FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
September 7, 2001
Common Mechanism of Action of Dithiocarbamates and Thiocarbamates
FIFRA SAP WEB SITE
OPP Docket Telephone: (703)305-5805
FRIDAY, SEPTEMBER 7, 2001
SHERATON CRYSTAL CITY HOTEL
1800 JEFFERSON DAVIS HIGHWAY
ARLINGTON, VIRGINIA 22202
- 8:30 AM Introduction and identification of Panel members - Christopher Portier, Ph.D (FIFRA SAP Session Chair)
- 8:50 AM Administrative procedures by Designated Federal Official - Mr. Paul Lewis (FIFRA SAP)
- 8:55 AM Introductory remarks - Ms. Marcia E. Mulkey, Director (Office of Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances, EPA)
- 9:00 AM Introduction, goals and objectives - Randy Perfetti, Ph.D.
(Office of Pesticide Programs, EPA)
- 9:05 AM Background - Alberto Protzel, Ph.D. (Office of Pesticide Programs, EPA)
- 9:10 AM Methodology - Alberto Protzel, Ph.D. (Office of Pesticide Programs, EPA)
- 9:40 AM Results, conclusions and summary of Agency questions - Alberto Protzel, Ph.D. (Office of Pesticide Programs, EPA)
- 10:15 AM BREAK
- 10:30 AM Public Comments James C. Lamb, Ph.D. and Janet Ollinger,
Ph.D. on behalf of the EBDC/ETU Task Force
- 11:15 AM Background Toxicology
- Alberto Protzel, Ph.D. (Office of Pesticide Programs, EPA)
- Sheila Piper, M.S. (Office of Pesticide Programs, EPA)
- 12:15 PM Results, conclusions and summary of Agency Questions - Alberto Protzel, Ph.D. (Office of Pesticide Programs, EPA)
- 12:30 PM LUNCH
- 1:30 PM Public Comments
- 2:15 PM Panel Discussion
1. 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.
Lead Discussants: Jeanne Harry, Ph.D., Michael McClain, Ph.D. and John O'Donoghue, Ph.D.
2. 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.
Lead Discussants: David Dorman, Ph.D. and Ernest McConnell, DVM
3. 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.
Lead Discussants: Diane Miller, Ph.D. and John O'Donoghue, Ph.D.
- 3:30 PM BREAK
- 3:45 PM Panel Discussion (continued)
1. 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.
Lead Discussants: John O'Donoghue, Ph.D. and Kendall Wallace, Ph.D.
2. 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.
Lead Discussants: Ernest McConnell, DVM and David Dorman, Ph.D.
3. 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.
Lead Discussants: Jeanne Harry, Ph.D., Diane Miller, Ph.D. and Ernest McConnell, DVM
- 5:00 PM ADJOURNMENT
Please be advised that agenda times are approximate. For further information, please contact the Designated Federal Official for this meeting, Mr. Paul Lewis, via telephone: (703) 305-5369; fax: (703) 605-0656; or email:email@example.com.