HED DOC. NO. 014029

CANCER ASSESSMENT DOCUMENT

EVALUATION OF THE CARCINOGENIC POTENTIAL OF

DICLORVOS (DDVP)

(SIXTH REVIEW)

FINAL  REPORT

1-MARCH-2000

CANCER ASSESSMENT REVIEW COMMITTEE

HEALTH EFFECTS DIVISION

OFFICE OF PESTICIDE PROGRAMS

                                                                        
                                                                        
 



DATA PRESENTATION:	                                                     
           

      			Joycelyn Stewart, Toxicologist

DOCUMENT PREPARATION:	                                                  
              

William Burnam, Chairman

COMMITTEE MEMBERS IN ATTENDANCE:	(Signature indicates concurrence with
the assessment unless otherwise stated).	

Karl Baetcke				                                                        
              

Kerry Dearfield			                                                      
               

Vicki Dellarco			                                                       
              

Sanjivani Diwan (Exe. Secretary)                                        
                                   

Virginia Dobozy			                                                      
                

Richard Hill     	   	                                                  
                                

Yiannakis Ioannou	   	                                                  
                                

Nancy McCarroll			                                                      
                

Esther Rinde				                                                        
             

Jess Rowland				                                                        
             

Clark Swentzel			                                                       
              

Linda Taylor				                                                        
             

NON-COMMITTEE MEMBERS IN ATTENDANCE 	(Signature indicates concurrence
with the pathology report and statistical analysis of data,
respectively)

John Pletcher,		Pathology		                                             
                         

Lori Brunsman,	Statistical Analysis	                                    
                                  

                                                                        
                                                                        
    



CONTENTS

 TOC \f 

EXECUTIVE SUMMARY 	iii

 

ATTACHMENTS	v



          SUMMARY

At the 6th Cancer Assessment Review Committee (CARC) meeting for DDVP
held on August 18, 1999, the Committee determined that DDVP should
remain classified as a category C carcinogen with low dose risk
extrapolation based on the incidence of forestomach tumor (squamous cell
papilloma and/or carcinoma) in female mice.  Previously, DDVP had been
classified as a category C, but the low dose linear extrapolation had
been based on mononuclear cell leukemia (MCL) in male rats.  

After the August 18 meeting, an E-mail message was sent out expressing
concern that the DDVP classification was not based on the Agency’s new
draft Cancer Risk Assessment Guidelines (1999).  In addition, the CARC
had previously (in its 5th Peer Review) decided not to use the
forestomach tumors for linear extrapolation.  The members of the CARC
were requested to consider changing the conclusions of the August 18,
1999, meeting on DDVP.  The CARC member’s opinions were at least two
to one in favor of changing the classification to “suggestive” and
not requiring a low-dose linear extrapolation.  The following is a
rationale to support this conclusion.

At the 5th Cancer Peer Review of DDVP (report dated August 2, 1996), the
conclusion was that the new information on MCL staging did not negate
the Committee’s previous conclusion that this tumor was treatment
related.  The mouse forestomach tumors were still considered caused by
DDVP but, since their relevance to human health was in doubt, they were
not included in the linear low dose extrapolation.  The Committee
concluded that the classification should remain a Category C based on
these two tumor types with a linear low dose risk assessment based on
the MCL.

The discussion at the 6th CARC meeting centered around the significance
of the MCL in the male rats and their relevance for risk assessment 
based on three separate papers sent to the CARC prior to the meeting (1)
the registrant’s July 27, 1998, “An Evaluation of the Potential
Carcinogenicity of Dichlorvos: Final Report of the Expert Panel”; (2)
the report of the FIFRA SAP meeting of July 30, 1998; and (3) a
memorandum of a phone conversation between Dr.Boorman of NTP and certain
CARC members. A few of the reasons are as follows:	

1) MCL is common in the Fischer rat and, in the males, appears to vary
in its background rate 	with the amount of corn oil in the animal’s
diet.

2) The tumor type does seem to be found mainly in this Fischer strain
and does not appear 	to be similar to leukemia in humans (adults or
children).

3) There was no dose response in the incidence and severity between the
two gavage doses 	of 4 and 8 mg/kg/day.     

The overall conclusion of CARC was that, while all of this information
somewhat lessened our concern, the MCL could not be totally dismissed as
not being relevant to humans.  This agreed with the opinion of Dr.
Boorman of NTP.

The CARC also agreed in principle, with the SAP’s statement
“overall, the high background and variability in the incidence of this
tumor, as well as its species and strain specificity, make it an invalid
response for human risk assessment.”  Based on these conclusions and,
after an informal poll of the CARC, it was determined that
“suggestive” under the 1999 Draft Agency Cancer Guidelines best
described the carcinogenic potential of DDVP.  The rationale can be
stated as follows:

1) MCL in the male Fischer rat has certain properties in terms of
variability and reliability 	which limit its usefulness for human risk
assessment.

2) The forestomach tumors, observed at gavage doses causing inhibition
of plasma and red 	blood cell cholinesterase and cholinergic signs, are
also limited in their use for human risk 	assessment.

3) The fact that DDVP is only positive by the gavage route and negative
by the inhalation 	route,which is the major route of human exposure,
indicates that any classification by the oral 	route may be limited
since localized effects in the forestomach may not be applicable to 
human risk assessment.

Attachments

   

Diclorvos (6th Review) 				 Cancer Assessment Document    	 	Final
Report

 PAGE  iii 

