2,4-D : How industry dominates the US EPA carcinogenicity studies that prove ‘not carcinogenic’.

2013-06-27 035This report is a dissection of the animal studies provided for the EPA Carcinogenicity Peer Review for 2,4-D dated July 17, 1996.

The 1996 Peer Review is the report that establishes the classification of 2,4-D : Human toxicity:   Classification Group D (not classifiable as to human carcinogenicity).

This report identifies the study authors and the companies that financed the studies.

Report Summary:

2 year carcinogenicity:

  • Mice:     1 study funded by Industry Task Force II. (Serota 2184-101);

2 studies prepared by Dow: (2 Stott et al 1995 MRID 43879801 & 43597201)

  • Rats:      1 study funded by Industry Task Force II. (Serota 2184-102);

1 study from Dow Labs. (Jeffries et al 1995 MRID 43612001).

Metabolism:

  • 1 study prepared in Dow Labs. (Timchalk et al 1990).

Mutagenicity:

  • Reveals a good selection of non-industry and industry based studies.

Structure Activity Relationship

  • 2,4-DB: 2 studies funded by Industry Task Force II. (Mackenzie 1987)
  • 2,4-DP: Study provided without references, author details provided.
  • MCPA: 2 studies by BASF: (Kuhborth 1986 & Kirsch 1986).
  • MCPP:  No studies
  • 2,4,5-T: 1 study: French university: (Muranyi-Kovacs et al 1976) ; 2nd study: Doesn’t give  Laboratory however scientists over this time are employed by Dow: (Kociba et al 1979).
  • 2,4,5-TP:  No studies.

Subchronic Toxicity Studies:

  • Mice:  2 studies by Industry Task Force (Serota 1983 (2184-100) & Schultze MRID 41991502)
  • Rats: 2 studies by Industry Task Force (Serota (2184-102) & Schultze MRID 41991501)
  • Dogs: 2 studies by Industry Task Force (Schultze MRID 41737301 & Dalgard MRID 42780001)

Chronic Toxicity Studies (same studies as 2 yr carcinogenicity with additional 52 week dog study):

  • Mice: Industry Task Force II: (Serota 2184-101,) Dow: (Stott MRID 43879801 & 43597201)
  • Rats: Industry Task Force II : (Serota 2184-102); Dow: Jeffries MRID 43612001)
  • Dogs: Industry Task Force II: (Dalgard MRID 43049001)

Neurotoxicity:

  • 1 study by Dow (Mattson 1994).

Epidemiological Studies

  • Mix of independent and industry.  Most recent study 1996.

Additional 2 year Carcinogenicity Studies (the EPA describes these as ‘independent’) P46. :

  • Mice:     2 studies prepared in Dow Laboratories (Stott 1995);

1 study by Industry Task Force II (Serota 1987).

  • Rats:      1 study prepared in Dow Labs (Jeffries et al 1995).
    1 Study by Industry Task Force on 2,4-D (Serota DD 1983a).
SafeSaysWho Notes:

SafeSaysWho notations in italics.

This paper extracts all studies from original Peer Review but adds references which includes companies that financed study.  This is not necessarily included on original EPA Memorandum stamped Jan 1997.

Industry Task Force II uses many studies earlier forwarded to different safety agencies by Industry Task Force I.  The first Task Force, Industry Task Force on 2,4-D Research Data, comprised a greater number of corporations.

In the case of the 1996 Carcinogenicity Peer Review, Industry Task Force II  supplies the studies for assessment. However if I am aware of the original firms that may have contributed initially to the study I have attempted to include them.

Industry Task Force (I): May comprise a mix of firms – Dow appears to be always a participant. Information providing details for companies from:  European Commission Review Report for 2,4-D. *: (INT)=INTERAG, (BAS)=BASF, (GIL)=GILMORE INC, (FAR)= FARMLAND, (GOR)= P.B.I. GORDON, (TRA)=TRANSBASS, (AHM)= A.H. MARKS, (AZC)= AKZO, (CHL)= CHEMIE LINZ, (AGL)= AGROLINZ, (DAS, DOE)=DOW, (MOB & FER)= MOBAY BAYER & FERMMENTA, (RPA, ROP)= RHONE-POULENC, (AGR)=AGROGOR (consortium Agrolinz ñ PBI Gordon), (NUF)= NUFARM http://ec.europa.eu/food/plant/protection/evaluation/existactive/list1_2-4-d_en.pdf

Industry Task Force II: Dow AgroSciences, Nufarm, Agro-Gor Corporation.

It would be useful if EPA requirements for citations required the study sponsors details, as the European Commission and the WHO makes this requirement.

 

NOTE: The original EPA Carcinogenicity Peer Review has no ‘Contents Page’, however description of actual studies included in the cancer review commence page 6 of the original document:

START OF EXTRACT:

Subject:   Carcinogenicity Peer Review (4th)              of 2,4-Dichlorophenoxyacetic Acid (2,4-D).
Pages dated: July 17, 1996.
From: Jess Rowland & Esther Rinde,
Through: Stephanie R Irene, To: Joanne Miller and Walter Waldrop.
Contents:                                                          EPA DocPage 

NB: Content is only extracted from the Carcinogenicity Peer Review where it contains citations of studies, as the purpose of this paper is to identify study authors who contributed to the peer review.

A. INDIVIDUALS IN ATTENDANCE AT THE MEETINGS.   4  

B. MATERIALS REVIEWED    5  

C. BACKGROUND INFORMATION    5  

1. First Peer Review   6  

  1. a.       Evidence of Carcinogenicity in Rats   6   
  2. b.      Evidence of Carcinogenicity in Mice   7     

2. Scientific Advisory Panel (SAP) Review   8

3. Second Peer Review of December 1987   9    

4. Third Peer Review of January 13 1988   9     

5. The meeting of the SAB/SAP Joint Committee   10    

6. Data call-in notice   10  

D. EVALUATION OF CARCINOGENICITY EVIDENCE   11  

I. EVIDENCE FROM ANIMAL STUDIES   11   

1. Carcinogenicity Study in Mice   11  

2. Combined Chronic Toxicity and carcinogenicity

                Study in Rats   13   

E. ADDITIONAL TOXICOLOGY DATA ON 2,4-D   16      

1. Metabolism   16     

2. Mutagenicity    16-19 

3. Structure-Activity Relationship    20    

4. Subchronic and Chronic Toxicity     22   

a. Subchronic Toxicity Studies   22  

                (i) Mice     22

                (ii) Rats    23          

                (iii) Dogs   25

b.  no section

c. Chronic Toxicity   26               

                (i) Mice and Rats    26      

                (ii) Dogs    26      

5. Neurotoxicity   27     

II. EVIDENCE FROM EPIDEMIOLOGIC STUDIES   28      

1.Evaluation of Studies    28    

(i) Soft-Tissue Sarcoma    28  

(ii) Non-Hodgkins Lymphoma   31    

2. Exposure Assessment    36      

F. WEIGHT OF EVIDENCE CONSIDERATIONS   43       

1. Evidence of carcinogenicity in animals    43       

2. Epidemiological considerations   45    

G. CLASSIFICATION OF CARCINOGENIC POTENTIAL   48          

 

Carcinogenicity Peer Review July 17, 1996.

After 3 evaluations, looking at the Hazleton study, CPRC (Carcinogenicity Peer Review) formed the opinion that 2,4-D should be classified  as Group C – possible Human carcinogen.

The highest dose in the study was then deemed ‘not adequate’ and the registrant was asked to repeat both studies at higher doses.  The Science Advisory Panel (SAP) disagreed with the CPRC and concluded 2,4-D should be classified as Group D.

CHRONOLOGY OF 2,4-d CARCINOGENICITY PEER REVIEW  p.6

1.       First Peer Review April 1987.

The CPRC, in this meeting, classified 2,4-D as an Interim Group C Carcinogen – possible Human Carcinogen based on the following weight-of-the-evidence.:

          a.       Evidence of Carcinogenicity in Rats.

Mistakenly the EPA have cited 2 studies under study number 2184-102, Serota 1983a, and Serota 1986. The study following is the correctly cited study 2184-103 Serota, 1986. However the WHO Serota 1986 study does not cite the colleagues involved in the Serota 1986 study.  There appear to be various citation inconsistencies.

Serota D.G., (Vargas K.J., Alasker R.D. and Matchotka S.M). (1986) Combined chronic toxicity and oncogenicity study  in rats with 2,4-D acid. Unpublished report No. 2184-103 OR Report No. 2184-102.  5/29/86. Accession No. 263112-263114. HED Document No. 004498 from Hazleton  Laboratories America, Inc., Vienna, VA, USA.

Funded by: INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP, NUF.  Submitted to WHO by  Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana,USA.  

Groups of 60 male and 60 female Fisher 344 rats were fed diets containing 2,4-D (97.5%) at 0,1, 5, 15, or 45 mg/kg/day for 104 weeks.

Astrocytomas: Table 1 Incidence of Astrocytomas mg/kg/day

Males:  0= 1/60 (a);  1= 0/60; 5= 0/60; 15= 2/60 (b) ; 45= 6/60 (c)      at 45 mg/kg/bw day 10% of male rats developed an astrocytoma.

Females:  0= 0/60; 1= 1/60; 5=2/60; 15= 1/60; 45= 1/60

a = Tumor seen in male that died on Week 21.    b = Tumors seen males sacrificed on Weeks 94 and 105     c = Tumors seen in 1 male sacrificed on Week 93 and in 5 at Week 104.

The CPRC concluded that the highest dose level tested (45 mg/kg/day) did not appear to attain an adequate level for carcinogenicity testing in males based on the renal lesions characterized as brown tubular cell pigment, pelvic microcalculi, and transitional epithelial cell hyperplasia, increases in kidney weights and ALT levels. The high dose was considered to be somewhat closer to an adequate level in females due to reduced
body weight gain (-5 to -10%), renal lesions similar to those seen in males, and the more marked renal finding of an increase in the frequency and severity of fine vacuolation of the cytoplasm in the renal cortex. Consequently, the Committee recommended that a repeat, modified, carcinogenicity study be performed in Fischer 344 rats using higher doses of 2,4-D than previously used.

Conclusion: 2,4-D produced benign (although life-threatening) tumor incidences of marginal statistical significance in one sex and species of animal in a single study that was inadequate in design (ie. Only a positive trend for brain astrocytomas in male rats in a single study where an adequate level for fully assessing carcinogenicity potential did not appear to be reached).

The initial request that the CPRC establish 2,4-D as a Group C Carcinogen is based on the Serota rat study.

          b.      Evidence of Carcinogenicity in Mice.

Serota DG. Oncogenicity study of B6C3F1 mice with 2,4-D acid (1987).  Hazleton Laboratories America Inc. Report No. 2184-101. 1/25/87.  MRID 40061801. HED Document No. 005794.  Dosed 0,1,15 or 45mg/day for 104 weeks.

Supplied by Industry Task Force I: INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP,NUF.

(NB Typo in original document citing 86C3F1 mice)

2.  Scientific Advisory Panel (SAP) Review –SAP disagreed with the Interim Group C Carcinogen decision.  The Panel concluded that present data for animals and humans were inadequate for determining carcinogenicity.

3. Second Peer review of December 1987– The CPRC disagree with the SAP’s Group D classification and reaffirmed the initial classification of Group C Carcinogen, but decided to re-evaluate this position after the repeat carcinogenicity studies in rat and mouse have been evaluated by the agency.

4. Third Peer review of January 13, 1988 – CPRC agree with Group D classification pending receipt of the repeat bioassays and additional forthcoming epidemiological data.

5. Meeting of SAB/SAP Joint Committee : meeting ‘feels’ there is only equivocal evidence of carcinogenic activity in mammals. Meeting concludes ‘data are not sufficient to conclude there is a cause and effect relationship between 2,4-D and NHL. Data, however, are sufficient to require continued examination of the issue through further studies.

6. Data Call In In 1988 additional carcinogenicity studies or rats and mice requested to be repeated because a high enough dosing for assessing carcinogenicity had not been achieved through the industry sponsored studies. (Industry Task Force II)

 

D. EVALUATION OF CARCINOGENICITY EVIDENCE

I. EVIDENCE FROM ANIMAL STUDIES                                                                   

1. Carcinogenicity Study in Mice.  P.11.

MRID 43879801 Stott, WT, Johnson KA, Gilbert KS, Ormand JR & Battjes JE (1995).  2,4-D: Dietary Oncogenicity Study in B6C3F1 Mice – 2 year Final Report. Study ID K-002372-063M. Unpublished. The Toxicology Research Laboratory, Dow Chemical Co. Michigan. (50 Male mice). 0, 5, 62.5, 125mg/kg/day

MRID 43597201 Stott WT,  Johnson KA, Gilbert KS, Ormand JR & Battjes JE (1995).  2,4-D: Dietary Oncogenicity Study in Female Mice B6C3F1 Mice – 2 year Final Report. Study ID K-002372-063F. Unpublished. The Toxicology Research Laboratory, Dow Chemical Co. Michigan. (50 Female mice). 0, 5, 150, 300mg/kg/day

A comprehensive Data Evaluation Record of the above 2 studies is available here and here.

2. Combined Chronic Toxicity and carcinogenicity study in Rats. P.13.

MRID 43612001 (1995) Jeffries T, Yano B., Ormand J, Battjes JE (1995).  2 year 2,4-D Chronic Toxicity/Oncogenicity Studies in Fischer 344 Rats – Final. Study ID K-002372-064. HED Document 011934. Unpublished. Prepared by Dow Chemical Co.  Health and Environmental Sciences.  50 females, 50 males. 0, 5, 75, 150mg/kg/day http://www.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC-030001_23-May-96_114.pdf

E. ADDITIONAL TOXICOLOGY DATA ON 2,4-D. P.16.

1. Metabolism.

Timchalk, C.; Dryzga, M.; Brzak, K. (1990) 2,4-Dichlorophenoxy- acetic, Tissue Distribution and Metabolism of (Carbon 14)- Labeled, 2,4- Dichlorophenoxyacetic Acid in Fischer 344 Rats: Final Report: Lab Project Number: K-2372-47. Unpublished study prepared by the Dow Chemical Co.

Michigan. MRID 41737302. 70p.

2. Mutagenicity:

These studies were also supplied to the WHO FAO 1996 2,4-D Toxicological Evaluation section [f] Genotoxicity. Difficult to extract on the FAO or WHO websites, 2,4-D Industry Organisation holds a copy on their site:    

Lawlor, T.E. & Valentine, D.C. (1990a) Mutagenicity test on 2,4-D acid in the Salmonella/mammalian reverse mutation assay (Ames test). Unpublished report No. 10979-O-401 from Hazleton Laboratories America, Inc., Vienna, VA, USA. Submitted to WHO by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA. MRID 41409801

Rashid, K.A., Babish, J.G. & Mumma, R.O. 1984: Potential of 2,4-dichlorophenoxyacetic acid conjugates as promutagens in the Salmonella/microsome mutagenicity test. Pesticide Research Laboratory, Pennsylvania State University. J. Environ. Sci. Health B19, 689-701.

Soler-Niedziela, L., Nath, J. & Zeiger, E. (1988) Mutagenicity studies of dioxin and related compounds with Salmonella arabinose resistant assay system. Toxicity Assess., 3, 137.

Kappas, A. (I 988) On the mutagenic and recombinogenic activity of certain herbicides in Salmonella typhimurium and in Aspergillus nidulans. Mutat. Res., 204,615-62 1. Institute of Biology, National Research Center Democritus, Athens, Greece.

Rashid, K.A. & Mumma, R.O. 1986: Screening Pesticides for their ability to damage bacterial DNA. Pesticide Research Laboratory, Pennsylvania State University. J. Environ. Sci. Health 21, 319-334.

Simon et al 1977:  No references supplied. Possibly: Siznmon et al. (1977). Mutagenic activity of chemicals identified in drinking water. -In Progress in Genetic Toxicology. Vol. 2 Scott, H.A. Bridges and F. H. Sodels (eds). Elsevier/North Holland:Amsterdam,pp. 249-258.

Mersch-Sundermann, V., Hofmeister, A., Muller, G. & Holf, H. (1989) Examination of mutagenicity of organic microcontaminants of the environment. III. Communication. The mutagenicity of selected herbicides and insecticides with the SOS-chromotest. Institut für Hygiene und Medizinische Mikrobiologie der Fakultät für Klinische Medizin Mannheim der Ruprecht-Karls-Universität Heidelberg.  26Z. Hyg., 189, 135-146

Kale, P.G., Petty, B.T., Jr, Walker, S., Ford, J.B., Dehkordi, N., Tarasia, S., Tasie, B.O., Kale, R. & Sohni, Y.R. (1995) Mutagenicity testing of nine herbicides and pesticides currently used in agriculture. Department of Biology, Alabama A. & M. University, Normal 35762, USA.  Environ. Mol. Mutag., 25, 148-153.

Zimmering, S., Mason, J.M.,Valencia, R. &Woodruff, R.C. (1985)Chemical mutagenesis testing in Drosophila. II. Results of 20 coded compounds tested for the National Toxicology Program. Environ. Mutag., 7,87-100.

Pavlica M, Papes D, Nagy N (1991). 2,4-Dichlorophenoxyacetic acid causes chromatin and chromosome abnormalities in plant cells and mutations in cultured mammalian cells. University of Zagreb, Yugoslavia.   Mut Res 263:77-81.

Galloway, S.M., Amstron, M-J., Reuben, C., Colman, S., Brown, B., Cannon, C., Bloom, AD., Nakamura, F., Ahmed, M., Duk, S., Rimpo, J., Margolin, B-H., Resnick, M.A., Anderson, B. & Geiger, E. (1987): Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ. Mol. Mutag., 10, l-175.

Bongso, T.A. & Basrur, P.K. ( 1973) In vitro response of bovine cells to 2,4-dichlorophenoxy acetic acid. In Vitro, 8, 416-417.

Mustonen, R., et al. 1986. “Effects of phenoxyacetic acids on the induction of chromosome aberrations in vitro and in vivo.” Mutagenesis 1(4):241-245.

Turkula, T.E. & Jalal, S.M. ( 1987) Induced clastogenicity in white rats by the herbicide 2,4-D. Cytologia, 52,275- 281.

Adhikari, N., & Grover, I.S. (1988) Genotoxic effects of some systemic pesticides: In vivo chromosomal aberrations in bone marrow cells in rats. Environ. Mol. Mutag., 12,235.: (2,4-D is clastogenic).

Mustonen, R., et al. 1989. ”Effects of commercial chlorophenolate, 2,3,7,8-TCDD, and pure phenoxyacetic acids on hepatic peroxisome proliferation, xenobiotic metabolism and sister chromatid exchange in the rat.” Archives of Toxicology 63:203-208.

Linnainmaa, K. (1983) Sister chromatid exchanges among workers occupationally exposed to phenoxy acid herbicides 2,4-D and MCPA. Teratog. Carcinog. Mutag., 3,269-279.

Ivett, J.L. (1990a) Mutagenicity test on 2,4-D acid. In vivo mouse micronucleus assay. Unpublished report No. 10979-o-455 from Hazleton Laboratories America, Inc., Vienna, VA, USA. Submitted to WHO by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA.

Ivett, J.L. (1990b) Mutagenicity test on diethanolamine salt of 2,4_dichlorophenoxyacetic acid in vivo mouse micronucleus assay. Unpublished report No. HLA 12216-0455 from Hazleton Laboratories America, Inc., Vienna, VA, USA. Submitted to WHO by PBI Gordon Inc, Kansas City, MO.

Ivett, J.L. (199Oc) Mutagenicity test on dimethylamine salt of 2,4-dichlorophenoxyacetic acid in vivo mouse micronucleus assay. Unpublished report No. 10981-o-455 from Hazleton Laboratories America, Inc., Vienna, VA, USA. Submitted to WHO by Industry Task Force II on 2.4-D Research Data, Indianapolis, Indiana, USA.

Cifone, M.A. (1990a) Mutagenicity test on 2,4-D acid in the in vitro rat primary hepatocyte unscheduled DNA synthesis. Unpublished report  No. 10979-0-447 from Hazleton Laboratories America, Inc., Vienna, VA,  USA. Submitted to WHO by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA.

Cifone, M.A. (1990b) Mutagenicity test on dimethylamine salt of 2,4-dichlorophenoxyacetic acid in the in vitro rat primary hepatocyte unscheduled DNA synthesis. Unpublished report No. 10981-0-447 from Hazleton Laboratories America, Inc., Vienna, VA, USA. Submitted to WHO by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA.

Cifone, M.A. (1990c) Mutagenicity test on 2,4-D-2-ethylhexyl ester in the in vitro rat primary hepatocyte unscheduled DNA synthesis. Unpublished report No. 10980-0-447 from Hazleton Laboratories America, Inc., Vienna, VA, USA. Submitted to WHO by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA.

Clausen, M., Leier, G. & Witte, I. (1990) Comparison of the cytotoxicity and DNA-damaging properties of 2,4-D and U46 Fluid (dimethylammonium salt of 2,4-D). Universität Oldenburg, Fachbereich Biologie, Federal Republic of Germany. Arch. Toxicol., 64, 497-501.

 

3. Structure activity relationship

2,4-DB:

MRID 40257501 Mackenzie, K. (1987) Lifetime Dietary Combined Chronic Toxicity and Oncogenicity Study in Albino Rats with 2,4-DB: Laboratory Project No. HLA 6158-103. Unpublished study prepared by Hazleton Laboratories America, Inc. 3095 p.

MRID 41936201   MacKenzie, K. (1987) Supplemental Raw Data: Lifetime Dietary Oncogenicity Study in Albino Mice with 2,4-DB: Lab Project Number: HLA-6158-104. Unpublished study prepared by Hazleton Laboratories America, Inc. 9 p

Above 2 studies: http://www.epa.gov/oppsrrd1/REDs/0196red_24db.pdf    Hazleton Labs studies sponsered by 2,4-D Task Force.

2,4-DP:  No references given.  Accession &I-DP: No evidence of carcinogenicity was seen following dietary administration of 2,4-DP (95%) to groups of male and female CD-1 mice (SO/sex/dose) at 0, 25, 100, or 300 ppm for 18 months or to groups of male and female Fischer 344 rats (SO/sex/dose) at 0, 100, 300, 1000 or 3000 ppm for 24 months (Accession No(s). 242035 b 255729).

MCPA (BASF Studies):

MRID: 40792301.   Kuhborth, B. (1986) Report: Carcinogenicty Study on the Oncogenic Potential of MCPA in Mice: Project No. 80S0046/8358. Unpublished study prepared by BASF AG. 1067 p. Data Quality: Acceptable Guideline (pre-1998).  Study Deficiences: Clinical Chemistry and Urinalysis Not Performed

MRID 40634101.  Kirsch, P. (1986) Report: Study on the Chronic Toxicity and Onco- genic Potential of MCPA in Wistar Rats: Final Report. Project No. 71S0046/8345. Unpublished study prepared by BASF Ag. 2026 p. Data Quality: Acceptable Guideline (pre-1998). Study Deficiences: LOAEL based solely on female effects at 80ppm or 5.7mg/kg/day.  Guideline No: 870.4300

MCPP: No studies

2,4,5-T:  Muranyi-Kovacs I, Rudali G, Imbert J. 1976. Bioassay of 2,4,5-trichlorophenoxyacetic acid for carcinogenicity in mice.  British Journal of Cancer 33:626-633. Laboratoire de Genetique, Fondation Curie, Institut du Radium, 26, rue d’Ulm, Paris 75005 (France). (We are highly indebted to Dr V. K.Rowe, Director of Toxicological Affairs, Health and Environmental Research of Dow Chemical U.S.A. for the analysis of 2,4,5-T used in our experiments. )

Kociba, R.J., D.G. Keyes, R.W. Lisowe, et al. 1979. Results of a two-year chronic toxicity and oncogenic study of rats ingesting diets containing 2,4,5- trichlorophenoxyacetic acid (2,4,5-T). Food Cosmet. Toxicol. 17: 205-221.  http://www.epa.gov/iris/subst/0262.htm ( Keyes and Kociba are employed by Research Laboratory, Dow Chemical, Midland, Michigan, 48640, USA over this time period)

2,4,5-TP: No studies

 

4. Subchronic and chronic toxicity. P.20

a. Subchronic toxicity studies

i. Mice.

Serota, DG. Subchronic toxicity and oncogenicity study in mice with 2,4-D acid. Hazleton Laboratories America Inc. Report No. 2184-100. 10/12/83. Funded by Industry Task Force: INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP,NUF. Accession No. 131303. HED Document No. 003888.

Schultze, GE. Subchronic toxicity and oncogenicity study in mice with 2,4-D acid.  Hazleton Laboratories America Inc. Report No. 2184-117.  8/16/91. Funded by Industry Task Force: ROP, AGR, NUF, DOE, BAS, AHM.  MRID 41991502. HED Document No. 008754.

ii. Rats

Serota, DG. Combined chronic toxicity and oncogenicity study in rats with 2,4-D acid. Hazleton Laboratories America inc. Report No. 2184-102. 10/12/83. Funded by Industry Task Force: INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP,NUF.  Accession No. 131304. HED Document No. 00388.

Schultze, GE. Subchronic toxicity and oncogenicity study in rats with 2,4-D acid.  Hazleton Laboratories America inc. Report No. 2184-116.  8/7/91. Funded by Industry Task Force RHONE-POULENC, AGROGOR (consortium Agrolinz ñ PBI Gordon), NUFARM, DOW, BASF, A.H. MARKS.  MRID 41991501. HED Document No. 008754.

iii. Dogs

Schultze, GE. Subchronic toxicity and oncogenicity study in dogs with 2,4-D acid.  Hazleton Laboratories America Inc. Report No. 2184-115.  12/14/90. Funded by Industry Task Force: ROP, AGR, NUF, DOE, BAS, AHM.  MRID 41737301. HED Document No. 008400.

Dalgard, DW. 13 Week Toxicity Study of 2,4-D in dogs. Hazleton Laboratories America Inc. Report No. 2184-125.  5/6/93. Funded by Industry Task Force: ROP, AGR, NUF, DOE, BAS, AHM. MRID 42780001. HED Document No. 010938.

c. Chronic Toxicity.  P.26

Rats & Mice: The two combined chronic toxicity/carcinogenicity studies in H6C3F1 mice and the two combined chronic toxicity/carcinogenicity studies in Fischer 344 rats are discussed earlier on Pages 6-12 of this document.   Which should result in the following studies:

i. Mice

Serota DG. Oncogenicity study of B6C3F1 mice with 2,4-D acid (1987).  Hazleton Laboratories America Inc. Report No. 2184-101. 1/25/87. Funded by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA.

MRID 43879801 Stott, WT, Johnson KA et al (1995).  2,4-D: Dietary Oncogenicity Study in B6C3F1 Mice – 2 year Final Report. Study ID K-002372-063F. Unpublished. The Toxicology Research Laboratory, Dow Chemical Co. Michigan. (50 Male mice). 0, 5, 62.5, 125mg/kg/day

MRID 43597201 Stott, WT, Johnson KA et al (1995).  2,4-D: Dietary Oncogenicity Study in Female Mice B6C3F1 Mice – 2 year Final Report. Study ID K-002372-063F. Unpublished. The Toxicology Research Laboratory, Dow Chemical Co. Michigan. (50 Female mice). 0, 5, 150, 300mg/kg/day

Rats

Serota, DG. Combined chronic toxicity and oncogenicity study in Fisher 344 rats with 2,4-D acid (1983a). Hazleton Laboratories America inc. Report No. 2184-102. 5/29/86. Accession No. 263112-263114. HED Document No. 004498. Funded by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA.

In pages 6-12 there is only one rat study.  Page 13:

MRID 43612001 (1995) Jeffries T, Yano B., Ormand J et al. 1995.  2 year 2,4-D Chronic Toxicity/Oncogenicity Studies in Fischer 344 Rats.  Unpublished. Prepared by Dow Chemical Co.  Health and Environmental Sciences.  50 females, 50 males. 0, 5, 75, 150mg/kg/day

ii. Dogs

Dalgard, DW. (1993d) 52 Week dietary toxicity study with 2,4-D acid in dogs. Unpublished report No. 2184-124 from Hazleton Laboratories America, Inc., Vienna, VA, (Or Hazleton Washington) USA. Submitted by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA. 12/2/93. MRID No. 43049001. HED Document No. 011271. 447p.

5.  Neurotoxicity.   P.27

Mattson JL., Jeffries TK., and Yano BL. 2,4-D: neurotoxicity study in Fischer 344 Rats – Final. The Toxicology Research Laboratory, Dow Chemical Co. Study ID K-002372-064N. 6/28/94.  MRID 43293901. HED Document 011614

 

II. EVIDENCE FROM EPIDEMIOLOGIC STUDIES.  pp28-42

1.Evaluation of studies

Epidemiological studies have suggested an association between exposure to chlorophenoxy herbicides (eg. 2,4-D and 2,4,5-T) specifically relating to soft tissue sarcomas and non-Hodgkins lymphoma (NHL).  Concludes studies are not consistent, associations’ found are weak and conflicting conclusions have been reached by the investigators.

(i) Soft-Tissue Sarcoma

Hardell L, Sandstrom A. 1979. Case-control study: soft tissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. British Journal of Cancer 39:711-717.

Eriksson et al., 1981: No reference

Vineis, P., Terracini, H_., Ciccone, G., Cignetti., A., Colombo, E., et al. (1986). Phenoxy herbicides and soft tissue sarcomas in female rice weeders, a population-based case-referent study. Scand. J. Work Fnvir. Hlth. 13: 9-17.

Smith A.H., Fisher, D.O., Giles, H.J., and Pearce, N. (1983). The New Zealand soft-tissue sarcoma case-control study: Interview findings concerning phenoxyacetic acid exposure. Chemosphere 12: 565.

Smith, A. H., Pearce, N.E., Fisher, D.O., Giles., Teague, C.A., and Howard, JK. (1984). Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. J. Natl. Cancer Inst. 73: 1111-1117.

Hoar, S., et al. 1986. “Agricultural herbicide use and risk of lymphoma and soft tissue sarcoma.” Journal of the American Medical Association 256: 1141-47.

Woods, J.S., Polissar, L., Severson, R.K., Heuser, L.S., and Kulander, H.G. (1987). Soft tissue sarcoma and Non-Hodgkin’s lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. J. Natl. Cancer Inst. 78: 899-910.

Coggon, D., Pannett, B., & Winter, P. (1991). Mortality and incidence of cancer at four factories making phenoxy herbicides. Brit. J. Ind. Med. 48: 173-178.

Saracci, R., Kogevinas, M., Alberto-Bertazzi, P., et al. (1991). Cancer motality in workers exposed to chlorphersoxy herbicides and chlorophenols. The Lancet. 338: No. 8774,

 

(ii) Non-Hodgkins Lymphoma

Hardell, L. (1981). Relation of soft tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids , chlorophenols and other agents- Scand .J. Work Environ. Health 7: 119-130.

Hoar, S., et al. 1986. “Agricultural herbicide use and risk of lymphoma and soft tissue sarcoma.” Journal of the American Medical Association 256: 1141-47.  As above

Woods, J.S., Polissar, L., Severson, R.K., Heuser, L.S., and Kulander, H.G. (1987). Soft tissue sarcoma and Non-Hodgkin’s lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. J. Natl. Cancer Inst. 78: 899-910.   As above

Pearce, N.E. (1989). Phenoxy herbicides and non-Hodgkin’s lymphoma in New Zealand: frequency and duration of herbicide use. Hrit. J. Ind. Med. 46: 143-144.

Pearce, N.E., Smith, A.H., Howard, J.K., Sheppard, R.A., and Teague, C.A. (1986). Non-Hodgkin’s lymphoma and exposure to phenoxyherbicides, chlorophenols, fencing work, and meat works employment: a case control study. Brit. J. Ind. Med. 43: 75-83.

Pearce, N.E., Shepard, R.A., Smith, A.H., and Teague, C.A. (1987). Non-hodqkin’s lymphoma and farming: an expanded case-control study. Int. J. Cancer. 39: 155-161.

Zahm, Shelia Hoar; Weisenburger, Dennis D.; Babbitt, Paula A.; Saal, Robert C.; Vaught, Jimmie B.; Cantor, Kenneth P.; Blair, Aaron (1990). “A Case-Control Study of Non-Hodgkin’s Lymphoma and the Herbicide 2,4-Dichlorophenoxyacetic Acid (2, 4-D) in Eastern Nebraska”. Epidemiology 1 (5): 349–356.

Weisenburger, D., Zahm, S.; Ward, M., et al. (1991). Non-hodgkin’s lymphoma associated with the agricultural use of herbicide: analysis by histologic type. Laboratory Investigation 62: 105A, Abstract No. 622.

Cantor, X.P., Blair, A., Everett, G., Gibson, R., Burmeister, L.F.,Brown, L.M. (1992). Pesticides and other agricultural risk factors for non-Hodgkin’s lymphoma among men in Iowa and Minnesota. Cancer Res. 52: 2447-2455.

Zahm, S.H., Babbit, P.A., Weisenburger, D.D., Blair, A., Saal. R.C., and Vaught, J.H (1993). The role of agricultural pesticide use in the development of non-Hodgkin’s lymphoma in women. Arch. Environ. Health 48:353-358.

Kogevinas, M., Kauppinen, T., and Winkelmann R, (1995). Soft tissue sarcoma and non-Hodgkin’s lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: two nested casecontrol studies. Epidezniology 6: 396-402.

Hayes et al 1991: Howard M. Hayes, Robert E. Tarone, Kenneth P. Cantor, Carl R. Jessen, Dennis M. McCurnin, and Ralph C. Richardson. Case-Control Study of Canine Malignant Lymphoma: Positive Association With Dog Owner’s Use of 2, 4-Dichlorophenoxyacetic Acid Herbicides.  JNCI J Natl Cancer Inst (1991) 83 (17): 1226-1231 doi:10.1093/jnci/83.17.1226. Cited by 134

Bond, G.G., Wetterstroem, N.H., Roush, G.J., McLaren, LA., Lipps, T.E & Cook, R.R (1988). Cause specific mortality among employees engaged in the manufacture, formulation, or packaging of 2,4- dichlorophenoxyacetic acid and related salts. Br. J. .Ind. Med. 45: 98-105

Wigle, D.T.,- Semeciw, R.M., Wilkins, K., Riedel, D., Ritter,. L., Morrison, H.I., and Mao, Y. (1990). Mortality study of Canadian male farm operators: non-Hodgkin’s lymphoma mortality and agricultural practices in Saskatchewan. J.-Natl. Cancer Inst. 82: 575-582.

Coggon, D., Pannett, B., & Winter, P. (1991). Mortality and incidence of cancer at four factories making phenoxy herbicides. Brit. J. Ind. Med. 48: 173-178.

Bolemen et al. 1993:  Not referenced. Possibly: Bloemen, L.J., Mandel, J.S., Bond, G.G., Pollock, A.F., Viteck, R.P., & cook, R.R. (1993). An update of mortality among chemical workers potentially exposed to the herbicide 2,4- dichlorophenoxyacetic acid and its derivatives. J. Occup. Med. 35: 1208-1212.

Persson B, Fredrikssan M,. Olsen R, Beoryd B,.and Axelson O. Some occupational exposures as risk factors for malignant lymphomas. Cancer 72:1173-1778, 1993.

Morrison HI; Semenciw RM, Wilkins K, Mao Y, and, Wigle DT (1994). Non-Hodgkin’s lymphoma and agricultural.practices in the prairie provinces of Canada. Scandinavian Journal of Work, Environment and Health 20: 42-47.

Waterhouse, D., Carman, W.J., Schottenfeld, D., Gridley, G., and McLean S. (1996). Cancer incidence in the rural cozmaunity of Tecumseh, Michigan: A pattern of increased lymphopoi.etic neoplasms. Cancer 77: 763-770.

2. Exposure Assessment – difficult to assess and therefore draw conclusions.

 

F. WEIGHT OF EVIDENCE CONSIDERATIONS.  P.43

1. Evidence of Carcinogenicity in animals.

The carcinogenic potential of 2,4-D has been evaluated in two independent studies with B6C3F1 mice:

(1)    MRID 43879801 Stott, WT, Johnson KA et al (1995).  2,4-D: Dietary Oncogenicity Study in B6C3F1 Mice – 2 year Final Report. Study ID K-002372-063F. Unpublished. The Toxicology Research Laboratory, Dow Chemical Co. Michigan. (50 Male mice). 0, 5, 62.5, 125mg/kg/day

(2)    MRID 43597201 Stott, WT, Johnson KA et al (1995).  2,4-D: Dietary Oncogenicity Study in Female Mice B6C3F1 Mice – 2 year Final Report. Study ID K-002372-063F. Unpublished. The Toxicology Research Laboratory, Dow Chemical Co. Michigan. (50 Female mice). 0, 5, 150, 300mg/kg/day

(3)    Serota DG. Oncogenicity study of B6C3F1 mice with 2,4-D acid (1987).  Hazleton Laboratories America Inc. Report No. 2184-101. 1/25/87. Funded by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA.  INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP,NUF. MRID 40061801. HED Document No. 005794.  Dosed 0,1,15 or 45mg/day for 104 weeks.

at doses ranging from 1 to 3oo mg/kg/day …

 

and in two independent studies with Fisher 344 rats at doses ranging from 1 to 150 mg/kg/day:

(1)    MRID 43612001 (1995) Jeffries T, Yano B., Ormand J et al. 1995.  2 year 2,4-D Chronic Toxicity/Oncogenicity Studies in Fischer 344 Rats.  Unpublished. Prepared by Dow Chemical Co.   50 females, 50 males. 0, 5, 75, 150mg/kg/day (Listed previously).

(2)    Serota, DG. Combined chronic toxicity and oncogenicity study in rats with 2,4-D acid (1983a). Hazleton Laboratories America inc. Report No. 2184-102. 5/29/86. Accession No. 263112-263114. HED Document No. 004498. Funded by Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana, USA. (Dow AgroSciences, Nufarm, Agro-Gor Corporation). 0, 1, 5, 15, 45mg/kg/day.

When administered in the diet of male and female 86C3F1 mice for 104 weeks at 0, l, 15 or 45 mg/kg/day, there were no increases in individual tumor types in any of the treated mice. The high dose was judged to be inadequate to assess the carcinogenic potential, therefore, another study was conducted at higher doses.  MRID 40061801. Serota DG 1987.

· In the second study, no increases in individual tumor types were seen when administered in the diet to male B6C3F1 mice at 0, 5, 62.5, or 125 mg/kg/day or to female B6C3F1 mice at 0, 5, 150, or 300 mg/kg/day for 104 weeks. (1) MRID 43879801 Stott, WT, Johnson KA et al (1995), (2) MRID 43597201 Stott, WT, Johnson KA et al (1995).

· Male and Female Fischer 344 rats were fed diets containing 2,4-D at 0,1,5,15,0r 45·mg/kg/day for 104 weeks. Astrocytomas of the brain were observed in both control and treated rats of both sexes. The incidences were: 1/60(1.6%),0/60,0/60,2/58(3.4%) and 6/60 (10%) in males and 0/60,1J60(1.6%),2/60(3.3%),1/60 (1.6%), and 1/60(1.6%) in females at O,1,5,15,0r 45 mg/kg/day, respectively  Serota, DG. (1983a) Report No. 2184-102.

· A positive significant trend (p = 0.0026) was seen in males. The incidence at the high dose (6/60;.10%), however, was not statistically significant (p = 0.702) when compared to controls (1/60; 1.6%). No statistical significance was seen in females. Serota, DG. (1983a) Report No. 2184-102.

· When compared to historical controls, the 10% incidence in males at the high dose slightly exceeded the historical control range (0 –4.4%) of studies conducted at the National Toxicology Program. Incidences in females were within the historical control range. Serota, DG. (1983a) Report No. 2184-102.

· The dose levels tested were judged to be inadequate to assess the carcinogenic potential, therefore, another study was conducted at higher doses.

· In the second study conducted to ascertain the astrocytomas seen in the first study, male and female Fischer 344 rats received 2,4-D in their diet at 0, 5, 75, or 150 mg/kg/day for 104 weeks. MRID 43612001 (1995) Jeffries T, Yano B., Ormand J et al. 1995.

· Astrocytomas of the brain were seen in 1/50 (2%) males and 1/SO (2%) females at 150 mg/kg/day compared to 0/50 in control males and 1/50 (2%).in control females. When compared to historical controls, the 2% incidence in both the control and treated rats were within the historical control range (0 – 4.4%). MRID 43612001 (1995) Jeffries T, Yano B., Ormand J et al. 1995.

· The lack of an increase in astrocytomas in the above study in which rats received 2,4-D at 150 mg/kg/day suggests that the astrocytomas reported in the earlier study (Serota 1983a) were an aberration and not treatment-related.

· In addition, characteristics generally attributed to a brain carcinogen were not seen in the earlier study in which astrocytomas were seen. There was no evidence of decreased tumor latency; the increase was limited to high-dose males, no preneoplastic lesions such as gliosis were present in treated rats, all tumors were solitary, and the tumors in treated rats were not larger or more anaplastic than generally seen in control rats.

In fact, the largest and most lethal tumor was the one – in the control male. Also, while most, if not all known brain carcinogens show clear genotoxicity in mutation assays,2,4-D was negative both in vitro and in vivo in most assays.

 

Note: Weight of Evidence considerations: all studies Dow or Industry Task Force II.

Note: Metabolism studies consist of only one Dow study.

The mutagenicity of 2,4-D has been studied extensively in a wide variety of in vitro and in vivo assays. 2,4-D was non mutagenic in several strains of Salmonella with and without metabolic activation, in a mouse bone marrow micronucleus, and UDS assays in rat hepatocytes. . Conflicting results were obtained in Drosophiliia; positive.effects were seen in larvae, while negative results were seen in adults after feeding or injection. Conflicting results were also seen in vitro mammalian cell cytogenetic assays; 2,4-D was negative for structural chromosomal damage up to an insoluble level but positive in the presence of metabolic activation at high doses. The positive evidence, however, tends to be weak and generally not supported by the data from in vivo cytogenetic assays. 2,4-D was non mutagenic in mammalian cell DNA repair assays. The lack of genotoxicity in in vitro bacterial and mammalian test systems with an exogenous source of metabolic activation provides evidence that 2,4-D is not metabolized to potentially reactive intermediates. Based on the overall pattern of responses observed both in in vivo and in vitro tests, 2,4-D was not mutagenic (although some cytogenetic effects were seen).  

Note: Mutagenicity studies consist of industry and independent studies.

2,4-D is structurally related to 2,4-DB, 2,4-DP, MCPA, MCPP, 2,4,5-T and 2,4,S-TP. No evidence of carcinogenicity was seen following dietary administration of 2,4-DB (Hazleton Laboratories, traditionally financed by Task Force II), 2,4-DP (no reference to author given) and MCPA (BASF studies) to mice and rats or 2,4,5-T (Kociba study by Dow affiliated scientists) to rats. No studies are available to assess the carcinogenic potential of MCPP or 2,4,5-TP.

Note: Structure-Activity Relationship studies consist of 2,4-D Industry Task Force, Dow, BASF and Dow connected research scientists.

 

2. Epidemiological Considerations.  P.45-46

Scientific Panels – please note the following panels review animal studies and epidemiological studies – this paper reviews the animal studies contained within these papers, which are used in combination with the epidemiological studies to assess cancer risk.

International Agency for Research on Cancer (IARC) 1987

A. Evidence for carcinogenicity to humans (limited for chlorophenoxy herbicides) Chlorophenoxy herbicides are possibly carcinogenic to humans (Group 2B).

Based on studies above: Coggon et al 1986; Hoar et al 1986; Woods et al 1987.

Other studies not included:  Wirklung et al 1987; Hardell & Axelson 1986; Balarajan & Acheson 1984; Kang et al 1986.

B. Evidence for carcinogenicity to animals (inadequate for 2,4-D  and 2,4,5-T)

IARC Monographs: 15, 111-138,1977; 15,273-299,1977; 30, 255-269,1983; Suppl. 6, 161-163, 233-236, 538-540, 1987.  Must be purchased – unavailable to general consultation.

  1. Long term study: Kociba, R.J., Keyes, D.G., Lisowe, R.W., Kalnins, R.P., Dittenber, D.D., Wade, C.E., Gorzinski, S.J., Mahle, N.H. & Schwetz, B.A. (1979) Results of a two-year chronic toxicity and oncogenic study of rats ingesting diets containing 2,4,5-trichlorophenoxyacetic acid (2,4,5- T). Food Cosmet. Toxicol., 17, 205-221. These scientists employed by Dow at this time.
  2. Newell, K.W., Ross, A.D. & Renner, R.M. (1984) Phenoxy and picolinic acid herbicides and small intestinal adenocarcinoma in sheep. Lancet, ii, 1301-1305

http://monographs.iarc.fr/ENG/Monographs/suppl7/suppl7.pdf

 Ontario Pesticide Advisory Committee of the Ontario Ministry of the Environment (Anders et al 1987).   “ Carcinogenicity of 2,4-D has been studied in 2 recently completed long-term cancer bio-assays, conducted in the US under the auspices of the Industry Task Force on Research Data”.   P. 30 & 34

  1. Serota D.G., Vargas K.J., Alasker R.D. and Matchotka S.M. (1986) Combined chronic toxicity and oncogenicity study  in rats with 2,4-D acid. Unpublished report No. 2184-103 from Hazleton  Laboratories America, Inc., Vienna, VA, USA. INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP, NUF Submitted to WHO by  Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana,USA.  0, 1,5, 15, or 45 mg/kg
  2. Serota, D.G. (1987) Oncogenicity study in mice with 2,4-D acid.  Unpublished report No. 2184-101 from Hazleton Laboratories America,  Inc., Vienna, VA, USA. INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP, NUF. Submitted to WHO by Industry Task Force II on  2,4-D Research Data, Indianapolis, Indiana, USA. 0, 1,15, or 45 mg/kg bw/day

 

Harvard School of Public Health Panel 1991 (Ibrahim et al 1991: Weight of the Evidence on the Human Carcinogenicity of 2,4-D Environmental Health Perspectives Vol.96, pp.213-333,1991 ). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1568222/pdf/envhper00416-0203.pdf  All animal studies quoted are Dow or Industry Task Force on 2,4-D.

Acute toxicity: Harvard Study quotes WHO (Dow and Industry Task Force) and Mattson (Dow) studies:

  1. Mattson. JL., Albee RR., Johnson KA., and Quast JF., Neurotoxicologic examination of rats dermally exposed to 2,4-D amine for three weeks. Neurobehav. Toxicol. Taratol. 8:255-263 (1986).  Dow Chemical Co. Michigan.
  2. Mattson JL., Johnson KA and Albee RR. Lack of neuropathalogic consequences of repeated dermal exposure to 2,4-dichlorophenoxyacetic acid in rats. Fundam. Appl. Toxicol. 6: 175-181 (1986). Dow Chemical Co. Michigan.  http://www.sciencedirect.com/science/article/pii/0272059086902745

Two carcinogen Bioassays:

  1. Serota D.G., Vargas K.J., Alasker R.D. and Matchotka S.M. (1986) Combined chronic toxicity and oncogenicity study  in rats with 2,4-D acid. Unpublished report No. 2184-103 from Hazleton  Laboratories America, Inc., Vienna, VA, USA. INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP, NUF Submitted to WHO by  Industry Task Force II on 2,4-D Research Data, Indianapolis, Indiana,USA.  0, 1,5, 15, or 45 mg/kg
  2. Serota, D.G. (1987) Oncogenicity study in mice with 2,4-D acid.  Unpublished report No. 2184-101 from Hazleton Laboratories America,  Inc., Vienna, VA, USA. INT, BAS, GIL, FAR, GOR, TRA, AHM, AZC, CHL, DOE, MOB&FER, ROP, NUF. Submitted to WHO by Industry Task Force II on  2,4-D Research Data, Indianapolis, Indiana, USA. 0, 1,15, or 45 mg/kg

 

  • 1992 Munro et al: Carlo, G. L., Cole, P., Miller, A. B., Munro, I. C., Solomon, K. R., and Squire, R. A. (1992). Review of a study reporting an association between 2,4- dichlorophenoxyacetic acid and canine malignant lymphoma: report of an expert panel. Regul. Toxicol. Pharmacol. 16, 245-252. Health and Environmental Sciences Group, Ltd., Washington, DC. (A department of Dow   PMID: 1293641.   This report paid for by Health and Environmental Sciences Group (a division/department of Dow) criticised the Hayes et al 1991 study:

Hayes et al 1991: Howard M. Hayes, Robert E. Tarone, Kenneth P. Cantor, Carl R. Jessen, Dennis M. McCurnin, and Ralph C. Richardson. Case-Control Study of Canine Malignant Lymphoma: Positive Association With Dog Owner’s Use of 2, 4-Dichlorophenoxyacetic Acid Herbicides.  JNCI J Natl Cancer Inst (1991) 83 (17): 1226-1231 doi:10.1093/jnci/83.17.1226. Cited by 134

US EPA: 1994 Joint Committee of the Science Advisory Board/Scientific Advisory Panel. Section 3.3. Animal Testing and Carcinogenicity: all studies supplied by Dow or Industry Task Force on 2,4-D.   P.17 Quotes the  (1) EPA 1996/7 review; (2) Harvard study (Ibrahim et al 1991); (3) Additional Rodent bioassays underway: Unreferenced but most likely:  Jeffries T, Yano B., Ormand J, Battjes JE (1995).  2 year 2,4-D Chronic Toxicity/Oncogenicity Studies in Fischer 344 Rats – Final. Study ID K-002372-064. HED Document 011934. Unpublished. Prepared by Dow Chemical Co.  Health and Environmental Sciences. MRID 43612001 (1995)  50 females, 50 males. 0, 5, 75, 150mg/kg/day.

Or this study by several of the same scientists:  Chronic Dietary Toxicity/Oncogenicity Studies on 2,4-Dichlorophenoxyacetic acid in Rodents. Charles, JM., Bond DM., Jeffries TK., Yano BL., Stott WT., Johnson KA., Cunny HC., Wilson RD., Bus JS., Bold highlighted Dow Chemical Co. employees.

“The data are however sufficient to require continued examination of the issue through further studies…..  to establish the exposure to 2,4-D and distinguish its effects from those of farming in general, and from other specific chemicals and pesticides used in the same environment”.

G. CLASSIFICATION OF CARCINOGENIC POTENTIAL.  P.48.

Nb.  Extract:  The CPRC agree that 2,4-D should remain classified as a Group D (not classifiable as to human carcinogenicity)….. There were no increases in astrocytomas in male rats (as were observed in the original study) ; however, the slides from all animals at the low and intermediate doses were not evaluated.   There was an increase in hemangiosarcomas of the spleen in the male mice at the low and mid-doses, which was not sustained at the highest dose; however, the slides from all animals at the low and intermediate doses were also not evaluated.

 

 

SAFESAYSWHO SUMMARY:

All rodent and animal studies to evaluate the carcinogenic potential of 2,4-D for this Peer Review (and indeed, all the scientific panels convened to assess 2,4-D) are prepared by Dow or directly funded by ‘Industry Task Force on 2,4-D’ or Industry Task Force II studies.

These studies cover:

  1. Long term Carcinogenicity
  2. Metabolisim
  3. Structure Activity Relationship (excepting one study).
  4. Chronic toxicity
  5. Sub-Chronic toxicity
  6. Neurotoxicity

Mutagenicity/Genotoxicity and epidemiological studies are supplied by a mix of industry and non-industry research.

However traditionally in risk evaluation it is results of the studies (1-6) that dictate permitted safe levels of exposure to the general population.

The Carcinogenicity Peer Review 1996 notes under 2. Epidemiological Considerations a number of other scientific panels, these panels evaluated rodent studies and epidemiological studies.

In epidemiological studies, it is difficult to quantify levels of specific pesticide exposure to the study participants due to the nature of farming – workers/sprayers over the farm year apply many different chemicals to the soil and plants.  Thus it is rare to see a distinct result in any evaluation. Most epidemiologic studies appear inconclusive.

It is interesting to note that in all studies, 2.4-D is never assessed in the complete form that it is applied to plants (with adjuvants etc), only in the pure chemical form.  Of the reproductive and developmental toxicity tests, it is accepted industry practice to never dose the study animal leading up to pregnancy or in the first 6 days (equivalent to the first trimester of the rat and mouse).

Similarly, there are no cumulative assessment studies currently held within these 2,4-D risk assessment papers which test more than one chemical.  Results of epidemiologic studies demonstrate the consistent difficulty in extracting results for a single chemical.  Workers traditionally apply a similar mix of applications year after year.  The EPA requirement that cumulative risk assessments require a common mechanism of toxicity.  However it would seem safer to evaluate based on the effect – for example neurotoxicity, and assess pesticides for (example: neurotoxic) properties rather than within pesticide families (Eg. Organophosphate) with similar toxicity mechanisms.

It is important to note that 2,4-D resistant corn and soy will act as a ‘stacked GMO trait’.  Therefore over the growing year both 2,4-D and the glyphosate formulation (commonly known as Roundup) will be sprayed on the same crop.  Yet at this stage there is no cumulative assessment requirement for 2,4-D and Roundup to be tested together.

And startlingly, current requirements for safety testing do not include developmental neurotoxicity.  Scientists are now finding that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides.

 

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