OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

RE : Meeting between Dow AgroScience s (DAS) and EPA to Discuss DAS’ Work and Possible Enhancements to the ir Physio logically Based Pharmacokinetic Model ( PBPK ) List of Documents 1. Meeting Summary Page 1 2. Meeting Sign in Sheet Page 2 3. DAS PowerPoint Presentation Page 3 Meeting Summary On Wednesday, May 23, 2012, EPA’s Office of Pesticide Programs met with DAS to discuss their PBPK model. DAS is considering enhancements to the model for dermal, pregnancy, and inhalation. The enhancements could take from as little as three months (dermal) to upwards of a year and a half (inhalation). DAS anticipates discussing the progress of any enhanceme nts with EPA at a future data

.EPA and Registrant Meeting Chlorpyrifos and PBPK May 23,2012
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# Review of curr ent model



# status/up dates Dow AgroSci ences May 23, 2012

P ag e 1

# History of Source - to - Outcome Modeling for Chlorpyrifos

• Three phases for the work

– ACC LRI project (2006

- 2010)

– SAP preparation (2010

- 2011)



# – Post SAP (2011

- 2012)

• Initial focus was research oriented

– Can models be linked?



# – Do models provide plausible predictions?

– What drives human variability?

• In exposure



# • In response Page 2

# The PBPK/PBPD model

• The fundamental model has a long history of use

– Initially developed and validated with animal study and 

# human volunteer data sets (Timchalk et al., 2002)

– Recently used to design and interpret results from Comparative Cholinesterase study conducted in adult and 

# preweanling rats (Marty et al., 2012)

– LifeStage version of PBPK model used to correlate in vitro substrate concentrations with in vivo exposure levels (Bartels et al, 2012; April 2012 SAP mtg )

# ACC - LRI Project 20 06 - 2010

• Goal can you do a non cancer r isk ass essment with out uncertain ty factors

• DAS /Dow/Battel le colla borati on

• Ba sed on e xisting meta bol ism data

• Focus on linkin g the model s and comparison of p redictio ns to pub li shed data



# • Oral rou te: Two ages,

– 3 year olds and adults



# • Two pub li cation s Price et a l. 2011, and Hind erlit er et a l. 2011 

# (Awarde d best mo del in g pap er of 201 1 by SOT)

P ag e 4

# Preparation for SAP (2010
– 2011)

• Develop new Lifestage model for age

- related changes of typical individual

• Incorporated human data on metabolism (Smith et al. 2011)

– Measured human variation in key enzymes for activation and detoxification of chlorpyrifos using chlorpyrifos as a substrate

– Reflecting human variation and impact of age

– Modest sample size (30 individuals)



### • Develop model of human variation for ages six months to adults

• SAP report

– Comparison to published data on human variation

– Conclusions on human variation in RBC response

• Variation in response is dose dependent (more variation at high doses)

• Minimal impact of age (infants are slightly more sensitive than adults)

• Variation is driven by interindividual variation in metabolism not physiology nor differences in levels of physical activity

– Modeled inter

- species and inter

- individual uncertainty factors

• Values of less than 2 are predicted to be protective Page 5

# Post SAP (201 1
– Now)

• Inv es tig ati on of is su es rais ed by SA P

– Questi ons co nc erning the m etab ol is m data

– Se ns iti vi ty anal ys is

– Al ternati ve approac h for as se ss in g sa fety fac tors (sepa rate mode li ng of unc ertain ty and v ariati on)

• Initial work suggests that findings presented to SA P are unlik ely to change after addr essi ng the S AP comments



### • P ublications

– Metabo lism da ta pu bli shed (S mith et al., 20 11 )

– Thre e ad ditio na l pu bli cations ar e un de r de velo pme nt

• 1) Lifes tage mo de l, 2) va ri ation mo de l, 3) mod eling of un c ertainty fac tors

• Mod el va li da ti on will be ba se d on Kisic ki hu man vo luntee r stud y da ta, pe nd ing EP A de c isio n on ethic al ac c ep tanc e

P ag e 6

# Future Work (needs to be priortized )

• PB PK mode li ng

– Extensi on of oral model s to in hal ati on and dermal



# – Exten di ng exi sting mode l fr om 6 months bac k to birth

– Lactation al route of exposu re

– De velo pi n g a late stage pregna ncy model



# • Evalu ati on of n on - die tary exposure sc ena rios

– Occupationa l, reside ntial , etc.

P ag e 7

# Question s?

# Refe rences

• B a rtels, M

. J., P o e t, T. S ., P ri ce , P

. S ., Hind e rl ite r, P

. M ., a n d Ju b e rg, D. R. (2 0 1 2 ). Use o f a va li d a te d P B P K /P D m o d e l fo r ch loryp yri fo s to co rr e lat e in vitro su b stra te co n ce n trat ion s wi th in vivo syste m ic e xp o su res. Th e To xicolo g ist, V o lume 1 2 6 : Ma rch 2 0 1 2

. # 6 5

.

• P a u l M

. Hi n d e rl ite r, Torka S P o e t, Mi ch a e l J B a rtels, Cha rl e s Tim ch a lk, P a u l S P ri ce (20 1 1 ), Deve lop m e n t o f a S o u rce - to

- Ou tco m e M o d e l fo r Di e ta ry E xp o su res to In se cticide Resid u e s: A n E xa m p le Usi n g Chlo rpyri fo s, Reg

. Tox icol

. P h a rm a co l ., 6 1 , 8 2

- 9 2

.

• P a u l S

. P ri ce , K a rl D. S ch n e ll e , Che ryl B

. Cl e ve lan d , M icha e l J. B a rtels, P a u l M

. Hi n d e rl ite r, Cha rl e s Tim ch a lk, a n d Torka S

. Po e t (20 1 1 ))

. A p p li ca tio n o f a S o u rce - to

- Ou tco m e M o d e l fo r th e A sse ssm e n t o f Hea lth Imp a cts from Di e ta ry E xp o su res to In se cticide Resid u e s. R e g
. Tox icol

. P h a rm a co l , 6 1 , 2 3

- 3 1

.

• S m ith , J N, Tim ch a lk, C, B a rtels, M J., P o e t, T S

. (20 1 1 ), In vitro a g e - dependent enz y m ati c m etabol i s m of c hl or py r i fos and c hl or p yri fo s - o xo n in h u m a n h e p a tic m icr o so m e s a s well a s ch lorp yri fo s - o xo n in p lasma. Drug M e ta b

. Di sp , 3 9 , 1 3 5 2

- 1 3 6 2

.

• M a rty, M

. S ., A n d rus, A

. K ., B e ll , M

. P ., P a ssa g e , J. K ., P e rala , A

. W ., B rzak , K

. A ., B a rtels, M

. J., B e ck,, M

. J., a n d Ju b e rg, D. R. (2 0 1 2 ). "C h o li n e ste rase In h ibitio n a n d Tox icokin e tics in Imm a tu re a n d A d u lt Rat s A ft e r Acu te o r Rep e a te d E xp o su res to Ch lorp yri fo s o r Chlo rpyri fo s o xo n ", Reg

. Tox

. P h a rm a co l, in p ress. [1 ]

• Tim ch a lk C, No lan RJ, M e n d rala A L

. A P h ysiolo g ically b a se d p h a rm a co kine tic a n d p h a rm a co d yn a m ic (PB P K /P D) m o d e l fo r th e o rga n o p h o sp h a te inse cticide ch lorp yri fo s in rat s a n d h u m a n s. Tox icolo g ical S cien ce s: A n O ff ici a l Jo u rna l o f th e S o ciet y o f To xic o log y 2 0 0 2 ; 6 6 :3 4

- 5 3 % U h tt p :/ /www .n cb i.n lm .n ih. g o v/p u b m e d /1 1 8 6 1 9 7 1

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# Opp ortuniti es for the PBPK/PD



# Lin ked Model to Assist wi th Exposure Question s Raised at

2012 SAP

# Dose Reconstruction for Columbi a Study

• Goal

- to transparently make the best use of the data on expos u res



# • Acc ess to raw data is very important

– Val ue of ass ess me nt wil l be limi ted by the lack of acc ess to expos ure data

• Priv acy of partici pants can be protected (acc ess to personal identi fiers are not needed)

P ag e 11

# Capabili ties Needed

• PBP K model of maternal and fetal bl ood lev els for late stage pregnancy



# • Oral, de rmal, and inhalati on routes of exposure

• Abi li ty to track indiv idual s for periods of 30 or more days

# Provide a Framework to Mak e the Best 

# Assessment of Exposu re Possib le

• A PB PK mode l c oul d s erve as a framework to in tegrate al l o f the ex pos ure - relate d da ta for an in di vi dual

– Cord b lo od , m at ern al bl oo d, ai r m on it ori ng , an d m econ iu m

– Tim in g of m ea s ure m en ts rel at ive to on e an ot he r

– Pe s ti c id e us e da ta in th e ho m e

– Cha racteri s ti c s o f th e ho m e



### – Ti m e o f yea r



## • Goal woul d be to us e al l o f the data to mak e a predic tio n of the co nc entrati on of ch lo rpyrifos in feta l and maternal bl ood at the tim e the mothe r le ft her home



## • This v al ue c oul d be us ed in regres s io n mod el s for v ario us effe c ts

# Clarify How Exposures Occurred

• Were bl ood le vels hi ghe r in the reside nces then in the hospi tal?

• Was t he major r oute of exposu re in hal ati o n, dermal, or oral?



# • Di d the route vary across in di vid u als?

• What wa s the contributio n of di et before and aft er 200 1?

• What impact wo ul d variatio n in route have on measured bl ood le vels?

# Improve the U nderstanding of Exposures

• Re move certain con founding factors

– Impac t of va riati on o f tim e si nc e la st resi dent ia l ex pos ure

– Impac t of va riati on i n bl ood ch emi st ry that co ul d affec t se rum le ve ls

– Resi dent ia l m obi li ty (did the mothe r mov e s in ce the firs t trimes ter?)



# • Provi de a check on the dose estimates

– Predi ct the dai ly dos es to the mothe r and co mpare the dos es to thos e predic ted b y EP A’ s resi dent ia l S OPs

# Inve stiga te Relatio nshi p of Biomonit oring data to 

# Historical Exposures

• De monstr ate if bi omoni toring data can estimate hi stor ical exposu res 

# and if so how far ba ck?

– Cr eate lo ngi tudi nal mode ls of aggrega te ex pos ure

– Cali brate the mode ls with the bi omon ito ring data



## – Dete rmin e c orrelat io ns bet ween s amp le d l ev el s and ea rli er ex pos ures



# • De term in e if biomoni torin g data can be used to predict categorie s of exposu re to chlo rpyr ifos

– Neve r ex pos ed

– Li mit ed pote nti al for ex pos ure

– Large pote nti al for ex pos ure