Agenda for the August 2000 Meeting
FIFRA SAP WEB SITE https://www.epa.gov/scipoly/sap/
OPP Docket Telephone: (703)305-5805
THURSDAY, AUGUST 17, 2000
HOLIDAY INN - BALLSTON
4610 NORTH FAIRFAX DRIVE
ARLINGTON, VIRGINIA
(703) 243-9800
- 8:30 AM Introduction of Panel Members - Mary Anna Thrall, D.V.M. (FIFRA SAP Session Chair)
- 8:45 AM Administrative Procedures by Designated Federal Official - Mr. Paul Lewis
- 8:50 AM Welcome - Steven K. Galson, M.D. M.P.H. (Director, Office of Science Coordination and Policy, Office of Prevention, Pesticides and Toxic Substances, EPA)
- 8:55 AM Introductory Remarks - Ms. Marcia E. Mulkey
(Director, Office of Pesticide Programs, Office of Prevention,
Pesticides and Toxic Substances, EPA)
SESSION 1: A Consultation on the EPA Health Effects Division's Proposed Classification of the Human Carcinogenic Potential of Malathion
- 9:00 AM Introduction/Background - Mr. William Burnam (EPA, Office of Pesticide Programs), Marion Copley, D.V.M., D.A.B.T, (EPA, Office of Pesticide Programs), and Mr. Jess Rowland (EPA, Office of Pesticide Programs)
- 9:10 AM Adequacy of Studies/Positive Tumor Findings - Marion Copley, D.V.M., D.A.B.T, (EPA, Office of Pesticide Programs)
- 10:15 AM BREAK
- 10:30 AM Weight of Evidence/Cancer Classification - Marion Copley, D.V.M., D.A.B.T, (EPA, Office of Pesticide Programs)
- 11:15 AM Negative Tumor Findings - Marion Copley, D.V.M., D.A.B.T, (EPA, Office of Pesticide Programs)
- 12:15 PM LUNCH
- 1:15 PM An Alternative Approach - Brian Dementi, Ph.D., D.A.B.T. (EPA, Office of Pesticide Programs)
- 1:45 PM Public Comments
- 3:00 PM BREAK
- 3:15 PM Public Comments
- 4:30 PM ADJOURNMENT
FRIDAY, AUGUST 18, 2000
- 8:30 AM Introduction - Mary Anna Thrall, D.V.M. (FIFRA SAP Session Chair)
- 8:45 AM Administrative Procedures by Designated Federal Official - Mr. Paul Lewis
- 8:50 AM Welcome - Steven K. Galson, M.D. M.P.H. (Director,
Office of Science Coordination and Policy, Office of Prevention,
Pesticides and Toxic Substances, EPA)
SESSION 1: A Consultation on the EPA Health Effects Division's Proposed Classification of the Human Carcinogenic Potential of Malathion (continued)
- 9:00 AM Panel Discussion
Issue 1. The HED CARC determined that all three new studies, a rat and mouse study with malathion and a rat study with malaoxon, were adequate to evaluate the carcinogenic potential of the test substance. Although excessive toxicity was present at the high dose or two high doses in all of the studies, the next lower dose was either adequate based on marginal evidence of toxicity or was less than one half of the excessively toxic dose.
Question 1: Does the SAP agree that each of the three above-mentioned cancer studies were adequate to assess potential carcinogenicity? If yes, why. If no, why not.
Issue 2. The HED CARC classified malathion as "suggestive." This is based on the occurrence of liver tumors in male and female B6C3F1 mice, and female Fischer 344 rats at excessive doses and the presence of a few rare nasal respiratory epithelial tumors in male and female Fischer 344 rats. The nasal and oral tumors could not be distinguished as either treatment related of due to random occurrence.Question 2.1: Does the SAP consider the statistically significant trend and pair-wise increases in liver tumors in male B6C3F1 mice at 8000 and 16,000 ppm (adenomas - 14/55 and 49/51 compared to 4/54 in controls; and adenomas/carcinomas - 15/55 and 49/51 compared to 4/54 in controls) to be related to malathion exposure? Why or why not? What weight should be placed on these data since there is evidence of excessive toxicity based on marked (brain) to severe (RBC and plasma) cholinesterase inhibition in all three compartments and decreased body weight at both doses?
Question 2.2: Does the SAP consider the statistically significant trend and pair-wise increases in liver tumors in female B6C3F1 mice at 8000 and 16,000 ppm (adenomas - 9/52 and 42/51 compared to 0/55 in controls; and adenomas/carcinomas - 10/52 and 43/51 compared to 1/55 in controls) to be related to malathion exposure? If not, why not? What weight should be placed on these data since there is evidence of excessive toxicity based on severe cholinesterase inhibition in all three compartments (RBC, plasma and brain) and decreased body weight at both doses?
Question 2.3: The CARC considered the April 2000 PWG report for female Fischer 344 rat liver tumors to be valid and used these values in the cancer hazard assessment.
2.3.1:The SAP agree that the female rat liver tumor PWG report (from April 2000) should be considered valid and that these values should be used in this hazard assessment for malathion? If yes, why? If not, why not?2.3.2: Does the SAP consider the statistically significant trend and pair-wise increases in liver tumors in female Fischer 344 rats at 12,000 ppm (adenomas - 5/38 compared to 0/41 in controls) to be related to malathion exposure? If not, why not? What weight should be placed on this data since there is evidence of excessive toxicity based on severe cholinesterase inhibition in all three compartments (RBC, plasma and brain) and mortality?
Question 2.4: The Committee could not determine whether the nasal tumors in rats were due to treatment or random occurrence because: on the one hand: (1)there was no dose response over a wide range of doses (100/50 to 12,000 ppm); (2) there was no statistical significance; (3) there were only adenomas, one in each of two doses for females and only one at the high dose in males; (4) the high dose in both male and females were considered excessively toxic; and (5) these tumors occurred in section 5 where there was little to no evidence of non-neoplastic lesions in the nasal mucosa. On the other hand: (1) an adenoma of the respiratory epithelium was seen in one female at 6000 ppm (not an excessive dose); (2) spontaneous nasal tumors are very rare in rats, there were no nasal tumors in the concurrent controls and the incidences exceeded the historical control incidence of the testing laboratory and NTP. It should be noted that the biological significance of the olfactory epithelial tumor is unknown since it is from a different cell of origin and these types of tumor (esthesioneural epithelial neoplasms) should not be combined with other tumors of the respiratory nasal cavity. The biological significance of this in relation to tumors of the respiratory epithelium is unknown. It should be pointed out that there were 5 nasal sections per rat. Historical control studies usually have only 1 or 2 sections.
2.4.1: Does the SAP agree that nasal respiratory epithelial tumors in Fischer 344 rats are rare tumors in light of the number of sections in the current study as compared to the historical control data base? Why or why not?
- 12:00 PM LUNCH
- 1:00 PM Panel Discussion (continued)
2.4.2: Does the SAP agree that the increase in these nasal respiratory epithelial tumors in Fischer 344 rats cannot be conclusively attributed to either treatment with malathion or random occurrence? If the SAP feels this increase can be attributed to treatment, why?
2.4.3: What, if any, is the significance of the adenoma of the olfactory epithelium in one male Fischer 344 rat at 6000 ppm?
Question 2.5: The CARC could not determine whether the oral cavity squamous cell tumors in Fischer 344 female rats (palate-one papilloma at 6000 and one carcinoma at 12,000 ppm; carcinoma of tooth alveolus at 100/50 ppm) were due to treatment or random occurrence because: on the one hand: (1) there was no dose response over a wide range of doses (100/50 to 12,000 ppm); (2) there was no statistical significance; (3) the high dose in the females was considered excessively toxic. On the other hand: (1) a squamous cell papilloma of the palate was seen in one female at 6000 ppm (not an excessive dose); (2) spontaneous oral tumors may be very rare in rats, there were no oral tumors in the concurrent controls and the incidences exceeded the historical control incidence of the testing laboratory and NTP; (3)due to the lack of systematic pathologic evaluation of the oral mucosa, there is uncertainty as to the actual incidence of oral tumors. The one papilloma in males at 100/50 ppm was considered incidental. It should be pointed out that oral epithelium (often palate) is usually present on nasal sections and that there were 5 nasal sections per rat. Historical control studies usually have only 1 or 2 sections. However, the CARC determined that a recut would not alter their conclusion.
2.5.1: Does the SAP agree that the oral squamous cell tumors in Fischer 344 rats are rare tumors in light of the number of sections in the current study as compared to the historical control data base? Why or why not?
2.5.2: Does the SAP agree that a recut of tissue would not significantly alter the conclusions of this study? If yes, why? If not, why not?
- 3:00 PM BREAK
- 3:15 PM Panel Discussion (continued)
2.5.3: Does the SAP agree that the increase in the oral tumors in Fischer 344 rats cannot be conclusively attributed to either treatment with malathion or random occurrence? If the SAP feels this increase can be attributed to treatment, why?
Question 2.6: Does the SAP agree with the proposed CARC classification of malathion as "suggestive?" Why or why not?2.5.4: What, if any, is the significance of the squamous cell carcinoma of the alveolus of the tooth in one female Fischer 344 rat at 100/50 ppm?
Issue 3. There were several other neoplastic lesions that the CARC considered and determined not to be indicative of a carcinogenic potential of malathion. These included: mouse liver tumors at low doses in males, male rat nasal tumors, male rat thyroid follicular cell tumors, male rat thyroid C-cell tumors, rat interstitial cell testicular tumors, male rat liver tumors, male rat leukemia, female rat pituitary gland tumors, and female rat uterine tumors (various types). The CARC considered and determined that leukemia in the male rat was not related to malaoxon treatment.
Question 3. Does the SAP agree that these tumors are not related to malathion treatment and as such do not contribute to the weight of the evidence?
- 5:00 PM ADJOURNMENT
FIFRA SCIENTIFIC ADVISORY PANEL (SAP) OPEN MEETING AUGUST 17 AND AUGUST 18