Joseph J. Quinlan, MD

• Professor
• Department of Anesthesiology
• University of Pittsburgh
• Chief Anesthesiologist
• University of Pittsburgh Medical Center?resbyterian
• Pittsburgh, Pennsylvania

Therefore acne under chin generic betnovate 20 gm on line, the values in this table skin care videos youtube order betnovate canada, although falsely labelled skin care not tested on animals order discount betnovate on line, are the standard error of their corresponding estimates acne on temples generic betnovate 20 gm free shipping. It random iz ed, dou ble-blind, m onthsonastable G abapentin(3 0 0 m g capsu les 3. N oneof thereportsex plicitly state ex clu dedfrom m eta-analy sisw hereitcanstill reflex es. Thedocu m ent E x clusionCriteria: therem ainderof thetreatm ent N B: The1 0 point(1 -1 0) Visu al inphase1 v s. Itisim possibleto reasonsasareasonfor approv edafterthe antidepressants, PlaceboG roup of the1 3 w how ithdrew andstates discernw how ithdrew, w hen, andw hy. N arcoticsw ereallow edthrou ghou tthistrial changedtootherreasons) sam plesiz erequ iredto m ex iletinediscontinu edthese P-v alu e: 0. The w hich grou p each of these5 m g/day, isprobably nom oreeffectiv ethan report. Theconclu sionintheabstractof N eu rology m akesnom ention notlistbaselinecharacteristics,only asParkeD av is of the1 3 patientsw hodropped finalv isitsof each treatm entperiod. O u rresu ltssu ggestthatfu rther Publishedas: Questionnaire): collectionisnotdetailedinthe the1 3 /5 3 patientsw hoarenot stu diesev alu ating higherdosagesof Abstractpu blishedin P: 3 3. TheprotocolstatesthatSubjectswillbe (Volu m e5 0 (4) Su pplem ent N ote: forthosew horeceiv edactiv e ev entsforthew holetrial. This TotalPatientswithAdverse readsPatientswerecontactedevery weekby G orsonK G,SchottC etal. G abapentinG roup seem soddthatthey hav ebeen eachtreatmentperiod,patientsratedtheir Baseline: 6. TheprotocolstatesthatThesubjectswillalso relief:none,mild,moderate,or N otethatherethedenom inatoris provideaverbalrating scaleof global ex cellent,ascomparedtothe Therearediscrepanciesbetw eenthe u nknow n, presu m able4 0; nu m berof assessmentof painatbaselineandevery 2 baselinelevelof pain protocolandreportsof thestu dy with patientsforplacebo, fordrow siness, weeksduring thetreatmentperiodasfollows: preceding thetrial. Itw ou ldseem report, nonoteastow hetherornot none,mild,moderate,orex cellent,as thattheactu alstu dy dev iated thisfailu retoretu rntobaselinew as Imbalance: comparedtothelevelof painpreceding each from theprotocolhere. C rossov erdesignsoftenhav egreaterpow er seem tohav ebeentheinitialplan calcu latedtodetectadifference thanparallelgrou p designsw ith m orepatients (initially pow erof stu dy w as of 1 gradeonthev erbalrating solong asw ithdraw alratesarenottoohigh, calcu latedinordertohav etheability scale(globalassessm entof pain theu nderly ing diseaseisnotrapidly changing, todetecta1 gradedifferenceonthe relief) at6 w eeksof am ean andthew ashou tperiodisadequ ate. Therefore, acrossov erdesign ou tcom etotheN R S (1 1 -Point w asprobably adequ atetodetectbenefit; L ikert) scaleu sedinm ostother especially giv enthepow erof thestu dy w as stu dies. C onsequ ently therew asalow probability of notdetecting abenefitw henoneispresent. Therefore, itisprobablethat 7 -pointscale, bu tw as0 = nopain certainpatients, asw ellastheirassessing relief; 1 = slightim prov em ent, 2 = phy sicians, w ereabletodeterm ineinw hich m oderateim prov em ent, phasethey w ereontheactiv edru g w hich 3 = com pletepainrelief cou ldeasily hav eaffectedbaselinescoresand (according topage5 of thestu dy ordereffects. O f thosew hocom pletedthestu dy, 3 1 w ere N u m berof patientsreporting m enand9 w erew om en. O new onders m oderateorex cellentpainrelief: 9 /5 3 w hetherornot, thesignificantly higher G abapentin: proportionof m enm ightaffectresu ltsatall. How ev erthestandard dev iations listeddonotm atch thoseinthe Itw ou ldseem thatthenu m bers earlierreports. Theprotocolisdifferentfrom w hatw as reportedinm any w ay s(seenotesthrou ghou t 10. Theauthors G /A= 9/12(75%),A/G = 10/13 G total= 18/23(78%) D ecember1997 adversereaction scaleof 13words to concludethat (77%) A total= 17/24(71%) togabapentinor numbers( Perry, July 27, 2008 max imum doseof 75mg/d cardiovascular D rug doses/titration(p. G abapentinwasdivided pharmacist,theonly unblended clearance<30 into3doses/day vs. This paindiary tonumericalequivalents previousanalgesics appearstobeclose using PainScaleRating Sy stem. G lobalrating scalescores scaleand Baseline analy siedwithpaired,2-tailed terminology is D isability:notreported characteristics: W ilcox onsignedranktest. Thescoresaredifferent any other nortripty linepreviously, from allotherstudiesbecausethenumericalscaleistotally commonly used and9/25weretaking different,andnotcomparable. Thismakesit None: G = 6/21;A= 3/21 virtually impossible W orse: G = 1/21;A= 0/21 thatpatientsremained blinded. Page27 264,298,299,306,308)itispossibleto D avis-associatedand treatmentof painful of finalreport(Table9) G = 84randomiz ed(84 identify theex perimentalgroupsto W eightgainfrom screening tostudy termination(Appendix C. Analy sis)isvery difficultto PainScores:Resultsof Analy sisof Covariance,whichreportsP understand. Atpage278:preliminary measure;repeatedstatistical meanof 7diary L ikertscores analy seswillbeperformedinordertoaidinstrategicplanning. If so, becauseitisapost-hocanaly siswhichcannotbeinterpretedfor any benefitobtainablefor statisticalsignificance. Thesameresponder analy sissuggeststhat sleepdisturbance mightbe P= 15/80[19%]vs. Thefollowing scores canbesummedfrom theraw datastarting atpage419forP (N= 76/81randomiz ed)andG (N= 79/84randomiz ed),where1= much improved,2= moderately improved,3= minimally improved,4= no change,5= minimally worse,6= moderately worse,7= much worse: Category 1:P = 12,G = 33 Category 2:P = 13,G = 14 Category 3:P = 13,G = 12 Category 4:P = 25,G = 18 Category 5:P = 5,G = 1 Category 6:P = 6,G = 1 Category 7:P = 2,G = 0 Thestudy publicationandreportgrouptheseintocategories1&2, 3&4,5,6&7. Enrichment bias: Patients who had previously taken gabapentin were excluded from this trial as were patients with a hypersensitivity to the drug this causes enrichment bias favouring gabapentin by excluding patients who may have been likely to experience adverse events, or who may have previously failed gabapentin therapy. This sacrifices 4 early dropout patients from gabapentin group, but 0 patients from placebo group. That is, any missing post-baseline value was replaced with the last available post-baseline observation regardless of the assessment date. Even the unpublished report does notexplain why 4 subjects randomized to gabapentin were not included in the efficacy analyses but were included in the safety analyses. Pages 25 and 26 of the unpublished report state criteria for assignment to each group.

Abnormalities of gene function Different types of genetic mutation have different consequences for gene function acne cyst purchase betnovate overnight. Loss of function mutations Loss of function mutations result in reduced or absent function Expression of the gene product skin care in 30s cheap 20gm betnovate mastercard. This type of mutation is the most common skin care qualifications order 20 gm betnovate mastercard, and generally results in a recessive phenotype acne home remedies purchase discount betnovate line, in which heterozygotes with 50% of normal gene activity are 2n chains n chains unaffected, and only homozygotes with complete loss of function are clinically affected. Heterozygosity for chromosomal deletions usually causes an abnormal phenotype and this is probably due to haploinsufficiency of a number of Assembly genes. This causes formation of intracellular aggregates that result in neuronal cell death. This feature makes the method applicable in prenatal diagnosis using chorionic villus or amniocentesis samples and in other situations in which blood sampling is not appropriate. In some instances, agarose gel electrophoresis alone is sufficient to demonstrate that a mutation is present. Determining the exact position of the deletion, however, requires additional analysis. This altered conformation affects its migration through a non-denaturing polyacrylamide gel, resulting in a band shift when compared to a sample without a mutation. The translation products are then separated by polyacrylamide gel electrophoresis. In some cases, the change detected may turn out to be a polymorphism that has no direct bearing on the condition under investigation. In chemical cleavage of mismatch analysis, particular types of base mismatch are cleaved specifically by the different chemicals employed; this yields limited information about the type of change observed. The technique was further refined using technology developed prior to the Human Genome Project and is now a routine method of analysis in many molecular genetic laboratories. The sequencing products are then separated with the use of long polyacrylamide gels with a laser being used to automatically detect the fluorescent molecules as they migrate. If the mutation is very common, however, methods may be used that specifically interrogate the site of the mutation. One of the simplest ways of doing this is by using a restriction enzyme (see above); however, this is not applicable in all situations. It is this basic principle that has been developed into the so-called gene chip technology. The large number of probes used enables the pattern of hybridisation to be translated into sequence information. In this technique an electric current is passed through the gel in timed pulses at the laborious sample handling steps involved. Note the In addition to improvements in sample throughput, hexagonal arrangement of the electrodes in this case molecular genetic laboratories are increasingly paying attention to the functional significance of the genetic changes that they detect. The vast quantity of information that has been generated by the Human Genome Project will undoubtedly increase the ability to predict the effect of specific mutations. This enables tests to be offered to other relatives to provide presymptomatic Invemess Aberdeen diagnosis, carrier testing and prenatal diagnosis as appropriate. In this chapter, examples of some of these Dublin Sheffield Liverpool common inherited disorders have been chosen to illustrate the Nottingham range of tests performed. Birmingham Leicester Oxford Cambridge Cardiff Haemoglobinopathies LondonLondon BristolBristol the haemoglobinopathies are a heterogeneous group of ExeterExeter Southampton inherited disorders characterised by the absent, reduced or altered expression of one or more of the globin chains of Figure 18. The haemoglobinopathies represent the commonest single-gene disorders in the world population and have had 2 1 profound effects on the provision of health care in some 5 developing countries. Direct detection of this point mutation permits carrier 2 G A 1 detection and first-trimester prenatal diagnosis. In the most severe type, Barts hydrops fetalis, all four copies are lost, leading to a severe phenotype associated with stillbirth or early neonatal death. The -globin gene cluster contains a number of repeat regions that increase the likelihood of unequal crossover during meiosis. As a result, relatively large deletions are the commonest type of mutations that give rise to Normal +trait +thalassaemia -thalassamia. Although a large Normal gene number of mutations have been reported, the prevalence of Gene deletion or mutation specific mutations is dependent on the ethnic origin. However, if individuals have between 55 and 200 repeats (although apparently unaffected), there is an increased risk of the repeat region expanding further into the full mutation range (200 repeats) that is associated with mental Full mutation retardation. After amplification, the size of the repeat from each chromosomal copy is determined by polyacrylamide gel electrophoresis. The expansion is translated into a 13 polyglutamine tract in the huntingtin protein gene product that is believed to cause a dominant gain of function leading to neuronal loss. In general, the greater the number of repeats an expansions within the pathological range as indicated by the arrows (courtesy of Alan Dodge, Regional Genetic Service, St. Most cases are inherited in an autosomal recessive fashion, although some affected families show dominant inheritance. Samples with deletions are indicated by the arrows (courtesy of and milder, chronic cause with affected children achieving Dr Andrew Wallace, Regional Genetic Service, St. The remainder of cases are due to a (courtesy of Dr Simon Ramsden, Regional Genetic Service, St. Genetic disorders may, however, be amenable to treatment, either symptomatic or potentially curative. Treatment may range from conventional drug or dietary Gene product management and surgery to the future possibility of gene therapy. In the future, treatment of common multifactorial disorders may be improved if genotype analysis of affected individuals identifies those who are likely to respond to particular drugs. In most single gene disorders, the primary defect is not yet amenable to specific treatment. Lay organisations often provide additional support for the patients and their families. Environmental modification the effects of some genetic disorders may be minimised by avoiding or reducing exposure to adverse environmental factors. These environmental effects are well recognised in common disorders such as coronary heart disease, and individuals known to be at increased genetic risk should be encouraged to make appropriate lifestyle changes. In individuals with glucose-6-phosphate dehydrogenase deficiency, drugs such as primaquine and dapsone, as well as ingesting fava beans, cause haemolysis. Myotonic dystrophy is associated with increased anaesthetic risk and suxamethonium must not be given to people with pseudocholinesterase deficiency. Exposure to sunlight precipitates skin fragility and blistering I R in all the porphyrias except the acute intermittent form. Many primary congenital malformations are amenable to successful surgical correction. The presence of structural abnormalities is often identified by prenatal ultrasound scanning, and this allows arrangements to be made for delivery to take place in a unit with the necessary neonatal surgical facilities when this is likely to be required. In girls with congenital adrenal hyperplasia, virilisation of the external genitalia is secondary to excess production of androgenic steroids in utero and requires reconstructive surgery. In other disorders, structural complications may occur later, such as the aortic dilatation that may develop in Marfan syndrome. Although direct replacement of the missing enzyme is not generally possible, enzyme activity can Homocystine be enhanced in some disorders. Vitamins act as cofactors in certain enzymatic reactions and can be effective if given in doses above the usual physiological requirements. For example, thiamine may permit a switch to pyruvate metabolism by means of pyruvate dehydrogenase in pyruvate carboxylase deficiency. In requires vitamin B6 cofactor 100 Treatment of genetic disorders other disorders the harmful substrate may have to be removed by alternative means, such as the chelation of copper with penicillamine in Wilson disease and peritoneal dialysis or haemodialysis in certain disorders of organic acid metabolism. In another group of inborn errors of the metabolism the signs and symptoms are due to deficiency of the end product of a metabolic reaction, and treatment depends on replacing this end product.

A skin compartment is included in the model acne natural remedies purchase on line betnovate, which may serve for simulating absorption and distribution following deposition onto the skin surface; however skin care giant crossword order genuine betnovate line, the dermal absorption model was not evaluated in Loccisano et al acne quizlet discount 20 gm betnovate fast delivery. The human model was calibrated to predict t1/2 values estimated for human populations acne 6dpo buy discount betnovate 20 gm on line. It is not currently possible to assess with confidence whether the human model can accurately predict doses to liver or any other tissues. Nevertheless, data on internal distribution were not available to allow evaluation of how well the monkey model predicts doses to the liver or other tissues. Optimization of the monkey models relied heavily on adjusting these same parameters and, for the human model, the target plasma elimination t1/2 was achieved solely by adjusting Tm. Thus, despite the complexity of the models, their potential to accurately predict plasma elimination kinetics and, therefore, steady-state plasma concentrations and associated oral intakes, depends largely on how well they predict plasma clearance. If plasma clearance and the free-fraction in plasma can be reliably predicted empirically for the animal species of interest, then far simpler compartmental models can be used for dosimetry extrapolation of steady-state free plasma concentrations. Complete lists of parameters and parameter values and the bases for parameter values and evaluations of model predictions in comparison to observations are reported in Rodriguez et al. Absorption from the gastrointestinal tract is simulated as first-order with complete absorption of the ingested dose. Transfer to the fetus is flow-limited and governed by a fetus/maternal partition coefficient and placental blood flow. Transfer from the maternal system to the pup by lactation is simulated as first-order governed by a lactation transfer rate constant. Data sets utilized in developing and evaluating the mouse model included oral gestational dosing studies. Residuals for predictions are presented, which provide a quantitative measure of how well the model predicted observations (Rodriguez et al. The model includes a central compartment, a secondary distribution compartment, and a renal glomerular filtrate compartment. A fraction of the perfluoroalkyl in C1 is free (Free) and available for exchange with C2 and C3. Transfer of perfluoroalkyl into the glomerular filtrate is first order and governed by the glomerular filtration rate (Qfilc, L/hour). Studies that provided data used to estimate parameter values are listed in Wambaugh et al. Complete lists of parameters and parameter values and the bases for parameter values and evaluations of model predictions in comparison to observations are reported in Harris and Barton (2008). The model includes systemic compartments representing blood (including a bound and free fraction of plasma and red blood cells), liver, and a lumped compartment representing all other tissues. The gastrointestinal tract is simulated as separate compartments representing the upper and lower tracts. Absorption occurs from both the upper and lower tracts, with distinct first order rate constants assigned to each. Elimination of absorbed chemical occurs by biliary excretion and urinary excretion. Performance of the model was improved by having renal clearance increase and the liver/plasma partition coefficient decrease as a function of time. The Harris and Barton (2008) model includes a red cell compartment that allows predictions of whole-blood concentrations. However, without basing distribution kinetics on the free concentration, it is not possible for concentration-dependent free fraction to be modeled. The kidney compartment was expanded to include compartments representing the proximal tubule lumen (glomerular filtrate) and proximal tubule cells. Values for kefflux (proximal tubule cell to kidney plasma) and kdif (diffusion between kidney plasma and the tubule cell) were also calibrated with in vivo data (Kemper 2003; Kudo et al. A sensitivity analysis of the model identified that following biokinetic parameters that had standardized sensitivity coefficients >0. Tissue plasma partition coefficients were re-estimated using data from human cadavers (Maestri et al. Values for parameters that control urinary excretion (Tm and Km for reabsorptive transport from glomerular filtrate to kidney tissue) were recalibrated based on plasma concentration data (Ericson et al. Better agreement with observations was achieved with partition coefficients based on cadaver data. Distributions for biokinetic parameters were established to achieve a coefficient of variation of 0. In addition, exposure durations required to achieve steady state would be expected to be much longer in humans than in monkeys or rats. Potential effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. Children may be more or less susceptible than adults to health effects from exposure to hazardous substances and the relationship may change with developmental age. A susceptible population may exhibit different or enhanced responses to certain chemicals than most persons exposed to the same level of these chemicals in the environment. Populations at greater exposure risk to unusually high exposure levels to perfluoroalkyls are discussed in Section 5. The possible association between serum perfluoroalkyl levels in children and health effects has been examined in participants of the C8 Health Project and in the general population. The studies examined a number of health effects including alterations in serum lipid levels, adverse renal outcomes, neurodevelopmental alterations, and reproductive development. Immunotoxicity has been examined in children in several general population studies. Additionally, a large number of studies have examined the possible association of elevated serum perfluoroalkyl levels and adverse birth outcomes. Increases in serum insulin and leptin levels were also observed in the mice exposed to 0. A number of studies of highly exposed residents and the general population have examined the potential associations between serum perfluoroalkyl levels and alterations in birth weight. Additionally, no increases in the risk of low birth weight infants were found in highly exposed populations (Darrow et al. No apparent alterations in the risk of birth defects were found in C8 Health Studies (Darrow et al. A more in-depth discussion of the developmental toxicity of perfluoroalkyls in animals is included in Section 2. No relevant studies were located regarding interactions of perfluoroalkyl compounds with other chemicals in children or adults. No information was located regarding pediatric-specific methods for reducing peak absorption following exposure to perfluoroalkyl compounds, reducing body burden, or interfering with the mechanism of action for toxic effects. The available epidemiology data identify several potential targets of toxicity of perfluoroalkyls, and individuals with pre-existing conditions may be unusually susceptible. Thus, an increase in serum cholesterol may result in a greater health impact in individuals with high levels of cholesterol or with other existing cardiovascular risk factors. Similarly, increases in uric levels have been observed in individuals with higher perfluoroalkyl levels; increased uric acid may be associated with an increased risk of high blood pressure and individuals with hypertension may be at greater risk. The liver has been shown to be a sensitive target in a number of animal species and there is some indication that it is also a target in humans. Therefore, individuals with compromised liver function may represent a susceptible population. Likewise, individuals with a compromised immune system may have an increased risk of perfluoroalkyl-induced immunotoxicity. If available, biomonitoring data for perfluoroalkyls from this report are discussed in Section 5. They also may not be directly adverse, but can indicate potential health impairment. Perfluoroalkyl compounds have been detected in the serum of workers, residents living near perfluoroalkyl facilities, and the general population. Although elevated serum levels are likely to be indicative of exposure to the parent compound, their presence in blood can also indicate exposure to other perfluoroalkyl compounds. Two studies have also evaluated the use of perfluoroalkyl levels in hair as a biomarker of exposure.

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• Serum immunoglobulin levels
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• Echocardiogram
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• Red birthmarks are made up of blood vessels close to the skin surface. These are called vascular birthmarks.
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Studies conducted in nonhuman primates and rodents have provided additional information on the distribution of absorbed perfluoroalkyls to extravascular tissues skin care korean products discount betnovate 20 gm amex. Distribution skin care in your 40s order betnovate 20gm visa, as assessed from tissue perfluoroalkyl concentrations and tissue:serum ratios acne 911 generic betnovate 20 gm with visa, exhibits profound species and sex differences as well as dose-dependencies skin care 40s cost of betnovate. These differences have been attributed, in part, to species and sex differences in elimination kinetics of absorbed perfluoroalkyls and dose-dependence of elimination kinetics (see Section 3. In general, a consistent finding across species is that the liver receives a relatively high fraction of the absorbed dose and may also experience relatively high tissue concentrations compared with other tissues, with blood. The most extensive investigations of tissue distribution have been conducted in rodents. For both low and high doses after 1, 3, and 5 days of exposure, 35S was distributed to the following tissues: blood, liver, lung, kidney, skin, whole bone, pancreas, spleen, thymus, heart, testes, epididymal fat, fat pads, brain, and muscle; 35S was also detected in tissues throughout the gastrointestinal tract. In low-dose animals after 5 days of treatment, the highest tissue concentrations (excluding the gastrointestinal tract) were liver (tissue:blood=5. In high-dose animals, the highest tissue concentrations were liver (tissue:blood=3. Liver:serum ratios for the 2, 20, 50, and 100 mg/kg/day diets were approximately 52, 42, 41, and 35, respectively, in males and 30, 47, 20, and 23, respectively, in females (Curran et al. Except for rats fed diets containing 20 mg/kg, the liver:serum ratio in males was higher than in females. This design allows a more direct comparison of patterns of tissue distribution in male and female rats at similar plasma concentrations, even though the elimination kinetics in the female rat are substantially faster than in male rats (see Section 3. The highest concentrations of 14C were observed in blood, liver, and kidney (Figure 3-1). Liver, blood, and kidney accounted for approximately 22, 22, and 2% of the administered dose of 1 mg/kg in male rats; and 6, 7, and, 3% in female rats (the sex difference reflected more rapid excretory elimination in females). Mean serum, kidney, or liver concentrations did not increase proportionally with dose in either sex. Kidney concentrations exhibited a disproportionate increase as the dose increased from 3 to 10 mg/kg/day, with little further increase at the 30 mg/kg/day dose. In male rats, the highest concentrations of 14C occurred in blood, liver and kidney, and all tissues combined accounted for approximately 60% of the dose. However, in female rats, concentrations of 14C in all tissues were below limits of quantification. In mice, liver concentrations were similar in males and females, and liver showed the highest concentrations; 14C levels in all tissues combined were lower in females compared to males. The opposite pattern was evident in hamsters and rabbits, with males having lower tissue levels than females, although, in common with rats and mice, blood, liver and kidney had the highest concentrations. Sex differences in elimination that give rise to sex differences in tissue levels following oral exposure to perfluoroalkyls in rats are not evident in studies conducted with nonhuman primates. Although limited to only one animal per sex, these results suggest that liver levels did not increase proportionately with increasing dose. A similar observation was made in a study of male Cynomolgus monkeys (Butenhoff et al. Mean serum concentrations measured after 6 weeks of exposure (which may have represented steady-state concentrations) were 77,000 ng/mL in the low-dose group and 86,000 ng/mL in the higher dose group. After 5 days, tissue:blood ratios (excluding stomach and small intestine) were >1 for liver (tissue:blood=1. At all-time points, approximately 90% of the ingested 35S was recovered in combined blood, liver, bone, skin, and muscle. The subcellular distribution of perfluoroalkyls has been examined in rats (Han et al. The distributions to other cell fractions were: nuclear/cell debris fraction, 30% females, 40% males; lysosomes, 12% females, 14% males; mitochondria, 8% females, 16% males; and ribosomes, <3% males and females. In liver, approximately 55% of cytosolic 14C was bound to proteins (>6,000 Da) in both males and females, whereas in kidney, 42% of the cytosolic fraction was bound to protein in males and 17% in females. Studies that measured perfluoroalkyls in maternal and fetal cord blood of matched mother-infant pairs found relatively strong correlations (r>0. With some exceptions, longer fluoroalkyl chain length and a terminal sulfonate group are associated with lower fetal/maternal ratios (Glynn et al. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant Pairs Perfluoro Perfluoroalkyl Maternal Cord Study alkyl chain length N (ng/mL) (ng/mL) Ratioa r Glynn et al. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant Pairs Perfluoro Perfluoroalkyl Maternal Cord Study alkyl chain length N (ng/mL) (ng/mL) Ratioa r Kato et al. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant Pairs Perfluoro Perfluoroalkyl Maternal Cord Study alkyl chain length N (ng/mL) (ng/mL) Ratioa r Yang et al. Studies that measured perfluoroalkyls in maternal serum (or plasma) and breast milk in matched mother-infant pairs found highly variable correlations (Table 3-3). Transfer to breast milk appears to be a significant route of elimination of perfluoroalkyls during breastfeeding. Concentrations of perfluoroalkyls in breast milk also decrease with breastfeeding duration (Tao et al. Serum concentrations in breastfed infants can be higher than maternal levels (Fromme et al. Matched Serum (or Plasma) and Breast Milk Concentrations in Humans Perfluoroalkyl Serum Milk Study Perfluoroalkyl chain length N (ng/mL) (ng/mL) Ratioa r Cariou et al. Perfluoroalkyls in plasma bind to serum albumin and various other plasma proteins including gamma-globulin, alpha-globulin, alpha-2-macroglobulin, transferrin, and beta lipoproteins (Bischel et al. Noncovalent binding appears to be at the same sites as fatty acids (Chen and Guo 2009). Mechanisms by which perfluoroalkyls enter the liver have not been elucidated and may involve interactions with organic anion transporters that function in the distribution of fatty acids or other organic anions (Andersen et al. Although no studies examining metabolism of perfluoroalkyls following inhalation, oral, or dermal exposure were identified, metabolism by these exposure routes is not anticipated. Findings suggest that the route of absorption has no substantial effect of rates of elimination of absorbed perfluoroalkyls (Butenhoff et al. As discussed in this section, perfluoroalkyls are primarily eliminated in the urine, with smaller amounts eliminated in the feces and breast milk (see Section 3. Perfluoroalkyls undergo biliary excretion, but substantial reabsorption occurs; therefore, biliary excretion does not represent a major elimination pathway. Perfluoroalkyls are eliminated in menstrual fluid, which appears to contribute to sex differences in serum elimination rates (Wong et al. Urinary excretion of perfluoroalkyls may show sex and age differences (Zhang et al. Rates of elimination of perfluoroalkyls vary substantially across chemical species and animal species, and show sex differences and age-dependencies within certain species. Table 3-5 summarizes estimates of the elimination t1/2 for perfluoroalkyls in humans and experimental animals. In compiling the estimates presented in Table 3-5, preference was given to the terminal t1/2 when multiple t1/2 values were reported. The significance of the terminal t1/2 is that it determines the time required for complete elimination of the perfluoroalkyl as well as the exposure duration required to achieve a steady state. Most of the t1/2 values in Table 3-5 were estimated from analyses of data on declining serum concentrations of perfluoroalkyls after a single dose or following cessation of a period of repeated dosing. Estimates of the terminal t1/2 based on serum concentrations can vary with the length of the observation period following the last dose and with the modeling approach used to estimate the t1/2. Longer observation times are required to estimate the slowest phases of elimination. Direct comparisons of t1/2 values should be made with consideration of whether or not the observation periods were comparable. Differences in estimation methodology can also contribute to differences in t1/2 values.

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