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2,4-D (Dacamine, Weed-B-Gon) Industry Task Force Report 5/92

2,4-D Dispatch                                                        May 1992
                  Industry Task Force on 2,4-D Research Data
                   Executive Summary:  Review Panel Report on
  "Case-Control Study of Canine Malignant Lymphoma:  Positive Association With
          Dog Owner's Use of 2,4-Dichlorophenoxyacetic Acid Herbicides"
     Last September, the Journal of the National Cancer Institute published a 
study suggesting links between lawn care uses of the herbicide 2,4-D and 
malignant lymphoma in dogs.  This study raised predictable concerns among lawn 
applicators and home owners.
     In response to these concerns, the Industry Task Force on 2,4-D Research 
Data commissioned an independent panel of scientists to review the study and 
its conclusions.  After careful review, the panel found that due to 
limitations in design, the study's data did not support an association between 
2,4-D and malignant canine lymphoma.
     Two primary reasons were given by the panel as to why the study was 
unable to show an association.  First. the study was based on responses of dog 
owners, using a questionnaire that gave too little information about which 
dogs were exposed to 2,4-D and how much exposure they had.  Second, the panel 
notes, that the effect reported by the study was small, so that it may have 
been due to chance or might be linked to other factors in the dogs' 
     The findings of the dog study review panel are summarized below.  These 
findings are consistent with the weight of the evidence based on extensive 
scientific testing which has not found a link between animal cancers and 2,4-
D.  The complete text of the review is also available through the task force.
                                                                 - The Editors
     In December 1991, an independent scientific review panel was convened by 
Drs. Ian Munro and George Carlo to evaluate critically the methodology and 
findings of the study by Hayes et al. entitled, "Case-control study of canine 
malignant lymphoma:  Positive association with dog owner's use of 2,4-
dichlorophenoxyacetic acid herbicides."(1)  The Study was published in the 
Journal of the National Cancer Institute's September 4, 1991, issue.  This 
independent peer review was supported by the Industry Task Force II on 2,4-D 
Research Data.
     The scientific panel reviewed the published study, media releases that 
accompanied the public release of the study, and the interview instrument 
employed by the study investigators which was provided by the National Cancer 
Institute.  A meeting of the panel took place during December 1991.  The panel 
was charged with evaluating the degree to which the study by Hayes et al 
supported the hypothesis that 2,4-dichlorophenoxyacetic acid (2,4-D) 
herbicides are associated with canine malignant lymphoma.
     Although the study, by virtue of its title, suggests a relationship 
between exposure to 2,4-D and canine malignant lymphoma, this hypothesis was 
not strongly supported by any of the results presented.  The increases in risk 
suggested by the odds ratios reported (e.g., OR=1.3) were small.  Therefore, 
it is possible that a small bias or confounder could be responsible for the 
elevated odds ratio instead of a biological link to any of the potential 
exposures studied.  Exposure quantification was very poor, and it is therefore 
difficult to discern what exposures were actually studied.
     A relatively large sample size was used and the number of controls was 
about twice the number of cases, which allowed the authors to conduct analysis 
of many subgroups of dogs. Control dogs were selected from the same hospital 
as the case dogs, which is important in addressing the potential problem of 
selection bias.  Two control pools were employed:  one pool consisted of dogs 
diagnosed with tumors other than lymphoma, the other pool consisted of dogs 
that had died of other causes.  This design should address the potential for 
biased recall among the owners of the case dogs.  The control dogs were 
matched with case dogs by location, age and year of treatment.  This matching 
should control confounding by these variables.
     Although the response rate was relatively low (about 45%) by mail, 70% of 
those non-responders were interviewed, which is considered a good response 
rate for a study of this type.  Combining the methods, the total response rate 
was about 83%.  In addition, the questionnaire did not draw the attention of 
the owners to the a priori hypothesis that 2,4-D exposure predisposed dogs to 
canine malignant lymphoma.  This approach should address the potential for 
recall and interview bias.
     The study was poorly designed to investigate the hypotheses that 2,4-D 
causes cancer in dogs.  Two sets of controls were combined in the final 
analysis but analyses specific to each control group were not presented to 
address the issue of potential recall bias.  The authors should have analyzed 
the control groups separately and, only if the risks were comparable, should 
they have combined the two control groups.
     Although the use of a hospital-based case-control design is generally 
considered to be less rigorous than a population-based design because of the 
greater opportunity for selection bias, the authors did not present what 
proportion of local dogs were seen at the three hospitals to identify possible 
differences between the groups.  It is also likely that some of the dogs 
diagnosed with fatal canine malignant lymphoma would be euthanized by the 
local veterinarian rather than be taken to a hospital for treatment, thus, 
raising questions about the representativeness of the case series as well as 
the generalizability of the findings of the study.
     There was substantial non-response to the mailed questionnaire.  Forty-
five percent of the subjects had to be phoned in order to obtain information 
and it is not clear whether these two groups were independently tested to 
assess potential biases and determine internal consistency for the study.
Misclassification and Confounding
     In this type of study, it is desirable to quantify exposure both 
objectively and accurately.  The questionnaire, however, is very non-specific 
and broad with regard to use of pesticides, and a list of names of home-garden 
products was not supplied.  The design of several questions restricted 
responses in such a manner that it is not clear whether 2,4-D was used alone 
or in combination with other herbicides.  Thus, the exposure quantification 
data were of no value and the combination of the two groups (commercial and 
homeowner) may not have been scientifically valid as there was no evidence 
that these groups were exposed to the same chemicals.  A market survey of 
home-garden herbicide use in the U.S.A.(2) has shown that of those products 
containing 2,4-D only 15% contained 2,4-D alone.  The remaining 85% contained 
other herbicides such as dicamba and MCPA in addition to 2,4-D.  It is thus 
very likely that a high percentage of the dogs in the exposed groups were 
exposed to herbicides other than 2,4-D further complicating any link between 
2,4-D and their cancer.
     Data from the Hayes et al. study suggest that 33% of owners reported 
using 2,4-D only, which is more than twice the percentage reported in the U.S. 
market survey.  This raises questions about the reliability (or possible 
misclassification) of the responses to the questionnaire.
     Also supporting the possibility of misclassification is the reported 
response that some of the case owners applied the herbicide three and more 
times per year.  Given the geographical locations of this study, it is not 
recommended and very unusual that 2,4-D would be used more than two times per 
year.  The significant trend test for number of applications per year is 
driven by a significant number of dog owners who reported using 2,4-D four or 
more times per year.  Since it would be surprising that even a small 
percentage of dog owners used 2,4-D four times per year, this raises serious 
questions about the reliability of the questionnaire with respect to 
quantifying this variable, as well as the reliability of the trend test.
     The questionnaire is also inadequate with respect to gathering 
information about the potential confounder of viral causes of lymphoma.  
Therefore, the potential impact of viruses could not be tested for, or 
Study Results
     In addition to the poor designs of the study and the questionnaire, the 
results did not support the authors' hypothesis.  The only statistically 
significant observation of a relationship between canine malignant lymphoma 
and lawn chemicals was observed when the data from three exposure groups and 
the two control groups were combined.  When each of these sub-groups was 
analyzed separately, no statistical significance was observed.
     The authors claim to have tested a number of associations in their study, 
listing some 35 factors in the tables and text.  It is to be expected that one 
or more of these tests will show statistical significance purely on the basis 
of chance, particularly when the OR is small (e.g., OR=1.3).  One would expect 
an OR of 2 or greater if a strong relationship existed.
     Although the authors claim that a statistically significant trend was 
observed for the number of owner applications per year, this is not a 
meaningful dose-response as the "0" application or unexposed group should not 
be included in the trend test.  With this point excluded, the trend is not 
significant.  In addition, there was no statistically significant trend 
observed for number of commercial applications of lawn chemicals per year, 
which is not in concordance with the authors' claim of a statistically 
significant trend for owner applications.
     Finally, other studies on humans(3) and animals(4)(5)(6)(7) exposed to 
2,4-D do not support the findings of this study.
     As a result of limitations in the design of the study, it may be 
concluded that it did not show an association between dog owner's use of 2,4-D 
and canine lymphoma.
George L. Carlo,
Ph.D., M.S., J.D. (Co-chair)
Chairman, Health & Environmental
Sciences Group, Ltd.
Adjunct Faculty, George Washington University
School of Medicine and Health Sciences
Washington D.C.
Philip Cole, M.D., Dr. P.H.
Professor and Chairman
Department of Epidemiology
School of Public Health
University of Alabama at Birmingham
Birmingham, Alabama
Anthony B. Miller, M.B., FRCP, FFPHM
Professor, Department of Preventive
Medicine and Biostatistics
Faculty of Medicine
University of Toronto
Toronto, Ontario Canada
Ian Munro, Ph.D., FRC Path. (Co-chair)
Director, Canadian Centre for Toxicology
Guelph, Ontario Canada
Keith Solomon, Ph.D.
Associate Director
Canadian Centre for Toxicology
Professor, Department of
Environmental Biology
University of Guelph
Guelph, Ontario Canada
Robert Squire, D.V.M., Ph.D.
Professor, Division of Comparative Medicine
Johns Hopkins University School of Medicine
Baltimore, Maryland
April 9,1992
(1) Hayes HM, Tarone RE, Cantor KP, Jessen CR, McCurnin DM, Richardson RC. 
Case-control study of canine malignant lymphoma:  positive association with 
dog owner's use of 2,4-dichlorophenoxyacetic acid herbicides.  J Natl Cancer 
Inct 1991; 83:1226-1231.
(2) Page D. Personal communication. Dow, 1991.
(3) Harris SA, Solomon KR. Bowhey C, Stephenson GR. Human exposure to 2,4-D 
following controlled activities on recently sprayed turf. J Environ Health Sci 
1992: B27:9-22
(4) Arnold EK, Beasley VR, Parker AJ, Zachary JF, Lovell R, Sawchuck S, 
Richardson B, Butcher M. The toxicological evaluation of the dimethylamine 
salt of 2,4-dichlorophenoxyacetic acid (2,4 D) in the dog. Report of the 
College of Veterinary Medicine, University of Illinois, Urbana, IL May 1987.
(5) Arnold EK, Lovell RA, Beasley VR, Parker AJ, Stedelin JR. 2,4-D toxicosis 
III: An attempt to produce 2,4-D toxicosis in dogs on treated grass plots. Vet 
Hum Toxicol 1991: 33:457-461 .
(6) Hansen WH, Quaife ML, Haberman RT. Chronic toxicity of 2,4-dichloro-
phenoxyacetic acid in rats and dogs. Toxicol Appl Pharmacol 1971: 20:122-129.
(7) Hazelton Laboratories. Combined toxicity and oncogenicity study in rats, 
2,4-dichlorophenoxyacetic acid. Final report. Volume 1. Hazelton Laboratories 
America, Inc., Vienna, VA. May 29,1986. Project No. 2184-103.