EPA Questions to Dow AgroSciences concerning ethical conduct of chlorpyrifos 

study by Nolan et al. (1982) 

The attached questions were transmitted to Dow AgroSciences on 29 April 2009 

Nolan, R.; Rick, D.; Freshour, W.; and Saunders, J. (1982) Chlorpyrifos: 

Pharmaco-kinetics in Human Volunteers Following Single Oral and Dermal 

Doses. Unpublished study prepared by Dow Chemical Co. Biomedical 

Research Laboratory. 28 p. MRID 00124144. 

Subjects were six healthy male Caucasians age 27-50 obtained by public advertisement 

and screened for general good health by a physician not otherwise involved in the 

research. (p. 4) 

All “were briefed and admitted to the study after providing their written informed 

consent.” (p. 4) 

No other information is provided relevant to a review of the ethical conduct of this study. 

Questions: 

• What did the public advertisement say? 

• What pool did the subjects come from? Of what population were they 

representative? 

• Was there any connection between any of the subjects and any of the researchers, 

or other interested parties? 

• What were candidates told in the briefing? 

• What did the consent form say? What did the subjects consent to? 

• Were subjects paid to participate? 

• Was there any independent oversight of the ethical conduct of the research? 

Perhaps Dow could find answers in their archive to at least some of these questions? 
From: "Racke, Kenneth (D)" <kracke@dow.com> 

To: Tom Myers/DC/USEPA/US@EPA 

Cc: Karen Santora/DC/USEPA/US@EPA 

Date: 05/06/2009 01:23 PM 

Subject: RE: Ethics Questions concerning Chlorpyrifos Studies 

Tom, 

Regarding the human volunteer study questions posed by John Carley which you 

forwarded, a hard copy reply will be coming via courier. In addition, have 

summarized below relevant points and also appended the reply documents of 

interest. Please forward to John Carley and let me know if additional questions 

arise. 

By the way, it would be helpful to know more about the HED rationale for 

bringing these studies to the HSRB at this time. Can you provide more details 

or ask HED to do so? Also, what is the complete list of studies to be evaluated 

by HSRB? Only Kisiscki, Nolan, and Coulston or others also? Finally, if there 

are any other ways EPA suggests we help support this HSRB please let me know. 

------------------------------------------------------------------------ 

First, regarding the Nolan et al. (1982) study (MRID 00124144), submitted to EPA 

on October 22, 1982, I append a summary which provides answers to the recent 

questions posed by the Agency. These answers were developed following an 

examination of the raw study file in the Dow archives. 

Second, regarding the Coulston et al. (1972) study (MRID 00095175), I can 

confirm that there is only one chlorpyrifos-related human volunteer study report 

authored by Coulston. In 1971 Coulston et al. reported on chlorpyrifos 

experiments in rodents, dogs, and primates (MRID 00043244) which were completed 

in advance of the human work. Since final reports for both the Coulston et al. 

(1971) study in animals and Coulston et al. (1972) study in human volunteers 

appear to have been submitted to EPA on more than once occasion, this may have 

led in part to confusion. The listing below clarifies the two main Coulston et 

al. studies with respect to MRID's, study report citations, and study topics: 

MRID 00043244 

Coulston, F.; Goldberg, L.; Abraham, R.; Bentiz, K.F.; Griffin, T.B.; Norvell, 

M. (1971) "Final Report of Safety Evaluation and Metabolic Studies on 

Dowco 179 (IN 151)." Institute of Experimental Pathology and Toxicology, 

Albany Medical College. Unpublished report dated March 18, 1971. 

Study of chlorpyrifos effects and metabolism in mice, rats, dogs, and 

Monkeys Submitted to EPA July 29, 1971; resubmitted September 18, 1980 

MRID 00095175 

Coulston, F.; Golberg, L.; Griffin, T. (1972) "Safety Evaluation of DOWCO 179 in 

Human Volunteers." Institute of Experimental Pathology and Toxicology, 

Albany Medical College. Unpublished report dated March 1972. 

Study of chlorpyrifos effects in human volunteers Submitted to EPA August 28, 

1972; resubmitted June 23, 1994 

With respect to the questions posed by EPA related to recruiting of volunteers 

for the Coulston et al. (1972) human volunteer study, we do not have detailed 

information in the existing study file to fully answer them. However, I am 
sending the Agency two documents which provide further background on the ethical 

conduct of this particular study. The first document is a 1999 letter from lead 

investigator Dr. Fred Coulston explaining the background for the human volunteer 

study, and the second document is a 2000 memo from Dr. Bill Chen and Dr. Joel 

Mattson of Dow AgroSciences concerning ethical and scientific considerations of 

the human volunteer study. 

Best regards, 

Ken 

Kenneth D. Racke, Ph.D. 

Dow AgroSciences 

Regulatory Sciences and Government Affairs 

9330 Zionsville Road, Bldg 308/2E 

Indianapolis, IN 46268 USA 

Phone: +1 317 337 4654 
Q&A on the Nolan et al. (1982) Study 

Nolan, R.; Rick, D.; Freshour, W.; and Saunders, J. (1982) “Chlorpyrifos: Pharmacokinetics in Human Volunteers Following Single Oral and Dermal Doses.” Unpublished 

study prepared by The Dow Chemical Company, Biomedical Research Laboratory. 28 p. 

MRID 00124144. 

Questions received from the U.S. EPA on April 28, 2009 and answers provided May 

6, 2009 by Dow AgroSciences after reviewing the raw data file for the study. 

Q1. What did the public advertisement say? 

A1. A questionnaire was sent to employees within The Dow Chemical Company 

Midland, Michigan location inquiring of their interest in volunteering for a chemical 

metabolism study. This specific questionnaire is not part of the study file, but was 

referred to in a letter sent to potential volunteers in which the metabolism study was 

identified as involving chlorpyrifos and inquiring as to whether they would still be 

interested in volunteering. 

Q2. What pool did the subjects come from? Of what population were they 

representative? 

A2. The pool of subjects was the ranks of salaried employees of the Midland, Michigan 

location of The Dow Chemical Company. The population they represented was healthy 

male Caucasian volunteers. 

Q3. Was there any connection between any of the subjects and any of the researchers, or 

other interested parties? 

A3. All volunteers were employees of The Dow Chemical Company Midland, Michigan 

location. 

Q4. What were candidates told in the briefing? 

A4. They were each given a copy of the protocol one week prior to meeting for the 

briefing. Essential features of the study were gone over and time allotted for questions. 

Topics covered during the briefing included: 

• Study objective – Define the pharmacokinetics of chlorpyrifos in male volunteers 

following a single oral and two dermal doses. 

• What chlorpyrifos is and background metabolism data. 

• A summary of the pilot and what participation in the study would involve – physician 

exams, what they will be asked to take and how they will be administered, collection 

of urine and blood specimens, abstaining from all drugs, collection of a 48 hour post 

dosing fecal sample, cholinesterase determination, analysis of samples. 

• Benefits of participation (i.e. benefit to science and will provide meals while at 

medical for sample collection but no money, gifts, or promotions) and the risks (i.e., 

Page 1 
venipuncture, expected to produce some depression of plasma cholinesterase but 

should not depress RBC cholinesterase or produce clinical signs of cholinesterase 

depression). 

• Certification of Volunteers (identity of volunteers is unknown when reported) and 

disposition of data resulting in a company report and could be submitted in for 

publication in a scientific journal. 

The volunteers were also informed that participation was entirely voluntary and they may 

refuse to participate or withdraw at any time and for any reason. If they had questions 

during the course of study they were advised to contact either Dr. Rich Nolan (study 

director) or James Saunders. Any adverse effects should be reported to either of the 

above or Dr. Fred Brenner. 

Q5. What did the consent form say? What did the subjects consent to? 

A5. The information included on the consent form utilized with the volunteers is 

reproduced below: 

Informed Consent 

PHARMACOKINETICS OF CHLORPYRIFOS IN HUMAN VOLUNTEERS 

I, _________, being ____ years of age hereby give my informed consent to participate in 

a study of chlorpyrifos phamacokinetics on the basis of the following: 

The nature and purpose of the study have been explained to me. 

The risks, discomforts and inconveniences attendant to the study have been described. 

I understand that the benefits of this study are to science, and that participation in this 

study will not be of any direct personal benefit. 

I have read the protocol, had full opportunity to ask any questions about the study and 

am satisfied with the answers given to my inquiries. 

I have been told that I am free to withdraw my consent at any time, and that no prejudice 

will result if I choose to withdraw. 

I have been told that The Dow Chemical Company will assume financial responsibility 

for any compound-related physical injury resulting from or in the course of this study. 

Signed:_______________/_______________ 

Name Date 

Witnessed:____________/________________ 

Name Date 

You are free to refuse to participate and to withdraw from experiments already begun 

and such refusal will not adversely influence future treatment at this institution. 

DOW CONFIDENTIAL INFORMATION 

Page 2 
Q6. Were subjects paid to participate? 

A6. The subjects were volunteers and they were not paid to participate. 

Q7. Was there any independent oversight of the ethical conduct of the research? 

A7. The “Committee to Review Grants for Clinical Research and Investigation involving 

Human Beings” at the University of Michigan Medical Center provided independent 

oversight of the ethical conduct of the research. 

Page 3 
From: "Racke, Kenneth (D)" <kracke@dow.com> 

To: Tom Myers/DC/USEPA/US@EPA 

Cc: Karen Santora/DC/USEPA/US@EPA 

Date: 05/08/2009 01:23 PM 

Subject: RE: Chlorpyrifos - ethics - additional information 

Tom, 

Thanks for your reply and look forward to receiving the additional information 

next week from you on the HSRB plan. 

Regarding the additional questions from John Carley (please forward to his 

attention): 

1. For the materials provided earlier to answer questions on the Nolan et al. 

(1982) study, Dow is not claiming any CBI status for the information provided to 

the Agency. The "Dow Confidential" designation was included on the original 

informed consent form so it was part of the answer we provided to EPA Question 5 

("What did the consent form say? What did the subjects consent to?"). There is 

no claim of CBI we are making but rather informing the Agency what the consent 

form had written on it. 

2. Regarding the question for additional information on the Nolan et al. (1982) 

study see the response below and appended documents (electronic copy sent now - 

hard copy to follow): 

Q. "Dow's response to Q7 reports that the research was overseen by the 

'Committee to Review Grants for Clinical Research and Investigation involving 

Human Beings' at the University of Michigan Medical Center. Please ask Dow to 

provide any available documentation of this review or of its conclusions." 

A. Upon reviewing further the study file for the Nolan et al. (1982) study, it 

appears that two ethical reviews of the protocol prior to study initiation were 

completed. The first was a review by the Dow Human Health Research Review 

Committee, which reviewed the protocol and approved on December 3, 1981. The 

second was a review of the protocol by the University of Michigan Ethical Review 

Committee (The Committee to Review Grants for Clinical Research and 

Investigation Involving Human Beings) which approved on December 10, 1981. 

Copies of the only documentation we have in the study file associated with the 

Dow and U of M ethical reviews are appended. 

Best regards, 

Ken 

Kenneth D. Racke, Ph.D. 

Dow AgroSciences 

Regulatory Sciences and Government Affairs 

9330 Zionsville Road, Bldg 308/2E 

Indianapolis, IN 46268 USA 

Phone: +1 317 337 4654 
-----Original Message----- 

From: Myers.Tom@epamail.epa.gov [mailto:Myers.Tom@epamail.epa.gov] 

Sent: Wednesday, May 06, 2009 5:56 PM 

To: Racke, Kenneth (D) 

Subject: Chlorpyriofs - ethics 

Ken, 

Thank you for the information on the human studies so far. I received the 

following message from John today. 

I will get back to you on your questions in your email next week. 

Tom 

From John: 

Thanks very much. These additional documents will be very helpful to me in my 

ethics reviews, and are likely to be of interest to HED as well. 

I have two follow-up questions specific to the attached "Nolan_Response2009" 

file: 

• At the bottom of the second page there is a banner reading "DOW 

CONFIDENTIAL INFORMATION." To what does this confidentiality claim apply? 

If the intention was to assert a claim of confidentiality covering all or 

part of this document, it should be substantiated; if necessary, I can 

explain what substantiation entails. But if that wasn't the intention--

if, for example, this was included in the quoted source document, but 

doesn't indicate a claim of confidentiality for this submission--then 

substantiation would not be needed. I hope no CBI claim was intended; I 

would like to be able to share this document (or a replacement that 

doesn't include the problematic claim of confidentiality) with the HSRB. 

Please ask Dow to clarify this, and let me know if an explanation of 

substantiation is needed. 

• Dow's response to Q7 reports that the research was overseen by the 

“Committee to Review Grants for Clinical Research and Investigation 

involving Human Beings" at the University of Michigan Medical Center. 

Please ask Dow to provide any available documentation of this review or of 

its conclusions. 

Please thank Dow for their very quick response to my questions, and express my 

hopes for a quick response to these additions.