FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
OPEN MEETING September 7, 2001
August 20, 2001
FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/
OPP Docket Telephone: (703)305-5805
SHERATON CRYSTAL CITY HOTEL
1800 JEFFERSON DAVIS HIGHWAY
ARLINGTON, VIRGINIA 22202
Common Mechanism of Action of Dithiocarbamates and Thiocarbamates
QUESTIONS TO THE PANEL
Issue: The results of metabolism studies submitted to the Agency and of metabolism and mechanistic studies reported in the literature show that carbon disulfide is a common neuropathic metabolite formed by the dithiocarbamates.
Question: Please comment on the evidence supporting the conclusion that carbon disulfide is a common metabolic product of the dithiocarbamates and that carbon disulfide is a neuropathic moiety.
Issue: Distal peripheral neuropathy was identified as the most common, sensitive effect for grouping the dithiocarbamates based on the potential to induce a common effect.
Question: Please comment on the evidence supporting the selection of distal peripheral neuropathy as the endpoint of choice for grouping the dithiocarbamates based on the potential to induce a common effect.
Issue: Although Na-dimethyldithiocarbamate and ferbam are presumed to form carbon disulfide during metabolism, results of studies with these pesticides have not shown neuropathic effects.
Question: Please comment on the recommendation that Na-dimethyldithiocarbamate and ferbam be excluded from the common mechanism group of neuropathic dithiocarbamates.
Issue: Although there are data available from the literature and from results of studies submitted to OPP that indicate the thiocarbamate pesticides share a common metabolic profile, there appears to be a lack of information on the specific mechanism of action that can account for the neuropathology that is induced in rats following treatment with a thiocarbamate. Unlike the dithiocarbamates, the thiocarbamates do not undergo conversion to the common metabolite, carbon disulfide.
Question: Please comment on the evidence that supports a presumption that the thiocarbamates may have a common mechanism of toxicity but a common mechanism of toxicity has not been linked to a critical metabolic moiety.
Issue: Treatment of rats with a thiocarbamate may result in the formation of neuropathological lesions, developmental/reproductive toxicity, or decrease cholinesterase activity. The current assessment identified distal peripheral neuropathy as the most sensitive, common effect of the thiocarbamates.
Question: Would the panel please comment on the selection of the neuropathological endpoint as the appropriate endpoint for grouping the thiocarbamate pesticides based on the potential to induce a common effect.
Issue: The document Thiocarbamates: A Screening Level Cumulative Dietary (Food) Risk Assessment presents a step-wise screening process for conducting a cumulative risk assessment. This screening level approach is intended to identify whether there is a need to initiate a more comprehensive cumulative risk assessment for a small group of structurally related pesticides that induce a common effect. It is not intended to identify a level of concern or risk for any one chemical or a group of chemicals that share a common mechanism of toxicity.
Question: Please provide general comments on the overall screening approach used in this preliminary cumulative risk assessment.