Ethical standards of studies involving human subjects.

In their letter, Sass and Needleman argue against the regulatory use of data from human subjects on both scientific and ethical grounds. The studies they evaluated were conducted in accordance with the same ethical standards that guide all studies involving human volunteers that are conducted by the federal government. Sass and Needleman claim, however, that these studies were not ethical and should not be used. We would like to address a common concern regarding the ethical conduct of these types of studies.

In a recent publication (Charnley and Patterson 2003), we reported the results of a study in which we sought to answer the question of ethical conduct of clinical pesticide testing performed since 1990 by evaluating whether those studies, performed according to good clinical practice guidelines [Food and Drug Administration (FDA) 1997]), provided volunteers with the same protections afforded volunteers in similar studies conducted by the federal government according to the ethical guidelines provided by the "Federal Policy for the Protection of Human Subjects," generally known as the "Common Rule" [Department of Health and Human Services (DHHS) 2001].

The Common Rule (DHHS 2001) was adopted by more than a dozen agencies by 1991, including the U.S. Environmental Protection Agency (EPA), the Department of Energy, the Consumer Product Safety Commission, the Department of Agriculture, the DHHS, the National Science Foundation, and other departments that conductor fund research involving human subjects. The U.S. EPA has chosen not to make the protections of the Common Rule legally applicable to privately sponsored studies of regulated substances.

We evaluated the documentation from 15 recent human studies of 12 insecticides conducted at four clinical laboratories provided to us by the pesticide manufacturers, including those addressed by Needleman and Sass. The studies we evaluated comprised all of the oral pesticide studies submitted to the U.S. EPA since 1996 and before the U.S. EPA suspended the use of human data (along with one earlier study) for the purpose of tolerance setting. There were some cases for which we could not verify compliance with certain Common Rule elements because the documentation was unavailable; however, based on our evaluation, it is apparent that the studies we reviewed were conducted in a manner substantially consistent with the fundamental protections of the Common Rule: voluntary participation, informed consent, and review by an ethical committee or institutional review board (which would have considered and discussed any potentially "scientifically misleading" protocols).

From this subset of studies, it is evident that the general practice among the clinical testing laboratories currently employed by pesticide manufacturers is to conduct studies in accordance with the two most commonly followed ethical guidelines for human studies by nongovernmental entities, the Declaration of Helsinki (World Medical Association 2002) and the international guidelines for good clinical practice (FDA 1997). In addition, although we noted some deviations from Common Rule specifics, we found that the reviewed studies were in substantial compliance with Common Rule provisos. In the context of the concerns raised by Sass and Needleman, it is of interest to point out that good clinical practice specifies that institutional review board approval be contingent upon scientifically sound study design and purpose; the Common Rule includes no such requirement.

Standard toxicity testing protocols using laboratory rodents are considered adequate for establishing sale exposure limits for most chemicals under most conditions. Nonetheless, because rodents are not perfect human surrogates, regulatory and other organizational guidance for establishing such exposure limits give priority to results obtained from observations of humans. When human observations are unavailable, results from laboratory animals are preferred but are treated as uncertain. A recent study (Dourson et al. 2001) has suggested that, in some cases, failure to use human data in regulatory safety assessment may threaten public health because using only animal data would lead to less stringent exposure limits for some chemicals than those that would have been derived on the basis of human data. When that is the case, failure to consider ethically obtained human data for setting limits on pesticide or other chemical exposures would itself be unethical.

Perhaps some of the concerns about the ethical conduct of studies conducted by clinical laboratories for third parties and submitted to the U.S. EPA might be avoided if application of the Common Rule were extended to such studies of if the recommendation of the National Bioethics Advisory Commission for a national oversight system for all research involving human subjects were implemented. In any case, our evaluation has shown that recently conducted industry-sponsored pesticide clinical studies were conducted according to the same ethical standards adhered to by federally conducted or funded studies. Needleman and Sass's contention that those studies were conducted unethically is not supported by the available data.

The article by Charnley and Patterson (2003) was partially supported by the pesticide industry, which wanted an independent review of its studies. Because they did not receive payment for writing this letter, the authors declare they have no competing financial interests.

REFERENCES

Charnley G, Patterson J. 2003. Review of procedures for protecting human subjects in recent clinical studies of pesticides. Regul Toxicol Pharmacol 38:210-223

DHHS. 2001. Federal Policy for the Protection of Human Subjects (Basic DHHS Policy for Protection of Human Research Subjects). 45CFR46. Rockville, MD:Department of Health and Human Services, Office for Human Research Protections. Available: http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm [accessed 10 February 2004].

Dourson M, Andersen M, Erdreich L, MacGregor J. 2001. Using human data to protect the public's health. Regul Toxicol Pharmacol 33:234-256

FDA (Food and Drug Administration). 1997. International Conference on Harmonisation; Good Clinical Practice: Consolidated Guideline; Availability. Fed Reg 62: 25691-25709. Available: http://frwebgate.access.gpo.gov/cgi-bin /getdoc.cgi?dbname=1997_register&docid=fr09my97-190 [accessed 9 February 2004].

World Medical Association. 2002. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Available: http://www.wma.net/e/policy/b3.htm [accessed 1 July 2003].

Gail Charnley

HealthRisk Strategies

Washington, DC

E-mail: [e-mail]

Jacqueline Patterson

Toxicology Excellence for Risk Assessment

Cincinnati, Ohio