polybrominated diphenyl 
 ethers ( pbdes ) were once among the most 
 widely used flame retardant chemicals applied to consumer products ; 
 however , concern over their persistence and toxicity led to their 
 phase - out beginning in the early 2000s . one class of alternatives consists of the organophosphate 
 flame retardants ( pfrs ) , which include chlorinated alkyl phosphates 
 [ e.g. , tris(1,3-dichloro-2-propyl ) phosphate ( tdcipp ) ] and nonhalogenated 
 aryl phosphates [ e.g. , triphenyl phosphate ( tphp ) ] . data suggest that 
 pfr use increased after the pbde phase - out , and they are now among 
 the most commonly detected flame retardants in furniture and electronics . for example , tphp 
 is used as a plasticizer and is found in a variety of applications 
 ( e.g. , nail polish ) . like pbdes , consequently , 
 they migrate into indoor air and dust , where they are ubiquitously 
 detected . in humans , pfrs are thought to be rapidly metabolized and 
 excreted 
 in urine ( t1/2 of approximately hours ) . pfr metabolites are used as exposure biomarkers and have been detected 
 in urine samples from people living around the world . although data suggest pfr exposure is widespread and potentially 
 increasing , past studies have been limited in their ability to assess 
 exposure trends because they have generally been conducted over relatively 
 short periods . in addition , comparisons of metabolite concentrations 
 across studies have been limited by differences in cohort composition 
 and potential interlab variability . however , 
 by compiling individual - level data from 14 u.s .- based epidemiologic 
 studies conducted by our laboratory in 20022015 , we are able 
 to more thoroughly evaluate temporal trends in urinary pfr metabolite 
 concentrations . here , we assess temporal trends in metabolites of 
 tdcipp and tphp , bis(1,3-dichloro-2-propyl ) phosphate ( bdcipp ) and 
 diphenyl phosphate ( dphp ) , respectively . data were compiled from epidemiologic 
 studies for which our laboratory group previously measured urinary 
 pfr metabolites [ 857 individuals ( table 1 ) ] . individual studies were primarily located in north carolina or the 
 northeastern united states , with the exception of one california cohort . several studies included measurements of the same individuals at multiple 
 time points ; however , because measurements were generally closely 
 spaced ( i.e. , days to weeks apart ) , we included a single measurement 
 per participant , selected as the first urine sample , or the last for the flare study that included only children at the 
 final assessment . in addition , two studies 
 were designed to assess contributions of specific exposure sources 
 ( fingernail polish and gymnastics practice ) . from 
 these studies , we selected the measurements intended to represent 
 background exposure . two participants from the original 
 cohort ( n = 349 ) who were < 18 years of age were 
 excluded from analyses . one participant in the original 
 cohort had very dilute urine and was excluded from analyses . individual participant ages were 
 not collected and were imputed as 32 years for further statistical 
 analyses . the participant 
 age was missing 
 for 11 participants and was imputed as a random number within one 
 standard deviation of the cohort mean for further statistical analyses . the participant age was missing 
 for two participants and was imputed as a random number within one 
 standard deviation of the cohort mean for further statistical analyses . the participant age and sex 
 were 
 missing for four participants and were imputed as a random number 
 within one standard deviation of the cohort mean for age , or randomly 
 for sex . briefly , samples were extracted and cleaned 
 with solid - phase extraction ( spe ) techniques ( table 1 ) , using identical columns and sorbent material 
 ( strata - x - aw ) . some studies included an enzyme digestion step prior 
 to spe for analysis of bciphipp sulfate and glucuronide conjugates , 
 but this is not expected to bias dphp and bdcipp concentrations because 
 they have no known conjugated metabolites . in all studies , deuterium - labeled standards of dphp and bdcipp were 
 used for quantification by spiking prior to spe , and recoveries of 
 internal standards through the extraction process were quantified 
 using c - labeled dphp . all samples were analyzed using 
 liquid chromatography and tandem mass spectrometry ( lc  ms / ms ) , 
 although ionization techniques differed between studies , either atmospheric 
 pressure chemical ionization or electrospray ionization . all studies 
 employed thorough qa / qc programs with laboratory blanks and duplicates . specific gravity was also measured in samples prior to analysis using 
 a digital hand - held refractometer ( atago ) . although included studies varied in 
 terms of collected covariates , all recorded the date that samples 
 were collected . individual participant ages were available for 97.1% 
 of participants . if missing , age was imputed as a random number within 
 one standard deviation of the study mean . however , eight women from 
 ref ( 18 ) were assigned 
 32 years of age as they were missing data on age but were known to 
 be pregnant . sex was available for 99.5% of participants and was randomly 
 imputed for the four participants for which it was missing . pregnancy 
 status was confirmed for many female participants ; however , if pregnancy status was not obtained , 
 we assumed they were not pregnant . while the majority of urine samples 
 were spot urines , 40 were first - morning voids and eight were 24 h 
 collections . previous publications 
 from each 
 study demonstrate frequent detection of bdcipp and dphp . if a particular 
 metabolite was not detected , we imputed the concentration as the method 
 detection limit divided by 2 . we visually assessed plots of metabolite 
 concentrations over time ( figure 1 ) and evaluated the shape of potential relationships 
 using smoothing . on the basis of plot and smoothing results , which 
 suggested that relationships between the date of collection and metabolite 
 levels were nonlinear , collection times were categorized into 2 year 
 periods for analyses . metabolite concentrations were not normally 
 distributed and were log - transformed in regression analyses . coefficients from these models were exponentiated for interpretation 
 and represent the multiplicative change in metabolite concentration . analyses were adjusted for age ( continuous ) , sex ( male , nonpregnant 
 female , and pregnant female ) , and season of collection , factors that 
 previous research suggests may be related to pfr metabolite concentrations . we also considered potential 
 confounding by the number of years a sample had been stored prior 
 to analysis ; however , storage time ( continuous ) was strongly collinear 
 with collection date as older samples tended to be stored longer than 
 newer samples before analysis . to address this issue , we dichotomized 
 storage time at 1 year . the dichotomized storage time was not associated 
 with urinary metabolite concentrations and was excluded from the final 
 adjustment set . although we do not expect the enzyme digestion step 
 or the differing ionization techniques to impact bdcipp and dphp levels , 
 we considered potential confounding by the analysis method . the method 
 was not associated with urinary metabolite concentrations and was 
 dropped from analyses . because previous results suggest that children 
 have greater exposure to pfrs than adults do , and children were concentrated 
 in later years of sample collection , we conducted analyses separately 
 for children ( 10 years of age ) and adults ( 18 years 
 of age ) . to account for urine dilution , we present results using specific 
 gravity - corrected urine concentrations ; however , uncorrected analyses produced nearly identical results 
 ( not shown ) . individual participant values 
 are shown for adults ( green ) and children ( blue ) . black dots indicate 
 the geometric mean in each cohort [ two geometric means are shown for 
 refs ( 20 ) ( blue fill ) , ( 19 ) ( yellow fill ) , and ( 6 ) ( red fill ) because samples 
 were collected over two sampling campaigns with different participants ] . we conducted sensitivity analyses 
 to determine the robustness of 
 results to assumptions about cohort composition , sample type , and 
 analysis . to evaluate the impact of including participants with missing 
 data , we conducted analyses restricted to participants with complete 
 data . in addition additionally , our final data set contained a number of pregnant women , 
 particularly the 20022005 set . to ensure that temporal patterns 
 were not driven by time - dependent differences in the types of participants 
 included ( e.g. , pregnant women ) , we conducted secondary analyses excluding 
 pregnant women . finally , data were collected in several different 
 geographic regions , including california , where exposure may be higher 
 because of stronger flammability standards . thirteen studies included adults who ranged in age from 18 to 67 
 years [ n = 741 ; mean age of 32.3  9.3 years 
 ( table 1 ) ] . three of 
 these studies included children , and one additional study focused 
 exclusively on children [ n = 116 ; mean age of 2.8 
  2.2 years ( table 1 ) ] . among adults , bdcipp and dphp were detectable in 
 > 83% of samples from each study 
 and were detected overall in 96 and 91% of samples , respectively . 
 individual study participants metabolite concentrations are 
 shown in figure 1 along 
 with geometric mean metabolite concentrations for each study . as reported 
 previously , samples from children tended to have metabolite concentrations 
 higher than the concentrations of those from adults , particularly 
 for bdcipp , a finding highlighted in many studies . bdcipp and dphp levels 
 also tended to be higher among pregnant women , suggesting differences 
 in metabolism and excretion or exposure behavior patterns during pregnancy . our results suggest that urinary bdcipp levels have increased dramatically 
 in recent years ( table 2 ) . among adults , samples collected in 2014 and 2015 had bdcipp concentrations 
 that were 16.5 times those in urine samples collected in 2002 and 
 2003 [ 95% confidence interval ( ci ) from 9.64 to 28.3 ( table 2 ) ] . although the range of collection 
 dates was narrower , samples from children displayed similar trends ; 
 children providing samples in 2014 and 2015 had urinary bdcipp concentrations 
 that were 3.90 times those in samples collected in 2010 and 2011 [ 95% 
 ci from 1.36 to 11.1 ( table 2 ) ] . time trends were similar and slightly stronger when we 
 excluded pregnant women ( table s1 ) . when 
 we excluded california participants , patterns of association remained 
 very similar ( table s2 ) . exponentiated  coefficients 
 represent the multiplicative change in metabolite concentrations relative 
 to the reference group . analyses stratified by age and adjusted for 
 sex ( male , nonpregnant female , and pregnant female ) , age ( continuous ) , 
 year of collection , and season of collection . previous research demonstrates that tdcipp is commonly 
 used in 
 residential furniture and is widely detected in indoor environments ; 
 however , there have been few evaluations of temporal trends in different 
 matrices . in a small california house dust assessment , additional data investigating the presence 
 of tdcipp in residential furniture suggest that use may have increased 
 after the penta - bde phase - out but has declined since 2014 . it will take several more years of data collection 
 to determine if these decreases will impact exposure . urinary 
 dphp concentrations were significantly higher for samples 
 collected in 20102015 compared to samples collected in 2002 
 and 2003 . for example , samples collected in 2010 and 2011 had urinary 
 dphp concentrations 2.98 times those of samples collected in 2002 
 and 2003 [ 95% ci from 1.99 to 4.46 ( table 2 ) ] . although concentrations were also significantly 
 higher in 2014 and 2015 , the magnitude of the effect ( i.e. , or = 1.93 ) 
 was smaller than the effect estimates for 2010 and 2011 or 2012 and 
 2013 , suggesting exposure may have peaked during this period and could 
 be in decline . we observed no trends in dphp concentrations among 
 children ; however , children s samples were collected over a 
 period narrower than that of adults ( table 2 ) . excluding pregnant women and california 
 participants had little impact on results ( tables s1 and s2 ) . our results showing increases in dphp are 
 consistent with a small 
 study showing tphp increases in household dust between 2006 and 2011 . although long - term human exposure trends have 
 not been assessed previously , to the best of our knowledge , short - term 
 trends were recently evaluated in pooled samples from chinese adults . reported no change in tphp concentrations 
 between samples collected in 2011 and 2015 in china , suggesting that 
 exposure levels were relatively constant during this period . our results suggest that tphp exposure may have 
 started to decrease post-2011 , suggesting that tphp use as a flame 
 retardant or in other applications could be decreasing . although urinary 
 dphp is thought to be an indicator of tphp exposure , other compounds 
 may be metabolized to dphp and dphp itself may be used in consumer 
 products . a seasonal trend was 
 observed in urinary bdcipp ; concentrations 
 were significantly higher in spring , summer , and fall than in winter . for example , bdcipp concentrations were 4.13 times as high in summer 
 as in winter [ 95% ci from 3.39 to 5.04 ( table 2 ) ] . dphp concentrations were also higher 
 in summer but to a lesser degree [ 10 = 1.54 ; 95% 
 ci from 1.27 to 1.85 ( table 2 ) ] and were not statistically different in spring and fall 
 versus winter . indoor temperatures are generally 
 more stable , suggesting that outdoor air or other microenvironments 
 could be more important drivers of exposure than previously thought . tdcipp is commonly used in automobiles , so it is possible that temperature fluctuations in automobiles ( e.g. , 
 from sitting in the sun ) are driving seasonal exposure differences . alternatively , seasonal behavior changes could explain patterns ( e.g. , 
 differences in time spent indoors or changes in ventilation ) . regardless 
 of the underlying reason , our results suggest the season of collection 
 could be an important factor to consider in epidemiologic studies 
 relying on single urine samples to assess long - term exposure . our results represent the first long - term assessment of human pfr 
 exposure and have the advantage of including numerous measurements 
 conducted by the same laboratory . however , our results should be interpreted 
 in the context of several important limitations . first , data were 
 collected for research of various , unrelated hypotheses ; therefore , 
 the study populations included are not representative of the general 
 population . a randomly selected population with longitudinal follow - up 
 would provide a stronger resource for evaluating trends . several other 
 groups have measured urinary pfr metabolites in different parts of 
 the world . with the exception of samples from australia , which 
 had substantially higher dphp levels , observed concentrations were similar or slightly lower than those 
 analyzed by our group in u.s . we analyzed samples at different points in time with variable storage 
 times and conditions . we did not find associations between concentration 
 and storage times greater than or less than 1 year ; however , we were 
 unable to evaluate differences with finer granularity because of collinearity 
 between storage time and collection date . it is possible that samples 
 could degrade over time and potentially impact concentrations ; however , 
 this seems unlikely to explain the patterns we observed because we 
 do not see patterns of decrease in analyses with srm 3673 , which we 
 have analyzed numerous times , with variable storage durations . storage 
 containers were also different across studies ; however , it is unlikely 
 that storage method ( i.e. , glass or plastic ) influenced our results , 
 as recent work by carignan et al . additionally , our analyses 
 primarily relied on spot urine samples . while previous research suggests 
 that spot urine samples are reliable estimates of exposure over time , 
 they are likely subject to greater variation in individual pfr concentrations 
 than first - morning voids or 24 h urine collections because of the 
 rapid metabolism of pfrs . using individual 
 average urine concentrations rather than spot urine measures would 
 reduce observed scatter in the data . however , we feel that it is unlikely 
 that our use of spot urine samples in this analysis is driving the 
 observed trends . finally , it is possible that residual confounding 
 may influence the observed differences ( e.g. , body mass index and 
 behavioral characteristics ) but would have to be very strong to explain 
 the entirety of observed trends . tdcipp exposure , as indicated 
 by urinary bdcipp levels , appears 
 to have increased over the past 15 years . similarly , our data suggest 
 that tphp exposure also may have increased 2002 to 2011 but may have 
 leveled off or decreased since 2011 . additional data are urgently 
 needed to determine whether levels of exposure experienced by the 
 general population are related to adverse health outcomes .
during the past decade , 
 use of organophosphate compounds as flame 
 retardants and plasticizers has increased . 
 numerous studies investigating 
 biomarkers ( i.e. , urinary metabolites ) demonstrate ubiquitous human 
 exposure and suggest that human exposure may be increasing . to formally 
 assess temporal trends , we combined data from 14 u.s . 
 epidemiologic 
 studies for which our laboratory group previously assessed exposure 
 to two commonly used organophosphate compounds , tris(1,3-dichloro-2-propyl ) 
 phosphate ( tdcipp ) and triphenyl phosphate ( tphp ) . using individual - level 
 data and samples collected between 2002 and 2015 , we assessed temporal 
 and seasonal trends in urinary bis(1,3-dichloro-2-propyl ) phosphate 
 ( bdcipp ) and diphenyl phosphate ( dphp ) , the metabolites of tdcipp 
 and tphp , respectively . 
 data suggest that bdcipp concentrations have 
 increased dramatically since 2002 . 
 samples collected in 2014 and 2015 
 had bdcipp concentrations that were more than 15 times higher than 
 those collected in 2002 and 2003 ( 10 = 16.5 ; 95% 
 confidence interval from 9.64 to 28.3 ) . 
 our results also demonstrate 
 significant increases in dphp levels ; however , increases were much 
 smaller than for bdcipp . 
 additionally , results suggest that exposure 
 varies seasonally , with significantly higher levels of exposure in 
 summer for both tdcipp and tphp . given these increases , more research 
 is needed to determine whether the levels of exposure experienced 
 by the general population are related to adverse health outcomes .