Study criticisms unjustified.
We disagree with their assessment for several reasons. First, human data are recognized by regulatory agencies and the scientific community as the most relevant data for assessment of human risk of harm [International Programme on Chemical Safety (IPCS) 2002; U.S. Environmental Protection Agency (EPA) 1989, 1993, 1994, 2002, 2003; World Health Organization (WHO) 1994, 2001). Sass and Needleman do not provide any authoritative reference for the automatic dismissal of third-party human data they propose. Data from laboratory animals used in toxicologic assessments are useful, but as a large cooperative study by the pharmaceutical industry has recently shown, animal data are prone to false-negative and false-positive results, significantly limiting their ability to predict human toxicities (Olson et al. 2000).
The validity and ethicality of the data from any study are not determined by the identity of the study's sponsor, the potential uses of the material being tested, or the author's affiliation; to do so would be arbitrary and without scientific merit. Studies should be considered if they are validly designed and implemented according to scientific and ethical standards of their time. The study on dichlorvos (AMVAC 1997), cited by Sass and Needleman, was conducted in accordance with the Declaration of Helsinki, including all amendments up to and including the Hong Kong revision of 1989 (World Medical Association 2002). Further, it followed the U.K. Principles of Good Laboratory Practice (Her Majesty's Stationery Office 1999), it was performed in accordance with the Organisation for Economic Co-operation and Development (OECD) Principles of Good Laboratory Practice (OECD 1998) and the requirements of the European Commission (1986, 1988). The fact that the AMVAC study complied with these practices was stated in the report (AMVAC 1997), but this was not mentioned by Sass and Needleman. Both the ethics and the scientific validity are established by meeting such stringent requirements.
Sass and Needleman incorrectly state that cholinesterase inhibition was the only biological end point measured in the study (AMVAC 1997). Signs and symptoms were obtained from the individuals on a daily basis, and the study was conducted under medical supervision requiring daily visits to the laboratory by each participant. In addition, medical assessments, including clinical chemistries, hematology, blood pressure, electrocardiograms, and lung function tests, were carried out before and after the study. We are not aware of any studies that demonstrate an effect more sensitive than blood cholinesterases at very low doses of dichlorvos. Sass and Needleman do not cite any scientific study in support of their allegation that some adverse effect would have been missed at the dose tested.
It is the regulatory agencies and the scientists that work for them who evaluate study results and make regulatory conclusions based upon them, not the laboratory performing the work, the study director, or the company sponsoring the study.
The AMVAC study shows a slight effect on red blood cell (RBC) cholinesterase that develops over the course of the study with maximal mean group inhibition of 16% measured at day 18, the last day RBC cholinesterase was measured (AMVAC 1997). The first sentence of the "Discussion" (AMVAC 1997) clearly states:
The results from this study showed that multiple oral dosing of dichlorvos (7 mg/kg, approximately 0.1 mg/kg/day) for 21 days caused some inhibition of erythrocyte cholinesterase activity.
This statement is consistent with the U.S. EPA review of the study (U.S. EPA 1998), AMVAC's interpretation of the data (AMVAC 1997), and the findings from other published studies (Funckes et al. 1963; Menz et al. 1974; Slomka and Hine 1981).
RBC cholinesterase values vary day to day, and any lower value cannot be assumed to be caused by the study chemical. In the AMVAC dichlorvos study (AMVAC 1997), before exposure began, RBC cholinesterase varied [greater than or equal to] 20% day to day in the same individuals. In the controls, variability was apparent during the study; one individual had a statistically significant lower RBC cholinesterase on day 16 of the study but had not been exposed to dichlorvos.
The "Discussion" (AMVAC 1997) addressed how the slight level of RBC inhibition observed during the study might be interpreted in light of the lack of any adverse clinical findings. The conclusion did not attempt to "dismiss the results," and the interpretation regarding the biological significance of effects was undertaken in the context of international guidelines and published data on the significance of RBC cholinesterase inhibition. The WHO has stated that RBC cholinesterase inhibition < 25% is evidence of exposure but not of a hazard (WHO 1986). Similar interpretations have been published that indicate RBC cholinesterase inhibition > 30% demonstrates an adverse effect (Gallo and Lawryk 1991; Lotti 2001).
The AMVAC study (AMVAC 1997) did not attempt to determine the response from a diverse population, and no attempt was made to state this as an objective or a conclusion. However, there are published studies showing the response in a variety of patients in clinical studies conducted to evaluate the possible medicinal use of dichlorvos as a treatment for intestinal parasites (Cervoni et al. 1969; Pena Chavarria et al. 1969). These studies have not shown an unusual increase in sensitivity to the substance.
Last, regarding the criticism of the limited study size, the AMVAC study (AMVAC 1997) is only one of hundreds of health studies of dichlorvos in animals and humans. The available health data on any substance should be evaluated as a whole when conducting a risk assessment.
In summary, although the AMVAC study (AMVAC 1997) was a relatively small study, the analytical methods used for measuring both the dose of dichlorvos and RBC cholinesterase inhibition were state of the art. The data derived are valid because the study complied with good laboratory practices, good clinical practice, and ethical standards, and should be considered as a part of the available scientific information on dichlorvos.
The authors declare a competing financial interest because they are employed by or are consultants to pesticide-manufacturing companies.
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Ian S. Chart
AMVAC Chemical Corporation
Newport Beach, California
Susan Hunter Youngren
The Acta Group, L.L.C.