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SUMMARY

(In accordance with 40 CFR part 152, this summary is available 

for public release after registration) 

STUDY TITLE

Benchmark Dose Modeling for Cholinesterase Inhibition from Exposure to Chlorpyrifos and 

Chlorpyrifos-Oxon 

DATA REQUIREMENTS

None

AUTHOR(S)

R. Reiss., B. Neal, J. Lamb 

STUDY COMPLETED ON

June 30, 2010 

PERFORMING LABORATORY

Exponent Inc. 

1800 Diagonal Road, Suite 500 

Alexandria, VA 22310 

SPONSOR

Dow AgroSciences LLC 

9330 Zionsville Road 

Indianapolis, Indiana 46268-1054 

LABORATORY STUDY ID

0900956.000 B0T0 06010 
Dow AgroSciences LLC 

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Benchmark Dose Modeling for Cholinesterase Inhibition from Exposure to Chlorpyrifos and 

Chlorpyrifos-Oxon 

SUMMARY

This report presents an analysis of cholinesterase inhibition data for chlorpyrifos and 

chlorpyrifos-oxon. Specifically, benchmark dose (BMD) modeling methodologies are employed 

to estimate possible points-of-departure (PODs) for risk assessment. 

The focus of the analysis is on the Marty and Andrus (2010) study. This study includes 

acute dose tests (i.e., single dose) for chlorpyrifos by gavage (pups and adults), milk (pups), and 

diet (adults). Also, acute tests were made for chlorpyrifos-oxon, the principal metabolite of 

chlorpyrifos and the proximal toxic agent, by gavage for pups and adults. Further, repeated dose 

tests were conducted for pups from PND 11-21 and adults for 11 days for both chlorpyrifos and 

chlorpyrifos-oxon via gavage. 

Additionally, literature data were reviewed for additional information on the 

cholinesterase inhibition of chlorpyrifos. Data were analyzed from the following studies: 

Betancourt and Carr (2004); Hoberman et al. (1998a,b); Mattsson et al. (1998, 2000); Maurissen 

et al. (2000); Moser et al. (2006); Timchalk et al. (2006); and Zheng et al. (2000). 

The cholinesterase inhibition data were found to fit well to the EPA recommended dose 

response models, leading to mostly reliable BMD estimates. This was particularly true for the 

Marty and Andrus (2010) study where there were as many as five treated groups for many of the 

tests. Data for both brain and RBC acetylcholinesterase (AChE) were evaluated. 

The biological basis for cholinesterase inhibition was also reviewed. It was concluded 

that brain cholinesterase inhibition provides the most appropriate compartment for establishing 

PODs for risk assessment. 

This is particularly true for chlorpyrifos because of data that demonstrate that the 

NOAEL for peripheral nervous system tissue AChE inhibition is higher than the NOAEL for 

RBC AChE inhibition, and consistent with or higher than that for brain AChE inhibition 

(Marable et al., 2007). 
Dow AgroSciences LLC 

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A meta-analysis was performed between the Marty and Andrus (2010) data and the available 

literature data, accounting for any reliability issues across the datasets. From this analysis, the 

recommended PODs based on the BMDL10 (lower limit of the BMD) for brain cholinesterase 

inhibition are: 

• Acute dose to young or adults: 1.7 mg/kg 

• Repeat dose to young: 0.46 mg/kg/day 

• Repeat dose to adults: 0.55 mg/kg/day 

Comparatively, EPA’s current POD for acute exposures is 0.5 mg/kg. However, the 2008 

Scientific Advisory Panel (SAP) agreed with a revised EPA analysis that the acute POD should 

be 0.1 mg/kg (EPA, 2008). The revised analysis for the SAP came with the caveat that the 

available data were insufficient to adequately characterize the dose-response near the POD. The 

Marty and Andrus (2010) study provides sufficient data at low doses to accurately estimate the 

BMDs. The POD recommendation in this report is the result of more accurate BMD estimations 

with the Marty and Andrus (2010) data and the use of brain cholinesterase inhibition instead of 

red blood cell (RBC) cholinesterase inhibition to establish the POD. 

References

Betancourt, AM; Carr, RL (2004) The effect of chlorpyrifos and chlorpyrifos-oxon on brain 

cholinesterase, muscarinic receptor binding, and neurotrophin levels in rats following early 

postnatal exposure. Toxicological Sciences, 77, 63-71. 

EPA (2008) Science issue paper: chlorpyrifos hazard and dose response characterization. Report 

to the FIFRA Scientific Advisory Panel, August, 2008. 

Hoberman, AM (1998a,b) Developmental neurotoxicity study of chlorpyrifos administered 

orally via gavage to Crl:CD(R)BR VAF/Plus(R) presumed pregnant rats. Argus Research 

Laboratories, Inc., Horsham, Pennsylvania, Laboratory Study No. 304-001, May, MRID 

44556901, 44661001. 

Marable, B.R; Maurissen, J.P.J.; Mattsson, J.L.; Billington, R. (2007) Differential sensitivity of 

blood, peripheral, and central cholinesterases in beagle dogs following dietary exposure to 

chlorpyrifos. Regulatory Toxicology and Pharmacology, 47, 240-248. 
Dow AgroSciences LLC 

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Marty, MS; Andrus, AK (2010) Comparison of cholinesterase (ChE) inhibition in young adult 

and preweanling CD rats after acute and repeated chlorpyrifos or chlorpyrifos-oxon 

exposures. The Dow Chemical Company, MRID 48139301. 

Mattsson, JL; Maurissen, JP; Spencer, PJ; Brzak, KA; Zablotny, CL (1998) Effects of 

chlorpyrifos administered via gavage to CD rats during gestation and lactation on plasma, 

erythrocyte, heart and brain cholinesterase and analytical determination of chlorpyrifos and 

metabolites. Health and Environmental Research Laboratories, The Dow Chemical Co. for 

Dow AgroSciences, August. MRID 44648101. 

Mattsson, JL; Maurissen, JP; Nolan, RJ; Brzak, KA (2000) Lack of differential sensitivity to 

cholinesterase inhibition in fetuses and neonates compared to dams treated perinatally with 

chlorpyrifos. Toxicological Sciences, 53, 438-446. 

Maurissen, JP; Hoberman, AM; Garman, RH; Hanley, T (2000) Lack of selective developmental 

neurotoxicity in rat pups with dams treated by gavage with chlorpyrifos. Toxicological 

Sciences, 57, 250-263. 

Moser, VC; Simmons, JE; Gennings, C (2006) Neurotoxicological interactions of a five pesticide 

mixture in preweanling rats. Toxicological Sciences, 92, 235-245. 

Timchalk, C; Poet, TS; Kousba, AA (2006) Age-dependent pharmacokinetic and 

pharmacodynamic response in preweanling rats following oral exposure to the 

organophosphorus insecticide chlorpyrifos. Toxicology, 220, 13-25. 

Zheng, Q.; Olivier, K.; Won, YK; Pope, CN (2000) Comparative cholinergic neurotoxicity or 

oral chlorpyrifos exposures in preweanling and adult rats. Toxicological Sciences. 55, 124-

132.