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Kisicki, J. (2009) “Re: Ethics Review of Chlorpyrifos Human Toxicity Study”. 

Unpublished letter dated June, 23, 2009 to K. Racke of Dow AgroSciences, 

responding to EPA Ethics Review of MRID 44811002 dated May 29, 2009. 7 p. 

Anon. (1998) Attachment to June 23, 2009 J. Kisicki letter to K. Racke with 

subjects de-identified. Unpublished Screening Logs dated September 21, 1998 

and October 6, 1998, used by MDS-Harris Laboratories in the execution of the 

study reported in MRID 44811002. Submitted to EPA on July 1, 2009. 18 p. 

 

I have reviewed the documents cited above, including the study report, the previous EPA 

ethics reviews, the 2009 report from the Human Studies Review Board, and the additional 

information submitted by Dow Agrosciences in connection with the HSRB’s 2009 review of the 

study. Based on the HSRB’s recommendations and my independent consideration of the relevant 

documents, I have concluded that EPA may rely on this study in actions under the Federal 

Insecticide, Fungicide, or Rodenticide Act (FIFRA) or the Federal Food, Drug, and Cosmetic 

Act (FFDCA). 

Background 

May 2009 ethics review by John Carley, EPA 

The ethical conduct of this research was reviewed by EPA in May 2009 (memorandum 

by John Carley to Anna Lowit dated May 29, 2009). In that review, Carley raised a number of 

concerns, the most significant of which related to the consent process. In particular, Carley 

believed that some subjects may have undergone screening procedures, such as providing 

medical history, submitting to a physical examination, or providing blood and urine samples, 

prior to providing informed consent. Below is an excerpt from Carley’s review. 

“As noted earlier in this review, by the time of check-in—October 1, for phase I—

subjects had given blood and urine samples, provided medical and surgical history, and 

been subjected to a physical examination at screening, had visited the clinic 48 h before 

check-in to obtain urine collection containers, and had been collecting their urine for two 

days. Notwithstanding that the QA Unit reported study initiation on October 1...in my 

judgment the subjects should all have provided written informed consent at or before the 

time of screening, which for phase I subjects was reported in Appendix 4.6.1 ... as 

September 23 or 30.” (p. 6-7) 

Primarily on the basis of his belief that some subjects may have given blood and/or urine 

samples and personal information prior to providing informed consent, Carley concluded that the 

consent process was significantly deficient relative to the standards that prevailed at the time the 

study conducted (FDA regulations at 21 CFR 50.20 and 50.25). He also concluded that the 

consent process did not meet the requirements in FIFRA §12(a)(2)(P) for fully informed, fully 

voluntary participation because he felt that study initiation may have preceded consent for some 

subjects. 
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Other concerns about the consent process that contributed, to a lesser extent, to Carley’s 

conclusions related to the content of the consent form. The following concerns were detailed in 

Carley’s memo: 

“The consent form includes extensive technical language taken directly from the protocol 

which was unlikely to be understood by subjects. The Flesch-Kincaid Grade Level score 

for the first full paragraph of the consent form is 17.7, equivalent to an advanced graduate 

student. The form is poorly organized and difficult to follow, shifting suddenly from the 

first to second persons and back again, and including both dire warnings of “very serious 

consequences for [subject’s] well-being” and reassurances that unidentified MDS Harris 

medical consultants think the risks involved should not deter the subjects from 

participating.” (p. 7) 

 Carley’s May 2009 ethics review was provided to the study sponsor and the HSRB in 

May 2009; the study was reviewed by the HSRB at its public meeting on June 24, 2009. 

Additional Information Provided by the Study Sponsor prior to HSRB Meeting 

On June 23, 2009, one day prior to the HSRB’s June 24th meeting, Dow Agrosciences 

submitted a copy of a letter from Dr. James C. Kisicki (the study director) to Kenneth D. Racke 

of Dow Agrosciences. In the letter, dated June 23, 2009, Dr. Kisicki provided details about the 

candidate screening process that were not clear in the study report, and he addressed the issues 

discussed in Carley’s May 29, 2009, ethics review. A copy of Dr. Kisicki’s letter was provided to 

the HSRB members, and the description in the letter of the candidate screening procedure was 

read aloud to the HSRB during the meeting. 

The relevant portions of the letter are as follows: 

“In 1998, when this study was conducted, our internal standard operating procedure 

(SOP) for screening was as follows: 

When potential subjects arrived at the research facility, they were given a packet 

of information about the study. The packet contained a copy of the IRB-approved 

Informed Consent Form. Prior to any screening procedures, the subjects were 

required to sit and listen to an audio tape of the Informed Consent Form and 

follow along with the written document. An associate was available to answer any 

questions. Documentation is available of the subject signing a log indicating that 

they had listened to the audio tape of the Informed Consent Form, they 

understood it, and that they had no further questions.” (p. 5-6) 

HSRB Meeting 

The study was reviewed by EPA’s Human Studies Review Board at its public meeting on 

June 24, 2009. During the meeting, Carley presented his review and conclusions. The Board 

discussed the consent process and other aspects of the study thoroughly, and ultimately indicated 

disagreement with the conclusion in the Carley review that the study was significantly deficient 

relative to the standards governing its ethical conduct. 
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Additional Information Provided by the Study Sponsor after the HSRB Meeting

On July 1, 2009, approximately one week after the HSRB meeting, copies of the subject 

sign-in logs referenced in the June 23rd letter, with the signatures redacted, were submitted to 

EPA and provided to the HSRB members for their consideration in developing their 

recommendations and drafting the HSRB report. 

 

HSRB’s Report 

In its report dated October 26, 2009, the Board concluded that there neither was clear and 

convincing evidence that the study was fundamentally unethical, nor clear and convincing 

evidence that the study was significantly deficient relative to the ethical standards prevailing at 

the time the research was conducted. 

Not fundamentally unethical. The HSRB concluded that the Kisicki study was not 

fundamentally unethical because it was not intended to seriously harm participants, nor was there 

a failure to obtain informed consent. The Board’s reported stated: 

“...the information contained therein [in the supplementary material provided by Dow] 

do not meet the evidentiary standard of clear and convincing evidence that the study was 

fundamentally unethical or significantly deficient relative to the ethical standards 

prevailing at the time. It is possible, for example, that the deficiencies noted in the logs 

are the result of sloppy record keeping rather than a serious impaired participant 

recruitment, consent and screening process.” [p. 24 of 40] 

Not significantly deficient. With regard to determining whether a study was significantly 

deficient relative to the ethical standards prevailing at the time the research was conducted, the 

standard applied by the HSRB was whether or not any ethical deficiencies identified could have 

resulted in serious harm based on knowledge available to researchers at the time the study was 

conducted, or whether the information provided to study participants could seriously impair 

informed consent. The HSRB concluded that there was not no clear and convincing evidence that 

the study was significantly deficient. Based on toxicological data that was available at the time 

for chlorpyrifos, study participants were unlikely to be at risk for serious side effects given the 

exposure doses used in the study. Furthermore, from the entirety of the evidence before the 

HSRB, the Board concluded that that informed consent process was not seriously impaired. 

Applicable Standards 

Standards Applicable to the Conduct of the Research 

This research was initiated in 1998, before EPA’s amended Rule for the Protection of 

Human Subjects of Research became effective on April 7, 2006. It was conducted in the United 

States by a Contract Research Organization laboratory, MDS Harris, and overseen by the 
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laboratory’s in-house Institutional Review Board. The standards that were applicable to the 

conduct of this study are the U.S. Food and Drug Administration rules relating to the protection 

of human subjects, as codified at 21 CFR parts 50 and 56, as well as the Declaration of Helsinki 

(as amended in 1996). FIFRA §12(a)(2)(P) also applied to this research because it involved the 

use of a pesticide. 

Standards Applicable to EPA’s Reliance on the Research 

EPA submitted this study for review by the Human Studies Review Board (HSRB) in 

2009 because 40 CFR §26.1604 requires HSRB review for pre-2006 studies intended for EPA 

reliance that were conducted for the purpose of identifying or measuring a toxic effect. This 

study meets those criteria. 

The Agency’s rule (40 CFR part 26 subpart Q) defines standards for EPA to apply in 

deciding whether to rely on research—like this study—involving intentional exposure of human 

subjects. The applicable acceptance standards from 40 CFR part 26 subpart Q are these: 

§26.1703. Except as provided in §26.1706, EPA must not rely on data from any research 

subject to this subpart involving intentional exposure of any human subject who is a 

pregnant woman (and therefore her fetus), a nursing woman, or a child. 

§26.1704 EPA must not rely on data from any research subject to this section if there is 

clear and convincing evidence that: (1) The conduct of the research was fundamentally 

unethical (e.g., the research was intended to seriously harm participants or failed to obtain 

informed consent); or (2) The conduct of the research was deficient relative to the ethical 

standards prevailing at the time the research was conducted in a way that placed 

participants at increased risk of harm (based on knowledge available at the time the study 

was conducted) or impaired their informed consent. 

Compliance with Applicable Standards 

All of the subjects in this study are age 19 or older. The thirty female subjects were not 

pregnant. Therefore, this research did not involve intentional exposure of any pregnant or 

nursing female subjects or any children. EPA’s reliance on the research is therefore not 

prohibited by 40 CFR §26.1703. 

The subjects provided written informed consent and the protocol underwent independent 

ethics review and approval. Based on these facts, and the absence of any information suggesting 

that the research was fundamentally unethical or intended to harm participants, I conclude that 

reliance on the research is not prohibited by 40 CFR §26.1704(1). This conclusion agrees with 

the recommendations of the HSRB in its October 2009 report. 

I also conclude that there is no clear and convincing evidence that this research was 

deficient relative to the ethical standards prevailing at the time in a way that placed participants 

at increased risk of harm (based on knowledge available at the time the study was conducted) or 

impaired their informed consent. Based on toxicological data that was available at the time, 
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subjects were unlikely to be at risk of harm given the exposure dose used in the study. 

Furthermore, there is no clear and convincing evidence that any subject did not provide informed 

consent, or that the consent process was seriously impaired. Based on these facts, I conclude that 

the study was not deficient relative to the prevailing ethical standards in a way that placed 

participants at increased risk of harm or impaired their informed consent. Therefore, reliance on 

this study is not prohibited by 40 CFR §26.1704(2). This conclusion agrees with the 

recommendations of the HSRB in its October 2009 report. 

Conclusion 

I find no barrier in law or regulation to reliance on MRID 44811002 in EPA actions taken 

under FIFRA or §408 of FFDCA.