EPA Questions to Dow AgroSciences con cerning ethical conduct of chlorpyrifos study by Nolan et al. (1982)

The attached questions were transmitt ed 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 Unpublished study prepared by Dow Chemical Co. Biomedical Research Laboratory. 28 p. MRID 00124144.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 heal thy 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 st udy 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 fr om? Of what population were they representative?

• Was there any connection between any of th e 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 arch ive 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.

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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 amsending 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 4654Q&A on the Nolan et al. (1982) Study

Nolan, R.; Rick, D.; Freshour, W.; and Saunde rs, J. (1982) “Chlorpyrifos: Pharmacokinetics in Human Volunteers Following Singl e 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 employ ees within The Dow Chemical Company Midland, Michigan location inquiring of thei r 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 inqui ring 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 th e 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 betw een 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 to ld in the briefing?

A4. They were each given a copy of the pr otocol one week prior to meeting for the briefing. Essential features of the study we re 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 a nd two dermal doses.

• What chlorpyrifos is and background metabolism data.

• A summary of the pilot and what particip ation in the study woul d involve – physician exams, what they will be asked to take and how they will be administered, collection of urine and blood specimens, abstaining fr om 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, gi fts, or promotions) and the risks (i.e.,

Page 1venipuncture, expected to produce some de pression 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 comp any report and could be submitted in for publication in a scien tific journal. The volunteers were also informed that partic ipation was entirely vo luntary and they may refuse to participate or wit hdraw at any time and for any r eason. If they had questions during the course of study they were advise d to contact either Dr. Rich Nolan (study director) or James Saunders. Any adverse e ffects 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 CHLORPYR IFOS IN HUMAN VOLUNTEERS

I, _________, being ____ years of age hereby give my informed consent to participate in a study of chlorpyrifos phamacokinet ics 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 ar e 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 resulti ng 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 2Q6. Were subjects paid to participate?

A6. The subjects were volunteers and th ey 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 C linical Research and Investigation involving Human Beings” at the University of Mich igan Medical Center provided independent oversight of the ethical conduct of the research.

Page 3From: "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.