric and adult trauma centers: a survey.

PURPOSE: Focused abdominal sonography for trauma (FAST) has been popularized for the initial evaluation of trauma patients. We sought to understand the scope of practice on a national level with specific attention to its use in the pediatric age group. METHODS: An electronic survey was sent to all American College of Surgeons level I trauma centers and the National Association of Children's Hospitals and Related Institutions that were freestanding children's hospitals. RESULTS: The survey was emailed to 124 centers, and 98 (79%) completed the survey. Of the surveyed centers, 23% cared for adults only, 28% were freestanding children's hospitals, and 49% managed both. At adults-only institutions, 96% use FAST and at children's hospitals, only 15%; it is used at 85% of centers that care for both. For the centers that use FAST on children, 88% have no age limit. Of all the institutions that typically use FAST, the individual performing the examination could be a surgeon (73%), an emergency department doctor (48%), or a radiologist (3%). Of the centers that perform FAST, 51% bill for the FAST examination. CONCLUSIONS: Adult hospitals are much more likely to perform FAST examinations in the trauma patient, and many adult centers routinely use FAST to examine pediatric patients.

A standard pediatric trauma laboratory panel: a plea for a minimalist approach.

BACKGROUND: Optimizing patient outcomes has promoted a protocol-driven environment within the trauma bay. No standardized laboratory panel exists during the initial evaluation of injured children. METHODS: In 2004, we implemented a standard trauma panel consisting of an i-STAT analysis (electrolytes, hematocrit, and blood gas), and type and cross. We reviewed the experience of this protocol 1 year prior (T1) and after (T2) its implementation. RESULTS: During T1, 23% of patients underwent a traditional trauma panel compared with T2 where 43.5% received the new standard trauma panel. Neither the mean number of laboratory draws per patient (T1 = 4.6 vs. T2 = 4.3, p = 0.77) nor the mean number of laboratory tests obtained (T1 = 15.0 vs. T2 = 12.7, p = 0.99) were significantly different between the two groups. The mean amount of blood drawn within the trauma bay was significantly more in T1 compared with T2 (10 mL vs. 3.8 mL, respectively, p < 0.0001). The initial laboratory costs were $307.97 during T1 and $177.51 during T2, although the mean total laboratory charges were not significantly different between the two groups (T1 = $2,119.97 vs. T2 = $2,143.77, p = 0.62). CONCLUSIONS: The implementation of a standard laboratory panel increased the uniformity of care without compromising quality. We limited the volume and initial cost of blood drawn which is advantageous in small children.

Cervical spine clearance after trauma in children.

OBJECT: Currently, no diagnostic or procedural standards exist for clearing the cervical spine in children after trauma. The purpose of this study was to determine if reeducation of nonneurosurgical personnel and initiation of a new protocol based on the National Emergency X-Radiography Utilization Study criteria could safely increase the number of pediatric cervical spines cleared of suspected injury without a neurosurgical consultation. METHODS: Data regarding cervical spine clearance in children (ages 0-18 years) after trauma protocol activation at Primary Children's Medical Center between 2001 and 2005 were collected and reviewed. Radiographic and clinical methods of clearing the cervical spine as well as the type and management of injuries were determined for two time frames: Period I (January 2001-December 2003) and Period II (January 2004-July 2005). Between 2001 and 2003, 95% of 936 cervical spines were cleared of suspected injury by the neurosurgical service. Twenty-one ligamentous injuries (2.2%) and 12 fracture-dislocations (1.3%) were detected, with five patients requiring surgical stabilization (0.5%). Between January 2004 and July 2005, 507 (68%) of 746 cervical spines were cleared by nonneurosurgical personnel. Six ligamentous injuries (0.8%) and 10 fracture-dislocations (1.3%) were identified, with three patients (0.4%) requiring surgical stabilization. No late injuries were detected in either period. CONCLUSIONS: The protocol used has been effective in enabling detection of cervical spine injuries in children after trauma, with the new protocol increasing by more than 60% the number of cervical spines cleared by nonneurosurgical personnel. Reeducation with establishment of the new protocols can safely facilitate clearance of the cervical spine by nonneurosurgical personnel after trauma.

Cervical spine clearance after trauma in children.

OBJECT: Currently, no diagnostic or procedural standards exist for clearing the cervical spine in children after trauma. The establishment of protocols has been shown to reduce the time required to accomplish clearance and reduce the number of missed injuries. The purpose of this study was to determine if reeducation and initiation of a new protocol based on the National Emergency X-Radiography Utilization Study criteria could safely increase the number of pediatric cervical spines cleared by nonneurosurgical personnel. METHODS: The authors collected and reviewed data regarding cervical spine clearance in children (age range 0-18 years) who presented to the emergency department at Primary Children's Medical Center in Salt Lake City, Utah, between 2001 and 2006 after sustaining significant trauma. Radiographic and clinical methods of clearing the cervical spine, as well as the type and management of injuries, were determined for two periods: Period I (January 2001-December 2003) and Period II (January 2004-February 2006). Between 2001 and 2003, 95% of 936 cervical spines were cleared by the neurosurgical service. Twenty-one ligamentous injuries (2.2%) and 12 fracture/dislocations (1.3%) were detected, and five patients (0.5%) required operative stabilization. Since January 2004, 585 (62.4%) of 937 cervical spines have been cleared by nonneurosurgical personnel. Twelve ligamentous injuries (1.3%) and 14 fracture/dislocations (1.5%) were identified, and four patients (0.4%) required operative stabilization. No late injuries were detected in either time period. CONCLUSIONS: The protocol outlined in the paper has been effective in detecting cervical spine injuries in children after trauma and has increased the number of cervical spines cleared by nonneurosurgical personnel by nearly 60%. Reeducation with the establishment of protocols can safely facilitate clearance of the cervical spine after trauma by nonneurosurgical personnel.

The prevalence of driveway back-over injuries in the era of sports utility vehicles.

BACKGROUND: Small children are vulnerable to serious accidents when a motor vehicle is placed in motion in a driveway. We describe a series of such accidents, consider the predisposing factors, and analyze the outcomes. METHODS: We conducted a retrospective review of the trauma database of a large, level I, freestanding children's hospital with specific attention to driveway auto-pedestrian accidents. RESULTS: During an 8-year period, 495 children were treated for injuries sustained in auto-pedestrian accidents, with 128 occurring in the driveway. The children's median age was 2.9 years, with 54% of the injuries sustained by boys. These often serious accidents carried an overall mortality rate of 6%. The most common injuries were abrasions, blunt head injury, and fractures. Chest trauma was associated with the highest mortality (11%), and both chest and abdominal trauma had the highest median Injury Severity Score of 13. Orthopedic injuries were the most common reason for operative intervention. Thirty-one percent of the children required intensive care unit monitoring, with their average unit stay being 3.9 days. Cars, trucks, and sports utility vehicles comprised 55%, 25%, and 12% of the accidents, respectively. Truck accidents carried the highest mortality rate (19%). Accidents were more likely to occur between 3:00 and 8:00 pm, between Thursday and Saturday, and between May and October. An increasing number of accidents occurred during the last 4 years of the study. CONCLUSIONS: Driveway injuries are an underrecognized often severe form of auto-pedestrian accidents. To prevent these family tragedies, drivers of large vehicles with children younger than 12 years old should be extremely attentive and account for children outside the vehicle before moving.

CT scan and the pediatric trauma patient--are we overdoing it?

BACKGROUND: Recent literature expresses concern for an increased risk of cancer in children exposed to low-dose radiation during computed tomography (CT). In response, children's hospitals have implemented the ALARA (as low as reasonably achievable) concept, but this is not true at most adult referring institutions. The purpose of this study was to assess the diagnostic necessity of CT in the evaluation of pediatric trauma patients. METHODS: A retrospective review was conducted of the trauma database at a large, level I, freestanding children's hospital with specific attention to the pattern of CT evaluations. RESULTS: From January 1999 to October 2003, 1,653 children with traumatic injuries were evaluated by the trauma team, with 1,422 patients undergoing 2,361 CT scans. Overall, 54% of obtained scans were interpreted as normal. Fifty percent of treated patients were transferred from referring hospitals. Approximately half arrived with previous CT scans with 9% of these requiring further imaging. Of the 897 patients that underwent abdominal CT imaging, only 2% were taken to the operating room for an exploratory laparotomy. In addition, of those patients who had abnormal findings on an abdominal CT scan, only 5% underwent surgical exploration. CONCLUSIONS: CT scans are used with regularity in the initial evaluation of the pediatric trauma patient, and perhaps abdominal CT imaging is being used too frequently. A substantial number of these scans come from referral institutions that may not comply with ALARA. The purported risk of CT radiation questions whether a more selective approach to CT evaluation of the trauma patient should be considered.

Sub-chronic dietary toxicity of potassium perfluorooctanesulfonate in rats.

Perfluorooctanesulfonate (PFOS) is a widely disseminated persistent compound found at low (part-per-billion) concentrations in serum and liver samples from humans and fish-eating wildlife. This study investigated the hypotheses that early hepatocellular peroxisomal proliferation and hepatic cellular proliferation are factors in chronic liver response to dietary dosing, that lowering of serum total cholesterol is an early clinical measure of response to treatment, and that liver and serum PFOS concentrations are proportional to dose and cumulative dose after sub-chronic treatment. PFOS was administered in diet as the potassium salt at 0, 0.5, 2.0, 5.0, and 20 parts per million (ppm) to Sprague Dawley rats for 4 or 14 weeks. At 4 weeks, effects included decreased serum glucose and an equivocal (

Interactions of fluorochemicals with rat liver fatty acid-binding protein.

Liver-fatty acid binding protein (L-FABP) is an abundant intracellular lipid-carrier protein. The hypothesis that perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and certain related perfluorooctanesulfonamide-based fluorochemicals (PFOSAs) can interfere with the binding affinity of L-FABP for fatty acids was tested. The relative effectiveness of PFOA, PFOS, N-ethylperfluorooctanesulfonamide (N-EtFOSA), N-ethylperfluorooctanesulfonamido ethanol (N-EtFOSE), and of the strong peroxisome proliferator Wyeth-14643 (WY) to inhibit 11-(5-dimethylaminonapthalenesulphonyl)-undecanoic acid (DAUDA) binding to-L-FABP was determined. The dissociation constant (Kd) of the DAUDA-L-FABP complex was 0.47 nM. PFOS exhibited the highest level of inhibition of DAUDA-L-FABP binding in the competitive binding assays, followed by N-EtFOSA, WY, and, with equal IC(50)s, N-EtFOSE and PFOA. The in vitro data presented in this study support the hypothesis that these fluorochemicals may interfere with the binding of fatty acids or other endogenous ligands to L-FABP. Furthermore, this work provides evidence to support the hypothesis that displacement of endogenous ligands from L-FABP may contribute to toxicity in rodents fed these fluorochemicals.

Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys.

This study was conducted to determine the earliest measurable response of primates to low-level perfluorooctanesulfonate (PFOS) exposure and to provide information to reduce uncertainty in human health risk assessment. Groups of male and female monkeys received 0, 0.03, 0.15, or 0.75 mg/kg/day potassium PFOS orally for 182 days. Recovery animals from each group, except the 0.03 mg/kg/day dose group, were monitored for one year after treatment. Significant adverse effects occurred only in the 0.75 mg/kg/day dose group and included compound-related mortality in 2 of 6 male monkeys, decreased body weights, increased liver weights, lowered serum total cholesterol, lowered triiodothyronine concentrations (without evidence of hypothyroidism), and lowered estradiol levels. Decreased serum total cholesterol occurred in the 0.75 mg/kg/day dose group at serum PFOS levels > 100 ppm. Hepatocellular hypertrophy and lipid vacuolation were present at term in the 0.75 mg/kg/day dose group. No peroxisomal (palmitoyl CoA oxidase) or cell proliferation (proliferating cell nuclear antigen immunohistochemistry) was detected. Complete reversal of clinical and hepatic effects and significant decreases in serum and liver PFOS occurred within 211 days posttreatment. Liver-to-serum PFOS ratios were comparable in all dose groups, with a range of 1:1 to 2:1. Serum concentrations associated with no adverse effects (0.15 mg/kg/day) were 82.6 +/- 25.2 ppm for males and 66.8 +/- 10.8 ppm for females. Comparison of serum PFOS concentrations associated with no adverse effect in this study to those reported in human blood samples (0.028 +/- 0.014 ppm) indicated an adequate margin of safety.