RISK ASSESSMENT OF COMBINED EXPOSURES TO MULTIPLE CHEMICALS: A WHO/IPCS FRAMEWORK 5 EXAMPLE CASE-STUDY B: CARBAMATES

Transcription

1 1 2 3 RISK ASSESSMENT OF COMBINED EXPOSURES TO MULTIPLE CHEMICALS: A WHO/IPCS FRAMEWORK 5 EXAMPLE CASE-STUDY B: CARBAMATES

2 Contnts 1. CONSIDERING THE NEED FOR A FRAMEWORK ANALYSIS PURPOSE AND FOCUS OF THE ASSESSMENT THE FRAMEWORK ANALYSIS Tir Exposur assssmnt Hazard assssmnt Tir 0 summary Tir Exposur assssmnt Hazard assssmnt Tir 1 summary Tir Exposur assssmnt Hazard assssmnt Tir 2 summary Tir Exposur assssmnt Hazard assssmnt Tir 3 summary CONCLUSIONS REFERENCES APPENDIX TO CASE-STUDY B: PERCENTAGE OF TOTAL CROP AREA TREATED WITH N-METHYL CARBAMATE INSECTICIDES FOR SELECTED CROPS IN 1992, 1997 AND

3 Not to radrs This cas-study was prpard by Anna Lowit, Unitd Stats Environmntal Protction Agncy, and Elizabth Shipp, Bayr Cropscinc on bhalf of th Europan Cntr for Ecotoxicology and Toxicology of Chmicals (ECETOC), and finalizd by th Planning Group Chair, Btt Mk. It was prpard for th purpos of illustrating and tsting th draft World Halth Organization/Intrnational Programm on Chmical Safty (WHO/IPCS) framwork on th risk assssmnt of combind xposurs to multipl chmicals. It is prsntd hr to facilitat th procss of public commnt. 3

4 This cas-study addrsss th N-mthyl carbamat (NMC) inscticids as an xampl of a group of substancs with a wll undrstood mod of action and a rlativly complt toxicity databas. Additionally, thy ar usd on a numbr of food crops, and th possibility may xist for ditary xposur to mor than on NMC inscticid during on day. Thy ar considrd as prioritis for a combind assssmnt, givn th potntial for co-xposur and thir potncy as actylcholinstras inhibitors. Ditary xposur, howvr, is not th only rout by which xposur to th NMC inscticids could occur. Exposur could also occur by ingstion of drinking-watr contaminatd with NMCs, by th occupational rout during psticid application or crop r-ntry tasks, or by rsidntial xposur following hom and gardn application of NMC inscticids. Owing to th high potncy of th NMC inscticids and th possibility of xposur via multipl pathways, th Unitd Stats Environmntal Protction Agncy (USEPA) has conductd an xtnsiv risk assssmnt of combind xposur to NMC inscticids via multipl routs and pathways (USEPA, 2007). This cas-study brifly xamins th toxicity of th NMC inscticids, thir uss and potntial xposurs via th ditary rout, and th assssmnt of th risk of ditary xposur to mor than on of ths substancs as an xampl of potntial tirs of considration. Th focus of th assssmnt is th risk of advrs halth ffcts posd by potntial combind xposur to multipl NMC inscticids via th ditary rout of xposur (xcluding drinking-watr), givn thir us on multipl crops and dtction in multipl agricultural commoditis. 1. CONSIDERING THE NEED FOR A FRAMEWORK ANALYSIS Th draft WHO/IPCS framwork prsnts a sris of qustions dsignd to dtrmin whthr or not it is appropriat to group substancs in an assssmnt group for a risk assssmnt. Thos qustions will b addrssd hr for th NMC inscticids. What is th natur of xposur? Ar th ky componnts known? Ar thr data availabl on th hazard of th mixtur itslf? Thr ar svral potntial routs of xposur to NMCs. Ditary xposur is possibl whn carbamat inscticids ar prsnt on food or in drinking-watr (usd in food prparation); this xposur may b to only on carbamat inscticid or to multipl carbamats. Occupational xposur may occur during th application of an inscticidal formulation on crops or in a rsidntial or othr stting. Finally, rsidntial xposur may occur through uss on lawns and gardns or on pts. Th ky componnts of this group ar known, although thir toxicity has largly bn assssd on th basis of singl compounds. Is xposur unlikly or vry low, taking into account th contxt? Exposur to at last on of th carbamats in th cours of daily lif is quit possibl. Th application of carbamat inscticids to all crops, including for both food and non-food uss, in th Unitd Stats in 1992, 1997 and 2002 (CropLif Amrica [CLA] databas) is summarizd in Tabl 1.

5 Tabl 1. Total quantity of carbamat inscticids applid to food and non-food crops in th Unitd Stats in 1992, 1997 and Compound Amount of activ ingrdint applid pr yar (lbs) a Aldicarb Carbaryl Carbofuran Formtanat hydrochlorid Mthomyl Oxamyl Thiodicarb a On pound (lb) = 0.5 kg. Quantifiabl rsidus of som of ths NMCs hav bn masurd in food monitoring programms in th Unitd Stats (USDA, 2007). Additionally, ths inscticids ar rlativly stabl in watr, and thus it can b xpctd that som of th applid amounts will b prsnt in drinking-watr aftr ithr agricultural or rsidntial application. As thr of th NMCs ar rgistrd for rsidntial uss, thr is also th potntial for rsidntial or non-occupational xposur to NMC rsidus. Howvr, givn that ths two potntial pathways of xposur ar lss significant than xposur through ditary routs, thy ar not includd in this illustration of th framwork. Is thr a liklihood of co-xposur within a rlvant timfram? Th CLA databas lists a numbr of instancs in which gratr than th total ara for a spcific crop in a spcific stat was tratd with carbamat inscticids (.g. 1% of th total swt corn crop in Alabama in 1992). It can b assumd that at last part of th ara in ach cas was tratd with mor than on carbamat. A wid varity of fruit, vgtabl and grain crops ar tratd ach yar with NMC inscticids. Givn th high us of NMC inscticids, th larg numbr of crops tratd and th frquncy with which NMC inscticids ar dtctd in monitoring programms, th possibility of xposur to multipl carbamat inscticids from multipl foods during on givn day nds to b invstigatd. What is th rational for considring compounds in an assssmnt group? Th NMC inscticids all act, in both targt inscts and mammals, by a rapidly rvrsibl inhibition of th actylcholinstras nzym. This inhibition lads to an accumulation of th nurotransmittr actylcholin, rathr than th usual dgradation of actylcholin shortly aftr its rlas into a nrv synaps. Accumulation of actylcholin thn lads to continuous stimulation of cholinrgic rcptors throughout both th cntral and priphral nrvous systms, lading to acut cholinrgic toxicity. Th NMC inscticids ar not th only inscticids that inhibit actylcholinstras; rathr, thy shar this sam mod of action with th organophosphat inscticids, such as chlorpyrifos. Howvr, th NMC inscticids caus rapid onst of ffcts as wll as rapid rcovry following inhibition, with maximal inhibition usually occurring btwn 15 and 5 min aftr xposur and rcovry following within a mattr of hours at most. Th organophosphat inscticids inhibit actylcholinstras in a largly non-rvrsibl mannr 5

6 and thus do not shar th sam tim cours of rcovry from inhibition. Owing to this diffrnc, organophosphat and NMC inscticids hav not bn considrd jointly in on common assssmnt group. Combind xposur to th organophosphat inscticids has bn considrd sparatly (USEPA, 2002, 2006). Th NMC inscticids wr stablishd as an assssmnt group (in th USEPA trminology, a common mchanism group ) by th USEPA in 2001 (USEPA, 2001), and th combind risk assssmnt subsquntly prpard for th NMC inscticids (USEPA, 2007) constituts th basis for this documnt. 2. PURPOSE AND FOCUS OF THE ASSESSMENT Th NMC inscticids considrd in this risk assssmnt hav food uss or maximum rsidu limits (tolrancs) in food crops in th Unitd Stats, and thus thr may b xposur to multipl NMCs via th ditary rout. Thy hav also bn assssd by th USEPA as an assssmnt group (USEPA, 2007), which constituts th principal basis for th currnt valuation. Figur 1 shows th WHO/IPCS framwork for considration of groupd compounds. It is important to not that only as many tirs as ar ncssary to st th compounds asid as nonprioritis for furthr considration or as a basis to inform subsqunt risk managmnt should normally b workd through; if crud stimats indicat that margins btwn stimatd xposur and hazard ar larg (and protctiv), thr is no nd to go on to highr tirs and dvlop mor rfind data, such as Mont Carlo xposur stimats. ls o d m r s u p o x f o n t m fin r g in s c r a In Sampl Tird Exposur and Hazard Considrations Tird Exposur Assssmnts Tir 0 Simpl smiquantitativ stimats of xposur Tir 1 Gnric xposur scnarios using consrvativ point s timats Tir 2 Rfind xposur assssmnt, incrasd us of actual masurd data Tir 3 Probabilistic Exposur Estimats Mixtur or Componnt Basd Ys, no furthr action rquird Input from xposur or hazard assssmnts (itrativ procss) Is th margin of xposur adquat? No, continu Ti rd Hazard Assssmnts Tir 0 Dos addition for all componnts Tir 1 Rfind potncy basd on individual POD, rfinmnt of POD Tir 2 Mor rfind potncy (RPF) and grouping basd on MOA Ti r 3 PBPK or BBDR; probabilistic stimats of risk In c r a s in g r fin m n t o f h a z a r d m o d ls (M O A ) Figur 1: Th framwork for considration of an assssmnt group, as proposd by WHO/IPCS (s txt for dtails). Th currnt cas-study, howvr, is basd on a pr-xisting risk assssmnt for an assssmnt group, rathr than bing an original work. Although not all agricultural or rsidntial psticids rquir dtaild xposur assssmnts prior to rgistration or r-rgistration, such data wr gnratd, in viw of th toxicity of th NMCs and th potntial for xposur to rsidus of multipl NMCs at on tim. For this rason, th typ and amount of data availabl 6

7 for this cas-study for xposur, particularly, do not align with th tirs outlind in th WHO/IPCS framwork. This valuation is not mant to stand as an indpndnt, original risk assssmnt of a spcific group of substancs, but rathr as an xampl in application of th WHO/IPCS framwork to an xisting assssmnt in ordr to dtrmin whthr th framwork is logical and workabl. Th uncrtainty factors and bnchmark doss (BMDs) ar thos prsntd in th USEPA assssmnt. 3. THE FRAMEWORK ANALYSIS A framwork risk assssmnt on groupd compounds would b basd on information rquird to dprioritiz th compounds from furthr considration or to inform risk managmnt. In th currnt cas of NMC inscticids, all of th tirs in th WHO/IPCS framwork ar xamind rgardlss of whthr or not thy would hav actually bn rquird; this is don in ordr to provid an xampl of information that might b usd. Th compounds to b considrd in this valuation, listd in Tabl 2, wr slctd basd on thir mmbrship in th NMC class of compounds and on th xistnc of maximum rsidu limits (tolrancs) in food itms and/or rgistrd food uss in th Unitd Stats. a Tabl 2. Unitd Stats food us rgistration status of NMC inscticids valuatd in this framwork analysis. Compound Rgistration Tolranc a Aldicarb Ys Carbaryl Ys Formtanat hydrochlorid Ys Mthomyl Ys Oxamyl Ys Pirimicarb Pnding Thiodicarb Ys Existnc of a tolranc is givn only whr thr is no rgistrd food us. 3.1 Tir Exposur assssmnt Th Tir 0 xposur assssmnt, according to th WHO/IPCS framwork, could rly on a simpl, smiquantitativ stimat of xposur. Such a scrning-lvl valuation could tak th form of totalling usag of NMC inscticids in ach stat and for ach crop for spcific yars. Slctd data ar prsntd in Tabls 8 10 of th appndix to this cas-study; th crops prsntd in thos tabls wr chosn on th basis of frqunt consumption, including by childrn, and on th basis of apparnt tratmnt of mor than 100% of th total crop ara in at last on stat and on at last on crop in ach yar xamind (CPRI, 2006). Although not all of th NMC inscticids includd in thos tabls ar includd in th USEPA s combind xposur risk assssmnt on which th currnt documnt is basd, thr is sufficint ovrlap btwn th compounds includd in this assssmnt and th compounds usd to prpar th appndix to cas-study B. As can b sn in Tabls 8 10 in th appndix to this cas-study, as wll as in Tabl 1 abov, th usag of NMC inscticids dcrasd in th 10-yar priod from 1992 to Th 7

8 numbr of crops and stats in which mor than 100% of th crop was apparntly tratd with NMC inscticids dcrasd as wll, with only on such xcdanc (cucumbrs in Illinois) vidnt in Nonthlss, th data availabl suggst that xposur to rsidus from a numbr of NMC inscticids on svral ditary componnts could occur. For xampl, using th data from 2002 NMC crop applications, a dit in which on day s mals contain appls from Washington stat, cucumbrs and graps from Nw York stat, grn bans from North Carolina and swt corn from South Carolina could xpos th consumr to a numbr of diffrnt NMC rsidus (food itms and stats slctd from Tabl 10). In ordr to nsur that such xposur dos not pos undu risk, furthr xposur assssmnt is ndd undr highr tirs of th WHO/IPCS framwork Hazard assssmnt At Tir 0 of th hazard assssmnt (s Figur 1), it could b assumd that only simpl dos addition is rquird for all componnts of th assssmnt group undr xamination and that all mmbrs of th group shar an qual potncy. Th data availabl on th NMCs ar xamind blow to tst that assumption. Th NMC inscticids ar known to shar th sam mod of action namly, a rapidly rvrsibl inhibition of th actylcholinstras nzym. A rcnt papr from th USEPA (Padilla t al., 2007) dmonstratd that whn NMC inscticids ar administrd sparatly to rats, thy shar largly similar tim courss for rvrsal of inhibition. Tabl 3 summarizs inhibition and rvrsibility data for th svn compounds invstigatd in that papr. Tabl 3. Actylcholinstras inhibition charactristics of slctd NMCs in rat brain and rd blood clls aftr oral administration (Padilla t al., 2007). Compound Dos Tim to Maximum % inhibition Tim to 100% rcovry (h) (mg/kg pak Brain Rd blood Brain Rd blood bw) ffct (h) clls clls Carbaryl Carbofuran Formtanat Mthiocarb Mthomyl Oxamyl Propoxur In gnral trms, it is clar that th NMCs tstd hr show similar charactristics in thir tim to pak inhibition of actylcholinstras and in th tim to rcovry of nzym activity. Howvr, comparison of th doss and thir ffcts shows that th potncy of th NMC inscticids is not quivalnt and that significant brain inhibition (>50%) occurs at rlativly low doss for svral NMCs. For xampl, an oxamyl dos of 1 mg/kg bw producs 50% inhibition of brain cholinstras at 30 min aftr administration, whras a carbaryl dos of 30 mg/kg bw producs only 0% inhibition of brain cholinstras at th sam 30-min tim point. Clarly, th potncy of th diffrnt NMCs assssd in Tabl 3 (and prsumably thos xamind in th currnt documnt, which wr not studid by Padilla t al., 2007) varis with rgard to maximum inhibition of actylcholinstras. Whil thr ar diffrncs in potncy of th various NMCs, should th margin btwn stimatd total xposur to all and th potncy of th most toxic NMC b larg, additional assssmnt would not b rquird. 8

9 Tir 0 summary A rcnt comparativ study (Padilla t al., 2007) showd that whil th NMCs shar a numbr of charactristics, including rapid onst and rcovry of actylcholinstras inhibition in both brain and rd blood clls, thr ar data on diffrncs in potncy that nabl an additional tir of th hazard assssmnt. Simpl analysis of NMC us on slctd crops shows that thr is th potntial for xposur to multipl NMC inscticid rsidus on multipl ditary componnts, and thus furthr xposur assssmnt byond Tir 0 is rquird. As thr is th potntial, aftr this first scrning tir of th framwork analysis, for combind xposur to lvls of NMC inscticids that could xcd rfrnc valus, furthr assssmnt in Tir 1 and possibly abov is rquird both to rfin th xposur stimats and to compar thm with mor rfind rfrnc valus/hazard valus. 3.2 Tir Exposur assssmnt At Tir 1, th xposur assssmnt could b basd on a gnric xposur scnario using consrvativ point stimats of xposur. With rgard to NMC inscticids, this could includ an valuation of stimatd consumption compard with th acut rfrnc dos (ARfD) for ach compound. Th minimum and maximum consumption, whr availabl, of ach ARfD ar listd in Tabl, as wll as th drivation of th rfrnc dos usd. Th data prsntd thr show that whil thr is only low stimatd xposur to som NMCs (pirimicarb, xposur to 7 10% of th ARfD is xpctd for all groups xamind), som NMCs that ar usd with gratr frquncy and on mor food crops ar stimatd to carry a gratr liklihood of xposur (carbaryl, with xposur stimatd to b 3 68% of th ARfD). Ths data wr xtractd from ithr th Unitd Stats Rrgistration Eligibility Documnts (USEPA, 199, 1998, 2007a,b,c,d) or th Unitd Stats Tolranc Ptition notics for ach compound (spcific documnts and thir onlin availability ar listd in th rfrncs). Th data in Tabl show that it is possibl for a varid dit to contain significant proportions of th ARfDs of compounds within th sam assssmnt group; for xampl, childrn 1 6 yars of ag could consum 19% of th ARfD for aldicarb by ating citrus, swt potato or potato, 81% of th ARfD for oxamyl by ating citrus, swt potato, cucumbr or appl, and 7% of th ARfD for pirimicarb through consumption of asparagus and lafy ptiol crops such as clry. Th ARfDs for aldicarb and oxamyl ar both basd on masurd inhibition of actylcholinstras, whras that for pirimicarb is basd on clinical signs of nurotoxicity most likly rlatd to actylcholinstras inhibition. 9

10 Tabl. Acut rfrnc valus for NMC inscticids with food us rgistrations or maximum rsidu limits/tolrancs, and stimatd consumption of thos rfrnc valus. a Compound Rfrnc valu (mg/kg bw pr day) Sourc study End-point Safty factors Ag group % rfrnc valu Aldicarb Human voluntr AChE inhibition 100 Childrn, 1 6 yars old 19 Carbaryl 0.01 Rat dvlopmntal FOB changs 100 Gnral population 3 nurotoxicology Childrn, 1 2 yars old 68 Formtanat Comparativ AChE study AChE inhibition 100 Adults, 20 9 yars old 16 hydrochlorid Infants 56 Mthomyl 0.02 Rabbit tratology Matrnal/ftal 300 Infants <1 yar old 27 toxicity Childrn, 1 6 yars old 72 Oxamyl Rat acut nurotoxicology AChE inhibition 100 Childrn, 1 6 yars old 81 Pirimicarb 0.01 Rat nurotoxicology Clinical signs 1000 Gnral population 10 Childrn, 1 2 yars old 10 Childrn, 1 6 yars old 7 Thiodicarb 0.01 Rat tratology Body wight gain 1000 Childrn, 1 6 yars old 31 Infants 60 AChE, actylcholinstras; FOB, functional obsrvational battry. a Whr availabl, th minimum and maximum pr cnt consumption for a givn compound ar givn to indicat th ovrall rang. 10

11 3.2.2 Hazard assssmnt In Tir 1, th hazard assssmnt calls for rfining th potncy of th individual mmbrs of th assssmnt group, basd on thir individual points of dpartur, as wll as rfining thos points of dpartur. Basd on th limitd data shown in Tabl 3 abov, th actylcholinstras inhibitory potntial of ach of th NMCs varis, mostly in th maximum xtnt of inhibition and somwhat in th tim to rcovry of actylcholinstras activity. Although not all of th compounds tstd ar considrd in th risk analysis (owing to lack of food uss or maximum rsidu limits/tolrancs in food itms) and not all compounds in th risk analysis wr tstd, it is saf to assum that this variation in potncy xtnds to thos compounds that wr not tstd by Padilla t al. (2007) (i.. aldicarb, pirimicarb and thiodicarb). In ordr to driv rlativ potncy factors, th inhibition of brain cholinstras by ach of th NMCs considrd in th assssmnt (USEPA, 2007) was dtrmind. Bnchmark dos stimation includd a mta-analysis of data submittd by th rgistrants in combination with data gnratd by th USEPA for ach of th substancs listd, as wll as publishd or othr xprimntal data. Th bnchmark dos and half-lif to rcovry stimats (not providd hr) wr drivd using a sophisticatd dos tim rspons xponntial modl. Th limit of snsitivity for dtcting cholinstras inhibition in ithr brain or rd blood clls is considrd to b 10% basd on an analysis by th USEPA (2002) using data from ovr 100 studis and mor than 30 organophosphats. Thus, th cntral stimat of th BMD 10 was slctd for us in driving rlativ potncy factors. Th BMD 10, BMDL 10 (lowr 95% confidnc limit on th BMD 10 ) and rlativ potncy factor for ach of th mmbrs of th NMC group ar prsntd in Tabl 5. Tabl 5. Bnchmark doss and rlativ potncy factors for th NMC inscticids xamind in this combind risk assssmnt. Compound Aldicarb a Carbaryl Formtanat hydrochlorid Brain RPF BMD 10 (mg/kg bw) BMDL 10 (mg/kg bw) 0.05 (fmal) 0.03 (fmal) 0.06 (mal) 0.03 (mal) 1.60 (rgistrant fmal) 1.35 (rgistrant fmal) (rgistrant mal) 0.99 (rgistrant mal) 5.6 (NHEERL mal).15 (NHEERL mal) 1.58 (combind mal) 1.11 (combind mal) 2.63 (Mosr) 2.03 (Mosr) Mthiocarb Mthomyl Oxamyl Pirimicarb Thiodicarb NHEERL, National Halth and Environmntal Effcts Rsarch Laboratory. 11

12 a Th sulfon and sulfoxid mtabolits of aldicarb ar not listd in th currnt risk assssmnt, although thy ar rprsntd in th highr-tir xposur assssmnts. Th modlling summarizd hr was conductd in ordr to covr ditary, rsidntial and occupational uss of th NMCs. As rsidntial and occupational xposurs assssd by th USEPA s (2007) combind xposurs risk assssmnt, in addition to xposurs through food and watr, may b by drmal and inhalation routs as wll as by th oral rout, th indx chmical for rlativ potncy factor drivation was slctd on th basis of a robust databas for actylcholinstras inhibition aftr administration by oral, drmal and inhalation routs. As th most robust databas by all thr routs blongd to oxamyl, that substanc was slctd as th indx chmical. Th data availabl for oxamyl includd six acut oral studis, including on study in humans and a comparativ cholinstras study in adult and juvnil (postnatal day 11) rats, and covrd a dos rang in th rat studis from to 15.3 mg/kg bw, thus providing a broad dos rspons rang. Although th currnt casstudy dos not covr non-ditary xposurs, oxamyl will b rtaind as th indx chmical for this cas-study. Th rlativ potncy factors for ach compound for childrn and adults, incorporating rlvant uncrtainty factors, ar shown in Tabl 6. Tabl 6. Rlativ potncy factors and adjustd rlativ potncy factors for childrn and adults for ach of th NMC inscticids of intrst. Compound Oral RPF Adjustd RPF, childrn Adjustd RPF, adults Aldicarb 16 8 Carbaryl Formtanat hydrochlorid Mthiocarb Mthomyl Oxamyl Pirimicarb Thiodicarb Finally, th assumption calld for in th prliminary (Tir 0) hazard assssmnt was that xposur to mor than on NMC inscticid would produc an additiv rspons in inhibition of actylcholinstras activity. As th potncy of th various NMC inscticids tstd was apparntly diffrnt, this assumption was tstd by conducting a mixtur study in which th proportion of ach compound within th mixtur was basd on its calculatd potncy. A dos rspons curv was gnratd using ovrall doss of th mixtur that wr prdictd to yild btwn 5% and 60% inhibition of brain and rd blood cll actylcholinstras activity. Th rsults obtaind indicatd th prdictd additivity, and th inhibition at ach dos was vry similar to th prdictd inhibition of actylcholinstras activity (data not shown). This work confirms simpl additivity of ffcts aftr simultanous xposur to mor than on NMC, dspit thir diffrncs in potncy. Th adjustd rlativ potncy factors for ach of th NMCs in this analysis (Tabl 6) wr thn usd in a rfinmnt of th initial xposur assssmnt. 12

13 Commonly, animal-to-human risk assssmnt for comparison of xposur with standard rfrnc valus uss dfault intr- and intraspcis safty factors of 10 or, altrnativly, a margin of xposur btwn animals and humans of 100. As th intrspcis factor is alrady includd in th rlativ potncy factor for ach NMC (basd on human data), only th intraspcis factor rmains. Thus, in th xposur assssmnt, a margin of xposur of 10 (rprsnting th intraspcis safty factor) or bttr is considrd adquatly protctiv of human halth Tir 1 summary Simpl additivity of th ffcts of NMC inscticids was confirmd through xprimntal invstigation, and rfind potncy factors for ach of th compounds of intrst wr dvlopd. Howvr, as thr is th possibility for significant xposur to rsidus of multipl NMCs in on day, vn if consumption of ach individual compound is blow th rfrnc dos, th Tir 1 assssmnt dos not provid a sufficint margin of xposur to nd th valuation at that tir. Furthr assssmnt of xposur is ndd, although rfinmnt of th hazard assssmnt may or may not b ndd. 3.3 Tir Exposur assssmnt At Tir 2, rfinmnt of potntial xposur could includ dtrministic stimats basd on actual masurd data. For th NMC inscticids or for any group of food-us psticids, sourc data could includ thos availabl from th Unitd Stats Dpartmnt of Agricultur (USDA) Psticid Data Program on dtction of psticid rsidus and mtabolits in ditary componnts. In an original valuation of combind xposurs, this assssmnt would b conductd bfor moving on to probabilistic stimats of xposur (Tir 3). Howvr, as an xisting assssmnt is bing usd as a data sourc, th probabilistic xposur assssmnts gnratd in that assssmnt ar usd in this cas-study. This should not b takn as an indication that such highly rfind stimats of xposur ar calld for in all cass; this is simply a us of xisting data in ordr to tst th WHO/IPCS framwork Hazard assssmnt Until th Tir 3 xposur assssmnt is tstd against th rfind potncy stimats drivd in Tir 1 of th hazard assssmnt, no furthr rfinmnt of th potncy or grouping basd on mod of action will b conductd. Clarly, if th Tir 1 rfinmnt of hazard assssmnt is not sufficint, additional rfinmnts will b conductd Tir 2 summary Ordinarily, a complt tir of both xposur and hazard assssmnt would not b omittd. Howvr, as th data on which this assssmnt is basd bgan with vry gnric xposur stimats and movd dirctly to probabilistic assssmnt of ditary intak, an xposur assssmnt for this tir is not availabl. Likwis, hazard assssmnt would not b furthr rfind until it is clar whthr or not such rfinmnt is ndd. 13

14 3. Tir Exposur assssmnt Food consumption data usd in th combind risk assssmnt for NMCs wr obtaind from th USDA food consumption survy in which ditary rcall data wr collctd from ovr popl ranging from infants lss than 1 yar old to adults ovr 50 yars old. Actual rsidu information for ach of th compounds was obtaind from th USDA Psticid Data Program (USDA, 2007), which analyss sampls of domstic and importd food at distribution cntrs. Unlik th data usd in Tir 0 or 1, th Psticid Data Program data rprsnt rsidu lvls aftr th food itm is procssd for consumption, shortly bfor purchas by th consumr, and thus prsnt a mor ralistic pictur of actual xposur. Mont Carlo simulations for xposur to th NMC compounds wr conductd for ach ag group using ditary consumption data and psticid rsidu data from th abov-mntiond USDA programms. Rsidu concntrations for ach compound wr xprssd as quivalnts to th indx chmical, rathr than as rsidus of ach spcific compound. Th margin of xposur for combind xposur to th NMCs was thn dtrmind at th 95th, 99th and 99.9th prcntils for ach ag group (Tabl 7). Tabl 7. Probabilistic analysis of ditary xposur to NMC inscticids and th rsulting margins of xposur. Ag group 95th prcntil 99th prcntil 99.9th prcntil mg/kg MOE mg/kg bw MOE mg/kg bw MOE bw pr day pr day pr day Gnral population Infants <1 yar Childrn 1 2 yars Childrn 3 5 yars Childrn 6 12 yars Youth yars Adults 20 9 yars Adults 50+ yars Fmals 13 9 yars Although prdictd xposur of childrn btwn 1 and 5 yars of ag xcds th margin of xposur of 10 at th 99.9th prcntil lvl of protction, th margin of xposur is qual to 10 at th 99.8th prcntil for ths ag groups. Th margins of xposur includd in Tabl 7 ar considrd by th USEPA to b adquatly protctiv of human halth. This was supportd, in part, by xtnsiv snsitivity analyss conductd on assumptions, data and modls usd in th risk assssmnt Hazard assssmnt As th combind xposur risk assssmnt passs with Tir 2 xposur assssmnt and Tir 1 hazard assssmnt data, thr is no nd to furthr rfin th hazard assssmnt in ithr Tir 2 or 3. 1

15 3..3 Tir 3 summary Bcaus th compounds xamind hr shar a common mod of action but hav diffring potncis, an indx chmical was slctd, and potncy factors for ach of th othr substancs wr drivd rlativ to that indx chmical using a highly rfind mta-analysis bnchmark dos approach. Probabilistic stimats of xposur wr dtrmind, and margins of xposur wr dtrmind for various ag groups. This highly rfind analysis dmonstrats that thr is no concrn for combind ditary xposur to NMC inscticids.. CONCLUSIONS Rfinmnt of th hazard assssmnt by driving rlativ potncy factors and intrspcis assssmnt factors and of th xposur assssmnt by using ralistic valus for psticid rsidus in food consumd rsults in th conclusion that combind ditary xposur to th NMC inscticids dos not rais concrns for any ag group. Basd on this, furthr rfinmnt of ithr hazard or xposur as providd for in th WHO/IPCS framwork is unncssary. Howvr, such rfinmnts could b conductd in othr cass whr combind ditary xposur to psticid rsidus xcds th accptabl margin of xposur. If th margins of xposur had not bn adquat with th NMCs considrd hr, furthr rfinmnts of th hazard assssmnt might includ: conducting comparativ cholinstras inhibition assays in juvnil and adult animals; or using pharmacologically basd pharmacokintic (PBPK) modlling, givn th rapid natur of onst of inhibition and rapid rcovry, to bttr valuat th dynamic natur of xposur to and ffct of NMC inscticids. Th xposur assssmnt prsntd abov addrsss th highst tir. Howvr, vn th scnarios listd abov could b rfind if th margins of xposur wr not sufficint. Th probabilistic xposur modls usd in th xposur assssmnt totalld consumption of all foods during a 2-h priod, rathr than sparating thm into mals or ating vnts. With compounds that hav a rapidly rvrsibl biological ffct, such as NMC-basd actylcholinstras inhibition, it is possibl that th inhibition from NMC consumption at on mal would b rvrsd bfor th subsqunt mal and potntial NMC consumption. Thus, valuation of th contribution of ach mal to th total daily NMC consumption might hav bn usd to potntially rduc apparnt xposur to NMCs; consumption at brakfast of sufficint NMC quivalnts to th indx chmical to caus 20% actylcholinstras inhibition followd by consumption at dinnr of NMC quivalnts to caus 30% inhibition diffr in prdictd hazard from consumption in on 2-h priod of sufficint NMC quivalnts to inhibit nzym activity by 50%. To th xtnt possibl with availabl modls, th USEPA has valuatd th within-day xposurs to NMCs through food. This analysis is byond th scop of this cas-study. In conclusion, us of th WHO/IPCS framwork for combind xposur risk assssmnt of food-us psticids is gnrally productiv. Th hazard assssmnt tirs ar fairly asily adaptd to th availabl data or to th data that can b gnratd spcifically for th purpos of th combind xposur risk assssmnt. Th xposur 15

16 assssmnt tirs ar lss natly dividd, as rgistration of an agrichmical psticid gnrally rquirs fairly rfind data, which may go as far as Tir 3. Howvr, th ovrall approach is still applicabl. 5. REFERENCES CPRI (2006). National Psticid Us Databas: Washington, DC, CropLif Foundation, Crop Protction Rsarch Institut ( Padilla S, Marshall RS, Huntr DL, Lowit A (2007) Tim cours of cholinstras inhibition in adult rats tratd acutly with carbaryl, carbofuran, formtanat, mthomyl, mthiocarb, oxamyl, or propoxur. Toxicology and Applid Pharmacology, 219: USDA (2007) Psticid Data Program: Annual summary, calndar yar Dcmbr Washington, DC, Unitd Stats Dpartmnt of Agricultur ( G&topNav=&lftNav=ScincandLaboratoris&pag=PDPDownloadData/Rports& dscription=download+pdp+data/rports&acct=pstcddataprg). USEPA (199) Rrgistration ligibility dcision documnt: Mthiocarb. Washington, DC, Unitd Stats Environmntal Protction Agncy, 30 March ( USEPA (1998) Rrgistration ligibility dcision for mthomyl. Washington, DC, Unitd Stats Environmntal Protction Agncy, Dcmbr ( USEPA (2001) Mmorandum from M. Mulky to L. Rossi: Implmntation of th dtrminations of a common mchanism of toxicity for N-mthyl carbamat psticids and for crtain chloroactanilid psticids, datd 12 July Washington, DC, Unitd Stats Environmntal Protction Agncy ( USEPA (2002) Organophosphat psticids: Rvisd cumulativ risk assssmnt. Washington, DC, Unitd Stats Environmntal Protction Agncy, Jun ( USEPA (2006) Organophosphat psticids (OP) cumulativ assssmnt 2006 updat. Washington, DC, Unitd Stats Environmntal Protction Agncy, 31 July ( USEPA (2007a) Rrgistration ligibility dcision for aldicarb. Sptmbr Availabl onlin at USEPA (2007b) Rrgistration ligibility dcision for carbaryl. Washington, DC, Unitd Stats Environmntal Protction Agncy, 2 Sptmbr ( 16

17 USEPA (2007c) Rrgistration ligibility dcision for formtanat hydrochlorid. Washington, DC, Unitd Stats Environmntal Protction Agncy, 2 Sptmbr ( Rports from othr yars ar availabl following links from: USEPA (2007d) Rrgistration ligibility dcision for oxamyl. Washington, DC, Unitd Stats Environmntal Protction Agncy, 2 Sptmbr ( USEPA (2007) Rvisd N-mthyl carbamat cumulativ risk assssmnt. Washington, DC, Unitd Stats Environmntal Protction Agncy, Offic of Psticid Programs, 2 Sptmbr ( 17

18 Appndix to cas-study B: Prcntag of total crop ara tratd with N-mthyl carbamat inscticids for slctd crops in 1992, 1997 and 2002 Tabl 8. Prcntag of total crop ara tratd with NMC inscticids for slctd crops in 1992 (CPRI, 2006). Stat % of crop ara tratd Appls Cucumbrs Graps Grn bans Potatos Swt corn Alabama Arizona 71 Arkansas California Colorado Conncticut Dlawar Florida Gorgia Idaho Illinois Indiana Iowa Kansas 6 Kntucky Louisiana Main Maryland Massachustts Michigan Minnsota Mississippi 10 Missouri Nw Hampshir Nw Jrsy Nw York North Carolina North Dakota 81 Ohio Oklahoma Orgon Pnnsylvania Rhod Island South Carolina

19 Stat % of crop ara tratd Appls Cucumbrs Graps Grn bans Potatos Swt corn South Dakota 23 Tnnss Txas Vrmont Virginia Washington Wst Virginia Wisconsin Tabl 9. Prcntag of total crop ara tratd with NMC inscticids for slctd crops in 1997 (CPRI, 2006). Stat % of crop ara tratd Appls Cucumbrs Graps Grn bans Potatos Swt corn Alabama Arizona Arkansas California Colorado Conncticut Dlawar Florida Gorgia Idaho Illinois Indiana Iowa Kansas 18 Kntucky Louisiana 3 Main Maryland Massachustts Michigan Minnsota Mississippi 3 Missouri Montana 95 Nbraska 7 Nw Hampshir Nw Jrsy

20 Stat % of crop ara tratd Appls Cucumbrs Graps Grn bans Potatos Swt corn Nw Mxico 12 Nw York North Carolina North Dakota 7 Ohio Oklahoma Orgon Pnnsylvania Rhod Island 50 7 South Carolina Tnnss Txas Utah 30 Vrmont Virginia Washington Wst Virginia 96 5 Wisconsin Tabl 10. Prcntag of total crop ara tratd with NMC inscticids for slctd crops in 2002 (CPRI, 2006). Stat % of crop ara tratd Appls Cucumbrs Graps Grn bans Potatos Swt corn Arkansas California Colorado 75 8 Conncticut Dlawar Florida 2 1 Gorgia Idaho 38 Illinois Indiana Kansas Kntucky Main Maryland 5 Massachustts Michigan Mississippi 12 20

21 Stat % of crop ara tratd Appls Cucumbrs Graps Grn bans Potatos Missouri 67 Nbraska 5 Nvada 5 Swt corn Nw Hampshir 32 1 Nw Jrsy Nw York North Carolina Ohio Oklahoma 3 Orgon Pnnsylvania Rhod Island 20 South Carolina Tnnss Txas 1 Utah 50 Vrmont 32 1 Virginia Washington 67 7 Wst Virginia 15 Wisconsin 1 21