Determinants of Chlorpyrifos Exposures and Urinary 3,5,6-Trichloro-2-Pyridinol Levels Among Termiticide Applicators

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1 Ann. oup. Hyg., Vol. 45, No. 4, pp , 2001 Pulishe y Elsevier Siene Lt on ehlf of British Ouptionl Hygiene Soiety Printe in Gret Britin /01/$20.00 PII: S (01) Determinnts of Chlorpyrifos Exposures n Urinry 3,5,6-Trihloro-2-Pyriinol Levels Among Termitiie Applitors CYNTHIA J. HINES * n JAMES A. DEDDENS Ntionl Institute for Ouptionl Sfety n Helth, 4676 Columi Prkwy, Cininnti, OH 45226, USA; Deprtment of Mthemtil Sienes, University of Cininnti, Cininnti, OH 45221, USA The exposures n work tivities of 41 pplitors in North Crolin using hlorpyrifosontining termitiies were hrterize. Personl ir n urine smples were ollete on multiple ys within one week. Detile informtion out hemil use, tsks, personl protetive equipment n hygiene ws reore. During the 202 pplitor-ys monitore, 415 tretment jos were performe. Full-shift hlorpyrifos exposures rnge from to 110 mg/m 3 (N=184), with geometri men (GM) of 10 mg/m 3. Urinry 3,5,6-trihloro-2- pyriinol (TCP) levels rnge from 9.42 to 1960 mg/g retinine (N=271) n vrie signifintly y y of the week (GM rnge: mg/g retinine). Preitive moels for hlorpyrifos ir exposure n urinry TCP levels were evelope using mixe-effets stepwise liner regression. Determinnts of irorne hlorpyrifos exposure inlue minutes hlorpyrifos pplie n enlose rwl spe trete (yes/no). Determinnts of TCP levels (epening on the moel) inlue y-of-the-week, the hlorpyrifos ir onentrtion one n two ys efore urine olletion, minutes of hlorpyrifos pplie one n two ys efore urine olletion, enlose rwl spe trete (yes/no), n ommeril struture trete (time-weighte). Within- n etween-worker vrility ws similr for irorne hlorpyrifos; however, for TCP, etween-worker vriility exeee within-worker vriility y six times. The elimintion hlf-life of TCP (26.9 h) n possily the short smpling intervl (one week) my explin the low TCP within-worker vriility. Applitors weekly men ln(tcp levels) n weekly men ln(hlorpyrifos ir onentrtions) were highly n positively linerly orrelte (r 2 =0.73, P ). In summry, mixe-effets moels were suessfully onstrute to preit irorne hlorpyrifos exposure n urinry TCP levels. Pulishe y Elsevier Siene Lt on ehlf of British Ouptionl Hygiene Soiety Keywors: hlorpyrifos; 3,5,6-trihloro-2-pyriinol; exposure eterminnts; mixe moels; vrine omponents; pestiie INTRODUCTION Chlorpyrifos [O,O-iethyl O-(3,5,6-trihloro-2- pyriinyl) phosphorothiote] is wiely use rospetrum orgnophosphorus insetiie. In 1995, n estimte 4 6 million kg were use for rop protetion n nother 5 8 million kg were use for nongriulturl purposes in the Unite Sttes (US EPA, 1997). Use of hlorpyrifos s termitiie inrese Reeive 31 Jnury 2000; in finl form 1 Ferury *Author to whom orresponene shoul e resse. Tel.: ; fx: ; e-mil: hines@.gov following the removl of hlorne from the US mrket in Chlorpyrifos exhiits moerte ute toxiity (Gllo n Lwryk, 1991), hving ose-epenent effet on epression of plsm holinesterse, while re ell holinesterse generlly remins unffete, exept t high oses (Griffin et l., 1976; Rihrson, 1995). Exessive exposure to hlorpyrifos n proue symptoms typil of ute orgnophosphorus poisoning (Hthwy et l., 1996). A moriity stuy mong mnufturing employees expose to hlorpyrifos, lthough sujet to severl limittions, reporte signifintly elevte os rtios for five ignosti tegories: iseses of the er n mstoi proess, 309

2 310 C. J. Hines n J. A. Deens ute respirtory infetions, other iseses of the respirtory system, generl symptoms, n generl symptoms of the igestive system (Burns et l., 1998). Limite eviene of neurologil effets ttriutle to hroni low-level exposure to hlorpyrifos hs een reporte (Ames et l., 1989; Kpln et l., 1993; Steenln et l., 2000). Chlorpyrifos is metolilly tivte in the liver to hlorpyrifos oxon, whih proues neurotoxiity y inhiiting trget esterses in the peripherl n entrl nervous systems. The oxon is etoxifie to iethyl phosphte n 3,5,6-trihloro-2-pyriinol (TCP) y A-esterses, suh s proxonse, in the liver n plsm (Rihrson, 1995). The men urine elimintion hlf-life of TCP in humns fter ministrtion of orl n erml oses of hlorpyrifos hs een estimte to e 26.9 h (Noln et l., 1984). TCP exretion rtes in ouptionlly expose workers hve een shown to e ner mximum t h post-exposure (Fenske n Elkner, 1990). In orlly ose rts, 88.4% of the ministere hlorpyrifos ws exrete in the urine, primrily s the gluuronie of TCP (Bkke et l., 1976). The hlorpyrifos exposure of group of termite ontrol workers ws monitore in this stuy. Termite ontrol work is often n entry-level jo n turnover mong pplitors tens to e high. Applitors typilly work 8 h per y, Mony through Friy, n trvel to multiple jo sites within y. In the Piemont region of North Crolin, where this stuy ws onute, termite ontrol work is typilly heviest from Mrh through June, lthough some level of tretment work ours throughout the yer. Builing onstrution, soil type n termite tivity influene tsks performe y pplitors. In this re, resienes re preomintely onstrute with rwl spes, lthough sement n sl onstrution re lso foun. Tretment tsks my inlue using n eletri rill to rete injetion holes in onrete sls or loks, using hn tools to ig trenhes in the soil roun the perimeter of struture, flooing trenhes with strem of termitiie from hose, injeting or roing termitiie into the soil or injetion holes, n pthing rille holes with mortr fter tretment. Applitors ten to mix their own termitiies n to use n open mixing system; i.e. the pplitor pours liqui termitiie prout from 7.57 l. plsti ontiner into l. tnk where it is ilute with wter, typilly to out 1% prout. Termite tretment work in strutures with enlose rwl spes n involve irty n rmpe onitions. Applitors my wer overlls, gloves, eye protetion, respirtors n ruer oots. Mehnil ventiltion is not use in rwl spes. Applitors my e expose to hlorpyrifos y inhltion n y skin sorption while mixing n pplying termitiie solutions. Exposures from spills, while eting, rinking or smoking, n from ontminte ojets re lso possile. Previous exposure ssessment stuies of termite ontrol workers hve involve smll numers of workers n hve h limite ility to exmine exposure ftors in etil (Jitsunri et l., 1989; Fenske n Elkner, 1990; Leiy et l., 1991; Gions et l., 1993). The ojetives of this stuy were (1) to hrterize the hlorpyrifos exposures n work tsks of group of termitiie pplitors, n (2) to ientify signifint eterminnts of hlorpyrifos exposure n urinry TCP tht oul e use to uil preitive moels. For TCP, we were intereste in eveloping moels tht resse two t onitions; the first, when oth ir n work ftor t re ville, n the seon, when only work ftor t re ville. Work ftors tht ompnies n their pplitors oul reily reor or mesure were espeilly of interest. METHODS Applitor reruitment Using stte reors, pest ontrol ompnies liense to tret strutures for woo-estroying pests were ientifie in 26 ounties in the Piemont region of North Crolin. Iniviul ompnies were ontte to etermine if the ompny employe fulltime termitiie pplitors n if pplitors use hlorpyrifos-ontining termitiies. Permission ws sought from ompnies meeting these riteri to reruit pplitors for the stuy. Prtiiption ws voluntry n informe onsent ws otine. Applitors were ompenste $70 for full prtiiption. This stuy ws pprove y the NIOSH Humn Sujets Review Bor. Air smpling n nlysis We ttempte to ollet full-shift rething zone ir smple on five onseutive workys (Mony Friy) for eh pplitor. No ir smple ws otine on ys n pplitor ws not t work. Smples were ollete oring to NIOSH Metho 5600, Orgnophosphorus Pestiies (NIOSH, 1994) n nlyze for hlorpyrifos y DtChem Lortories (Slt Lke City, UT). OSHA Verstile Smplers (OVS) with 11 mm qurtz fier filters n two setions of XAD-2 resin (SKC, In., Eighty Four, PA) were use t nominl flow rte of 1 l./min. Smpling time inlue lunh n reks. Smpling pumps were pre- n post-lirte with Gilirtor flow meter (Sensiyne, In., Clerwter, FL). Fiel lnks were ollete in similr mnner, exept no ir ws pulle through the smple. Smples were invertently nlyze using two vritions of the NIOSH metho. In metho vrition no. 1, the qurtz filter, the two sorent setions, the polyurethne seprtor etween front n k sorent setions, the Teflon retining ring for the filter, n rinste of the insie wlls of the OVS tue were

3 Determinnts of hlorpyrifos exposures 311 nlyze, ut only the qurtz filter n two sorent setions were nlyze in metho vrition no. 2. Components were esore or rinse with 2 ml of 10:90 etone:toluene n rotte t 6 rev/min for t lest 1 h. Chlorpyrifos ws etermine on Hewlett- Pkr Moel HP5890 gs hromtogrph with flme photometri etetor in the phosphorus moe. A30m 0.25 mm fuse sili pillry olumn ote internlly with 0.25 µm DB-5 ws use. The oven ws initilly set t 75 C for 2 min, then inrese to 150 C t rte of 50 C/min, followe y n inrese to 210 C t rte of 10 C/min. Two µl were injete t 250 C. The th limit of etetion (LOD), ompute from liner regression of low level stnrs (Burkrt, 1986), ws µg/smple ( µg/m 3 for n 8 h smple t 1 l./min). Urine smpling n nlysis Prtiipnts were ske to ollet first-morning urine voi for seven onseutive ys strting on Tuesy. Seven urine olletion kits, eh ontining plsti olletion up n pre-lele smple ottles, were given to eh prtiipnt. Eh evening preeing smple olletion, prtiipnts were ske to empty their ler efore going to e. After voiing the next morning, prtiipnts poure pproximtely 25 ml of urine into smple ottle n reore the te n time of smple olletion. On one of the seven ys, seon smple ws sve s lin uplite. All smple ottles were store in sele plsti ontiner in the prtiipnt s home freezer. After seven ys, the frozen urine smples were retrieve from the prtiipnt, trnsporte on ry ie, n store t 20 C. Urine smples were nlyze for TCP y Pifi Toxiology Lortories (Wooln Hills, CA) using metho evelope n vlite y Dow AgroSienes (Olering, 1997). Frozen urine smples were rought to 35 C in wter th to issolve ny solis. After thorough mixing y shking, 1 ml liquot of urine from eh smple ws fortifie with 10 µl of 20 µg/l. 13 C 2 15 N - 3,5,6 - TCP (in etone) s n internl stnr n 100 µl of onentrte (12 N) hyrohlori i. The smple vils were sele with Teflon -line ps n vortexe for 5 10 s. Smples were then hyrolyze in n 80 C wter th for 60 min. After hyrolysis, smples were rought to room temperture n 1 ml eh of 20% queous soium hlorie n 1-hloroutne were e to eh smple. Smple vils were then ppe n vortexe for 10 min. After vortexing, smples were entrifuge for 5 min t 2700 rev/min. The top 1-hloroutne lyer ws trnsferre to 2 ml utosmpler vil n 100 µl of the erivtizing gent N-methyl-N- (tertutylimethylsilyl)-trifluoroetmie (MTBSTFA) ws e to eh utosmpler vil. The smples were vortexe for 5 10 s, ple in n oven t 60 C for 60 min, n nlyze for TCP y gs hromtogrphy with mss-seletive etetion s esrie elow. A Hewlett-Pkr 6890 gs hromtogrph (Wilmington, DE) equippe with Hewlett-Pkr 5973 mss-seletive etetor n Duron-17, 30 m 0.18 mm i.., 0.3 film thikness, fuse sili pillry olumn (J&W Sientifi, Folsom, CA) ws use for etermintion of TCP. The injetion n interfe tempertures were 280 C. An initil oven temperture of 80 C ws hel for 1 min, then rmpe t 10 C/min to 180 C, followe y seon rmp t 20 C/min to 280 C where the temperture ws hel for 2 min. The rrier gs ws helium. The mss-seletive etetor use eletron impt ioniztion. Ions t m/z = 254 (quntittion) n m/z = 256 (onfirmtion) were monitore for the tert-utylimethylsilyl (TBDMS) erivtive of TCP, n n ion t m/z = 261 ws use for the erivtize internl stnr (TBDMS erivtive of 13 C 2 15 N - lele TCP). The LOD, ompute s three times the stnr evition of the lnk (Keith et l., 1983), ws 2.0 µg/l. Cretinine onentrtions were etermine y Pifi Toxiology Lortories using Bekmn SYNCHRON LX System (Fullerton, CA). This system uses the Jffé rte metho in whih retinine forms re olor omplex on retion with piri i uner lkline onitions (Finy n Ertingshusen, 1971). The LOD ws 0.10 g/l. Qulity ontrol Qulity ontrol for the mesurement of hlorpyrifos in ir inlue (1) lortory-fortifie smples run lin y the nlyst, (2) fiel-fortifie smples sumitte lin with fiel smples, n (3) lortory-fortifie smples expose to mient fiel onitions in hlorpyrifos-free re n sumitte lin with the fiel smples. Qulity ontrol for the mesurement of TCP in urine onsiste of (1) fielfortifie smples sumitte lin with fiel smples n (2) splits of selete fiel urine smples sumitte s lin uplites to the lortory. Other t ollete Demogrphi t, suh s ge n yers worke s termitiie pplitor, were otine y interview. During n pplitor s smple week, numer of ftors were reore for eh termite tretment jo performe using hlorpyrifos. These ftors inlue res trete, tsks performe, numer of meters trete, urtion of hemil pplition, prout pplie, prout ilution, mount of ilute prout pplie, numer of tnk mixes prepre, use of personl protetive equipment, hn wshing, smoking, n hewing too. An ouptionl hygienist ompnie the pplitor uring ll work tivities for the entire week n otine informtion on the ove ftors y either iret mesurement, oservtion or interview. In this pper, hlorpyrifos use is

4 312 C. J. Hines n J. A. Deens ompute n reporte s kilogrms of tive ingreient. Sttistil nlysis Mixe-effets liner regression moeling ws use to evlute eterminnts of irorne hlorpyrifos exposure n urinry TCP levels. Mixe moels hve een use previously to investigte the fixe effets of ovrites on levels of exposure n the withinn etween-worker vrine omponents ssoite with rnom worker effets (Rppport et l., 1999; Burstyn et l., 2000; Symnski et l., 2001). The hlorpyrifos ir onentrtion n the TCP urine onentrtion normlize to retinine were use s epenent vriles. These epenent vriles were highly skewe n nturl log trnsformtion ws pplie. Air smple vlues elow the LOD were estimte y iviing the LOD y two (Hornung n Ree, 1990). A stepwise regression proeure ws one using PROC MIXED in SAS version 6.12 (SAS Institute, In., Cry, NC) to uil liner moels. One moel ws evelope for hlorpyrifos n two moels were evelope for TCP, one of whih inlue the hlorpyrifos ir onentrtion. Sujet ws trete s rnom effet. To ress the orreltion of mesurements within sujets, two ovrine strutures, first-orer utoregressive [AR(1)] n ompoun symmetry (CS), were evlute in oth the hlorpyrifos ir moels n the TCP urine moels. Stnr mximum likelihoo estimtion methos were use. Covrites with P-vlues greter thn 0.10 were roppe from the moels. Akike s Informtion Criterion (AIC) ws use to ompre moel fit mong likely logil moels. The within- n etweenworker vrine omponents were estimte from the rnom effets portion of the moels. In orer to otin within- n etween-worker vrine estimtes uner n AR(1) ovrine struture, oth the REPEATED n RANDOM sttements in PROC MIXED were use. Totl vrine ws ompute y fitting moel with only worker s rnom effet (Burstyn et l., 2000). Covrite vlues from the y the ir smple ws ollete were use in ir moels n ovrite vlues from ys preeing urine olletion were use in urine moels. Chlorpyrifos exposures on Stury n Suny, n ys worker i not show up for work, were ssume to e zero. Three mesures of hlorpyrifos use, kilogrms, meters n minutes, were exmine seprtely in the ir n urine moels. The mesure tht gve the est fit ws use in susequent regression moels. For the selete mesure of hlorpyrifos use (minutes), vlues the y efore n two ys efore urine olletion were teste seprtely in the moels. Similrly, the hlorpyrifos ir onentrtions the y efore n two ys efore urine olletion were teste seprtely. Fixe effets in the finl ir moel were exlue from the urine moel tht inlue the hlorpyrifos ir onentrtion. A term for nlytil metho (1 or 2) ws lso teste in the ir moel. Other ontinuous ovrites teste in oth the ir n urine moels inlue numer of jos performe, meters of enlose rwl spe trete, meters of outsie perimeter trete, numer of tnk mixes prepre, squre meters of rost spry, pplitor ge, yers worke s termitiie pplitor, n yers worke for urrent ompny. Tretment of n enlose rwl spe ws lso teste s tegoril vrile (ever/never) n s perentge of the totl numer of meters trete for the y (0 100). Ctegoril ovrites tht vrie y jo within y were initilly teste s ever/never performe, n then weighte y the numer of minutes of hlorpyrifos use to evlute whether tking into ount mesure of jo size woul improve the moel. Covrites of this type in oth the hlorpyrifos n TCP moels inlue onstrution sttus (ol/new), three tsks (floo-in-trenh, ro-in-sl n ro-in-lok), use of helper, use of Dursn TC, n tretment of ommeril (i.e. non-resientil) struture. Covrites of this type in the TCP moels only inlue glove use uring mixing n pplying (teste seprtely), respirtor use, wering overll, rolling up long sleeves, n wering roer oots. Smoking (yes/no), hewing too (yes/no), n hn wshing in the fiel (yes/no) were teste only s tegoril vriles in the TCP moels. RESULTS Stuy popultion A totl of 155 ompnies liense to tret strutures for woo-estroying pests were ientifie. We were le to ontt n esrie the stuy to 117 ompnies (75%). The remining ompnies either oul not e rehe or i not return phone lls. Of the 117 ompnies ontte, 61 (52%) were not eligile euse the ompnies either i not use hlorpyrifos-ontining termitiies or i miniml to no termite tretment work. Of the 56 eligile ompnies, 22 (39%) gree to prtiipte. The 22 ompnies h 49 full-time termitiie pplitors. All 49 pplitors onsente to prtiipte in the stuy. Forty-one pplitors, ll mle, in 21 ompnies were eventully sheule for smpling over the fourmonth stuy perio from erly Mrh to erly July, The tivities of the pplitors were monitore for totl of 202 pplitor-ys (38 pplitors for five ys eh n three pplitors for four ys eh). The mein ge ws 33 yers (rnge 18 54), the mein numer of yers pplitors h pplie termitiies ws 2 (rnge ), n the mein numer of yers pplitors h worke for their urrent ompny ws 1.2 (rnge ). The 41 pplitors performe 415 termitiie pplition jos using hlorpyrifos. One pplitor

5 Determinnts of hlorpyrifos exposures 313 i not perform ny hlorpyrifos termitiie pplitions uring the smple week. Chrteristis of these jos n the personl protetive equipment use uring pplition n mixing of hlorpyrifos-ontining termitiies re given in Tles 1 n 2. For the 202 pplitor-ys, minutes of hlorpyrifos use ws highly orrelte with kg n meters of hlorpyrifos use (r = 0.70 n 0.58, respetively, P = ), n kg n meters of hlorpyrifos use were lso highly orrelte (r = 0.68, P = ). Person s oeffiient ws use to evlute orreltion etween vriles. Tle 1. Chrteristis of termitiie tretment work with hlorpyrifos Frequeny Builing By tretment jo (N = 415) Constrution New 116 Ol 299 Design Resientil 374 Bsement 25 Crwl 219 Sl 80 Comintion 50 Commeril 41 Proess Prout Dilution (%) Dursn TC Equity Cyren TC 1 15 Other Numer of los mixe per jo Tsks performe Drill holes 161 Ro in sl 155 Ro in lok 59 Pth rill holes 115 Dig trenh 187 Ro in trenh or liner pth 67 Floo in trenh or liner pth 301 Cover trenh 125 Personl protetive equipment Mixing (N = 191) Applying (N = 415) Gloves Ruer oots n 38 Goggles Sfety glsses 8 22 Fe shiel 0 0 Apron 0 0 Cloth overlls Respirtor use Any time uring jo 96 Speifi res e Enlose rwl spe (N = 137 jos) 59 Insie sement (N = 23 jos) 4 Glove omposition f (N = 312 jos) Nturl ruer, unline 125 Nturl ruer, flok-line 16 Neoprene 55 Nitrile 51 Ltex surgil 38 Polyvinyl hlorie 2 Cloth 20 Lether 5 Continue overlef

6 314 C. J. Hines n J. A. Deens Tle 1. Continue Frequeny By pplitor-y (N = 202) Smoke too 120 Chewe too 7 Respirtor type (N = 91 pplitor-ys) Hlf-fe, pestiie rtrige 33 Hlf-fe, orgni vpor rtrige 10 Dust mist isposle 6 Nuisne oor isposle 42 Wshe hns in fiel when hlorpyrifos use ( 110 N = 166 pplitor-ys) Clothing Shirt long sleeves 48 short sleeves 154 Pnts long pnts 202 Ht 148 Jket or swetshirt (t lest prt of y) 54 Work shoes/oots lether 161 thleti 27 ruer 14 Dow AgroSienes, Ininpolis, IN. Cheminov, In., Wyne, NJ. More thn one tsk possile per jo. n = not ville. e Respirtor my hve een worn in more thn one re per jo. f Inlues gloves worn while either mixing or pplying hlorpyrifos. Tle 2. Chlorpyrifos usge N Mein AM SD Rnge By jo Liner meters trete with hlorpyrifos All jos By lotion Outsie perimeter Crwl spe enlose Pillrs Other Grge enlose Grge open Insie perimeter enlose Crwl spe open Insie sement Insie perimeter open Brost spry (m 2 ) Time hlorpyrifos pplie (min) Amount of hlorpyrifos pplie (kg) By pplitor-y Durtion of worky (min) Liner meters trete with hlorpyrifos Time hlorpyrifos pplie (min) Amount of hlorpyrifos use (kg) Totl numer of jos = 415; totl numer of pplitor - ys = 202. AM = rithmeti men. SD = stnr evition. Inlues lunh n reks. Exposure levels In totl, 202 ir smples were ollete. Of these, 184 ir smples were nlyze y metho vrition no. 1 (N = 110) n no. 2 (N = 74) The remining 18 smples were exlue from t nlysis ue to gross nlyst error (not nlyzing the qurtz filter). Three of the 184 smples (1.6%) were elow the LOD. Chlorpyrifos ws not foun in ny lnks. Geometri men (GM) levels of hlorpyrifos y y of the week rnge from 8.9 to 11 µg/m 3, with n overll

7 Determinnts of hlorpyrifos exposures 315 GM of 10 µg/m 3 (Tle 3). The highest single-y exposure to hlorpyrifos ws 110 µg/m 3. Inhltion oses in µg/kg/y were lso estimte (Appenix A). Prtiipnts provie 285 urine smples. Fiel reors inite tht the olletion protool ws not followe y two prtiipnts n these smples (N = 13) were omitte from t nlysis. An itionl smple ws omitte euse the retinine onentrtion ws elow the LOD n the smple ws onsiere suspet. For the remining 271 urine smples, GM TCP levels y y of the week rnge from 169 (Mony) to 262 µg/g retinine (Friy) (Tle 3). Levels for iniviul smples rnge from 9.42 to 1960 µg/g retinine. TCP levels not normlize to retinine rnge from 21.3 to 3260 µg/l. Applitors weekly men ln(tcp levels) n weekly men ln(hlorpyrifos ir onentrtions) were highly n positively linerly orrelte (Fig. 1, r 2 = 0.73, P ). For ll nlytes n types of qulity ontrol smple, men reoveries rnge from 95 to 103% n men reltive stnr evitions were 10% or less (Tle 4). Exposure moels Chlorpyrifos ir moel. A liner moel for irorne hlorpyrifos exposure (Tle 5) ws uilt using t from the 37 workers with n ppropritely nlyze ir smple (184 pplitor-ys). A ompoun symmetri ovrite struture ws ssume s it proue etter fit thn first-orer utoregressive. Minutes of hlorpyrifos pplition on the y the ir smple ws ollete n whether or not the pplitor trete t lest one enlose rwl spe were signifintly ssoite with inrese exposure to irorne hlorpyrifos. All other ovrites, inluing nlytil metho, were not signifint (P>0.1). TCP urine moels. Two liner moels were evelope for TCP (Tle 6). The first, Moel A, inlue the hlorpyrifos ir onentrtion n the seon, Moel B, i not. Moel A inlue t from 35 pplitors (173 pplitor-ys) who h oth irorne hlorpyrifos n urinry TCP levels. Moel B inlue Tuesy through Stury urinry TCP t from 39 pplitors (194 pplitor-ys). A first-orer utoregressive ovrite struture ws ssume s it proue etter moel fit thn ompoun symmetry. A signifint y-of-the-week effet ws foun in oth moels, lthough less so in Moel A. TCP levels were signifintly (P 0.05) lower on Tuesy, Wenesy n Thursy s ompre with Stury in Moel B, wheres in Moel A, TCP levels were signifintly lower on Wenesy s ompre with Stury, n mrginlly lower on Tuesy (P = 0.107) n Thursy (P = 0.072). TCP levels on Friy n Stury were essentilly similr (P>0.9) in oth moels. In Moel A, the hlorpyrifos ir onentrtions one n two ys efore the urine smple ws ollete n tretment of ommeril struture weighte y the minutes of hlorpyrifos use on the jo were ssoite with inrese TCP levels. A moel ws lso onstrute using one y of ir smpling; however, moel fit ws reue (i.e. higher AIC vlue) s ompre with the moel with two ys of ir smpling. In Moel B (ir onentrtion not in moel), oth minutes of hlorpyrifos pplition one n two ys efore urine olletion, tretment of n enlose rwl spe (yes/no), n tretment of ommeril Tle 3. TCP in urine n hlorpyrifos in ir levels y y of week Dy N AM SD GM GSD Rnge Anlyte: TCP (µg/g retinine) e Tuesy Wenesy Thursy Friy Stury Suny Mony Anlyte: hlorpyrifos (µg/m 3 ) f Mony Tuesy g 59 Wenesy Thursy Friy g 100 AM = rithmeti men. SD = stnr evition. GM = geometri men. GSD = geometri stnr evition. e First-morning urine voi. f For ll smples (N = 184), AM = 19 µg/m 3,SD= 21 µg/m 3,GM= 10 µg/m 3, GSD = 3.5. g Less thn the LOD. The LOD vrie y th n y smple ir volume.

8 316 C. J. Hines n J. A. Deens Fig. 1. Exposure iomrker reltionship for 35 termitiie pplitors expose to hlorpyrifos. Eh point represents the estimte men vlue of TCP (rw t given in µg/g retinine) for n pplitor, plotte versus the estimte men ir exposure (rw t given in µg/m 2 ) for tht pplitor (slope = 0.854, interept = 3.42, r 2 = 0.73, P ). Tle 4. Qulity ontrol results Anlyte N Rnge Men reovery (%) Men RSD (%) TCP in urine Lortory , Fiel spike , Fiel uplites e NA f 3.1 Cretinine in urine Lortory Fiel uplites e NA 2.7 Chlorpyrifos in ir Lortory Fiel spike not expose to mient onitions Fiel expose to mient onitions TCP in µg/l., retinine in g/l., hlorpyrifos in µg. RSD = reltive stnr evition. Bkgroun-juste nominl onentrtion. Fortifition rnge. e Rnge of levels foun. f NA = not pplile. Tle 5. Prmeters of the hlorpyrifos-in-ir regression moel Moel,e SE P-vlue Depenent vrile: ln(hlorpyrifos, µg/m 3 )(N = 184 pplitor-ys, 37 workers) Interept Minutes hlorpyrifos pplie Enlose rwl spe trete (yes/no) Compoun-symmetri ovrine struture ssume. = regression oeffiient. SE = stnr error. Dy ir smple ollete. e Exmple lultion where minutes hlorpyrifos pplie=56 n enlose rwl spe trete=yes: µg/m 3 hlorpyrifos = exp[ ( ) + ( )] = 14.

9 Determinnts of hlorpyrifos exposures 317 Tle 6. Prmeters of the TCP-in-urine regression moels Moel SE P-vlue Depenent vrile: ln(tcp, µg/g retinine) A. Air onentrtion in moel,j (N=173 pplitor-ys, 35 workers) Interept Dy of the week (4 DF e test, P=0.041) Tuesy Wenesy Thursy Friy Stury 0 f ln(hlorpyrifos ir onentrtion, µg/m 3 ) g ln(hlorpyrifos ir onentrtion, lgge 1 y, µg/m 3 ) h Commeril struture trete, time-weighte g,i B. Air onentrtion not in moel,k (N=194 pplitor-ys, 39 workers) Interept Dy of the week (4 DF e test, P 0.001) Tuesy Wenesy Thursy Friy Stury 0 f Minutes hlorpyrifos pplie g Minutes hlorpyrifos pplie, lgge 1 y h Enlose rwl spe (yes/no) g Commeril struture trete, time-weighte g,i First-orer utoregressive ovrine struture ssume. β=regression oeffiient. SE=stnr error. Urine smple ollete the morning of the inite y. e DF=egrees of freeom. f Eh y is ompre with Stury. g Applies to 1 y efore urine smple ollete. h Applies to 2 ys efore urine smple ollete. i Eh jo with ommeril struture ws weighte y the numer of minutes of hlorpyrifos pplition to ount for ifferenes in jo size. Expresse s proportion (0-1). j Exmple lultion where y of the week urine smple is ollete = Thursy, hlorpyrifos ir onentrtion on Wenesy = 11 µg/m 3, hlorpyrifos ir onentrtion on Tuesy = 11 µg/m 3, n proportion of time spent treting ommeril struture = 0.25: µg/g retinine TCP = exp{5.145 ( ) + [0.102 ln(11)] + [ ln(11)] + ( )} = 236. k Exmple lultion where y of the week urine smple is ollete = Thursy, minutes hlorpyrifos pplie on Wenesy = 56, minutes hlorpyrifos pplie on Tuesy = 56, enlose rwl spe trete = yes, n proportion of time spent treting ommeril struture = 0.25: µg/g retinine TCP = exp[5.333 ( ) + ( ) + ( ) + ( ) + ( )] = 252. struture (time-weighte) were ssoite with inrese TCP levels. All other ovrites were not signifint (P>0.1) in these two moels. The intertions etween minutes of hlorpyrifos use n glove use, n etween minutes of hlorpyrifos use n respirtor use, were highly non-signifint in Moel B (P>0.7). Exposure vriility. Vrine omponent estimtes re presente in Tle 7. Error-r plots illustrting within- n etween-worker vriility for hlorpyrifos ir exposure n urinry TCP re shown in Fig. 2. Over the one-week smpling perio, withinworker vriility ppere to e higher for hlorpyrifos in ir thn for TCP in urine (Fig. 2) n the proportion of the within-worker vriility to the totl vriility ws lower for TCP in urine s ompre with hlorpyrifos in ir (Tle 7). The within-worker n etween-worker vrine estimtes were similr for irorne hlorpyrifos exposure (Tle 7); however, for TCP, the etween-worker vrine estimte ws pproximtely six times lrger thn the withinworker vrine estimte in oth urine moels (Tle 7). The perentge of the totl vrine expline y fixe effets vrie y moel (rnge 13 28) n in eh moel the fixe effets expline sustntilly smller perentge of the totl vrine thn the rnom effets. The perentge of the totl vrine expline y fixe effets ws pproximtely twie s high in urine Moel A (with ir onentrtion) thn in urine Moel B (without ir onentrtion), lthough ifferenes in smple size my e ftor when ompring these moels. When only one y of ir smpling ws inlue in Moel A, the perent-

10 318 C. J. Hines n J. A. Deens Tle 7. Vrine omponents for the ir n urine regression moels Moel TS 2 y WS 2 y (%) WGSD e BS 2 y f (%) BGSD g FS 2 y h (%) rˆ i Rˆ 0.95B j Air (39) (44) (17) NA k 26 Urine Moel A (10) (63) (28) Urine - Moel B (12) (76) (13) Inlues worker, fixe effets n interept. T S 2 y = estimte totl vrine from moel ontining only worker s rnom effet. W S 2 y = estimte vrine of the within - worker istriution. Perentge of the estimte totl vrine. e W GSD = estimte geometri stnr evition of the within - worker istriution. f B S 2 y = estimte vrine of the etween - worker istriution. g B GSD = estimte geometri stnr evition of the etween - worker istriution. h F S 2 y = estimte vrine expline y fixe effets. i rˆ = estimte lg one utoorreltion. j Rˆ 0.95B = exp[3.92 ln(gsd B )] = rtio of the 97.5th n 2.5th perentiles of the etween - worker istriution. k NA = not pplile. Fig. 2. Chlorpyrifos exposure (A), (µg/m 3 ), n TCP levels in urine (B), (µg/g retinine), for 35 temitiie pplitors. Estimte men vlues n stnr errors re shown. Error rs represent ±1 stnr error of the men exposure. Within eh worker, n = 5 for oth hlorpyrifos n TCP, exept for workers 11 n 13, where n = 4 for oth hemils.

11 Determinnts of hlorpyrifos exposures 319 ge of the totl vrine expline y fixe effets erese to 19% (moel not shown). DISCUSSION Airorne hlorpyrifos exposures n urinry TCP levels were reily mesure in this popultion of termitiie pplitors. Full-shift rithmeti men hlorpyrifos ir exposures were pproximtely 50% higher thn those reporte y Fenske n Elkner (1990). Exposures i not exee the ACGM- n NIOSHreommene 8 h time-weighte verge hlorpryrifos ouptionl exposure limit of 200 µg/m 3 (ACGIH, 2000; NIOSH, 1992); however, the highest exposure (110 µg/m 3 ) ws 55% of the limit. 1 It shoul e note tht 22% (N = 40) of the smpling times exeee 10 h. The pplition of exposure limits intene for 8 h work ys my not e pproprite for longer ys. Also, these exposure limits my not e suffiiently protetive if erml sorption ws signifint. TCP levels were generlly in the sme rnge reporte y Jitsunri et l. (1989) for six workers, ut oul not e ompre iretly to results reporte y Fenske n Elkner (1990) n Gions et l. (1993) euse their t re expresse s exretion rtes or totl mss exrete per y, respetively. Given TCP urine elimintion hlf-life of 26.9 h (Noln et l., 1984), if worker sore the sme hlorpyrifos ose every y for five ys (Mony through Friy), TCP levels in the urine woul reh stey stte on Thursy, Friy n Stury, ssuming the worker strte the week with no TCP in the urine. Although the hlorpyrifos ose workers sore eh y in this stuy oul not e ontrolle y investigtors, GM TCP levels y y of week followe this preite kineti profile. In two generl popultion stuies, TCP hs een etete in the urine of 82% n 96% of US ults, with men levels of 3.1 n 5.8 µg/g retinine, respetively (Hill et l., 1995; MIntosh et l., 1999). These TCP levels re presumly relte to ietry n non-ouptionl exposures to hlorpyrifos n to TCP resiues. TCP levels in ll pplitor urine smples exeee these vlues y n verge ftor of 70. TCP is lso mjor metolite of hlorpyrifos-methyl n minor metolite of trilopyr (Apre et l., 1997; Crmihel et l., 1989); however, pplitors in this stuy i not use these ompouns while eing monitore t work. TCP levels similr to those foun here hve een ssoite with erements in few sulinil tests of neurologil funtion n in some self-reporte physil n 1 Eitoril note: ACGIH hve given notie of intent to hnge their TLV for hlorpyrifos to 100 µg/m 3 inhlle prtiulte in psyhologil symptoms; however, no linil effets hve een reporte (Steenln et l., 2000). The highly signifint ssoition etween urtion of hlopryrifos pplition n inrese levels of hlorpyrifos in ir n TCP in urine my e relte to the mnul pplition of hlorpyrifos-ontining solutions using open elivery systems. The ssoition etween urtion of hlorpyrifos pplition, lgge one y n inrese TCP levels is onsistent with the urinry elimintion hlf-life of TCP, i.e. TCP levels in the urine shoul reflet hlorpyrifos exposure over 2 3 ys. Treting n enlose rwl spe ws most likely n importnt preitor of inrese irorne hlorpyrifos exposure euse these spes hve limite ess n, therefore, poor nturl ventiltion. In oth TCP moels, tretment of ommeril struture, weighte y the numer of minutes of hlorpyrifos use, ws eterminnt of inrese TCP levels. The explntion for this ssoition is not reily pprent. Approximtely 10% of the tretment jos involve ommeril strutures n less fous ws ple on reoring hrteristis tht my hve vrie etween these strutures n resientil strutures. We were not le to show n ssoition etween respirtor or glove use n TCP levels, nor i we fin signifint intertion etween respirtor or glove use n minutes of hlorpyrifos pplition, highly signifint preitor of TCP in Moel B. Applitors were pproximtely four times s likely to wer respirtor, n pproximtely two times s likely to wer gloves when treting enlose rwl spes s ompre with treting other spes. The preferentil use of respirtors in enlose rwl spes s ompre with other spes is most likely relte to regultory requirement to wer respirtors in non-ventilte spes. Proper respirtor n glove use shoul result in erese TCP levels if exposure is vi inhltion (respirtors) or vi the hns (gloves). Even though pplitors wore respirtors n gloves on some jos, it is possile tht the evies or the mnner of use i not provie the expete protetion. Asene of respirtor effet oul lso our if sustntil portion of the exposure ws erml. Similrly, lk of glove effet oul our if exposure ws mostly y inhltion or if erml exposure ws vi oy res other thn the hns. The strength of the orreltion etween hlorpyrifos exposure in ir n TCP in urine, s well s stright-line slope of the log log reltionship tht ws lose to unity (r 2 = 0.73, slope = 0.854, Fig. 1), suggest tht TCP is useful iomrker of hlorpyrifos exposure n tht liner (first-orer) kinetis previle (Rppport et l., 1995). This reltionship oes not exlue the possiility of signifint orreltion etween erml exposure n TCP n oes not inite the mgnitue of ny erml ontriution to exposure, whih ws not evlute in this stuy. In

12 320 C. J. Hines n J. A. Deens very smll stuy of termitiie pplitors using hlorpyrifos (7 mesurements), Fenske n Elkner (1990) foun tht erml ose, ut not respirtory ose, ws signifintly orrelte with TCP for ertin urine olletion intervls over 72 h perio. They estimte tht 73% of the totl sore ily ose ws y the erml route, lthough two of three workers who spent time in rwl spe n one worker who onute len-up in n enlose spe were estimte to reeive 40 45% n 48% of the estimte ose y inhltion, respetively. Our finings n those of Fenske n Elkner (1990) inite tht for termitiie pplition work, espeilly work involving rwl spes, inhltion exposure shoul not e ignore. The low within-worker vriility for TCP my e relte to physiologil mping, i.e. the ttenution of exposure vriility in the oy ssoite with the elimintion hlf-life of sustne (Roh, 1966; Rppport, 1985; Rppport n Sper, 1988). It my lso e relte to the short smpling intervl in this stuy (one week). Perhps greter within-worker vriility woul hve een foun if smpling h een onute over the ourse of yer. Metoli ifferenes etween iniviuls my explin some of the etween-worker TCP vriility (Bltter Grin et l., 1997). Applitors preferre short-sleeve shirts, even though long-sleeve shirts were require. This preferene my e relte to omfort in the het. Complints out goggles fogging up were ommon n my explin limite protetive eyewer use. Interestingly, pplitors were more likely to wer gloves while pplying ilute prout thn while prepring tnk mixes with onentrte prout. Coverll use ws most likely higher uring pplition thn uring mixing to protet work lothes in irty rwl spes. This stuy hs limite generlizility. Applitors were reruite from speifi region of North Crolin n it is not known if termitiie pplitors t non-prtiipting ompnies were sustntilly ifferent from stuy pplitors. Also, only exposures uring Mrh to July were mesure, reportely usy time of yer. Derml exposure t woul hve een esirle for more omplete hrteriztion of exposure routes. Although pplitors preomintely use hlorpyrifos for termite tretment work, on 7% of the smple work ys, pplitors use hlorpyrifos-ontining prout for other purposes, suh s generl pest ontrol or lwn re. Five pplitors my hve use some hlorpyrifos on Stury. Potentil soures of hlorpyrifos exposure tht ourre infrequently, suh s leks from hoses n pumps, spills, thwing tnks with kerosene heters, rinsing jugs, n instlling rwl spe vpor rriers or vents fter tretment, were not evlute s exposure eterminnts. In summry, the GM exposure of termitiie pplitors to irorne hlorpyrifos ws pproximtely 5% of the reommene ouptionl exposure limit, while iniviul exposures rnge up to 55% of the limit. GM TCP levels were lowest on Mony n rehe plteu on Friy n Stury. Signifint eterminnts of irorne hlorpyrifos exposure n TCP levels inlue the urtion of hlorpyrifos pplition n the type of spe trete. In the TCP moels, y of the week n the hlorpyrifos ir onentrtion were lso signifint eterminnts. These finings suggest tht ontrol mesures ime t reuing hlorpyrifos ir exposures, espeilly in enlose rwl spes (e.g. portle mehnil ventiltion) or hnges in pplition tehnique tht reue the urtion of hemil hnling, woul le to lower TCP levels in the oy. We were not le to show tht respirtor or glove use ffete TCP levels; however, pplitors were more likely to wer protetive equipment when treting enlose rwl spes, itself preitor of exposure, n therefore some onfouning is possile. Withinn etween-worker vriility ws similr for irorne hlorpyrifos; however, for TCP, etween-worker vriility exeee within-worker vriility y six times. Aknowlegements We grtefully knowlege the ontriutions of Ronl Howell, Christopher Lyu, Dunn MChesney, Frnes Ptterson, Roger Pettit n Kelly Thoms in onuting the fiel stuy, n of Lin Aston, Jensen Groff, Brr MKenzie, Ewr L. 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