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.
AMVAC. 1997. Dichlorvos: A Single Blind, Placebo Controlled, Randomized Study to Investigate the Effects of Multiple Oral Dosing on Erythrocyte Cholinesterase Inhibition in Healthy Male Volunteers. Report No. CTL/P5392. Study No. XH6063. MRID No. 442488-01. Newport Beach, CA:AMVAC Chemical Corporation.
Cervoni WA, Oliver-Gonzalez J, Kaye S, Slomka MB. 1969. Dichlorvos as a single-dose intestinal anthelmintic therapy for man. Am J Trop Med Hyg 18(6):912-919.
European Commission. 1968. 87/18/EEC Council Directive of 18 December 1986 on the Harmonization of Laws, Regulations and Administrative Provisions Relating to the Application of the Principles of Good Laboratory Practice and the Verification of Their Applications for Tests on Chemical Substances. Brussels:European Commission. Available: http://europa.eu.int/smartapi/cgi/sga_doc?smartapi !celexapi!prod!CELEXnumdoc&lg=en&numdoc=31987L0018&model=guichett [accessed 16 December 2003].
--. 1988. 88/320/EEC Council Directive of 9 June 1988 on the Inspection and Verification of Good Laboratory Practice. Brussels:European Commission. Available: http://europa.eu.int/smartapi/cgi/sga_doc?smartapi!celexapi!prod !CELEXnumdoc&lg=en&numdoc=31988L0320&model=guichett [accessed 16 December 2003].
Funckes AJ, Miller S, Hayes W. 1963. Initial field studies in Upper Volta with dichlorvos residual fumigant as a malaria eradication technique. Bull WHO 29:243-248.
Gallo MA, Lawryk NJ. 1991. Organic phosphorus pesticides. In: Handhook of Pesticide Toxicology, Vol 12 (Hayes WJ, Laws ER, eds). San Diego, CA:Academic Press, 917-1123.
Her Majesty's Stationery Office. 1999. Statutory Instrument 1999 No. 3106, Health and Safety, The Good Laboratory Practice Regulations 1999. Available: http://www.hmso.gov.uk/si/si1999/19993106.htm [accessed 16 December 2003].
IPCS. 2002. Report of the Meeting on Bridging the Gap Between Clinical and Regulatory Toxicology. Geneva:International Programme on Chemical Safety. Available: http://www.who.int/pcs/emerg_site/hdi/Bridging_Gap_Final%20Report.pdf [accessed 16 December 2003].
Lotti M. 2001. Clinical toxicology of anticholinesterase agents in humans. In: Handbook of Pesticide Toxicology, Vol 2 (Krieger R, ed). San Diego, CA:Academic Press, 1043-1085.
Menz M, Luetkemeier H, Sachsse K. 1974. Long-term exposure of factory workers to dichlorvos (DDVP) insecticide. Arch Environ Health 28:72-76.
OECD. 1996. OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring Number 1: OECD Principles on Good Laboratory Practice (as revised in 1997). Paris:Organisation for Economic Co-operation and Development. Available: http://www.olis.oecd.org/olis/1998doc.nsf/LinkTo/env-mc-chem(98)17 [accessed 9 February 2004].
Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, et al. 2000. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56-67.
Pena Chavarria A, Swartzwelder JC, Villarejos VM, Kotcher E, Arguedas J. 1969. Dichlorvos, an effective broad-spectrum anthelmintic. Am J Trop Med Hyg 18(6):907-911.
Slomka MB, Hine CH. 1981. Clinical pharmacology of dichlorvos. Acta Pharmacol Toxicol 49 (suppl V):105-108.
U.S. EPA. 1989. Toxicity assessment. In: Risk Assessment Guidance for Superfund (RAGS) Part A. EPA/540/1-89/002. Washington, DC:U.S. Environmental Protection Agency, 7-1-7-23. Available: http://www.epa.gov/superfund/programs/risk/ragsa/ch7.pdf [accessed 18 December 2003].
--. 1993. Reference Dose (RfD): Description and Use in Health Risk Assessments. Washington, DC:U.S. Environmental Protection Agency. Available: http://www.epa.gov/iris/rfd.htm [accessed 16 December 2003].
--. 1994. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. EPA/600/8-90-066F. Washington, DC:U.S. Environmental Protection Agency, Office of Health and Environmental Assessment.
--. 1998. Memorandum from JE Stewart, Registration Action Branch II, to C Scheltema, Risk Characterization and Analysis Branch. Review of Toxicity Studies on DDVP Using Human Volunteers (Data Evaluation Reports for MRID Nos. 44317901, 442408-01, and 442488-02). Washington, DC:U.S. Environmental Protection Agency.
--. 2002. A Review of the Reference Dose and Reference ConCentration Processes. EPA/630/P-02/002F. Washington, DC: U.S. Environmental Protection Agency. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=55385 [accessed 18 December 2003].
--.2003. Draft Final Guidelines for Carcinogen Risk Assessment, Washington, DC:U.S. Environmental Protection Agency. Available: http://oaspub.epa.gov/eims/eimscomm.getfile?p_download_id=36765 [accessed 16 December 2003].
WHO. 1986. Organophosphorus Insecticides: A General Introduction, Environmental Health Criteria 63. Geneva:World Health Organization. Available: http://www.inchem.org/documents/ehc/ehc/ehc63.htm [accessed 16 December 2003].
--. 1994. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health-Based Exposure Limits. Environmental Health Criteria 170. Geneva:World Health Organization. Available: http://www.inchem.org/documents/ehc/ehc/ehc170.htm [accessed 16 December 2003].
--. 2001. Neurotoxicity Risk Assessment for Human Health: Principles and Approaches. Environmental Health Criteria 223. Geneva:World Health Organization. Available: http://www.inchem.org/documents/ehc/ehc/ehc223.htm [accessed 16 December 2003].
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 16 December 2003].
Ian S. Chart
AMVAC Chemical Corporation
Newport Beach, California
Susan Hunter Youngren
The Acta Group, L.L.C.
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|Author:||Youngren, Susan Hunter|
|Publication:||Environmental Health Perspectives|
|Date:||Mar 1, 2004|
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