Document 2R5zzexoOgO3NgVOd73ZZq4bg

*L V ..... .-^ T g r k 10ul Lju-. S s n u ^ b ' d O .M ^ C M iJ u LM X . 8864 Mog EVALUATION OF TEE MUTAGENIC POTENTIAL OF 2,4,5-T AND TCDD IN RESPONSE TO A RPAR ON 2,4,5-T By B. A. Schwetz, D.V.M., Ph.D. Research Manager and K. S. Rao, D.V.M., Ph.D. . Research Specialist Toxicology Research Laboratory Health and Environmental Research Dow Chemical U.S.A. Midland, Michigan 48640 O DW 798844 Under tfie anunended Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the basic environmental standard for major regulatory determinations is "unreasonable adverse effects on the environment". The term is defined in Section 2 (bb) of the act to mean "any unreasonable risk to man or the environment taking into account the economic, social, and environmental costs and benefits of the use of any pesticide". The Environmental Protection Agency's registration guidelines establish the data requirements * for registration of a pesticide. Sections 162.84-1 to 162.8'*-5 of these guidelines establish the requirements for testing to establish the safety of compounds for mutagenic effects in order to register a compound. In making the determination that a rebuttable presumption has arisen, the registration regulations require the agency to take into account the type of effect, the statistical significance of the findings, and whether the tests were conducted in accordance with the material requirements for" valid tests as recognized by exper he- field. Section 162.3 (y) of the registration regul ^defines the term "mutagenic" as "the property of a substance or mixture of substances to induce changes in the genetic complement of either somatic or germinal tissue in subsequent generations". An important aspect of this definition is that the EPA considers the demonstration 17312 i 2^886A\OQ of heritable change as fundamental to identifying a compound as mutagenic and of potential concern for the health of humans. Multi-test evidence is necessary for assessing the mutagenic potential of a test substance since it is well recognized that it is unlikely that a single test system is capable of assessing all potential types of genetic change with sufficient sensitivity and, in addition, incorporate the toxicological concerns relevant to mammalian physiology and metabolism, as well. V J 1*i Many new test systems have evolved in recent years or are in the process of being developed presently, especially in the area of in vitro short-term tests to evaluate muta genic and carcinogenic potential. Nearly all of these tests suffer from lack of validation between laboratories and across different classes of chemicals. Until a satis factory. degree of reliability has been demonstrated for these tests, it does not seem appropriate to use the results of such tests for making critical regulatory decisions. For example, in regard to the microbial tests in particular, consideration must be given to the fact that it is impossible to simulate the route of exposure encountered by man in these tests, liver microsomes are not an accurate reflection of 17313. DOW798846 the integrated metabolic processees of an intact animal or even of an intact liver, such test systems circumvent the natural ability of the intact animal to deal with foreign substances through disposal of the material or its metabolites, and the influence of dose level upon response is not inter pretable. Therefore, the usefulness of these test systems even for the process of defining the needs for further testing has significant limitations. DOW 798847 The Environmental Protection Agency has issued a rebuttable presumption against registration (RPAR) of 2,4,5-T on the basis of two triggers, oncogenicity and teratogenicity/fetotoxicity (1). They concluded that there were insufficient data on the mutagenic potential of 2,4,5-T and TCDD, and that further testing was needed. Mutagenicity was not a trigger for the RPAR. The results of the laboratory tests to assess the mutagenic potential of 2,4,5-T and TCDD are summarized in Tables 1 andi 2, respectively. Our review of the literature revealed considerable additional information to that included in the RPAR Position Document 1. TESTS IN NON-MAMMALIAN SYSTEMS Negative results were reported by Anderson et_ al_. (2) in spot tests with salmonella; ten different phenoxyalkanoic acids and five commercial formulations containing these compougjda^ did not increase the frequency of back mutations. A group7of 110 different herbicides was evaluated for their ability to induce point mutations in one or more of four different microbial systems using histidine-requiring mutants of Salmonella typhimurium. The amount of 2,4,5-T used in the test plates was not indicated. 17315 Division of Pestici.ce j -- . _> .. ......... entitled "Mutagenesis Induced in Mutant Strains of Salmonella CO typhimurium by Pesticides" by Ercegovich and Rashid (3). 2,4,5-T was found to be "doubtfully mutagenic only after activation". In the absence of enzyme activation, 2,4,5-T was not mutagenic in any of the five strains of organisms (TA-100, TA-1535, TA-93, TA-1537, or TA-1538). In the presence of enzyme activation, there was no increase in the number of revertants in the frameshift strains (TA-98, TA-1537, or TA-1538); the increase in the number of revertants in the base substitution strains (TA-100 or TA-1535) was less than two-fold. This increase of less than a two-fold magnitude was referred to by the authors as a doubtful mutagenic effect; increases less than two-fold are generally not considered to represent a positive response in this test. Seibert and Lemperle (4) tested 32.herbicides for their ability, to induce mitotic gene conversion in a diploid strain of the yeast, Saccharomyces cerevisiae. The culture medium contained 1000 ppm 2,4,5-T; no evidence of mutagenic activity was found for 2,4,5-T. Shirasu and co-workers (5) conducted tests with the REC-assay procedure using H17 REC+ and M45 RECTM strains of Bacillus subtilis. The "dose" of 2,4,5-T was 20 yg/plate; no evidence of mutagenicity was found. 172IS as an in vitro cytogenetics test using cultured human lymphocytes. In all cases, no evidence of mutagenicity v;as observed with 2,4,5-T. The methodology employed was not described in sufficient depth to critically review che procedures used. Another study in Saccharomyces cerevisiae RAD18 has recently been reported by Zetterberg (7). 2,4,5-T was found to be mutagenic at an acidic pH but not in solutions with neutral pH. 2,4,5-T concentra tions in the range of 0.02-0.06 mg/ml were' evaluated over a range of pH values. The authors concluded that while 2,4,5-T caused mutations in acidic conditions, it was unlikely that mutations would be induced at neutral pH, such as would be found in gametes. Cells would apparently not take up the dissociated form of 2,4,5-T. Numerous:, mutagenicity studies have been conducted in the frui t : Drosophila melanogaster. In a study by Davring 'tx'if. ------ and Sunner (8) chromosomal defects in oocytes and nurse cells of Drosophila females were reported at very low concentrations of a commercial formulation of 2,4,5-T butcxyethyl ester. The significance of these observations 17317 250 ppm in the medium provided for the flies; Magnusson gave 2,4,5-T at a concentration of 1000 ppm. Several sex-linked recessive lethal studies have been reported in Drosophila. In a study reported by Mujumdar and co workers (10), Drosophila were given 2,4,5-T at concentra tions of 250 or 1000 ppm in their diet. A slight increase in sex-linked recessive lethals was found at the high concentration, 1000 ppm. In contrast to these positive findings, Vogel and Chandler (11) found no effect on the incidence of sex-linked recessive lethals in Drosophila given 2,4,5-T at concentrations of approximately 1000 and 2000 ppm in their diet._ As already indicated above, Magnuaaon- (9) found an increase in the incidence of direct recesi&ve^lethals in Drosophila given 1000 ppm 2,4,5-T in their diet. This was not accompanied by cytogenetic changes in the insects. 17 8 strain w m c n was unstaoie iui cue w i m e x u w u s w u x ^ . i 1 on introduction of foreign DNA in the white region; the system is based on forward mutations in the inserted D M A . There was no evidence of mutagenicity at 100 ppm of 2,4,5-T. TESTS IN MAMMALIAN SYSTEMS In addition to the above tests in non-mammalian systems, numerous tests have also been conducted in mammalian systems. Dominant lethal tests were performed in mice by Buselmaier (13) by injecting 100 mg 2,4,5-T/kg intraperitoneallv. The males were subsequently mated during six weeks after treatment with untreated females in order to assess all stages of spermatogenesis. There was no indication of an increased pre- or postimplantation loss. Buselmaier (13) also tested for point mutations in the host-mediated assay using Salmonella typhimurium and Serratia marcescens. 2,4,5-T caused no effect at a dose level of 500 mg/kg. Thus, 2,4,5-T was found to be negative in both the dominant lethal test and the host-mediated assay. 1721$ ........... i . . erythrocytes from the mouse bens marrow. In another ....... host-mediated assay by Styles (15), serum from rats treated with 2,4,5-T was used with h i s mutants of Salmonella typhimurium. 'Jo increase in the number'of mutants was observed. The results of several cytogenetic studies appear in the 2,4,5-T literature. In a study by Yefimenko (16) rats were administered 2,4,5-T at dose levels of 0.001-1 mg/kg. Chromatid.aberrations and chromosome adhesions were reported after a dose of only 0.01 mg/kg of the butylester of 2,4,5-T to male rats. This interpretation is based on the information contained in an English abstract and a -translation of the original article from the Russian literature. In a study translated from the Japanese literature (Fujita, 17), the effect of 2,4,5-T on cultured human lymphocytes is reported. The concentrations of 2,4,5-T ranged from 0.025-25 ug/ml. Chromosome and chromatid aberrations were reported, but as mentioned in the RPAR position document 1, it is not possible to distinguish whether this was a toxic effect or a potential genetic effect of 2,4,5-T. 17320 3853 An in vivo cytogenetics "study'was 'reported" o y inujumuai -w-* .. Hall (13) in which gerbils were given 2,4,5-T at dose levels of 10-100 mg/kg/day. Aberrations of chromosomes and chromatids were observed which may have been related to toxic effects rather than mutagenic changes. The judgment of the authors in their classification of aberrations has been challenged (Ramel, 19) and leaves the value of the data reported in this paper highly questionable. Another in vivo cytogenetics study was reported by.Davring and Hultgren (20) in which mice were dosed with a commercial 2,4,5-T ester formulation. Chromosomal aberrations were observed in the mouse bone marrow cells in this study but close examination of the data reveals that the effects may well be caused by the solvent and/or emulsifier used in the herbicide preparation and not by the 2,4,5-T itself. The same preparation was used in Davring's experiments in Drosophila (8). In addition to these published reports on studies of the mutagenic potential of 2,4,5-T, several additional pieces of unpublished data are included. An abstract published by Babbitt and co-workers (21) is attached regarding studies of the effects of 2,4,5-T on two human cell lines - spleen fibroblasts and lymphocytes. No data were included in the published abstract. 17321 O O C 3 n t L a l , t i n s r e S U JLU S U - 3 u ~ s u `n-x o .j n w _i_v_ . *w _ __ y . : -- in the overall assessment of mutagenic potential. In the case of 2,4,5-T, a study was conducted at the Dow Chemical Company in which Sprague-Dawley rats were maintained on diets providing dose levels of 2,4,5-T of 3, 10, and 30 mg/kg/day for three successive generations (22). Effects were not seen in this reproduction study which were suggestive of mutagenic effects of 2,4,5-T. If 2,4,5-T were a potent mutagen which caused changes v/hich were transmissable to subsequent generations, a reproduction study would reveal the effects of a potent mutagen. The results of this repro duction study, considered together with the rest of the data from all of the mutagenesis studies, indicate that 2,4,5-T is not a'mluUKi mutagen, r-- a-- ; m n 'yhrm i>w > The results of the mutagenicity studies on TCDD are summarized in Table 2. Hussain and co-workers (23) reported that TCDD was mutagenic by causing intercalation in bacterial systems. An increased frequency of mutations was found in E . coli Sd-4. No effects were seen in Salmonella typhimurium TA-1530, but increased mutation frequencies were seen in strain TA-1532, a i:i-'. c c University of California at Berkeley, to Dr. tv.iii .\ear U.S.D.A., dated 11 March 1974 contains additional information on the effect of TCDD in the Salmonella tester str ains developed by Ames (24). No evidence of mutagenic effects was observed in these tests. u\ Cl Two different mammalian tests have indicated a lack of mutagenic potential for TCDD. Khera and Ruddick (25) reported the results of a dominant lethal study in Wistar rats that were dosed with 4 or 8 yg TCDD/kg/dav for .7 consecutive days. The male rats were caged with untreated virgin females for 5 days during 7 sequential mating trials after dosage with TCDD. The dose levels administered were clearly toxic, since 11 of 20 and 2 of 20 male rats died after receiving 8 or 4 yg/kg/day, respectively. No dominant lethal effects were observed. An in vivo cytogenetics study in rats has been reported by Green and Moreland (26). In their study, rats were given 10 yg TCDD/kg orally five times in one week; additional groups of rats were given 5, 10, 15 or 20 yg TCDD/kg as a single dose intraperitoneally. Examination of the bone marrow of these rats revealed no increase in the incidence of chromosomal aberrations relative to control rats. Another unpublished study by Green is mentioned in a 17.3 TCDD/kg twice weekly for 13 weeks. An increase in the number of chromosome breaks occurred at dose levels of 2 arid 4 ug/kg in male rats and at 4 pg/kg in female rats compared to the frequency of chromosome breaks at the lowest dose level. The results of this latter study are not available for review and inclusion in this response. The results of the mutagenesis tests on TCDD indicate that under some test conditions, this chemical may be mutagenic in microbes. In whole animal mammalian tests, TCDD has not been found to be mutagenic in the reports of studies that have been available for review. The recent data of Sidney Green's representing rats which were dosed on a subchronic basis with TCDD will need to be examined before a more definitive answer can be_given regarding the mutagenic potential of TCDD in mammalian systems. Based upon the definition by EPA of the term "mutagenic" (the property of a substance or mixture of substances to induce changes in the genetic complement of either somatic or germinal tissue in subsequent generations), the results of studies of che mutagenic potential of 2,4,5-T do not indicate that this herbicide represents a mutagenic hazard. 17.324 demonstrated. CONCLUSION In conclusion, numerous studies have been conducted to evaluate the mutagenic potential of 2,4,5-T and TCDD in nonmammalian and mammalian test systems. None of the studies in microbial organisms indicate a significant mutagenic effect., for 2,4,5-T. One study in yeast indicated mutagenic changes at acidic pH's but not at a neutral pH as found in mammalian tissues. Positive and negative results were seen in studies in Drosophila. Tests in whole-animal mammalian systems have either indicated negative results (dominant lethal test, host-mediated assay and micronucleus test), or uninterpretable results (cytogenetic studies). Thus ,2,4,5-T S/iouU m mneos^sa^bfsis.stmC^isr=vavsx^ieeise3hsescait. 3 mutagen/ and might be classified, at most, as a weak mutagen in some test systems. 1 Additional data from on; laboratory which have not been published are reported to indicate a positive cytogenetic change in rats dosed subchronically with TCDD. The final evaluation of the mutagenic potential of TCDD should take these data into account when they become available. Saocharozyces revistan D, 3acillui suot H i s Z. coli (5-MT resistance) E. coll W<*L ft* strain) L000 ?po 2 yg/pUce 32 Herbicides were tested 166 Pse toldes were cesced N 1 ....... :.oc u s t e a 1 Not listed Serrada zarcescens (.a 1i aca a 7*2 strains) S. coll (screp. res iscanee) Saccharczvces cerevtsiae In Viera Cycogenetic (huzan ivzphocyces) Saccharczvces cerev:lae RAO 13 31 Pesticides were tested, verv liede descripcin or mvtnods O.2-O.C6 zg/ol J +> Mutations only ac pH < 4.5; nutations unlikely ac neutral pH as in gametes 6 7 Drosophila melano^aster (effect on oogenesis) 250 ppz In diet 50.1 Decrease in fortuity ac 2:0 ppz chromosome effects seen; unsubstan tiated in ocher teses 3 Orosophlla zelanogafrer (sex-licked recessive Lechal) 250, 1000 ppm in diet + Slight increase In sex-linked recessive Lechis ac 1000 ppm 10 Drosophila aeiar.oqascer 3.6, 7.2 zM (sex-Linked recessive lechal) (0.92, 1.34 zg/al) No effect on sex-linked recessive lecnaLs li Droaoohila melanogascer (in vivo cytogenetics) 1000 ppz in diet Same sample used by Davrlng and Sunner (1971) 9 Drosoohila zelanogaster (direct recessive lethal) 1000 ppz In diet" 9 Orosoohila melanoxaster (sooacic mutations) 25-200 ppra in diet Tested in genetically stable and unstable strains 12 Host-Mediated Assay and Dominant Lachal (mice) Micronucleus east (mouse) 100 mg/kg IP 100 33/Vg 13 U Host-Mediated Assay (salmonella typhlmurLua) 7 Used serum from rats dosed with 2,4,5-T (abstract) 15 In Vivo Cytogenetics (rats) 0 .001-1 zg/kg + Abstract and translation only 16 la Vitro Cytogenetics (human lymphocytes) 1 0 *7 -lO"1*) (0.025-25 -g/al) +? ' Not possible to cell If effect was mutagenic or toxic 17 In Vivo Cytogenetics (gerblls) 10-100 mg/kgMay + at 70 & Questionable classification ICO mg/kg of aberrations 18 In Vivo Cytogenetics (nice) Noe stated + Effect may have been due to solvent oc emulsifier .20 \'oc listed Not listed 172 173 Not listed Not L isted Not l i s t e d Not l l s t c c lot liste. Not l i s t * Not list*- 151 149 169 171 TABLE 2 Summary - Laboratory Teals l'or Mutagenicity of TCDD Test System Dose(s) Tested TCDD: Non-Mammalian Mutagenic Tests Ames Test and E. Coli up to 4.0 pg/plate Results + Ames Test Not stated i _ Comments - A memo to U.S.D.A. TCI)l)j__ Mammalian M u tagenic Tests Dominant Lethal (rats) 0, 4, 8 |ig/kg - High dose level lethal to some of the males In VJ_vo Cytogenetic (rats) 0, 5, 10, 15, 20 pg/kg - Abstract plus text of oral presentation Reference Number RPAR ' Reference Number 23 24 24 Not listed 25 6 26 119 CO to 00 098862. MOQ T98861 * Q O 1) Federal Racister, Dec. 73-10340, p 17115, April 31, xi' / Andersen, K. J., Leighty, E. G., and Takahashi, M. T. (1972) Evaluation cf herbicides for possible mutagenic properties. J. Agr . Food Chem. 20, 549-555. 3) Ercegovich, C. D. and Rashid, X. A. (30 August 1977) Mutagenesis induced in mutant strains of Salmonella typhimurium by pesticides. 174th American Chemical Society National Meeting, Division of Pesticide Chemistry. 4) Siebert, D. and Lemperle, E. (1974) Genetic effects cf herbicides: induction of mitctic gene conversion in Saccharomyces cerevisiae. Mutation Research 2_2, 111-130. 5) Shirasu, Y., Mori ya-, M., Kato, Furuhashi, A., and Kada, T. (1976) Mutagenicity screening of pesticides in the microbial system. Mutation Research 0_, 19-30. 6) Fahrig, R. (1974) Comparative mutagenicity studies with pesticides. IARC (International Agency for Researcn on Cancer) Scientific Publications 10, 151-131. 798862 7) Zettarberg, G. (1373) Genetic effects cf thencty acids on microorganisms. Ecol. 3uli. 27_, 193-204. 3) Oavrir.g, L. and S u m e r , M. (1971; Cytogenetic effects cf 2,4,5-trichiorophenoxyacetic ester on oogenesis and early embryogenesis in Drosophila melanogas ter. Hereditas 3[, 115-122. 9) Magnusscn, J., Ramel, C., and Eriksson, A. (1977) Mutagenic effects of chlorinated phencxy acids on Drcsoohila melar.ogas ter. Hereditas 85_, 121-123. 10) Majumdar, S. X. and Golia, J. K. (1974) Mutation test of 2,4,5-trichlorophenoxyacetic acid on Drosophila rr.eianogas ter. Can. J. Genet. Cvtcl. l_o_, 465-465. 11) Vogel, E. and Chandler, J.L.R. (1974) Mutagenicity testing of cyclamate and some pesticides in Drosoohila melanogaster. Experientia 30-, 621-623 . 12) Rasmuson, B. and Svahlin, H. (197S) Mutagenicity tests of 2,4-dichlorphenoxyacetic acid and 2 ,4 ,5 -trichlorophencxyacetic acid in genetically stable and unstable strains or Drosophila melanoaaster. Ecol. Bull. 27, 190-192. 13) Buselnaier, V. W., Rohrborn, >1utaganizacs-ur.cersuchuger. m assay ur.d mia dem dcainar.-ar. <7 i 0"' *?1 ' ;or JW -- * X f -U- 14) Jar.ssan, D. and Renberg, L. (19 76) Distribution and cytogenetic test of 2,4-D. and 2,4,5-T chencnyacecic acids in mouse blood tissues. Chen. Biol. Inceracc. 14_, 291-295. 15) Styles, J. A. (1973) Cytoucrcic effects of various pesticidas in vivo and in. vicrc . Mutacibn Research 2 1 , 50-51 (abstract). 15) Yefimenko, L. P. (1974) Materials for assessing the gonadotropic and mutagenic accicn of the herbicide 2.4.5- T butyl ester. Gig. Tr. Prof. Zabol. 13_, 24-27. (Pesticide Abstracts 1_, abstract =74-2335) . 17) Fujita, K., Fujita, H . , and Funazaki, Z. (1975) Chromospheric abnormalities brought about by the use of 2.4.5- T. J. Jap. Assoc. Rural Med. 24_, 77-7 9. 13) Majumdar, S. K. and Hall, R. C. (1973) Cytogenetic effects of 2,4,5-T on in_ v ivo bone marrow cells of Mongolian gerbils. Journal of Heredity 4_, 213-215. 7 OW 798864 13) Racial, C. (1973) Chlorinated phencxy acids dioxins : ganatics - summer-.-. Eccl. Bull. 27, 23) Davri.ng, L. and Hulcgren, (1977) Cytogenetic effects of in_ vivo bene marrev; calls of Mus musculus induced v/ior. a commercial 2,4,5-T ester product. Hereditas 33, 123-134. 3 a b b i t t , 3,., R i s e n , S . , C h o f f n e s , E . , K a l is , J . , Zupar.ic , B c o d y , G ., B e n s o n , D ., S p i e r , S., K l e e s e , R ., a n d W i c k s t r c m , J. (1972) E f f a c e s o f - ,-t, _ c n h u m a n chromcsoras. Generics 71, s3 (abstract) . Smith, F. A., Scnwetz, 3.' A., Murray, F. J., Crawford, A.. A., John, J. A., Kociba, R. J., and Humiston, C. G. (1973) Three-generation reproduction study of rats ingesting 2,4,5-- trichlorophenoxyacetic acid in the diet. RID Report Dow Chemical Co., U.S.A., Midland, Michigan. 23) Hussain, S., Ehrenberg, L . , Lofroth, G., and Gejvall, T. (1972) Mutagenic effects of TCDD on bacterial systems. AMBIO 1, 32-33. 24) Ames, B. M. (1974) Comnunication from D to Dr. ?. C. Kearnev. B. M. Ames i OW 798865 25 ) Kher a, K. 3. and Ruddi c :, J . A . (1973) Polpe c-di oxins : perinatal effects and "i*!" cr?rp.C issar rase . Chen:. Ser. 120, / o4 . Gresr., S. and Moreland, ?. cf several dioxins in the ra A. (1973) Tonisi ;-dio:<in. Chlorinated Pher.c Ecoi. Bull. 27, 134-144. 17233 6e8se^M oc 1062 M0?1 RESPONSE BY THE DOW CHEMICAL COMPANY TO THE ENVIRONMENTAL PROTECTION AGENCY'S DECISION AND EMERGENCY ORDER SUSPENDING REGISTRATIONS FOR CERTAIN USES OF 2,4,5-TRICHLOROPHENOXY ACETIC ACID (2,4,5-T) AND 2-(2,4,5-TRICHLOROPHENOXY) PROPIONIC ACID (SILVEX2 IN A NOTICE TO REGISTRANTS DATED FEBRUARY 28, 1979. 17334 DOW 7 9 8 8 4 0 -1- The Environmental Protection Agency (EPA) banned certain uses of '2,4,5-T and Silvex on February 28, 1979. This action was taken on the basis of reported miscarriages in certain areas of Oregon. The EPA concluded a causal relationship between the occurrence of these miscarriages and spraying of forests with 2,4,5-T. The Dow Chemical Company believes that such a conclusion is totally unjustifiable for numerous reasons, the most important of which are summarized as follows. 1) Inadequate data are reported to support EPA's conclusions.. The critical data needed to substantiate their conclusion (and therefore their action) are neither in the report nor available from EPA. 2) The data are uninterpretable because of sampling problems. EPA did not even measure the spontaneous abortion rates. Significant differences in medical care between the three areas make it impossible to draw conclusions because comparable data were-not collected in each area. In addition, the data were collected by two different teams off investigators, a practice which can easily bias results. DOW 7 9 8 8 4 1 -11- 3) EPA's evaluation of the data would more appropriately be called manipulation of numbers to support a precon ceived bias. A more objective evaluation showed no cause and effect relationships. 4) EPA's conclusion is in marked contrast with findings in other human populations throughout the world that have been exposed to 2,4,5-T and TCDD. Exposure of people to sufficient TCDD to cause non-reproductive toxicity (chloracne) did not cause malformations, abortions, stillbirths, or chromosomal damage. 5) Measurements made on animals and humans exposed to 2,4,5-T indicate that the maximum amount of 2,4,5-T and TCDD which could possibly have been absorbed, if any, by the residents of Alsea, Oregon, would be far too"low to be of any toxicological significance. A more in-depth critique_of EPA's report is included in the two attached documents entitled: 1. Critique of "Report of Assessment of a Field Investigation of Six-Year Spontaneous Abortion Rates in Three Oregon Areas in Relation to Forest 2,4,5-T Spray Practices". 173315 2 . Analysis of EPA Decision to Declare an Emergency Suspension of 2,4,5-T as Related to Studies in Animals. *oO 798842 17337 TABLE Summary - Laboratory Teats For Mutagenicity of 2,A,5-T Tost System Dnsu(s) Tested Husuits MPoustintgiuvne Employed Coiniucul s 2.A.5-T: Non-Mammullun Mutauenic Tests Ames Test Not stated _ Yes 110 Herbicides were tested Ames Test Drosophila Drosophila A.9 ug/plate 250 ppm 0, 250, 1000 ppm + + + Yes Doubtfully mutagenic after activation No 50X Decrease in fertility at 250 ppm chromosome effects seen Yes Slight increase in sex-linked recessive lethals Huloruncu Andersen. K. J. et al. 1972 J. Agr. Food Sci. ^20, 6A9 Ercegovich, C. D. and Kuuhid, K. A., 197 (unpublished) Davring and Summer, 1971 Heredltas* 68, 115 Mujumdar, S. K. and Golla, J. K., 197A Can. J. Genet. Cytol. 16, 465 2,A,5-T: Mammalian Mutagenic Tests Ilnst-Msd lai iul Assay uiul Dominant Lethal (mice) 500-1000 rag/kg IP to Vitro Cytogenetics (human iywphocyte) -7 -A 1U -11) M 7+ No No In Vivo Cytogenetics (garbila) in Vivo Cytogunetics (ml 10-100 mg/kg/day + St 70 & 100 mg/kg Not Minted + No ? - Not pussibls lu toll it' effect wns mutagenic or toxic - Uuselmaier, Von W. et al. 1972 Biol. Zbl. 91, 311 FuJItu ut nl . 1975 J. Jap. Assoc. Kurol Mud. 2A, 77 Mujumdar, S. K. and Hall, R. C., 1973 J. Heredity 64, 213 Dnvrlng and llultgren, 1977 llurwdltits. Bj), 12J-1JA o O * -can CooO ro M U1 DOW 798823 rug Chlordane Diazinon Phaltan Lmidan Paraquat TABLE A-3 (Continued) Safety Factor 5 21 470 20 10 Specleu Rat Rabbit Rabbit Rabbit Hice Route No-F.ffecc DoBe Dietary 1000 ppm Oral 7 ng/kg Oral 80 mg/kg Oral 35 ng/kg Oral 20 mg/kg Embryotoxic Effect - Teratogenic Effect - Observations - Reference Number 30 31 32 32 33 ' *Based on che no-effect dose level In teratology atudiej. C.Q CJ> C43 Maneb Zlneb Cnrb/iryl Thlrnm Ethylene Thiourea (ETU) Malatliion Trinzlne Cnptnn Dinoseb Mircx Dimechoate TAIiLtt_A-3 Snfety Factors For Selected IVai Ic U ch Embryotoxlc Teratogenic Safety Factor Spuciea Route No-Effect Done Effect I'.ffui-.t Obiter viic 1 1,852 Rat Oral 0.5 g/kg - 1 R/kg Exencep.-utly Phocomcj la 392 Rat Oral 1 .0 R/kg - 2 R/kR F.xencr:'ily Phocon>v ila 47 G. Pig, Oral 125 rag/kg lIuniHcer 250 mg/kg 300 mg/kg Cervlc*' 1 vi flJAClJ 543 Not Calculable Hamster Rat Oral Oral 0.8 Not Calculable Rat Rac Oral 7 125 mg/kR - 105 mg/kg ' - 250 mg/kg Skeletal. d< - 10 mg/kg Hydrocepha neural tu - 205 mg/kg Hydronephr - 30 mg/kg Cleft pale ai>Hcnt mi 223 Rabbit Oral 38 mg/kR 4 M ice Oral 20 mg/kg 75 mg/kg - Reaorptloi 32 mg/kg - Decreased; length Not Calculable Rat Dietary - 5 ppm - Decreased sire Not Calculable M ice 2.5 Rat Water Oral 25 mg/^g 60 ppm - Decreased eur\ ival 50 mg/kg " Subcu tarn min"; si effects S2886MO(7 $ Drug Vinyl Chloride Acrylonitrile Methyl Ethyl Ketone Chloroform ), l-Ulchliiruethans Carbon Tetrachloride Pentachlorophenol Cnptan 2,4,5-T TABLE A-2 Safety Factors For Selected Industrial Chemicals* No-Effect Dose TLV TLV Species 50 1 ppm Mice 2 20 ppm Hats <5 200 ppm Re t <3 10 ppm Rats 19 200 ppm Mu in <30 10 ppm Rats 5 0 .5 mg/m^ Rats ja 3 nig/in^ Rabbi L 10 10 mg/in'* Mice Route No-Effect Dose Inhal, 50 ppm Inhal, Intuii . 40 ppm <1000 Inlial, <30 Inini1, intuii. 3800 <300 PO S mg/kg PO Oral 37.5 mg/kg 20 Embryotoxic Teratogenic Effect Effect 500 ppm - 1000 ppm BO ppm - 30 ppm - 6000 - 300 - 15 og/kg - 75 Observations Reference Number Skeletal variants 13 Mulf. - variety 14 Skeletal variants 15 Skeletal variants Kkulutal variunLs 16 r.. Skeletal variants 15 Skeletal variants 17 Malformations lb 22 ^Based on the no-effect dose level in teratology studies. TABLE 5 Summary - Laboratory Tests For Mutagenicity of TCDD Test System Doae(s) Tested Results Positive Mutagen Employed Comments TCDD: Non-Mammalian Mutagenic Tesca Ames Teat and E. Coll up to 4.0 Mg/plate + No - Ames Test Not stated - Yea A memo to USDA TCDD: Hatomullan Mutagenic Tests Dominant Lethal (rata) 0, 4, 8 pg/kg - In Vivo Cytogenetic (rats) 0 , 5. 10, 15, 20 ag/kg - In Vivo Cytogenetics (rata) 0.001 - 1 mg/kg + No Highest dose level lethal to some of the males No Abstract only No Abstract and translation only # DOW 798826 Reference*I Hussain, S. et al, 1972 Amblo. _! 32-33 Ames, B. N., 1974 (unpublished) Khera, K. S. and Ruddlck, J. A., 1973 Advances In Chemistry 120, 70-84. Green, S. , 1975 Toxicol. Appl. Pharmacol. 33, 161 Yeflmenko, L. P., 1974 Gig. Tr. Prof. Zabol. 1, 24-27. i inI DOW798827 .J i i Dominant Lethal tests conducted at extremely high dose levels have shown negative results. This is a significant observation, especially when considered in conjunction with the results of other tests that have been conducted on these compounds. Vdfc-s. DOW 738828 also reported on a Dominant Lethal test with 2,4,5-T in NMRI mice at a dose level of 1,000 mg/kg administered intraperitoneally, with no indication of a dominant lethal effect. One additional piece of unpublished data is attached, consisting of a communication from Bruce Ames, Professor of Biochemistry, University of California at Berkeley, to Dr. Philip Kearney, USDA, dated 11 March 1974. Dr. Ames has evaluated the muta genicity of TCDD in his tester strains of Salmonella and has not found positive responses. An abstract published by Babbitt et al. is also attached regarding work in progress on the effect of 2,4,5-T on two human cell lines, spleen fibroblasts and lymphocytes. No data are included in this abstract. As indicated ir. the Document prepared by the Working Group on 2,4,5-T, there are significant limitations in the majority of the reports cited on mutagenicity studies on 2,4,5-T and TCDD. Considered collectively, the results of the tests do not indicate that either chemical is a potent mutagen. Generally, the results from iii vivo mammalian tests which assess germ cell mutation are the most relevant for predicting risks to humans. With each of these materials, the 17344 B288GA moo RPAJR OF 2,4,5-T: MUTAGENICITY The EPA has concluded that there are insufficient data on the mutagenic potential of 2,4,5-T and TCDD and that further testing is needed. The results of the laboratory tests to assess the mutagenic potential of 2,4,5-T and TCDD are summarized in Tables 4 and 5, respectively. Our review of the literature revealed very little additional information to that included in the RPAR Document No. 1 on 2,4,5-T. Two additional references on mutagenicity studies on 2,4,5-T are submitted to supplement the review by the EPA. A paper by Andersen et al^. (1972) is included which was an evaluation of 110 herbicides for their ability to induce point mutations in four different microbial systems. None of the herbicides, including 2,4,5-T, caused point mutations in 3 strains of Salmonella typhimurium as well as the T4 bacteriophage and E . coli. The second paper is by Buselmaier et_ al_. (1972) who evaluated a number of pesticides, including 2,4,5-T, in the Host-Mediated assay and the Dominant Lethal test in mice. The Host-Mediated assay was conducted in NMRI mice using mutants of the bacteria Salmonella typhimurium and Serratia marcescens introduced into the mice by intraperitoneal injection. No mutagenesis was found at 2,4,5-T dose levels of 500 mg/kg, and doses of the n-butyl ester of 2,4,5-T of 1,000 mg/kg. These investigators 5-, 1 '/ % 00886iM O Q 10u'4 RPAR OP 2,4,5-T: TERATOGENICITY/FETOTOXICITY AS A TRIGGER Summary The Environmental Protection Agency has issued a rebuttable presumption against registration (RPAR) of 2,4,5-T on the basis of two triggers, oncogenicity and teratogenicity. Regarding the latter, the EPA has concluded that an ample margin of safety does not exist for the population at risk (women of childbearing age) for dermal and inhalation exposure and for cumu lative oral, dermal, and inhalation exposure to both 2.4.5- T and TCDD. Dow contends that the risk is negligible to the developing embryo and fetus from the proper use of products containing 2,4,5-T. The teratogenic potential of 2,4,5-T and TCDD given to laboratory animals alone or in combination has been extensively investigated. In fact, few if any other pesticides, drugs, or industrial chemicals have been challenged to the extent that 2,4,5-T and TCDD have been studied. TCDD is teratogenic in mice but not rats. 2.4.5- T is teratogenic in mice but not rats, rabbits, hamsters, cattle, or primates at dose levels below one which produces maternal toxicity. Years of experience conducting teratology studies have taught us that mice are highly susceptible to any form of stress, including airplane travel, high temperatures, or high doses of materials as common as sugar, salt, 17348 DOW 79SC01 -2- and vitamins. Positive results in mice but not in other species of laboratory animals is generally not considered sufficient evidence to identify a chemical as a significant teratologic risk for humans. Studies in laboratory animals have shown that the presence of TCDD in 2,4,5-T products does not contribute to their teratogenic potential. In fact, TCDD must be present at concentrations many times greater than the present specifications will permit before the toxicity of TCDD becomes detectable. Thus, measures which protect against toxicity from 2,4,5-T are sufficient to protect against TCDD as well. Whether or not there is an ample margin of safety for any chemical depends on many factors, including the toxicity of the chemical, the likelihood of over exposure, and the effectiveness of control measures to prevent exposure. The EPA has used exaggerated figures for calculating the exposure level of applicators to 2,4,5-T products. This tends to decrease the apparent margin of safety. In the real world, the margin of safety for 2,4,5-T is at least as great as it is for other pesticides, drugs, or industrial chemicals which are not considered to pose a significant hazard to the population at risk. V '"2 DOW798803 -4- teratogenic effect is very often an acute exposure at a critical organogenetic period to an agent such as a chemical, infectious organism, or some form of energy. Chronic exposure is certainly not needed to cause a teratogenic effect. Teratogenicity is not dependent upon delayed toxic effects. The observation of the result of the insult might well be delayed on the basis of the duration.of gestation, but the injury is coincident with the time of dosage. There fore, I assume that this Toxicologic endpoint was classified as other chronic or delayed toxic effects simply as a matter of convenience rather than for a scientific reason. On page 66 of the document, the statement is made that a rebuttable presumption shall arise if chronic chemical exposure in test animals produces injury for the reproductive system and/or the fetus. This is inconsistent with the widely accepted principle of teratogenesis which states that tera togenic effects are related in a very time specific manner to dosage with an agent which results in an adverse effect. This point is important because the margins of safety that are considered appropriate for oncogenic effects are based on the assumption that animals or humans will be exposed to the potential oncogen on a chronic basis. The margin of safety for teratogenic potential must take into account DOW 798S04 -5- that this insult may be incurred on the basis of an acute exposure and chronic exposure is not necessary or may not be sufficient. Throughout the document, the majority of references to studies in the literature ignore the fact that the chemicals were given only on certain days o f .gestation. The dose levels used in the studies are defined on a mg/kg basis; in teratologic studies, it is critical to indicate that these dose levels are on a mg/kg/day basis on specified days of gestation only. Dosage in the majority of the studies ranged from a single day to periods of time greater than the duration of major organogenesis. Since the days of major organogenesis vary between species, it is critical to define the number of days of gestation during which the administration of chemicals is conducted. It is unfortunate that no attempt was made to standardize the terms used to describe the developmental variations observed in the reports. Such terms as "anomalies, malformations, fetotoxic, teratogenic, embryotoxic, deformities" were used in an apparent interchangable manner, usually quoting directly the phrases used by the authors in their reports. Admittedly, definitions vary between laboratories but perhaps the data could be made less inconsistent between laboratories if an effort 1 OOVV798805 -6- was made to standardize terms in reviewing literature. Another short-coming of the review is that all data appeared to be given equal weight and validity in the eyes of the Working Group. No judgement was made on the quality of the studies, which in some cases varied considerably from what would be considered an appropriate experimental design. In cases where studies have significant limitations based on experimental design, these short-comings should have been pointed out and taken into consideration in interpreting the results of the study and accepting the interpretations of the authors. For example, one of the studies cited was written by Sokolik, I. (1973; RPAR reference no. 131). The value of the information presented in this report is questionable compared to many of the other reports for several reasons. There are insufficient data presented to allow the reader to draw conclusions independent from those stated by the author; the amount of control data included is negligible; the number of animals per group is not stated; the author concludes that the teratogenic action of the compound is due to the presence of "dioxide" (I assume he means dioxin) but he does not specify the level of dioxin in the sample of 2,4,5-T; no reference is made to the maternal toxicity which surely must have been existent at the dose levels utilized; there is no indication of the number of fetuses examined or the number of resorptions observed in the litters. In addition, the findings in this study are 1735! DOW 798806 -7- inconsistent with those found with the trichlorophenoxyacetic acids in numerous other studies in rats. Because of all of these limitations, it is difficult to give the same credence to the results of this study as to the other studies which were conducted in a more appropriate manner. Another study was cited in a manner which precluded comparison of the data to the results of other studies cited. In the paper by Courtney (1977; RPAR reference no. 134, correct reference is Arch. Environm. Contam. Toxicol. , 33-46, 1977), the dose levels were expressed on a millimolar basis, thus requiring conversion to a weight basis for comparison to all other data. The conversion is as follows: 1.00 mM/kg = 255.5 mg/kg, 0.80 mM/kg = 204.4 mg/kg, and 0.45 mM/kg = 115.0 mg/kg. The number of pregnant mice per experimental group in this study was very small. Half of the 2,4,5-T - groups consisted of only 5-6 litters; a significant proportion of the fetuses from these few litters was resorbed, leaving very few fetuses upon which to make a scientific judgement. The Working Group was also fairly selective in citing conclusions by authors. For example, in the study reported by Collins and Williams (1971; RPAR reference no. 124), the conclusion of the authors is included, that 2,4,5-T is teratogenic in the hamster, but no mention is made of the 1 < 2 0 9o-~*N W* DOW 798807 -8- author's conclusion that based on these data, there is no indication that 2,4,5-T represents a hazard to humans. With in this report, the authors state that "there is a wide margin of safety between the exposure levels of 2,4,5-T permitted by registered uses existing prior to April, 1970, on food crops and the levels producing teratologic changes in the hamsters used here. Since April, these uses have been cancelled so that the amount of 2,4,5-T now in use has still further decreased the possible hazard to humans". Such conclusions by authors should not have been, ignored by the Working Group. The results of reproduction and teratology studies should have been kept separate and distinct from each other. Since teratologic studies are acute in design and reproduction studies are designed to evaluate the effect of chronic exposure to chemicals, the findings of the two different kinds of studies cannot be equated. For example, on page 79 of the document, reference is made to "preliminary data from Dow (110) indicate that TCDD may have effects at 0.01 yg/kg in rats". This statement is in reference to the results of a reproduction study but is included in the middle of a paragraph describing the results of teratologic studies. Such statements should be amended to indicate that it is in reference to a threegeneration reproduction study to avoid the possible confusion between the two types of studies. 1 ."V DOW 738808 -9- Overview on Teratogenicity of 2,4,5-T and TCDD: The risk to the developing embryo and fetus of humans from the proper use of products containing 2,4,5-T is negligible. The teratogenic potential of 2,4,5-T and TCDD given to laboratory animals alone or in combination has been exten sively investigated. In fact, few if any other pesticides, drugs, or industrial chemicals have been evaluated to the extent that 2,4,5-T and TCDD have been studied. A large number of teratology studies have been conducted using a variety of laboratory and non-laboratory animal species. Studies have been reported on mice, rats, hamsters, rabbits, sheep, Rhesus monkeys, and reindeer, using samples of 2,4,5-T with varying degrees of purity. The content of the contaminant TCDD ranged from <0.01 ppm to approximately 45 ppm. In certain studies, 2,4,5-T and TCDD were administered simultaneously, using dose-levels of 50 to 100 mg/kg/day of 2,4,5-T in combina tion with 0.01 to 3 ug/kg/day of TCDD. Considered overall, the studies indicate that purified 2,4,5-T is teratogenic in mice; dose levels of 45 mg 2,4,5-T/kg/day or higher were generally associated with cleft palate and/or kidney malfor mations in mice. Studies conducted at the National Center for Toxicological Research (Highman el: al_. 1977, RPAR reference No. 45) indicate that the reported fetal "cystic kidneys" in offspring of mice given 2,4,5-T were due to a retardation 17354 DOW 798809 -11- sub-human primates at dose levels below one which produced maternal toxicity. Such a data set would generally not be considered sufficient evidence to identify a chemical as a significant teratologic risk for humans. Regarding the effects of 2,4,5-T and TCDD in combination, studies in three different species of animals have indicated that a TCDD level in 2,4,5-T of 1 ppm or less does not enhance or potentiate the toxic effect of 2,4,5-T. In a teratology study conducted here at The Dow Chemical Company (unpublished data) the effect of 2,4,5-T alone was compared to the effect of 2,4,5-T administered in combination with TCDD to Sprague-Dawley rats. Purified 2,4,5-T was administered on days 6 through 15 of gestation at one dose level, 50 mg/kg/day. In addition, these rats were dosed with 0.01, 0.03, 0.06, 0.125, 0.5, or 1 yg TCDD/kg/day. Both materials were administered orally. Hemorrhage in the intestineal wall was observed at dose levels of 0.06 yg/kg/day TCDD and higher. Cleft palates were observed at 0.5 and 1 yg/kg/day given in combination with 50 mg/kg/day of 2,4,5-T. Therefore, at a dose level of 50 mg of 2,4,5-T/kg/day, 2,4,5-T would have to contain more than 1 ppm TCDD to cause intestinal hemorrhage and would require more than 10 ppm to cause a teratogenic effect, that is, cleft palate. A copy of this reported data is attached. 0T8861Moa in fetal renal development and down-growth of the renal papilla into the pelvis of the kidney. Thus, 2,4,5-T is not a renal teratogen in mice but simply retards the normal development of the fetal kidney. Cleft palate, then, is the one malformation in mice which is relatable to dosage with 2.4.5- T. Cleft palate is the most easily induced malformation in most strains of mice, being induced by most forms of stress including such things as airplane travel, high temperatures, or high dose levels of materials as common as sugar, salt, and vitamins (Golberg, 1971, Fd. Cosmet. Toxicol. 9_, 65-80). 2.4.5- T was not found to be teratogenic in other species of mammals. The one study in rats in which malformations were found is a study which is difficult to interpret because of the lack of information included in the report (Sokolik, 1973, RPAR reference No. 131). Even at high dose levels, administration of 2,4,5-T to mammalian species other than the mouse was associated primarily with adverse effects on the development of the skeletal structures, changes which reflect retarded development rather than malformations and are very likely associated with the stress of being given large doses of 2.4.5-T rather than the direct action of the agent with the genetic material of the embryo or fetus. Collectively, 2.4.5- T has caused cleft palate in some strains of mice and is not teratogenic in six other species of animals, including 17358 DOW 798811 -12- Courtney and Moore (1971; RPAR reference No. 128) , conducted a study in which mice were dosed with 100 mg/kg/dav of analytical grade 2,4,5-T plus 1 ug/kg/day of TCDD. The additional TCDD did not potentiate the effect of 2,4,5-T given alone; thus, a dose equivalent to 2,4,5-T containing 10 ppm TCDD was no more toxic to the developing embryo and fetus of mice than 2,4,5-T with less than 0..05 ppm of TCDD. In hamsters, Collins and Williams (1971; RPAR reference No. 124), studied the effect of 2,4,5-T containing various levels of TCDD. No fetal abnormalities were observed at dose levels of 2,4,5-T at or below 80 mg/kg/day. Among groups of hamsters dosed with 2,4,5-T containing 0.1, 0.5, 2.9 and 45 ppm of TCDD, only the highest TCDD level (45 ppm) clearly increased the toxicity of 2,4,5-T to hamster embryos and fetuses. In another teratology study in mice, Neubert and Dillman (1972, RPAR reference No. 127) studied the teratogenic effects of 2,4,5-T in mice along with TCDD. A potentiation of the teratogenic effect of 2,4,5-T and TCDD (based on the incidence of cleft palate) was observed when teratogenic doses of one substance were combined with a threshold dose of the other. However, for such potentiation to occur, more than 1.5 ppm TCDD was required. The authors concluded that a TCDD content of less than 1 ppm did not cause such an effect. 17357 DOW 798812 TCDD is teratogenic in mice but not in rats. As with 2,4,5-t , the manifestations in mice include abnormalities of the kidney and cleft palate. In rats, the primary effect observed was death of the embryos or fetuses rather than malformations. The no-effect dose levels of TCDD, as noted in the RPAR document No. 1, are such that TCDD does not contribute to the potential hazards of 2,4,5-T. In summary, numerous studies in laboratory and non-laboratory animals have indicated that the risk is negligible to the developing embryo and fetus from the proper use of products containing 2,4,5-T. In addition, the presence of TCDD in 2.4.5- T does not contribute to the teratogenic potential of 2.4.5- T. TCDD must be present at concentrations many times greater than the present specifications will permit before the toxicity of TCDD becomes detectable. Comments On The Margin Of Safety Of 2,4,5-T: The margin of safety for any chemical depends on numerous factors, including the inherent toxicity of a chemical, the likelihood of over-exposure and the effectiveness of control measures to prevent exposure. The hazard associated with exposure to a chemical is a function of inherent toxicity and the amount of exposure. As already discussed in the preceeding section, 2,4,5-T and TCDD are not considered to be DOW 798813 14 potent teratogens across species. TCDD is embryotoxic and fetotoxic at very low dose levels in laboratory animals but the exposure of humans is such that the hazard is considered negligible. The EPA has estimated the amount of exposure of applicators using 2,4,5-T products. Their estimates of exposure are based on assumptions and exaggerated figures which are not supportable by actual observations on people spraying 2.4.5- T. Based on pharmacokinetic data in humans and the excretion of 2,4,5-T by spray applicators, an estimate of the actual dose of 2,4,5-T has been calculated and is presented elsewhere in this rebuttal. Based on those calculations, the lowest margin of safety under any condition of use of 2.4.5- T products is greater than 50. This is considerably greater than the margins of safety calculated by the EPA. Their use of exaggerated figures for calculating exposure tended to decrease the apparent margin of safety. In reality, the margin of safety for 2,4,5-T is at least as great as it is for many other drugs, industrial chemicals, or pesticides which are not considered to pose a significant hazard to the population at risk. For example, the informa tion summarized in Table 1 includes calculated safety factors for selected drugs. Many of the drugs, including ones which -15- , 798814 are routinely taken by pregnant women, have margins of ^ safety somewhat lower than 50. For example, based on a tera- ^ tology study, the margin of safety for aspirin is only 3; on the basis of results of a reproduction study, the margin of safety is less than 2. The margin of safety for meclizine, a drug commonly used to treat the symptoms of morning sickness during pregnancy, is only 12. The safety factors for a number of chemicals commonly encountered in the industrial workplace are summarized in Table 2. Again, the margins of safety for this group of widely encountered industrial chemicals are all in the range of 50 or less. A Threshold Limit Value (TLV) has been established for each of these chemicals and defines what is accepted to be a safe level of exposure for a 40 hr work-week. The TLV for 2,4,5-T 3 is 10 mg/m of air; based on the tidal volume of humans doing light work the margin of safety is 10. Thus, the branches of government which regulate the exposure limits for chemicals in the workplace consider a margin of safety of 10 to be sufficient for 2,4,5-T. The safety factors for a number of pesticides is, summarized in Table 3. Pesticides were selected on the basis of the use of the compound and the availability of teratologic data. In searching for references on these chemicals, it was obvious that in no case was there as much teratologic data 11 6 ^ DOW 798815 -18- Positive results in mice but not in other species of laboratory animals is generally not considered sufficient evidence to identify a chemical as a significant teratologic risk for humans. Studies in laboratory animals have shown that the presence of TCDD in 2,4,5-T does not contribute to the teratologic potential of 2,4,5-T. In fact, TCDD must be present at concentrations many times greater than present specifications will permit before the toxicity of TCDD becomes detectable. Thus, measures which protect against toxicity from 2,4,5-T are sufficient to protect against TCDD as well. Whether or not there is an ample margin of safety for any chemical depends on numerous factors including the inherent toxicity of a chemical, the likelihood of over-exposure, and the effectiveness of control measures to prevent exposure. By using exaggerated figures for calculating the exposure level of applicators to 2,4,5-T products, the EPA has estimated margins of safety which are somewhat lower than the margins which actually exist under use conditions. Based on data collected on spray applicators, the margin of safety under real world conditions exceeded a factor of 50. This is at least as great as the margin of safety for many other drugs, industrial chemicals, or pesticides to which women are exposed during pregnancy which are not considered to pose a significant hazard to the population at risk. Thus, 2,4,5-T 736 Conclusions : oO 798816 The PA has issued a rebuttable presumption against reregistra tion of 2,4,5-T on the basis of two triggers, oncogenicity and teratogenicity. Regarding the latter, the EPA has concluded that an ample margin of safety does not exist for the population at risk (women of childbearing age) for dermal and inhalation exposure and for cumulative oral, dermal, and inhalation exposure to both 2,4,5-T and TCDD. The hazard associated with the use of any chemical is a function of the inherent toxicity of the chemical and the amount of exposure. In the case of 2,4,5-T, the risk to the developing embryo and fetus from the proper use of products containing 2,4,5-T is negligible. The teratogenic potential of 2,4,5-T and TCDD given to laboratory animals alone or in combination has been extensively investigated. In fact, few if any other pesticides, drugs, or industrial chemicals have been evaluated to the extent that 2,4,5-T and TCDD have been studied. TCDD is teratogenic in mice but not rats. 2,4,5-T is teratogenic in mice but not rats, rabbits, hamsters, cattle, or primates at dose levels below one that produces maternal toxicity. The evidence of teratogenicity in mice is limited to cleft palate in certain strains of mice, a finding which is shared by many other chemicals or other forms of stress including such things as airplane travel, high temperatures, or high doses of materials as common as sugar, salt, and vitamins. uuw 798817 -16- as for 2,4,5-T. In some cases, the published data on these chemicals is limited to studies in chick embryos. The safety factors were calculated using the same assumptions as were used by the EPA for 2,4,5-T regarding the amount of exposure and the absorption through skin. The directions on the labels of these pesticides were used to calculate the dose level to the user of the pesticide. Approximately half of the materials have a safety factor of less than 50. The lowest safety factor, less than 1, was found for malathion. The information contained in Tables 1 through 3 indicate that margins of safety in the range of 5 to 50 are not uncommon for a large number of common chemicals to which women of childbearing age are routinely exposed. This includes widely used drugs, chemicals in the work environment, as well as pesticides. In the case of 2,4,5-T, the margin of safety under work conditions with no special precautions exceeds a factor of 50. This far exceeds the margin of safety for many chemicals to which the population at risk is commonly exposed. Thus, in addition to 2,4,5-T and TCDD not being potent teratogens, the margin of safety based on level of exposure also indicates that there is negligible risk to users of 2,4,5-T products. DOW 73gi -19- and TCDD are not considered to pose a significant risk to the developing embryo and fetus under conditions of use of 2,4,5-T products. CO 619861 MO -20- D TABLE 1 Safety Factors For Selected Drugs _________ Drug___________ Dilantin (anticonvulsant) Valium (tranquilizer) Phnobarbital (anticonvulsant) Meclizine (antihistamine) Norethindrone (progestin) Norethynodrel (progestin) Vitamin A Acetazolamide (diuretic) Morphine (analgesic) Aspirin: teratology - reproduction Acetaminophen (analgesic): reproduction - Safety Factor* 20 170 10 12 50 4 40 7 666 3 <2 <6 *The no-effect dose level in teratology studies divided by the therapeutic dose for humans. See Appendix Table A-l for further data on the drugs listed. -21- ZOa TABLE 2 Safety Factors For Selected Industrial Chemicals G00O0 roo Drug Vinyl Chloride Acrylonitrile Methyl Ethyl Ketone Chloroform 1,1-Dichloroethane Carbon Tetrachloride Pentachlorophenol Captan 2,4,5-T Safety Factor* TLV 50 1 ppm 2 20 ppm <5 200 ppm <3 10 ppm 19 200 ppm <30 10 ppm 5 0.5 mg/m^ 3 38 5 mg/m 10 10 mg/m^ *The no-effect dose level in teratology studies divided by the current TLV. See Appendix Table A-2 for further data on the chemicals listed. 0'S' \ Dow 738821 -22- TABLE 3 Safety Factors For elected Pesticides __________ Drug_________ Maneb Zineb Carbaryl Thiram Ethylene Thiourea (ETU) Malathion Triazine Captan Dinoseb Mirex Dimethoate 2,4-D Chlordane Diazinon Phaltan Imidan Paraquat Safety Factor* 1,852 392 , 47 543 Not Calculable** 0.8 Not Calculable** 223 4 Not Calculable** Not Calculable** 2.5 5 21 470 20 10 *Based on the no-effect dose level in teratology studies. **A no-effect dose level was not established. See Appendix Table A-3 for further data on the pesticides listed. 17  DOW798822 TABLE 4 Summary - L ab o rato ry T e sts For M u tag en icity o f 2 ,4 ,5 -T T est System D ose(s) Tested R esults P ositive M utagen E m ployed Comments 2 ,4 .5 -T : Non-Mammalian M utagenic T e s ts . Ames T e st Not sta te d - Yes 110 H erb icid es were te ste d Ames T est D rosophila D rosophila 4.9 p g /p late 250 ppm 0 , 250, 1000 ppm + + + Yes Daocut bi vtfautliloyn m u ta g e n ic a f t e r No 50% D e c re a s e in f e r t i l i t y a t 250 ppm chrom osom e e f f e c t s seen Yes S lig h t In crease in sex -lin k ed recessive leth als 2 ,4 ,5 -T : Mammalian M utagenic T e sts H ost-M ediated Assay and Dominant L eth al (m ice) 500-1000 mg/kg IP - No - In V itro C ytogenetics (human lym phocytes) In Vivo C y to g en etics (g e rb ils ) In(mViciveo) C y to g e n e tic s 1 0 " 7-10"*M ?+ No 10-100 m g/kg/day Not sta te d + at 70 & 100 mg/kg + No ? Not p o ssib le to t e l l if e ffe c t was m utagenic or to x ic - - R eference A ndersen, K. J . e t a l. 1972 J . Agr. Food S ci. 20, 649 E (ruc ne gp ou vb ilcishh,e dC). D. an d R a s h id , K. A ., 1977 DHa verriendgitaansd. S68u^m, m1e1r5, 1971 M ujumdar, S. K. and G o lia, J . K ., 1974 Can. J . G enet. C ytol. 16, 465 B u s e lm a ie r, Von W. e t a l . 1972 B io l. Zbl. 91, 311 F u jita e t al_. 1975 J . J a p . A ssoc. R u ra l Med. 2 4, 77 M ujumdar, S. K. and H a ll, R. C ., 1973 J . H ered ity 64, 213 D avring and H ultg ren, 1977 H ered itas. 85, 123-134 ( :j C'J E38864 MOQ Drug C hlordane D iazinon P h a lta n Im idan Paraquat TABLE A-3 (Continued) Safety Factor 5 21 470 20 10 S p e c ie s Rat R abbit R abbit R abbit M ice Route N o-E ffect Dose D ie ta ry 1000 ppm O ral 7 mg/kg O ral 80 mg/kg O ral 35 mg/kg O ral 20 mg/kg Em bryotoxic E ffect - T eEr aftfoegc et n ic - O bservations - RNe fuemrbeenrc e 30 31 32 32 33 *Based on the n o -e ffe c t dose le v e l in te ra to lo g y s tu d ie s. G "s7. CCw'J Q TABLE A-3 Safety Factors For Selected P esticid es* Safety Factor 1,852 S p e c ie s Rat R o u te O ral N o-E ffect Dose 0.5 g/kg E m bErfyfoetcotx ic - 392 Rat O ral 1.0 g/kg - 47 543 Not C alculable GH.a mPsitge ,r Ham ster Rat O ral O ral O ral 125 rag/kg 125 mg/kg - 250 mg/kg - 0.8 Rat Not C alculable Rat O ral 105 mg/kg ?- - 223 R abbit O ral 38 mg/kg 4 Mice O ral 20 mg/kg 75 m g/kg 32 mg/kg Not C alculable Rat D ietary - 5 ppm Not C alcu lab le Mice W ater - 60 ppm 2.5 Rat O ral 25 mg/kg 50 mg/kg T eratogenic E ffect 1 g/kg 2 g/kg 300 mg/kg 250 mg/kg 10 mg/kg 205 mg/kg 30 mg/kg - - - O bservations R eference Number Exencephaly and Phocom elia 20 Exencephaly and Phocom elia 20 C ervical vertebrae fused 21 S keletal defects 21 H ydrocephalus, neural tube d efects 22 H ydronephrosis 23 C left p a la te and absent m andible 24 R esorptions 25 D ecreased fe ta l le n g th 26 D ecreased li t t e r size 27 Dseucrrve aivseadl pup 28 Subcutaneous edema and m inor sk e le ta l e ffe c ts 29 798S24 DOW 798825 Drug V inyl C hloride A crylonitrile M ethyl E thyl K etone C h lo ro fo rm 1 ,1-D ichloroethane Carbon T etrac h lo rid e P e n ta c h lo ro p h e n o l C ap ta n 2 ,4 ,5 -T TABLE A-2 S afety F acto rs For S elected In d u s tria l C hem icals* N o-E ffect Dose TLV TLV S p e cies 50 1 ppm M ice 2 20 ppm R ats <5 200 ppm R at <3 10 ppm R ats 19 200 ppm R ats <30 10 ppm R ats 5 0 .5 rog/m^ R a ts 38 5 mg/m^ R ab b it 10 10 mg/ra^ M ice R o u te Inhal Inhal Inhal Inhal Inhal Inhal PO PO O ral N o-E ffect Dose 50 ppm 40 ppm <1000 <30 3800 <300 5 mg/kg 37.5 mg/kg 20 E m bryocoxlc E ffect 500 ppm 1 00 0 ppm 30 ppm 6000 300 15 mg/kg T era to g e n ic E ffect 80 ppm 75 O bservations R eferenci Number S k e le ta l v a ria n ts 13 M ali. - v ariety 14 S k e le ta l v a ria n ts 15 S k e le ta l v a ria n ts 16 S k e le ta l v a ria n ts 15 S k e le ta l v a ria n ts 15 S k e le ta l v a ria n ts 17 M alform ations 18 22 *Based on the n o -e ffe c t dose le v e l in te ra to lo g y s tu d ie s. TABLE 5 Summary - L a b o r a to ry T e s ts F o r M u ta g e n ic ity o f TCDD ___________T e s t S ystem ___________ D o s e (s) T e s te d R esults P ositive M utagen E m ployed _____________ Comments________________ TCDD: N on-M am m alian M u taR enlc T e s ts Ames T e s t and E. C o li up to 4 .0 p g /p la te + No - Ames T e s t Not sta te d - Y es A memo to USDA ________________R e fe re n c e H u ssain , S. e al^. 1972 Ambio. 1 , 32-33 Ames, B. N ., 1974 (u n p u b lis h e d ) fCDD: M am m alian M u ta g e n ic T e s ts Dominant L eth al (rats) 0, 4, 8 ug/kg in Vivo C y to g en etic (rats) 0, 5, 10, 15, 20 pg/kg in Vivo C y to g en etics (rats) 0.001 - 1 mg/kg + No H ig h e s t d o s e l e v e l l e t h a l to some of th e m ales No A b s tr a c t o n ly No A b s tr a c t and t r a n s l a t i o n only K hera, K. Advances S. in and Che R u d d ick , m istry 12 0J,(. A 70 ., -8 4 1 . 973 G reen, S ., 1975 T oxicol. A ppl. Pharm acol. 33, 161 Yefim enko, L. P. , 1974 G ig. Tr. P rof. Zabol. 18, 24-27. DOW 798826 U,1l  DOW 798827 -3Dominant Lethal tests conducted at extremely, high dose levels have shown negative results. This is a significant observation, especially when considered in conjunction with the results of other tests that have been conducted on these compounds. 17373 DOW 798828 -2- also reported on a Dominant Lethal test with 2,4,5-T in NMRI mice at a dose level of 1,000 mg/kg administered intraperitoneally, with no indication of a dominant lethal effect. One additional piece of unpublished data is attached, consisting of a communication from Bruce Ames, Professor of Biochemistry, University of California at Berkeley, to Dr.- Philip Kearney, USDA, dated 11 March 1974. Dr. Ames has evaluated the muta genicity of TCDD in his tester strains of Salmonella and has not found positive responses. An abstract published by Babbitt et al. is also attached regarding work in progress on the effect of 2,4,5-T on two human cell lines, spleen fibroblasts and lymphocytes. No data are included in this abstract. As indicated in the Document prepared by the Working Group on 2,4,5-T, there are significant limitations in the majority of the reports cited on mutagenicity studies on 2,4,5-T and TCDD. Considered collectively, the results of the tests do not indicate that either chemical is a potent mutagen. Generally, the results from in vivo mammalian tests which assess germ cell mutation are the most relevant for predicting risks to humans. With each of these materials, the 17374 RPAR OF 2,4,5-T: MUTAGENICITY D O The EPA has concluded that there are insufficient data on the mutagenic potential of 2,4,5-T and TCDD and that further testing is needed. The results of the laboratory tests to assess the mutagenic potential of 2,4,5-T and TCDD are summarized in Tables 4 and 5, respectively. Our review of the literature revealed very little additional information to that included in the RPAR Document No. 1 on 2,4,5-T. Two additional references on mutagenicity studies on 2,4,5-T are submitted to supplement the review by the EPA. A paper by Andersen et al. (1972) is included which was an evaluation of 110 herbicides for their ability to induce point mutations in four different microbial systems. None of the herbicides, including 2,4,5-T, caused point mutations in 8 strains of Salmonella typhimurium as well as the T4 bacteriophage and E. coli. CO OO OO ro CO The second paper is by Buselmaier et^ al. (1972) who evaluated a number of pesticides, including 2,4,5-T, in the Host-Mediated assay and the Dominant Lethal test in mice. The Host-Mediated assay was conducted in NMRI mice using mutants of the bacteria Salmonella typhimurium and Serratia marcescens introduced into the mice by intraperitoneal injection. No mutagenesis was found at 2,4,5-T dose levels of 500 mg/kg, and doses of the n-butyl ester of 2,4,5-T of 1,000 mg/kg. These investigators 17375 # Dow 798830 TABLE VIb S afety F actors For S elected Drugs3 Drug N o-E ffect Dose T herapeutic Dose S pecies Route N o-E ffect Dose Em bryotoxlc E ffect T eratogenic E ffect O bservations R eference D ilantin (anticonvulsant) 20 M ice O ral 100 mg/kg 125 mg/kg 150 mg/kg C le ft p a la te M urray Pharm a caot _l . a l. 19 7 T 8 o , x . I n Ap P pi re . s s Valium (tra n q u iliz e r) 170 M ice O ral 100 mg/kg 140 mg/kg C le ft p a la te M ille r e t a l . TAPb 3 2 , 53-61, 1973 Phnobarbital (anticonvulsant) 10 R abbit O ral - 50 m g/kg S k e l e t a l d e f e c t s M cC oll e t a l . TAP 1 0 , 244-252, 1967 M eclizine (antih istam ine) 12 Rat O ral 5 mg/kg 25 mg/kg C le ft p a la te m icrostom ia K ing, C .T .G ., Science 141, 353-355, 1963 N orethlndrone (progestin) 50 M ice O ral 0 .5 mg/kg 1 .0 mg/kg - Andrew e t a l. T erato lo gy 5, 249, 1972 N orethinodrel (progestin) 4 M ice O ral 0 .1 5 mg/kg 0 .6 mg/kg C ra n ia l re ta rd a tio n G idley e t a l. T eratology 3, 339-344, 1970 V itam in A A0 M ice O ral -- 400,000 IU /kg Exencephaly Glroud e t a l. C. R. Soc. C le ft p a la te B io l. 156,' 449-450, 1962 M icrophthalm ia A cetazolam ide (d iu re tic ) 1 Rat D ie ta ry 40 mg/kg 150 m g/kg Limb d e fo rm itie s L ayton e t a l . S cie n c e 149, 306-308, 1965 M orphine (an alg esic) 666 M ice SC 200 mg/kg 300 mg/kg E xencephaly Johanneson e t a l. A cta Pharm. T oxicol. 31, 305313, 1972 A spirin: teratology re p ro d u c tio n 3 R at O ral 200 mg/kg 225 mg/kg <2 M ice D ie ta ry E ffe c ts a t lo w e st d o s e , 130 m g/kg Thompson e t a l. R eport o f Dow C h em ical Company, (unpublished data) W rig h t, H. N. TAP 1 1 , 280-292, 1967 A cetam inophen (a n a lg e s ic ): re p ro d u c tio n <6 M ice D ie tary E ffe c ts a t lo w est d o se, 130 mg/kg W2 8r0i-g2h9t2, , H1. 96N7. TAP _U, Based on the n o -effect dose le v e l in terato lo g y stu d ie s. bTAP - T o x ic o lo g y and A p p lie d P h a rm a co lo g y . V--*1 "vE O 55 tow 798831 Drug )llancln (anticonvulsant) /allum (tra n q u iliz e r) 'h e n o b a r b l ta l ( a n t i c o n v u l s a n t ) lecllzin e (antihistam ine) Jorethindrone (progestin) lorethynodrel (progestin) 'ltam ln A N o-E ffect Dose T herapeutic Dose 20 170 10 12 50 A AO .cetazolam lde (d iu re tic ) lorphine (an alg esic) sp lrin : teratology re p ro d u c tio n cetam lnophen (a n a lg e s ic ): rep ro d u ctio n 7 666 3 <2 <6 TABLE A-l S afety F acto rs For S elected Drugs* S p e cies M ice M ice R abbit Rat M ice M ice M ice Rat M ice Rat M ice M ice R o u te O ral O ral O ral O ral N o-Effect Dose 100 mg/kg 100 mg/kg 5 mg/kg Em bryotoxic E ffect 125 mg/kg - T eratogenic E ffect 150 mg/kg 1A0 m g/kg 50 mg/kg 25 mg/kg O ral 0 .5 mg/kg O ral 0.15 mg/kg - 1 .0 mg/kg - 0 .6 mg/kg O ral 400,000 ID/ kg D ietary SC O ral D ietary D ietary A0 m g/kg - 150 mg/kg 200 mg/kg - 300 mg/kg 200 mg/kg - 225 mg/kg E ffe c ts a t low est d o se, 130 m g/kg E ffe c ts a t low est d o se, 130 mg/kg O bservations C left palate C left palate S keletal defects C left palate m icrostom ia C ranial re ta rd a tio n ECx el ne cf te pph aa llya t e M icrophthalm ia Limb d e fo rm itie s E x e n c ep h aly R eference Number 1 2 3 A 5 6 7 8 9 10 11 12 Baaed on Che no-effect dose level In teratology studies. "nI DOW 798832 REFERENCES Dilantin : Murray, F. J. and Hammond, P. B. (1978) Teratogenicity CNS toxicity, and plasma levels of diphenylhydantoin in pregnant mice and rats. Toxicol. Appl. Pharmacol. (in press). Diazepam: (valium) Miller, R. P. and Becker, B. A. (1973) Teratogenicity of oral diazepam and diphenylhydantoin in mice. Toxicol. Appl. Pharmacol. 32^, 53-61. Phnobarbital : McColl, J. D., Robinson, S. and Globus, M. (1967) Effect of some therapeutic agents on the rabbit fetus. Toxicol. Appl. Pharmacol. 1, 244-252. Meclizine : King, C.T.G. (1963) Teratogenic effects of meclizine hydrochloride on the rat. Science 141, 353-355. Norethindrone: Andrew, F. D . , Williams, T. L . , Gidley, J. T. and Wall, M. E. (1972) Teratogenicity of contraceptive steriods in mice. Teratology 5, 249. -28- DOW 738833 6. Norethynodrel: Gidley, J. T . , Christensen, H. D . , Hall, I. H., Palmer, K. H. and Wall, M. E. (1970) Teratogenic and other effects produced in mice by norethynodrel and its 3-hydroxymetabolites. Teratology 3^, 339-344. 7. Hypervitaminosis A ; Giroud, A. and Martinet, M. Biol. 156_, 449-450. (1962) C. R. Soc. 8. Acetazolamide; Layton, W. M. and Hallesy, D. W. (1965) Deformity of forelimb in rats: Association with high doses of acetazolamide. Science 149, 306-308. 9. Morphine: Johanneson, T. and Becker, B. A. (1972) The effects of maternally administered morphine on rat fetal development and resultant tolerance to the analgesic effect of morphine. Acta Pharm. Toxicol. 11, 305-313. 10. Aspirin: Thompson, D. J., Strebing, R. J., Gerbig, C. G. and Molello, J. A. (1971) Teratogenicity study on aspirin in the Spraque-Dawley rat. Report of Dow Chemical Company. Unpublished data. -29- DOW 798834 11. Wright, H. N. (1967) Chronic toxicity studies of analgesic and antipyretic drugs and cogeners. Toxicol. Appi. Pharmacol. LI, 280-292. 12. Acetaminophen : Wright, H. N. (1967) Chronic toxicity studies of analgesic and antipyretic drugs and cogeners. Toxicol. Appi. Pharmacol. LL, 280-292. 13. Vinyl Chloride: John, J. A., Smith, F. A., Leong, B.K.J. and Schwetz, B. A. (1977) The effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats and rabbits. Toxicol. Appi. Pharmacol. 39, 497-513. 14. Acrylonitrile : Murray, F. J . , Nitschke, K. D . , John, J. A., Crawford, A. A., Murray, J. S., Rampy, L. W. and Schwetz, B. A. (1978) Teratologic evaluation of inhaled acrylonitrile monomer in rats. Report to Manufacturing Chemists Association, Washington, Washington, D.C. 15 Methyl Ethyl Ketone: Schwetz, B. A., Leong, B.K.J. and Gehring, P. J. (1974) Embryo- and fetotoxicity of inhaled carbon tetrachloride 1,1-dichloroethane and methyl ethyl ketone in rats. Toxicol. Appl. Pharmacol. 28_, 452-262. o 80 -30- DOW 798835 16. Chloroform: Schwetz, B. A., Leong, B.K.J., and Gehring, P. J. (1973) Embry- and fetotoxicity of inhaled chloroform in rats. Toxicol. Ap p l . Pharmacol. 2B_, 442-451. 17. Pentachlorophenol: Schwetz, B. A., Keeler, P. A., and Gehring, P. J. (1974) The effect of purified and commercial grade pentachloro phenol on rat embryonal fetal development. Toxicol. Appl. Pharmacol. 28_, 151-161. 18. Captan: McLaughlin, Jr., Reynaldo, E. F . , Lamar, J. K., and Marliac, J. P. (1969) Teratology studies in rabbits with captan, folpet and thalidomide. Toxicol. Appl. Pharmacol. 14_, 641. 19. 2,4,5-T: Roll, R. (1971) Studies on the teratogenic effect of 2,4,5-T in mice. Fd. Cosmet. Toxicol. 9^ 671-676. 20. Maneb & Zineb: Petrova-Vergieva, T. and Ivanova-Tchemishanska, L. (1973) Assessment of the teratogenic activity of dithiocarbamate fungicides. Fd. Cosmet. Toxicol. 11, 239-244. 17381 -31- 21. Carbaryl & Thiram; Robens, J. F. (1969) Teratogenic studies of carbaryl, diazinon, norea, disulfiram and thiram in small laboratory animals. Toxicol. Appl. Pharmacol. 15, 152-163. 798836 oo 22. Ethylenethiourea: Khera, K. S. (1973) Teratogenic effects of ethylene thiourea in rats and rabbits. Toxicol. Appl. Pharmacol. 25, 455-456. 23. Malathion: Kalow, W. and Marton, A. (1961) Second-generation toxicity of malathion in rats. Nature 192, 464-465. 24. Triazine: Murphy, J. L., Dagg, C . P. and Karnofsky, D. A. (1957) Comparison of teratogenic chemicals in the rat and chick embryos: An exhibit with additions for publication. Pediatrics. 19^, 701-714. 25. Captan: Kennedy, G. L., Fancher, D. E. and Calandra, J. C. (1968) An investigation of the teratogenic potential of captan, folpet and difolatan. Toxicol. Appl. Pharmacol. 13, 420-430. 17 Q ? t -32- 26. Dinoseb; Gibson, J. E. (1973) Teratology studies in mice with 2-sec-butyl-4,6-dinitrophenol (dinoseb). Fd. Cosmet. Toxicol. 11, 31-43. o O 798837 27. Mirex: Ware, G. E., and Good, E. E. (1967) Effects of insecticides on reproduction in the laboratory mouse. Toxicol. Appl. Pharmacol. 1, 54-61. 28. Demeton: Budreau, C. H . , and Singh, R. P. (1973) Teratogenicity and embryotoxicity of demeton and fenthion in CF1 mouse embryos. Toxicol. Appl. Pharmacol. 24_, 324-332. 29. 2,4-D: Schwetz, B. A.. Sparschu, G. L. and Gehring, P. J. (1971) The effect of 2,4-dichlorophenoxyacetic acid and esters of 2,4-D on rat embryonal, fetal and neonatal growth and development. Fd. Cosmet. Toxicol. 9, 801-817. 30. Chlordane; Ingle, L. (1952) Chronic oral toxicity of chlordane to rats. Arch. Ind. Hyg. Occup. Med. 6_, 357-367. r-. r oba OOVV 798838 r -33- 31. Diazinon: Robens, J. F. (1969) Teratologic studies of carbaryl, diazinon, norea, disulfiram, and thiram in small laboratory animals. Toxicol. Appl. Pharmacol. 15, 152-163. 32 . Phaltan & Imidan: Fabro, S.,.Smith, F. L. and Williams, R. T. (1966) Embryotoxic activity of some pesticides and drugs related to phthalimide. Fd. Cosmet. Toxicol. 3_, 587-590. 33. Paraquat : Bus, J. S., Preache, M. M . , Cagen, S. Z., Posner, H. S., Eliason, B. C., Sharp, C. W . , and Gibson, J. E. (1975) Fetal toxicity and distribution of paraquat and diquat in mice and rats. Toxicol. Appl. Pharmacol. 33, 450-460. H  tcVr .rV\ Ml ' t - Ur \- Ur I \d IaY^ I T0: L , L . W R ITE-00 NOT T YPE % ? P.1.3piB rme*,r D . 0 . yAA QrdLu 'is)__% % M>l, l ; 9P l\. J . K crt< K, S. Rajr- lOo N 0 7 1 0 J 6 _IP9W 9 S 7 9 9 A ,D A T E IiI ik^vu-- n/ 'Oc l%03 bL jY z ;s C Ar. c j 120 3 y i2 c 3 m k erv\ 'i H.5~l --- A \ A^tsLOUyU/li JJl4LfT!rn/i~t4_ ~i * \~ S U n jru _s t- " w A (\cnrY^MYY\Jls\vCttl . -IHIj * A n S A ^ u ^ L 1A _^c v \ A u JI(lA t r u L f lLm x L -tLJ M o u ^ jju u X jL L j2m ^ * j3^L0s>vs__ S G -O IL 'S ] FROM: NO EN VELO P E REOUIREO S T O C K F O R M C* 5 0 2 0 P R I N T E D R - S - 7 1 9PATvUvT-flollClNG ANC O DO NOT FOLD DROP IN DO* MAIL USE REVERSE SIDE FOR R EPLY 17385 # DOW384739 MN 05 33 0 3 9008 Building May 16, 1978 1072 D O W C H E M I C A L U.S.A. MIDLANO. MICHIGAN 48640 B. B. Holder H&ER Medical 2030 Dow Center cc: J. H. Davidson fi, M. J. Traynor, 2030 re. SEVESO AND 2,4,5-T RPAR Attached are the twfLsTeferences on the Seveso incident cited in the 2,4,5-T RPAR. No.^ 9 9 j is a bi^ief letter by C. D. Dewse in The Lancet, August 14, 1976 while N o . n . 0 0 ^ s a brief article by Hay in Nature, October 14, 1976. In our rebuttal to the 2,4,5-T RPAR we will likely include an update of that situation, with additional references as appropriate. A brief summary from you and copies of additional documents would be of great help. Due to time constraints, I would need your comments by June 15. //1 Marguerite L. L e n g_____ \ Government Registration Health and Environmental Research Attachment abc AN OPERATING UNIT OF THE OOW CHEMICAL COMPANY 17386 10V7 M - 4. i- D O W C H E M I C A L U.S.A. 9008 Building July 28, 1978 MIDLAND, MICHIGAN 48640 E. H. Blair, 2020 R. W. Boeker, 2040 R. D. Cooper, 2040 *J. H. Davidson, 9001 *E. E. Kenaga, 9008 *R. J. Kociba, 1803 F. R. Lehman, 2040 J. W. Mansion, 172 J /y y.1-\' j' ^ D..W. Davis, 2040 P. S. Martin, 2040 J. D. DeVrieze, 1710 *D. D. McCollister, 9008 J. D. Eadie, 2040 *A. H. Morgan, 9008 *T. H. Fiero, 2040 P. J. Gehring, 1803 *M. E. Getzendaner, 9008 R. L. Glomski, 2040 X *J. A. Gray, 2030 D. J. Roberts, 2020 *B. A. Schwetz, 1803 M. J. Traynor, 2030 -- R. D. Vatne, 9008 **MM. A. Weaver, 2040 % /yf. V, R. L. Hagerman, 2040 J. D. Hembree, 2040 __^*B. B. Holder, 2030 C. S. Williams, 9008 M. E. Winquist, 2040 C. D. Woods/J. M. Capriccioso, 2030 oo ? )0. K. Jantz, 9008 Action File (2) o 2,4,5-TRICHL0R0PHEN0L RPAR/P0SITI0N DOCUMENTS VJICO wCO Mary Reece, OSPR/EPA, informed 2,4,5-TCP RPAR had issued, and me on Monday, July 24, 1978, mailed an unofficial copy of wo that the UO1t-oa the Notice 05 (11 pages) and the Position Document (65 pages plus 98 references) to me which arrived on Thurs., July 27, 1978. The official RPAR Notice and Position Document was mailed (certified) to all registrants on July 25, 1978, and is scheduled to be published in the Federal Register on Aug. 2, 1978. We have 45 days (Sept. 18, 1978) to submit evidence /Vtv'. / 7 in rebuttal of the presumption and may request an additional 60-day extension. The public will also be given an opportunity for comment and for submitting additional information relevant to the presumption. Registrants and other interested parties nay also submit, for consid eration, data on benefits which they believe would justify registration or continued registration. According to the Position Document, the "2,4,5-TCP and its salts have been registered for pesticidal use since 1948. Current EPA records indicate that 42 registrants have 94 Federally-registered products and one State-registered product containing 2,4,5-TCP or its salts. These t products are usually formulated as wettable powders, emulsifiable con centrates, dry powders, liquids, or ball briquettes. Dow Chemical Company is the major manufacturer of technical grade 2,4,5-TCP (DOWICIDE 2) and Na-2,4,5-TCP (DOWICIDE B ) . The 2,4,5-TCP and its salts are frequently mixed with other pesticides including pentachlorophenol, tetrachlorophenol, and sodium pentach l o r o p h e n a t e ." y Trademark of The Dow Chemical Company. AN OPERATING UNIT OF THE DOW CHEMICAL COM PANY 2,4,5-TCP RPAR - 2 - July 28, 1978 "2,4,5-TCP is available in both a technical and analytical form. Tech nical grade 2,4,5-TCP (DOWICIDE 2) currently contains 95% active ingre dient and 5% inert ingredients in.which TCDD is present at a maximum of 0. 099.ppm. Technical grade Na-2,4,5-TCP (DOWICIDE B) contains 85% Na-2,4,5-TCP and 15% inert ingredients in which TCDD is present at a maximum of 0.099 ppm (Dow Chemical Company Sales Specifications, 1976). The dioxin content in both of these products does not exceed the limit of 0.1 ppm recommended by the Advisory Committee to the EPA A dministra tor on May 7, 1971." "2,4,5-TCP and its salts are used in the textile industry to preserve emulsions used in rayon spinning and silk yarns, in the adhesive indus try to preserve polyvinyl acetate emulsions, in the leather industry as a hide preservative, and in the automotive industry to preserve rub ber gaskets. The sodium salt is used as a preservative in adhesives derived from casein, as a constituent of metal cutting fluids and foundry core washes to prevent breakdown and spoilage, as a bactericide/fungicide in recirculating water in cooling towers, and as an algicide/slimicide in pulp/paper manufacturing industry. There are some minor uses of 2,4,5-TCP and its salts in disinfectants which are of major importance relative to human exposure. These include use on swimming-pool-related surfaces; household sickroom equipment; food processing plants and equipment; food contact surfaces; hospital rooms; sickroom equipment; and bathrooms (including shower stalls, uri nals, floors, and toilet bowls)." DOW360377 The triggers for the RPAR are discussed in the Position Document and include: 1. Oncogenicity - based on the oncogenic effects of the contaminant, TCDD. The Working Group has concluded that there is evidence to indicate that TCDD can produce oncogenic effects in rats. 2. Fetotoxicity - based on the study by Neubert and Dillmann (1972) entitled, "Embryotoxic Effects in Mice Treated with 2,4,5-Trichlorophenoxyacetic Acid and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin." The dermal and inhalation exposures for 2,4,5-TCP or its salts were com pared to the no-adverse-effect level for fetotoxicity, 0.9 mg/kg body weight/day (Neubert and Dillmann, 1972) . Since the difference between this no-adverse-effect level and the calculated exposure did not represent an adequate margin of safety, the Working Group recom mended issuance of the RPAR based on fetotoxicity. Other data have associated TCDD with mutagenic and teratogenic effects, and chemical carcinogenesis in test animals, and toxic effects on humans and other mammals; however, these data are not presently sufficient to support issuance of an RPAR. EPA solicits information regarding these or any additional adverse effects on man or the environment caused by TCP/TCDD. The RPAR Notice states that it is "the first of several which will give public notification of the Agency's progress in reviewing this chemical." It emphasizes that "a notice of rebuttal presumption against registration and continued registration is not a notice of intent to cancel the r egis tration of a pesticide, and may or may not lead to cancellation." 1 *7^8 2,4,5-TCP RPAR -3- July 28, 1978 Copies of the official RPAR Notice are attached, and the Position Docu ment (with the references) are attached for those whose names on the distribution list are preceded by an asterisk. I would appreciate it if these people would review the Document and comment on any errors or weak points as soon as possible, so said comments can be considered for our overall response. Persons designated to assist in preparing the rebuttal will be notified as soon as Mr. McCollister returns (Aug. 2). If I have inadvertently omitted anyone who should be advised of the subject notice and document, please let me know and I will rectify the situation. Also, if anyone else needs a copy of the Notice and/or the Document, please advise me. Margaret L. Wulf Government Registration 6-6376 rdp OOV/ 360378 17329 MN0 6 15 9 3 May 31, 1978 D O W C H E M I C A L U.S.A. 1706 MI01AN0. MICHIGAN 48640 TO: PROPONENTS OF PHENOXY HERBICIDES SUBJECT: GROUP MEETING TO COORDINATE EFFORTS ON RPAR' MEETING TIME AND PLACE: June 7, 1978 - 9:00 a.m. Ramada O'Hare 6600 Mannheim Rd. Des Plains, Illinois Tel. (312) 827-5131 2,4,5-T is a useful and necessary tool for the following: 1. Right-of-way brush control 2. Rangeland brush control 3. Forestry 4. Weed control in rice In order to better coordinate the activities of these i n t e r e s t s , it was thought desirable to assemble a group of individuals that could mobilize the necessary effort to respond to the RPAR. Reasons for the meeting: 1. Establish lines of communications among the key groups present. 2. Determine capabilities of each organization in regards to making key political and user contacts. 3. How to achieve m a x i m u m effect w i t h the news media on forth coming benefit statements from user groups. 4. Review of RPAR process and the necessary jobs that need to be done. 5. Review of legal actions in various states regarding 2,4,5-T. Come prepared to participate by reporting what work your organization has underway and difficulties encountered to date. We will see you June 7. nc AN OPERATING UNIT OF THE DOW CHEMICAL COMPANY 17390 T8S69T MOa* FRIDAY, PAAPRRTILII21,197I8O J l o A .e-' "vi NO ENVIRONMENTAL PROTECTION AGENCY PESTICIDE PROGRAMS RReegRbisuetgtrCtiasatotbirnolaetntaioPionnrfiensaPgunemsd2t,picCt4iidoo, nne5t-iAPTnrguoaeddiuncstts 17331 8SS9T MOO 17116 NOTICES fO [6560-01] ENVIRONMENTAL PROTECTION AGENCY tPRL 882-2: OPP-30000/26] 7EST10M PROGRAMS RlaPbnrvodldtaubcCtl**anClPionrneutsaaudimnipnltgaiog2n,l4iAMA-gIlaMinst ofs jP- r>sHciiwd AAgrgGaemEnNsc,yC(YE:EPAnOv).firfoicnemeonftaPl estiPcridoetecPtiroon sAuCmTpItOioNn:. Notice of rebuttable pre sTswc4rfbtSaehoeuoh0cxeUhhgernbeecniimMimstmesecCsiAehfcatMitFiidrgcottntaRaisaeAwoocacnnlsne.tniiRutcildo1rsyclbyYt6foea'm(osg2:an2i.itnnp,i1tvh4ithdtr1se,2ehroi5.risr,eegs-4potTTkbrdh,utep5)huphabecs-riettehlrsTestaisiraacstfirtousleniiinscicrnrnmnosibrhiodaeatttetlpeinetvohectisrdirifeneoeeeooicfsctwrnpofhtiarfohetiseetsonhaeukdiqmegornnensuvtnordidhpteeacxhrsnieatoytnaiitrldoonssf-l. DibneAffooTrrEme:aJtuRinoeenb5um,tt1au9ls7t8e.vbiedernecceeivaendd oontheorr ATDRDPro.eDiCovwggDi.isers2iRrato0,emEn4r46Ss0(0,S1WS. eMHMcEt-PSi5AoA6tnTr9,,eE)e,RTtROISeAofcWfohLimc.n,eiTWcoaO4fla:0sP1hSeF,iesnertgdviEcteioicardneaseslt, STscFOhCauinaUOhOdfPcEHmdsfeeiPReNiadacpdsPcpserTetDtoevtLriiAoctPnoeTeEeiFoydCtnrpodrMiofUumunwTegcWtuER:eeirytPenxaRsNrTaed,emiceAmTssHdEvottrsAissiPEeinccsteg(ARhitRikwWdasiaa,Y.stiesgantHt2,raOniI0aa-niIPNOt25nftNgrfi-6rsFfAooi7Feft6c2Ogn5ibOde),c5r,4RumreoaR-,eRto55MmftigM7f-anooaTis5AbofislA.Ss4.llmtT1*t.erpTPrpEaIaeIOeetp4PtOcisso4roNiAtteaN7riin,:,l, I. R egulatory Provisions RscCF(eapr8iuhrteesoo6Aimsrksdsddot.eeSeieepnqcrGtntc.iiiaaio)dcfterol,tifien.cnttphiee9FtrdmIrroe7oneeiaax3evasdAgl,eieiAecdatc8gTrsrceti9aeeintsicnleotlSsl(tiafcrtedhFRtftyaeieeIane4tc,Erxdt.g0gtecRes,au7geFt8AlJeieratus1redso)1ttn,meibsr6og7atau2iinaastn.ctUi1ncsteoifaa1udyHsonm,bfetr.oel,tooCteehrhffsn.aphaadttt1thhrahnne3ieldedeneda6l ptsitsihueoeaa'nnAlnd.sAcioaxepgnpoeodousnfifbcotlityrotiheshniWhfeseerdrondeomronkwctcaiuiicnetmteeghs,r,eitOnhahbtlaria,osspccukenboprgoentrteiiootnncanueeinnp.n2dirtn,e4tgpI,o5na-afrtToehndremaanbipasdy RmmccctjspsorsnimncdeCrpoIotmiatmwtwleteaw1scnragrwlsaaeepsmsdpttatbilunoooiriemeeeuuyeuhuoyiiffruuniuonrflvm6fngofeyreeaooreneraeFindiih1zAB((caegagffeasxxeasArgbammitgerm'ele2mictbndnsdtattrt2e1nttsnegoespeoeafielty6yyiRutddeiepcniiciihes.ieusitlbh.iimaigesetct)oesh)lccscccltnodeesira1l2gmopertnapnulhfuritnhnr,oantteshrswnriaiettriitmtownddIIcyc1m.pnenntttern1ftvasmiaimscspttaertt1oeIInorsrIf,nanioaictcotoauodn(yyrcasrhceitcgai6"tspeln.noeerooneboi1reinatetayitdnelttorlaaregaentpRspeeitreobtnnete2iegsnroihnfo(eyrrdA)tnrufegiziohi(tegimcnractgsledoaclatvta(mte.ueceiooiostif4echo.rIertega.gi(tartisa1tieet4otsnitno)itcosadfirtdaughfibnnaehnoirofd0MtHrriernadpnspsecon(saikidt1erh)smmirtfcItitohnliodinra3bnbiouseeentnslttahicirrheefennnyt(soetuceetsCeeraaaatieanrecaetcn)wtlkeoesfupaasmuottauiehasginohsetfarfasuf.athtialnptto,roynetneat)srsarptFrsrsnftnstdasuachcho,cteyeeaciect6nnheda(PaotriloioesdpratardnemstseIiphdodrpaadetno4t,Raegtldr,ktrga"a(oogbdiadtag2lnftft,rvtiltelphtmsscrisadese),tupvtaibraisiouyoee5trfnaireitfnopracoaioeteebriuehoutnthc)ntnaotapiooaertii1rod,nineoinnltldcndehhuroo(intnihstfpnondruntae"vnnoAsraetRat6etntffitocio1ertcdceailoufimnlerteded1sseoocsaotuhtsirttr2itsset5totsocavaohn)ndoboiigorhicarfttnmhusr9uecuu,oeteeiftoimtft.scnaevstro1enateimpit1osnnev,ioderueeiuaphan7eroomaaosbebcnatamkipsafditwic,nrodpa6bgncpusinsnir6soernmnfdsrtblrhasenfaaoknynicmnuetitrocnne2(toteiientesesse;ltei,sbcotSoepdhansnteoommitdorseahaetcFeapshngitpieolages.rtrsfsynanilfrteinienttmsdiu4,ot1tpapbdpp)btenetnpsuaciwi:slorIuueceitleitidoalimitor,t(n1caryyata1,snonitogrFilafdieheesssppctie.tpsnetrtam4erotueelcslnsaiaehfoippbbp(.m*itaslosAssetonmdtuoRsaeronsrilnteoepIXtiqrFosriadicbnheoetrtceeproanylnieronieuthpetssotacnavtrfeiiur)grtteetcueeAaonysEneiRdiodcefotwesasscplcvcdsvpto(hithotaefetloarintpseencean)aibuunstditiu3unlccyitirldiycehp.utonrgrg)udseteenoonhihoeddndoiedenccfaStatae)kenehumsmsiom;reekc2asuGohledtoolildid.cngsn.ceepadhddeteedndeeireaarwnniutdtoeossAe1nststdyrnrpaerleincintaetpevvtruastcguttritcoldf4nntitetIyddaooxomCoecttciyceTcrcdirgpitypteteeappifuptraieaaim0tgohehhszhtttrtbtciiauaoinraruonupainiosdfsrrelaarriarrnahhnnoohhioi2edaeeuin4sraaoonsnsatasstttltlniunilngoetdegineeecisiriitrrio)iiddnndoyooddayeneenndee0eeeeeceesscssssrrtttt,. uoFctpespmamhlcnrptractpraos3ttnptapt11oioeohhhioeeihvchnopsur6(rpauroe8kreIuad(CraciogcboeeeteeeF2iradntpst2attep3rtmeidy)iwiloviw.v.ss.lsuttlossRll.r)a(1eor"chiseelu1fuyuluniiii6utmAcoinlveeoetcodindldnudnAt1sn,mmIib)r"is(Iapi.eeiaerectescedd(meagiagfsgbmhnldtsaraosnsBetprbpeeutom)shibIheiou)oelte,nSatr(rgoyptttaneefit(oytnthedi4siifartandih4ppntoitnuhssootttnneoens)etdaes)hhoiek(ettasaotrebnar(nh(if(nit.hhsvhicusescleeessftlns"hiryttret)nlngmieieieuetnoedtsets)ihi)ttowfoeasirooessr)pMIueca)vreritsodoeaafsf)rk;xctiphtiAsaetbrwnletrai.nseeisutnriaietahocsrereeintoevccopektokrngnnotpdehlhreosrscgteiseriwn6rsplsniemeosgnoerfhdttAteeayiiue,i,ie(oieenorekoon"deesminrspotecb,dld6oiffdrsdsch.Ivtettinbsndnifu)if.(mmhegutprhsymde,ttee(ceecnreear5eathhm1reAIenaereaer)pnctsebmaroncimnni,e)1thn1netnturaeenreoltpthtatsyAstA6t6oiimvytvawirfttioaatiefhunf"tlt2eoa2o,e"sioseriyitcinfhdndotee.b.rido"hmrtnttonn1as1anbatnrmhetmfon"atsjenner.vtnarllphee(eaatteebinpet6atns((tttse<4tiihghiccosnIyaptceoheahampgopr(nnc40bienAnehteronboe))evae0leureipwisislu(A(ieinta)sfyshnacsrlret2lecu5Idef5ha(iiipettnooztectkarosmilctl2cnarCCabr.)ed)dayctlaetmssrtstala(t(n)i,rtmodu,itnttdaeFFsrtiu,imidtetththhoiidibertoninoooooettosabRRceriiiitiyeeenoodeea"a),r)asttmfttrffr,fi,oin II. Presumptions rtCaeFRignRieisngtrg1ias6tt22rioa,.41tn.1i5o(-oanTf)s(3pm)eaesnrteidistckiodarceprpeiptlxericcoreiadaetuidocrnettshlsaectiofn4ong0r spuupaptrputtputpasdwahorhehbebsesneserrrsueh3548l12eoooetseoeoesesisdceaao.....l.*stdtdtdvdduritviiiltfmDtiIIeIuccuuclrIuARamopyaobfddddoedb,iiicnccseelen.rdydndseetelyueettettnodgtioasteseehcsinsnennnrtcitdev.,w.isoipsocerttcihrttlfrsuitiinmoinoafuooleitrsoofffcufnIyafftspmiiiIfiiruromeiwotnccnmndg)icnittdsgotataeoarcavfciophspfiheasmanerdnorttlltrtirreaihuiotueuirhjetgtoroooiooosoyacbomdydpomvusnnrsrtountrtjliairnsiieih(uebdnnsfaisogdneugocooceabemggnuuoo.nniuestursffggtrnmyfcpefsiheissi.lrigfnhs,aos,tttteganeitiierheehhtgpocshntcaytgueriasstteib.eeaepuamflieigolttvnoyeeasnqenflaiilIisnaiommtlvommnaicnngusttcduutlii',datghtretsiahaloaoeaiercavetiaeaafpnwtiaetlhnrthjwtribinsaInaeeoeoelhootreqmnillfbdgdidrrrrieesfnecIoutuneclepmitnho.raearaunueostaatcmm(nhtliedspspfqsqmsacloIinroederetuuetanm)tuueapeasmsriscbbptsccyaaeorrmtaogtiatuooesninssonooionndvancottbrtassaftfadtnuidiisriieiitdtvtmtctttidtpdtspstohittiiutuai/iio(eeorahihveondeoiee2oittetostssnnneleoesneseserr):sr.. FBM 9AL IHMSTHb V O L 43, NO. 78--FRIDAY, ATRIL 21. 1978 173S2 PRS69T MOO nonets 17117 fdcvsSclbbicptccetmhuatTrpcada4wtipaoahptgiioSSabwMEc2f1pbOIwnatchitetanynnniohiehlal1elalainfnmrnrninoelfeuuegruioo6oer0oiepuuCteovuuaiPdcionnBaeOOroffAefgainhiitrtaedrfonodladss2ysa2nfrmnssnoenoasdtedestdrraliltveFmAifasxdbDshone.estcdtlipdupntelo.a.et-oniniicrxocsriisicsot1ecleieepg"na,id7chRelrrel/sforesain.cuunOaruDoneEmcnitmiapnleaoDDrdohnd1niptlnetrb5rm2eatagtsitusr.niebefccg.hegancamscbshrsb4tce(hrdsIaphRcogt,tgaa5ulnolosdtatt4aaskaevtr2ehttnsttnehrathor0eofeSnalvaeauee-oibeescpsehfbcchhorhP,aitoieaoX1nttinieasit5eet5gonefoftisedPcdWfnxitoskirOimuumtlcrolfdotl4atlooliafaoaonesooicpok7ri-ryrebbieCtuoi3el"eo,rtncgchorceteiTfmcermm0Hseewroootrnnnre5cnntthnrnCqGmXaoeoeaps(e.nclaishaodt*taa.SFxwd2e,lm:wnodatlt4ecitnsacIytseeaaghratutbet)ennn.eoepctau)l.pRsuias.ftnioiolittinFshshdporrmirnrtWnhlclscrer4aresodoosuesirxt)ahoucueiwallrsmAingfPTpeevtP*mr.eTdreo(risiiebt4nnttdncnnaeaSdtmiiasotcdodoeAmaligg,merestro,noudnbcnosui7FIhaohe1ttnagfuiCsetista*eibpcnufaoynneeitiefewmmnhhmtefaanb,s)o6insp/iucesisRstolthemaDttproleeimegrrtlnguoeoclcixs,ioihheslgeiititen2het\islittnettotfncdirffcneEcaatgeAahpccirsirgin"cWprpgR--trocs.itatsit.aMiaofesiccisaoeetd"1tcoesmoAttiinnalsiahhate,oPiamp*etseocgwranitery*tirfsreaxetrias1eyrnetnnrnruts2tgobrnaccinsuoona'feairdiesige'dnAhfcipbm*nAv-ic(.eiuzaechniiasstaa,t(tsrssnstoorvcncsoealrdfmsiusnee4teaaiTto*icleoaeteatstsutsog2intesthgoteXkivnhitfndteantecei,diIeee(incAenstdiDdetThriDrpo5tf,ehrwCfeniiaoeniMoolddilnfcied4dcieetc3sincdiosaidin,eano-ntnseaipocnnsenoaacngi"soytncd,eekeitXTDsppiromIsHqlopAdo5yaacsoncwtneuwclha,nctrre'cylsadsDcnt4"srb.i,ansslrrexsetau-fUrtyutnfryseDsuyontiunsuibe(0etttsTite(ameeIsteywtaaudkead.oiiydsioops1dur,huaadWCXgOtmiamitmensoocmtsarssr)rsnbunm*cpmphee02hapntnhroRhcmlruhiurdti,udailputtarhtBtrs.odnasddbet5afehaitfeeieashoPieaoHemicemhcscetitcmliioeahsfcmtbaceeoiues4asc,>cennesPnncsee/isomsxniers2rbsloeetrveadxaonnifale0ncftthon-itgeesrtssp*tttsgapiaat10rttPipPofneiaiif5CumRpicnh1ertup,istdciceeooecctiepcpo9e4ettitsatcejataA6ncehhtouiopttonnowiecofiaFiiapoeficixiei7/fnr6ccirrarniaut1oonheeadi6ooldsvoscooeansMoeroonlsoaniururcxottt6ooadeleeiR0tilrfikdisn.nnidl)npndneia*yeeeraeecssarrreiesefrf"tcss;ft-t,i,. HL AssmoirAX, Oaouiros vox Rxvxsw TTtbtaftsmTTaItaPoihhhnonnrlcCChhoAerucefeeiicasosdeeDiDrteslaiaapnrayettDDtddmigeoosiAdseofmoivve.ittidasnasgnefneiwctedstenrauiatiDucncesoih2tlawstoenfinco,hseaefd4nayicecireftl,neRcted5urhfeftacaide-efsoomeeiiTidbepccrsnnxbnfcvieete,eeiaioutstaiencsdncmvannstprrtgite.tienasfo,ieneatanidoeAldfaccsbyyngfwotaeit/lesllo2welmefsleactrolif,resocsy4nrteienetrtosr,Pcgh5vttTmaaatdsihrt-heissnovTnhCneatem,retalseiaetseDiimuarinacssteehslihmDeainptcnauthaatebeltselagmupnafpsslcbcfewdtsidoteapfsahiaaoius/scinannneesosttauntrissshdidodgrsst.. IV. RXSOtjIbSjTxBcAtTtIoOitrahkASNSoPnbeosducxs Jnpwsspaltsnntrbt"ddmrbtdtptisctebtmt(ntfsaoocwenrreh4hohheuiihhpeteeeuoxralusleaoueuoefofgArAiadTahI1ideIagrigtgoaubeeseiepeesnltnnncrtrnvttaeefaftmtlreteceiwsitiichmttalipyfiiceotyntersAscd,hdkiintpFrnrloaionoatdorIiibonntetoonRdrnenaeiadtoaievenagpelpoirnrne5Rdrostanfeenttbfctdc,rrllee,aagchaft,rltitsobmonisatrEroogoieyof.rtopiemhoseotieuwtmescdoea1rrnernaiyagd.sg3rciniPfnrdnimoduodnicawmobom9ngeutcilrfsad6lhnaoimoaIaAf.sfrrrrltsnluboeEg7nfneidsautln9tniy.icnipciihystiaitptedadnhbd8rrhlsicctmandn0PtuNors,tlittolslftntittmo,itothlat4ryeteeote6secaositts,renfmaAiiiisifbaiid"oitcsnaordo0snchtnhff;o.yetaa.notntsmaeoeliotta.thhnhntnetsn,tnietspoat.asetn"rlItehtiodSCtnhen,iioinnuecntswEitipeedeaunetlioorsdtaaTrdnaeeesoglereritcytrFubctatevdratlfPlnlbaipxlisgntodhipimshisnonaba.RumibaahettitcauiAoyiia"ttunvoneucnypolnynissstpmtaleetesdatsnaealafteimflahoittftrbarhemlfdumuphtoapoErdondrtipdwhacdororyAiyivaebnleeieiraifetorellpetslwPpegiicrme,sbtaipii,lrscaEtlnhdgtmuorlgucdrtaalcbnmtlueeefeAai,ailewaepi4httaoiemfloieecPpvsalebtloaucaprrsaadhasfaibdo5aipgpangnhenreimri2ahopArnoyttlmgtgipsitsdofieyeilnremlhltan,etcc1mmis,leor.seipiaagil."onadeadbisncteoclt.tisefeatocnrocitrfnwncnbrlpooHanulTamhlnrefnahoefareooyo1yacsatobco6mrroyetnumiowbtogsenrhhuossrscod9enteetm0erinsrytctrtbuapuistnewitv7eoepnciebchtsam"olccotesctdririblcaIbsxg6eehtarosfyuanntbpyiheuoocnerdaseeFrldrucrofmar)tmtpnavpofunnlntggtu.tinaaefoiafftimokarrorrermieohtiiIniieibooiinsfifaotynmasnmopnieeeleadeIlcnsrredstsHilnidtygreereesefsstss-l-tfs,t- mscesfctdohhedoleertepoanamniuoyttnrtiullaaadwyftatlliiliclaboslecIlbhine.ondoborTfeiveduodnehcrelapt.dlemninalfaticifbeamiceicedrteaies.wdodldtnietTictnolhocehapltttaeetshhyihdmee.ewce*Tfpipdoilwurlhnrsbwbaeoftlicseidisceeecetdxccrconcuooeonetrmnapipfeatdiystl 7. 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VL PUBLICCOMBUSTS AJTOIHSPXCTIOW smscfwilvcwAlflmtmatcid(2sFdcaaninieiaeloaohea.eYnactooere4rgihDdcAiXefaleimreliiotttenyJdntrivo.letntnhsileecshsyuu5Saelsctseeernepr.stlitao,loi-,dhcrddlrmt)ssacmmTadl.eonoaeiftag.ei.yEbnaotndarofmannyltiiecritSngofavnePnbnfnnt2modterweaoriiddmeaRfateA.dbmometfc4a.rrtnbiafahtttnfotulhewAaormetihhyadseosraicooce--gndtrmlaeaeue-leieslautnraietibTlsitenqatftsusnrifyosmbsetgaloiottmePlrn,putlimotraaenreoyv,eHhhiaeserpeoov,rantt,dnmqetattveanesueseneussoduh,eprntsuiiaitmSrdmeamdotuafdeiaeiaaadenpiimsfdletnedttaomnatirssslauyuihihensocittnontlnpaynnpapthseabitipawtceenednotcfasoisfudnhroeelttropDotu,oieisflieb,rtsuenocOynoobirsdtdmwttlnsiposs.amaoidsohmrnteiobpofficoitirbsrpmftainIaesefsiadmuiloeemrobolsaionlrsrsetttfycketscuerdmaeseth,ooeneea.siiferibturgrmofpetsonasoSntsiefitiahemtmroocunhauacronoron,ipnlueet1necfltbrebfefiffstiatsiec6ardcsmroftsvtcmamsoatcaeiiXoiteroatacnattpibaesminrameooohhthoinru1ftiodndoaoldshefltiinonfeir1eeesftl,. hmrai u se r n v o t u , wa T s-m utr, Aren, n , iw 173 3 '869TMQ V P rtHer ' 17118 HOTK llnsosppnfctmcrnbttRtnrsfdtfpfeA1iiiihoiioiiooepaessfxoeea6oeonfoemool1sTgAarinrchtmeyterrtr2etrttvn6tqcnihtemmyeeiesismiioaenet.caleeho1cinogO1niprliendsuttv:vdegd1eafaa1dhfmeecruiigaxitwersarfdonr1stny.(tlalift(l.zdoiaeiiemiiunn(ohieiw1foevocralnnrmmaXcdOfwamrrproina)eenneeetaaXtitbiaSno`nnlophamthainyyt1alptalbtoAelOlsp5Xrid8csdoeihtegsleyohrufsnikbefiyo):meersllstPbleten3,ereltoFrluireetsetiofp)cnn0hPlnsundcrnhi.uaaro.rrIexeotouFugooo-oevnmtngoalrehT,io3namidafmrbvbostergsiode0dssFmxtchpnbney.tmclepnyra0tmbilnmhaaduoteedoaws(ohos0duC.emya2ssedhtlienrst0etaeebcsedaitcpls)oeeoonlIt/sodoraaRI.ralee3losuorniirint.tmirlsnscfowbsoaImItrnshcrsltttlsMtbnphLanlRueehlafe4sefamhoeiwtiaaruciskoetcRimrt"nenrrsshsctphwetenscimrapeeiAsoikhittsoeisetrmelimoedniInsenxpCmyfhitog.reeagcrdnni4tedtswifreonaestiadeasofyedisrgos0.etcardFborntn.stmvniixteAlicateyintfreelfcckdatoitadthtfownbIoomorhgyoieeneuon.ndifwrdCunfeptddohcyStrpfmeibiwwnbattttuutnimieFiineeiirIthhnuhnnbeccgunnntibraniiarcaeBtnhdyollgggeiyeeeesst-lll.l Dated: April 11.1978. Deputy AssfEiosdrtawPniehtsAtLicd.imJdoeihnPwirssotorgawrta,omrs. qTcsarpbntweTshvaitdabra(uttpncct1Ilathnoiiouta1etiomsbatad1ettueruaeoooacCaeahtTDoItgTixme3uaperumnui.morpmmatdtasnnnnneoeDim1cysisihehalCsssivnucenocecstaistppnsrto1ecebucdienDinhteiroDtetsfusottsooo2i-seoryoIiiIenhwdhdacasoeofp-ntrno1su1n9rnatfDnlrip,pdtelocneedhe-fmTcafa6geohnlohr9se2d-(oreeynntr02leiasIfeddaHait3o,tsmlott,tswepsrncptt*2th.,tne4oonshslrtp4sdTtadsaahcohJootCem,oeosmd3xethobT4ea.rikliS(ctusCer5eptrtsnnsoctoxJi-tis.omuhlenunsnihhOica5cs>-aTxapanoeHD.xtdolitTfprceotitohgfd-ctcie.raptrehtbi.iuhsroaTiraeD(a)wc,cnnhtlDcirpIrpo2elTtcn2tydnseilepaseaeaaoosoefcIsoma,al5neehdcimidConmn4(snstsantmadaooe'grrraue(o7o.lotpCrtltreeDee1h5xaxletts2anabtnaoakwsr1ntemeaoohfronla4-tinlyei,i,tdenaofoDyssfe4(Tconwnt*dice)witsg7uoHpdioudlp.t.upprr.e,dt)tnn5ihnhT)rinlIobieeafarnshu,hcrrpnln.loTes-3tnoauiilIaaodoypCreoIoTtciInteygegorauf,aatcntehmtisdrddhe3emxoieDdgnthlpmcbxtcwceXidyuhaueft.fuwsfidsdglb2ot7aoceipocDuopnycocc.cth.ilereiiu.edeonmn.oinoitcir3rt4liotrehopel8t,dettsrmnhamhirifyutdhxsey3yh.x.lslolssr-e5pr7eagotaysebsti,liotthitoiemaxee-tocrocdevehontoo,ri3iTlceepumdacdlaihtioitxlrtelrpmfafaen,oontndiaelorilt.latknfyittannealsrraewnpdnmacccyoTht(igoooacsI,tdstnuedAntcapthhuc,enerh.hecoeosbehetadhmndreerrllfIdhtepwSe8ydeneanoooae8annvairlyspsiAonolusedentt70rtrtdtceguapsiaaortuoaoxciodteral0ovltuurothn(rtfohmfmpeiuodxrlibtcb4idhnhig'aanuncabnideliseeHCcdoXniredideyedisacoeeeniie-sesss-cs--t.., Salvati Solubility' A4A-T: Pniuio Docmasrt 1 1.4,-* woaariseoaamcotmors,tusoam. oskitu u im u r u Dt*tmSfcetay1i1ndfoxide_______ <0in0i0.0-o.00#1U1*f i. Background sTheoCwo(eptmsTw(stnhepcoocmetrifahCAABlhrhhpaoeedelrsnmue2bteuimtcti.a.,PCethuifbs5milecnCrapc)esmat)VMs8iw.eollisien.1bhcihdca24rOathtalroreueaty9ae,tadsuiyin4mlklrl.btnaetedss2su3uahlTtlIiigt5e)f-hntcnncrTaiaaT*nhIeaogsledmt0hcotiswaheomslrnI:atm/efs,a.lsUupalaaanuommIJsrtheptnw2tmabdd,epei4.reoy5dn,linIrrau4auoe>slhsniidgtnTtnr3aimdhIilietXceaiysngl-eeunaraalptgte4hwscrhHsa3ilariomap3es7yrcprpdkocatande-eaH8ffiphsnoTrtdcCaMhpddleoaiom%iUlpfmrusrgmMnclonrwii--usfacsrKcasttnnton.obiurlhnaauMcldiIatrMplirsplsltsssimewoueeeaohsrbirrnNsdfe1pletuitsaoioutuane5eidsneenoncpstrtrot8ceofraiBmircidhasol.ilcaodl6lucnaeemchl*nwe2du*nuyhnre((.ns,te0l2rtAi4aeoltIoawalbeso.Tor,li3xtn(4imyginIhiho-Asybiaaha3tthTdehhlneaea'ioss-i-iti.,b(IcdmInnRoluoen`Pat1rxtttnAchaa,i4iinmbimaR.s5ll(ie)aT-ndT2lPOaP.oCe4onDrcx.Pe5sutpDsi-mIteTusi)romeitmamn2hnnp3taeeDdty.in7bsootuhIe3ncnceb-.uatjepA2meutr.csr4geeaeta3nscoie-thnb.TfnlsoIaottSttrIhsRoMnIedsepsinigotbaip'tmiareliseianitrsemtrudeacueotoRssi-omiaepetidna-l 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N a 7t--nUDAY, ATflft 98S69TMOQ ! 17120 Nono _"'__ 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FBWtAL MHHSTIS, VO L 43, NO. 78--TODAY, A9KR 31, 1978 1 K{O'rynJfO% 171 NOHCKS boC0O5 cn cbOJ 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VOL 43, NO, 75-fglO A r, AM * 21, 1978 1t>7%'- ' OttPQT AAOn Nonets 17133 cpc0s0gDpfdsaamtpsrtpBtco(dlafdtIesNiaob1tltl21dmpSrasdal3ms9t1aTmpapkm2oeaaioioeyrryeskhrnhaiaihioho.ph.xh74rn9outomol,peoelmf0otefine..ndo0polod1ipipea4vf(F(ruseW3omaesEOlmd4.tlataoXaiedL8anuanept0pesuctacsupu8sun9ntn00di9uahmmaenismmne.0syhseeadsnsuDtuootr49wittn3aimaditIetaltrttoea)i9kaeog)olheptdttdllpoeynio0telet-hcapsgayeenynphnwh-gtdp-eesdvaeuadsdaAsfsIdoafeelesTalwrdlniTTee.t,imheitrpitb1ddr.kyoeg*,idelnap8Hpeoseaueeiryeefnareoynte1ccdotehreftyao3letisapAamTet.t*nowehipicspemlLsWumtap,uttmbrnsm9ac1erfMyaia(Tihre3eaylSofuo.vtit0,padaltdeaaNcnoosteernrI1aSh0c(splm8(no,hinodlyweode-etittfeesmwemdianSed7uneonnMwcxpe(ww0a-.ong4oi(firierv1PttdTddnpui2eaamoprcvftsdosnnslOmtn9hTme.eiheodo.tmnprdttalo0ndln3oveeo1nr,eaaaV.orAaaadaaneeagooinfC38hidripe3rcnsn4n)leaatmtoae.SkElmori0svooemalJmdeenwmebtmarenTfppem.hh,4sp0ht.8tr,anf,emvfvrpathDa4hIip(stctefu8eihbaedydelitvlsoafAtkon.seeroDodr9Chpa(,.iiIauaeepsytaelosAa1vpRtedpepDoteoc-0pevres*asste9oi,Dieeonasctil.rueJasn9sodTaedtvSdp3ttavs-clenlafcTilD,ltt.u.iUs,u,tBxaatbt1r-t1eioun,tuyasem3TtaeeiniTras)tve7dhaflpFcuty.erihetaeTeofCtteateootnanplro9sea)hTptfeihvecsf4ssyD.lrhg,dtdauatue.noowlCaderorrheaaihaoaryxraBpstnotaudxeTPoooaOTee1fp3edsoicTihf.thsrticsesteafonpTeriIsUt.nenofenianDbrnltsaooo.abrlrbnktht.nftesrrdnCinspe.uCneaeeppC3exefa0yndpteofreuowlh4gwdn.oolteg1lypnrrtce3nhrAnlvepyfptvlaeasretDse3ioesnoopioeA1Dn.lkeluareDxrrlmei9Jeeeuemdmlfeetcd.pgtkaaomaaerodecsoo8mo-aonmenwxm8teo4aewfnrIsr-hac7iloceontcnteehDAsnppdv0tDteTllwmatSriloTeticdavAsmai(tmvhf4tilivlivvtinbimtfacoedawfn,0atcnBftFm.trdeeemnivtvieeviaeteohnituCo0epun3aCerabiltiriita:shog-dneveo.1utfpltdunvde.cDsinetedlanbedooe1i.tga,neraoT0dlrcrede.iDo0aeh.SoatrdeenhfuddeenlavvPheeovpl3fnl0ghed8wg8seuetnefflvat3seWlenAbylorf6ya1lfaswsfeteeruetiloebeoeetel7t.Dalsodsereoatdsyeul,mmeetssro0p3evrfioy9.veodanotd4a11eslsvfy1rubrolprua)ffwbouno,soetue.lm*llmn0v3ddyvnpho8ptdvmny.rn,.s,wfn0Ctteoaeis<pspelrnwoaae868aecl9rtorlafdliheme9afdstisaeim"ateekoIilwda1rht9ntnepeoepiemnn0n4bt-eidepda0apaticsslatafi,udtiOtdnsmli3uysesanenehTm,.ennffraadc0to9rahhl0pgtiredt89edoailmpptn1ia.rrhvst8)reaorhtsgiyt3<troafAtttgtnfttn0raehaotcmnentes9millep,stiepe803Tftheeotfwtot9ha.vI1I;nAcIFtendXfllip0v.m0d0aghihhoori4of3aSnisnhoopssrnuvlia.fppedp08Uotoo,rphCel4tieiatpaso,evOl.et)re9mefeiiioee3to-tiy.np0rfn0a6tmehreOlcrsirpMfdnpafspfiAluT4tnssloh.rvIrpet7Dehmee0dOsdo3ak3htd10donsheymetaUlroIhreesnlaeppueIsitdsectJedrivud,*evIs0ts.nn-.-i8jdedtglieronory)tneTcDtn4pns4,,tad:xmf-umrdeTfurcdctsPeyhTgahamweoa)Gipaadatrau<rTroditrAdhgrAfaioagootaasaaafatpolrnhtaeclisioolchorc93t11lcpanlkwimioteipeircu.aomnIInyicrnrmmannn*auheevnnccleeee8evtece-n9-080em>mtoaloeeIiiinmIiIcsoeexoatstealTdTnshdnIddddnt^idnny7ddsonrnyedeeriedn4den80es0seeeerfft-t--.' 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TsovUtdnsShotuoe3ofTlOtednblXwivvohecsfeHe9fi'et4escmar4tHr>etihIneefhineTiefeetecnfiapwa:3eatci10lcettashi3ohtposoeos.fidev;nMesfseonim3ptusdtshd.pihtb4eswaeelleAonsistrtantdcue-aehaekTetspnoiswiI,inlttnlsiiiaepgsfaonsgontrul,dke9ord3fceidepvfn.si4wiv.treocgAcifiinhdouoeM-eei3rTnmrctn,4htIecdUsn.tep5eBoitvvstai-6hspTointodtneorlthvoedfirtaneeeveo12lmce,3ehew4ete,pihovoin5aniinde-sft R D O U l U O V T R , V O L 43, NO. 78-- O A T . ATM. 31. 1978 rv ^ 'O I O3O ."b * co o 17134 NOYKSS TshdmocbwpdtcdptsTccpItof(etIaiSwntnoiniupoaniluipeeowflasdOmcduaiwaytmmesnenitonhnruoindehosttbntsad,tstdpi.ichroyenphta,e,ncaotesonereewsed22mtpmeiletAaeaotdyrsp,gdrdr4sd.ehlmseoten4;dceaaetieueiir'.iessoshr8,nfoeaodmdssts5cciepoenenxmnedaOnoab-afeedpbaaenTcetwretifwnforcinsegoposiryowiawafo;epsjdcsstht,esewsee;inuusoihsneusaearrev.cwev2un*deoiesnisidrrIaentfcr2,tsedeetldeTsnwi4iiooolivtoisci.nesdI.tsyecidcr1-dwfhrnruo,fnhIidDiniesr,i-necttduondlvsldaDw.oygetseX)voTapueheoaunen;udwaetdnoTeesslhnefAknhafI1lvrfdlgaostctaRnttreetwtiin,aeeetlleaweQtt4fnvacimnaodeddmaawrtflisrew-aeiielnmdvonoDfnf-dearnoU.otta2tivIeo.edmaphrennehnanitent,owrtfolpin4epeIoaapaseekrhf)soelnur.trweliitvcotbta5iisesfbssriwavntcnefrdotofo-eiorofnaicieeitovnT0dbiceecn;fvIadthrrdothd.ohchIunsiriet0lmeendceeenewo,silowvuhn--m3Isvdsivnoetunoaafdmo0dekaeeooatsinlna,reuaImidiItnvl0lbteateanlnnhnkvydselshlI0etspponv;evvIeine.dredf0eoinnpdetsdoosoo--AwwhrTcatlpAih.;0llluftihas4gvv(votwweic.ieertiInoenr0Asleeeehinonrtenarelrnhddion2odeddeerst--;l' II. Regulatory History 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Tabu v.--arMiaonrtttaelvietyi*ino/TraCteDiDngesting D o* lWitedeekaothf Numetb0er8othf rwaeteekd*ead sggnarkrraoKrtpeiandlarsdain8tniocpm4pn0aboapdT.enOCrleDnaaeDnort;tat(twt4h(/o110SaUn)pivaemenfeaetalnhanthd)arIddanatetbthisotietb1-- StvPoXe0.cbnegonrnaoat*efoohfaaotdhd.hienpceooUnthtereocriaadr.coisHneoemgpraaotulocpoamtu(ptraanbroelde 1 111IDose01(nob) J1I111_00MVHM//oae11o.tod00spullKaII!iassi_00*tt_hl_o 111>i11 BcCB01a/O/ah11rt.o00acllanW|1in!:ogiaf0itlohaos- 11I 11 M0CM1//ao1o1r.d00oulnlWII1e!I!osmi101thap0alus 1!1!!I AJat_n,//_d__oTDwSho_oo_t_l_aa__nnf_ri_gmo__laoja. cl aATa Zar nohIOai ndMo1bai loal etsh.r n( 1e20o /9p1)lQ.a s ! tl so4 on '! od n/10 u les o I! f is47 ! th e liv e r crxldeeuttpc"tteiaihhrlantouaopoxveatTelatincbenntaelinohtutotsslr,mrefgTslear.nloea"dtanksCtettduleitooioCeeDotds5(ron5dfnIcc4naattDn.uhyoredt(tgdTte6,lp5tyueneoaoen.0C7oe,vrts,mn"0nuroeVtDatplcim,lrmohunsn1oeeesaDannge,dpatnrn.p0a"gcaweat50ateUssdArlwh.0we(,tinea5vx1ar.Icdttk0aemenedt0)carrilr.otg/ddnekl.(4o3osrrend0ns~Td5oiorseoinyi)bpucthe55yn--)reosrpe,r0tg,0isleneArb0sosUnr0ecaetwivefgo0pL^evfde(terreenpte0dplfGnehrdartfnt/repc.Ui1Aset(aoeyoat30sfmsnOtlonuaeM3)aicdt'ruddlbes/baSIat5e1tnlaneecleact0cdtreoovsua)netuetfmharlnatoeaetatloee5---rf. gapOtooXreot.retcTehavdhefihrwre5aea-idptnhopaebfmosteodhivnoaeetsrreOtoeelgnlnireavondeuiermnpaIintmawhflssaaeirrwc(eiptnih-aoi0tcntth.hr.0ie5bo)u5c0ct(eu0tad-rpbreptlodet PTTDwbt3afe1oaOCaeDAx0dewrDD.royewaieDDaweerwfny'rSedtidCeoetdorhiauhcsg3ttaehes0h3heem.ret1.pdopl,irGeddncpaevaia0islrtceeiil..o0mlctlyusT1Botw,opi.JnnfJgxesotaotBrirhhoercrJroyeLtflad30aepr5dx.fec00pyfpio0eregar1ooncaanxt)rcrtsitsMieemhm.ongtaofoaTtarsfilaTtaoseSetpCsliaopyportDuocfrrna3ohvdDseg,viy3dasu/i0kcdeeooe0dxhgef-r. A0i5SsiS11p*t00,ppt0epppopp0pppptp0pt*pblr-tepp>*-e---pe-----b--_------*_-----------_------_------------_------_------------_-__--____ aiMmh1i7JS1 11111S144S00000/////11111/////11111000000S000 (((((11111(((((1500044000000000000t%%%%%%%%%%>))))))))) `A8CaporpnvrtMoroxnlimggrauotutempwiaDelesikeeltyeoedortoofslteeeeiwndeaidst0nM.o00Tw0C1eDekDs.l body wwwww'**'`1eeeeeAAAAAAiiiiigggggpppppphhhhhpppppptttrttrorrrroooooxxxxxxiimiiiimmmmmaaaaaatttttteeeeee weekly weekly weekly weekly weekly weekly dose was 0.001 dose was &01 dose was Od dose was 0.4 doss was XS dose was 34 jic/kg v*Jkg p a /k s pc/ka ss/k g pg/ka body body body body body body 'Approximate weekly dose waa-340 pg/ka body wswwdtmduue`ieeeLmareAaieevgiattkknopihhpvsptrtSaa.aisronrionunoCgrzordetivboomadtismwmavhaeeitreorpisnroevrinlgefsueweltdegeettwieehhhnk.weeeihlrmyasnteenhenrdrefpadproelndesti-Mt-pettrMiatfstweowettseetidruatae-Nmfseunosw5awensd0tdkaeOe0.metirahlRkpelnpee,tsahdl/dextaaceeosnaloanldwnw7bterto8eaeradMarotrtwlyheetll c8ssTsomcieio0hfgxhTr)enovnne.tuetlheeircsxmfodooonoipclpvdogmIealegsnrlarnopirrisgwatomrcamealaruleneter(psre1cdlnIe..c"n0ttieTauwcn8oail)shdi.msntegteehvhddrnsNeyodsct0iuiteoesfotpoofipxxaes"opfermiaflwcleraltoicnhdsnaweetceseinfIfeceon3fltslep8lpita(tcvnle0bdpatHosess/oeestr1dmasrl0ucwetwsi)lesegeentiisrirrnntcoee(au-att3olophnhl3bbysdee/-. I11f io s e X1 * 88t J l / .lLOA|11.JB6U.a_n_iaTLnOo Uta.1l Tuwaoora MTaulaiconraa n Inni t gl aattas T ota lIlanAg|1fleT8lsaaotusit.aina_mo_g_rsW__lTi_iCDth3Dt_rD_r_*._/_______IL1' 11 01 p p t 11 00 1i 00 1I 00 I1 00 //1100 003i* ' 11 i 5 ppt 1 1 1 5 I 6A / 1 5 /1 0 50*A / i iso ppt i 2 1 1 ! 3 ^ ! 3/10 303 ! JXgAUoAAAAnpe(saf(fadweTt,1iI.1olllaebJ/sody/a/e/ioh////bb.uecoaa5edrateet1nrrhrrnoidoasuneeoonadOgaOOTtiTTPODllBfpoasoaalnelaoaoQw)nrhphpnnnhotaoalayaae.s&e)beblelteeep)rartrlosaic,t(eas,otottrosneyeOrrnelhr((ffrowcaiooaadariarsaoasn(iflI1!vvvaannentllertndertttitnll_eenrodaeeaotduooeg_idldrghahrhrah(ltsfiwwal_lnldesaaeaooab)aaa(082pttdldd.daetiiisiusateVr.snnneusla(dunarrtdatgglhrlaaaa)rse_ineo(isgeailqaTno,khowttaotrtvndhdaawaunsHttoior)rei1ileuudaaeeeeaa_ou.helden_nanaaavannwriudats)k_lydon)ooratrvee,sseuol_si.aaupeegrer5or_(atyua.lhedsbatseser252tl0ptl)oos:qdktsnit),),lyysocTa.ulaa,eea(iitpphm1naeonw5asapthsvllaeaaearrpl0t0oro)laeoedoalelonsTasc,al0o9oroaelelirruegho,siann)ysogcewwtas.l11itrmnootuolnnihrlnaaaenoeentaaaaadnnsaofclosarrrnoaoaaaooddtefedonelaaoaarlhaaLr1w5u*tlllaaanasreeoalk0n1le>h^oncaanaehhgJ(o(,weyee0adool.datrtnflb(pldeuui0adhahoeois(s1jLioltnin9gaktaoktelkarlynggrooos7araiu(o44i.idova)qns.orpablblr/n//o1p1ll1eanukppntss)degeyu0d0h0lbaaee,ei(eoeldnntnnaaorryirrotvvodaoo,whc)sikl)aneeau,noayti.areiedddaaidsnnttlrtrolageeeo7te44o)ynrn0ncha0iil,s1n(o-onnp0ln4o3t8ereeepltuodseeealsilal^ldelbcnaslalortotanlurydlaalonnn)soogak.eetweltnt1(i1use-i:potttecthmaher-rerooeaaaasrairt.ttaita?::-i. s ) , FHM9A1 tSO iSTBI, V O I. 3, NO. 78 teJDAT, A T** 31, 1978 NOTICES MmnbTplpclIabteaonhotoriihvDiarnxtoimedcu/*eetaidkmoy,hchyliatu.wgoteiaey*aitcDfssanywprge(,tlyIdto.o1resrdenhywo,f1oraHiceapgu0nuitdrlda)hepIhdvltaenrliepetr.asesvepcenraoliAtneiorpugacotnleraoereruaonasetlecsiawnreqgsn,peotnggeduuee,lomfdlwd,lardeauredmaahnthhol"eenmIadeiamfodondccdrprubirmhstdsoeauqntssrchactareaumooestcsphrrataaduyrecvesaoamtnludgeleinlrligtltdlagsobaygehlIlctueulstane,eiaaesilsnssc/nratt0anidcIecrddd.nntaid1,ieoehtnencdachlpcnsirolaa*jeeersacimareblcaegneclladsalvv/es0aictoeskronueev.rosce0ogosoroee'ri*dd1eeff.l rstrlccpcdemaChaeetreovvdauAceDlreirtnaaeatdeanoQtlionttisheiultcirevewaubeeodyaaIdisbedlmslnt'rtes..elted"cgtedhIdoapoonuaeeAprtrrtIcrthfeutTnaarishftfldimoeCeli,tisfin0ameacncseqD.octnatd0ttmeiuuilsclrsoD0snyaterwart1suaIrineeirlnceotrndaee;ptjryfdasfiivyeorDot/liaaka.ro[mrerorfetItmtgtbTwtieanwmypavsfv.aialieoo"taeeneebcht-"rrrigirnvo'lodoeytse.rtentsnriatdhapbdehs7.btoistilaess.edeeDiwdnrcCs]oesoeaetarnAnsouwsecurnwceonddoQstdrueteoynhintmblh,cIhafaloaneeuesswinoscnssmrs"rhlsridustmuehuiahIIcidonnennlbseihee-t-t , Tabi* 7 Tunors in Sprague-Dawley Hats 11111u00.r.00/01l0t1r / d s vPoa1111_*____2a_12cI_0_n20t__g__e__11s1tI t i n g TCDD*7 Tumors -H--e--p--a t o o e l l u l a r Modules . 11. I1 11 11! 11 SAqluvaemool ausr HC eylple rCpal ar cs ii an o m a ^ 11 10 . X 1 2 ,2 2 0 i H e p a t o o e l l u l a r Carcinom a1^ 1 ]AonL_n//a/_/a_s_s_SHDOlf_eq_abam_uttsruaaeda_mrr_lpvbe_ofa_reiul_odnsra1s!_aatt_eoott_e_.Dne_,osll_ywql_u_o_acirCmnalh_rote_oou_fmlneaSnimgocouucamaaelelma.el lUsoo.SuAcsbas rC(c1ei1nl l0o)m,Caaar erved in coipbnsroeemrl viamAe di/n ai1nr y o rnelyp o lungs, hardpalat r e t / . - slicTeIdPtbtpcTee((IplbmcstQmlltawitrbatiaoeaihA1nahnithhrdnyayneevyovoliCshrsvs(TnggKh1lnoa--lelaclzgotHdaeekoetbietleoeeDy2ieiuhtttaeyteihy4ertraictvos)hhylsgraH)ncnueosutnmbn5ciDhetn..eau-QraeorTeoietisassEmae0tttt)aIhecedrchTurcneefeFtircaCrcnbllcolnfunamItl(serttccsioaorpahfltaraoanhiiaihcUeDaeesnifodmeeeireootvnnvfuervconrrpinlrcaosdiotelccaiisaaDesanSc(tceioftTomtlzmptnrilM(eeptui*eetrtlrriolrpyaa.stoesgynygescifyoCoyixereLdarmioravsootniMlemoaldictomCccnt(larenhasDclgkbnaiuneat1fIegt*ilnmatsgai()tbntaeieniC)ositonpts1aoDe.pe"sfenoa)llibhlnepoItclf5olhtpitnynshpnobnleyneteaeMhgodrTahmce).onlpyIarIyoscTotlotnorIedaainvreoui)nywnschnoaesmdddc,sauaCvarolo.deiffldyedrgreakacbranisistoecrtelmfuffieDdtrtupotue"TotsteiMsnlyceethuseueuPircpATeiencilsct4nrnevilnCDvbinncbehercdmaeomeooaCs0ozcICe*csHsecteydtedDenrtdetcirbylarshiyhf.lueesuD;IabahbewdctHidiyttpamDnneIeedsadndxeoItnrhalcboueTtuhsDt.mhnrthyceditrdsdaniyrohyunmaaeotcamhdirotaueAihhrscdwrMltdoIrgina9etvpbcIusebiecimuneoeiaeenHc3arelihtetiwyog)ycelat3silgsnnrsxnAoalne-.voahveraHhmlol-emt*cghUooascliPIlnyztawtemdhHneylacynfbLiyledereagyycloorrfrleldi(lyItlsielHdssndle,eomhahdols1doltnnonen(rtno,lodahnclettnin,yy1e1gyoicavdhgohtpdTfedPnsofysItddci3gd1dTehtmxaeyuefnnoolrf.eudolnConh)ano-7rbrreooylm-Cnlcrdtnpttoosdopvlcecc)oxisTDrrehceeultasaau.cDottomhxthxemaiybheoaeirtrhhinnnonhcaiDnIsstmnnoooayvryncoslraDtnoddtidneeideeteaeyeats----ft-t. . ; -. wcswdAf(opAwtwpsPeatmtattIIieeoThnnouimonrfomotoaHhneAnhrdioorgrhantTtrel.rpdeeipueicnlhxeaHgtleelcctbdeCmeyrneyllaacksnyeahheoetadsctittDoeIsdl9nwnicynaoishiamayfatyoa5olbsditeDeeisfy,eswsisaafnnsiddmteremoimnsponhhttaoge.ifmthhpafTddnodeuoxetinapyrnitoetstCere5wndopalfo.ohhhhrceQst0LeaostDmTeofi*eparanehn0hrIntso.alnpnesCrhDtteaooeobgdwd(teupttotuepad2wnvwDoolaearuisasi..paichefeadcb0angtDtesuttloptrassoay7sicdMai)silTnhrlca0thrs(tiobeTotIMmegfe.taetCCoyls1casygihipaaCnrpiednp8ol.DtcoCeatsreta3aniaeaDe.nhoy)tennnln.nDtttnIhr9tPddu.likeaDcgnio.rhtccc5TeaultooeirTdnedfhoe,entV,TrccyComlouumdeahymagchatsiph1Dmareccnnendyneapbo0hwedepecpdydnrpDttndueaoyromeaoapoeigi>tta,rrrrrsnstcaeterlsoeeehbwvoouotTceeaaeitrfahdslftoeouarllrrtsaasih.pfatyehablomnmslktesetiLftreThrquXpooeosunhoddooom3eupodedchnramsIpbegrf(8pnsedienryte1toaearo,ptacadnhitt5tha1phnstnehhhminrltaeec4amio7eyIaolieiitssxdldeeynyc0sass)tf.. I.I ` SlTms"cb2b3at0h.eeww4hth(eyeee3,yeeonu5nnmn)der-rt]eTteldiaaiPspwennliphwxeirrgd.ieexpe"tetperhcupolorimiaIteomosfmnpteadsisIhoedoinuenfnrlaovrirdcotvasetfoebrger.cenyiay1oTaI2cosn0csm,aHfsh4aeelu.tetsdppa58oshmeria-7tBstdedTureu2eaneodd0cmpomtngfiiaevevlyfmsoilsr(eooeses1errhlalslroi0yaoeg,aln1sinngceegmusp)hidxncnmeIesaplsasar[dtmsomiawulnstoIstypinithedavucspmrdotaedrauoyoe.lugefdrtTesohhcrhtl1eeafehaaatt0neroaoddae-t-- DOW 169593 17127 F8DCRAL RfQOTHt, V O L 43, NO. 78--TODAY, A K A 21, 1978 17402 17128 NODOS odalfnotahgveaenr8ae7gtispaa.wtTiiethhnetsastdadetovismitaiitcneadalntdceeiasmtorifbthtuuetmionnoatioo.fnla7 T3cTpgsNaInlectcvnpdodOofTrcoamspic4h1ahniaos.huepeaoCotunab.9liefa0f4puCtTeartcTndenBlwnbmmsihl4turtir.circlmDamvnipih8nleDmceuoichic1aCuutnsa.eoibcnenneee-.ehrled'tetewDfeet)suxtroagTDyxnidiaFgidgaqdiOfr,trtnecmaasonri.as;op.oietse.lcRW.uwa.rac,ftanoafnlsi.sb"nbfIehf1olfloB(aaslUiligpandafya(uiacroeyra19nlrclroftte17roaeieh.ougoohhyn892fttraaimrcc49ibfanTtem84crnktta9ftneahpoth3hp1htecUncu3hhTgasiaeC)inhirn.eooni/p3cdeauheo.rtnUoentnie7CahyrervoDnewTtgg,arrinrmryxsiee49at"osem(toiDatrenrAoahvuCdvceDdrapAy,e1heeeGendrs5c1filrnioXmeoDevaicdo1aDeroildncsttt9-dgdrigenerxrmie/saewctT)ar3nca4m.tmo!on3pDeeewatercitllearat)X1lumpaos,enynuHDlthg.neotnoocpia.i4omibdtdrllftpnUcosaiatanaciehueyraaerucJfhlTtlm*opinotabrfOnareeynoamuas-XetarscacoadneethTpanlu3edlic*dtplaaonhslinldbBefrrcnentcfeInnmul--ltnhfmawpevig*nllseaetctldah)aoetocaMuoatoc,aeendpalnlo)emctgugatsalptarxpte1llrs--sniut(erpaehtisletgencltcri9tvieosu,paaotpbndcos*oetcnsdaeaha8thlarnrapftreaioreuwuennvnderint3.nesaftceooesoetesinvtInfsiloi3dJtt'ssioVhyfdadcdttdcdielItcep(t,ers3fs<t,otoo4xigiiut4eltpwtoumlheh:aiacee.i1wh,tof,ifesI4ca-mooecnrc8ccrtshcna8eaoaftDw1t"evae.eirio.bftoc-hne98rtt"tnss9itarailrTdrehenelo/tsnIan-laAeie4BssaaSwotdy.dtTnfy0r3atmpdraantShftotainlgn4e<aiaree.,0poehniatse.0*4tnremtaaa4nivem3cceiet.ouaeiainesbne.90nhecrn3nInc.onto8dsbn"ea*g4stbnSdei9dgs8ee>arasehiyds--tar.-et.t, eotrtcsfapfkats31aapptscsttedtTgGm3uahhilerhehuixhetnrgnf.dvrntre.onelCegu4Tmb4Teacoperreeacaaee,indedtddneaoAvnddaJotuglDsadmrhmthsthriisegoL/.il/egutssieincinlua-ooB0eoffeeTDlse/trdeTitiipTiofisackc.(neecsnnrrsrsdthd1cCeMpisreneha.Wigtsatsn,at)matnatutumscrhfoDhhacuirlcy.uhjna3edmfllodowadiyfaataolotieimO.edagDesitx,tv"tnntniisvc4srsrensxuaoesieieaiwlekijieteattae.^nfTttnloerpmsfcsusarhhralaeaaeisnTnf-ycawaoak-oniCrorepleTttsnytpapbrryshmttussghsoehtureeptDfo(lirotueuayaioxs-3newaoidataotessaeattbGgompr0Dtpftsgwontdfttsedalnoooconnrnei0ortrommunmfs3eo4/omxddthrsaio.iksit0aeect1s0dtn.scnheyieduaehu4giaIsgw.d,ecxec3se8ictnmmesrhr4/ppnattaf8ietislekiineetaeehfau-nrsoctNtmypogrgjesTodoahnehltdtidnewhpl/fattg.avdtataadekopomioomnibiilcsdaeTg/nrtdnaanbrwthlodaionxe,.enrecCecrirxrtdt/inifTaosehtllotmatoshsodTalDiu.hnherBeeCentttfrwba-dcahshdmceDfaebdfpDltltltlateottaiieateeanipaisosu/vninfDtnsrakaxrtttdhperntpegadsorWgnatttaaaos1rcdibrnclhtnxisTsde0ootwTitTtfuih.rteoygon0eivardlnrCel:eCrdcCrmstsrrg_mtucombpdirDakHtstahDa_deDceaunuogopueitanr_agDaenmfDotytfepltainDydesfes/tgr-t)t,,-- dTcpstdmmpdgfs2pmfsttcbfthhehietoeouee.reeoaCgeu4(p(cocaeeioeansrtnmsta1snfAsdDaetetntcdtreiru)ttese)idOiceiinrtaanddu-cfDelrdalsmSTnoiotemyilPsecstcpenldaertud-foienaeuuiaet(tfetmihI3tsnndh3yennnIflasdnouaI4Iaanter3ay.eustnaantUi4esvIntttlchneod,.mannehypbdt4eJdMtSdstetinnots,p-iIohedt>mtms/ceTsncurihmmeoeteoien,aTa<cikeIhstsf-aentrtfntaletafeiatt.ihle,itodcrTwaiosnhynotiU2faefirdotlnefbshmenCfdsneheeehn,cbtMeee4ttlatduai/taDiesotatryecce4osWTislhtmdxIrmdMothtrhuD-etrCesatwsayiTtenfehddae,at.omTb.exDTUtvBo,dnilyerautiCoC,tSeTxafkaDaooueh-nttklcnalupnDD(inCtmtthstos..dn3hoaornbiruddplDeDeDnegAbi)3axnaadsetn/mfaglplhef.oiDtt.ttxipc4eeaeGbteaIeqfBeraepcirpnioJreTrarpuanpnodreotat-leih,TaCodoaoeTertsqdtscsntaeodClvwnudenDtuhuoanlsdi(agdetpieaDccnnep.euaDnmfrat,teinsfrdpsmiUiDdrntitoTd3tcoaecepreXouesvlm...mlyCnpo,rre4fd-tyiTeaootfeFdDR<iJitiiirerteaxocethnoh-eIoeoaaoaxD>ofsTfvaingndeeer-,tl|.. ewwpwosmCtp4pccUcwreCittfkkthraeoestmiofeflaeieeSaaoandedtirfarauntnnrlrtthaesl7ceoinubdanehbctnenlttgtdeccoByerothroeerhsnldhedsrs(totameyynn1Lmeaaeynimfastdlsaeg,a8ottinds/satspea8lmtsasnfaCoIy.n(dydml)nacnun4otcnxtMioStUcrwoif4hosbalfopa3ofaenieoibTeianomneccanm3tstardefaim)frtgilBkteusatlidetetlvrspaatotgaceetanettLoprhedheptalaoltoteslrfhsdrtMirlahi/eyenanltenras8netetamyrshCslsclre0sIa:hdsiedtosattcenaanero3lircuadeootmoooneca>dpn7iUteou1sltrnrnrnlnf-id1Ctet*etmst.1eon(csvoeotc.atl.r1<ThatrDDyarleTr.Uacrplr0%aeoaemspD9direaaleCa0tSB-s-e2CfatlldbeyitinIorsMtipdSs>noDncecrpSAslp.i,stgeUp0seec-neodsoBgTetDTbedCer/afe<rs.mr3ttsfcoBeetOtanolDnT%htcxohtAa.TeesdtitpuipLltteeJaCnthbcruennyCCetr0aadnw/sT)lsoetu8tDadr<BwiDiti.3phee,aodeouwt(tnmtOeDD(sd%haaeDduateOnttnVdjf)etr/h)rtidjiceBf/sottegcganirnikTeoeoho3g)v)dhietAhia/efgcCdornhskweeimoenaIjtI0sttntDf/iltnsgntbfede3tgosrdcublcpDosr.na,.<pla/tt1ttosreupekhtfhed%hhnye*30ee0Inioedfetrgynoe0de4odees>sf--tr. Jg11l1I111t11I1_CMCP4/33_5SIto_Cr7-ttne1O_/DBia2isnLa(tJ/Ja11I|D111|K110_0_00(<_(_outDM(r__0sg0Ho*3-311/0Q0k*_300_g00))C>-))111LI11111I11aCuS000250VI1raU/*//////t29227919a_f3030s_ty-_P_s7f31aaD10i00010ld_a_'tM_s.11l1111i1i111_ol.1io_0T253adyV0r/////e//n92T2998e1_a33_0_(y1__2_8_n)1t.ao035a1isIe0a3893la__l__is__a_iLIl111111lil__0__8_2__tO.4o02000a1it/i///////s/e7229991(_f*L330_'t'_P_2311a712t00000l_a_ta_lM1Il1i1M1ln_K4_.1...ia6t50da111//9_/n//////4192792_e033y___n_a_652isO15it0044a_l_is_a_;_::!__ 11I1Lil11lt11 (TwoTjtdptoisTogwrCCtIMJeaMas/nODDcknlrblaoegyOlDDnmaedr-obtontptaaTwtoooff9dgol(dCdXisat/etmtkhuCayrbyDhxe*bXeeOiweapaDen.r>dpnobtnie1,ldbashssHtiataiurgtesmedoautnrhdrnaxeUmdcieetjtciow9yodianeatotm7tnoe,etsrIsdc7tprCenp)asoafsdeulomteiturrlawmbouetctobpocdderhtrcotrtunhoa1nioweuucDts8etesaxthnaaieyynitU(dneeohoelesadeeUfto,rstatvotxauenSbreumlw3rsdoD)lyssd8lsyuiltlatyttaoutrheetfnoatsetoraiaildxstaDuaoUatth4ttbnSne37nSoMetneddd89y-.r-- mmonfcc(p3daeool0nesfreotaront9odu4asftetcuitstletjoapee)se.rnognnpee*sgto/dsthr*kceioa*oanorg1aomnuhlOn4autdt*pi(huthosfps'r.cnemmuocee1ootblChrrp3awmcec4eel0yeuofenpp9o--ntmrlfaeareoeteamnrnyoptniaceundepeedleoas,rsdnteeuoa,t4hdotsna0keooh)0dtribbtoodaeo1ngscspbdsnree0lrpsagpeuortrkeelyhp/vveburkicsdaereeevpgt.cfdndrniesoevcAdde3(wotneeey0anlwtsnltxe0l.ynumthrfEe.oobeteojir)afdfibtcefcgulTeuiaftltt/htsmohekhhntheeyafrddgeeeeast M|tifVnat. 0-1 UtfliV MDOatOa TroClaCsotbuyrtlasvuylfo(1x3ld3s).. rCDOBAL m H i . V O L 4 * NO. 7 9 -flU B A Y , AM B. 31, M9B- 17403 NOTICES bindlccicwiltnyinneareeaat.NMicyrtunnyntCNseiohssettdtor5eMteueso(o(07d1x.nbH`xmr0RBHhpcee<i9fiILiceret)e4cbteh>r/mtei6hactooratpaoneeiaftnaemcnownduddLderdtxtigcehkccitD((eIhrceee8i.lTnen1de6srica7ala1tnaefli4bt3ttpnmedgo()lyaede1pi1eogvaanrHnapfenaceloclt1snnnegaeegm0o()notir/)e1eca(.tamtosf2vs%gtlotIfo.O7eaiaaneut)fagrlAtH)tsfiynidehtoeeotideimnsencnwnn)s,3iteg,.itctsaatntehprshrCtndieroaeegsdedesoafa1ttot/psemt0cthtsp1,TTeerg0oee9epocdpCC.nsdtnaprpieDtOtresvUreemhoeeogoDDerrndets-fl TcpdprpCaptd!t1ieepon3eaeaeeoClrs.<nymrderrrnsoDceccfcsaK0rptedeeenD8p.nan6nwpdu3dtw8rtttiai7,iaoc(t)plit8(o0bfrlahtnH3oepeeh.lts3pesrfree)I.pctptrSrtoheOUoowecetopUorenpefcotiataclatnttosfotlceiel9athcvriornootglotese(intbefpe%cornl,tsyewvsogrtnatre)ts,rionhesa/tiraoostltsovtetbhl3rrgtipfevapoloo.v)eedtfaltranf4alce.ilesliU..olutbtSlsntuiutneiyvo.tAehcUstssaeraesaee,tlptlInwrUlstywntse9dio)eyrtfroeaehurfesprw9netssbatetpgishuhd>ha8g93eas/etenatc3eiardgngponitesnU/fiak.ngdsvitdcntgcoo/eote1dateUr0tlo(mvg0anypr3.tni700sl,t., Tabi 1 0 . Embryotoxlo and Teratogenic __Effects of TCDD on NMRI Mice*7 1 1Litters Affected/Viable Litters i 1 Dosaci Resorptions 1 Cleft Palate 1 J(ua/ka) ! O'! 1 oil 11 03.. 30 ! 4.5 1 9.0 1 -- 9a.Q .. A/ Data !1 23/9 5 ! 24 1 21/651 ! ! 1 76 //21 43 ! ! 32 54 67 ! 5/ 12! 42 1 3/3 1-.,3 / 6 ! 100 I,_IQ__ from Neubert 1 1 ! ! ! ! ! ! and _ 6/ 4/ 1 93 55 .A ! ! 1 6 6 07// 2143 ! ! 6/12 ! 0 2590 D53i// 63llma1!n__1I0(L013_2_7_)_* ! ! ! ! ! ! ! L ./ All doses administered on days 6 to 1 5 , except second 9*0 ug/kg dose which was administered on days 9 to 13. sdbk0gvpptt1yho.0agriaae1ISv-yrr0yllrno.uopeamoTpndnettus11Cetieseia0.ghots0yDrwah.hnip,cwlsseDiteeaetoe1dansrhantr5nctteoCtudaedoocsnoLdPnilf3fn36ye5-t4d(.gg1ft,001opahtel3paeymfepsepp5etrestgia)acrvd8hcircltenioaceaieaTepngodsetbnberCeltnnmvleotyetifDd(aiwooofnrgTUubnDoerhraiclatsasreev/UtebtdolkenaedUlUarrtggdertpsye4eteotr:tt1tbd5resieef3so11oesrrr30)p1nosdosw..o.srg0ypmTfhwp.i0C/gthta1twhS4idi/ogd.teo5teahnegc0nvypwpetil.er0gseermogoIane1frhnn6/sl-t.t,. cC0oUdotpNonthrie.ffeiergl0ootlenyetra1rttldectfssdhht,artiUe.ciefseleoggfnodaprtrnetttntmUUraerei0teofeolrndrtt.iaasfttn0ofcteetit0alrarehyerrste1elnsshadnshotpdpoettoaacierringrglncceetlUplv/hlcuaayp3tteitretrtgis.etfeeeo0rereil.teaddnvnrspNdipssisnesgoaaaotitpclht/ttinrnwatrceneeg3eet1uraae7..aesr00(t1ai1rti0eome.entopp0d/rhpddd3bpggeae4splai/i/mrbraen)tntgtcgnnrgciove/c23;tol.1tfnaeee81gr.b0adtfttmiptpthniohlogpeaeadpeanafrrrltgatoccnceiwl/kt0euneoatrhi.gnnpaaintd1ene5stl..t. Table 11. Fetotoxlc and Teratogenic Effects of TCDD in CF-1 Mlflg Incidence of CleftLitters With Litters With Dilated Palate in Litters IResorbed Fetuses!Renal Pelvis per 1Dose Iner Live Litters !oer Live Litters ILive Litters-------- HUg/kg)I __L I 0 1 0/34 I 0.001 1 2/41 1 0.01 1 0/19 10 15 10 i 25/34 I 74 I 30/41 1 73 1 17/19 I 89 I 0/34 I 0/41 I 0/19 1 1 1 0 0 0 1 1 1 I 0.1 1 1/17 I 6 I 16/17 1 94 1 0/17 1 0 1 1 1.0 f 4/19 ! 1 18/19 I 95 1 1/19 1 5 1 1 1.0 Il0/14 I 71*/ I 11/14 I 78 ... 1 4/14 1 284/ 1 */ Data fron Smith et al. (135). Jl/ Statistically different from controls by the Fishers exact probability test (p < 0*05)* kfdoguNrripcenluegerbfdetdrapatyayselat6(tTeatoLaIbn1(l51efe7ot51uf)3sg)ee.esssTtttiamohteiabotenneod4w0-etaifhsifgeeeTcsEttC-lDlmDe-vaD5et0-/l pwmedrhiontenoinostbue3enrec3pdegpdoTgnC/ftedDgtaaDyplse/kr6mgdtooabryto1a5dfUoyotryfwNpeMrweigagRshnItaomnwbciscayees.r.vaNeddo KDfRAL tKHSTBL VOL 43, NO. 78--flUOAY, A H * 21, 197S DOW 1G9585 17129 96969T MOQ 11110 mi i iit. OoOaaceoImf mCaleefot fPCallaetfetaPpealarta iIntffIaMoTtkandfinLwlttoaPraK/tTnnetFaeldLTitOtWorFal f|'crC--Pe*t . ). r. . JMI1_C/_3_7_BD_1a_ta . 0 012 9 fro04 1i1t11 _ "<0.3 <108.7 Mleu_b_e_r_t _a<2t12_a_l_. __(1_7__5_)*___ 11II11li 1017020V0///////Td2221213430690 J111111I__ _ U2420006002_______1111111L ASc0n3cS6ctoo0.eeapp1tt(gnnnhlrab2pe8atttrr8)hreng.ao(0o,(reiuc41uc0)cmhe8/geJ7if-u/dSnahcD,1a)/ttrta2*k2uuaIraBt(7.hdadwc03t)aaaio0l1aagpeloo/fn0y0eefrhUgda04ratpe)fhtl0dedgeata.ettat/ai0taatkotaynUrfukgpta.OetohMoe;gtbaxaJnnann/nyiakthlpoc(fnaTgTengnfaiCgaeaaa/epekratOlatbfaate(frgetlheDa0atre;dcaee0g/d2ta1pad.mea1nI43ryn2T(o0)da18.a4dC)ro0T18rtupnoD0h47ncgfatdOe0rcppp/ctad.aka0beeeeyttgt3ratrtaoras-;e.raTccaTae(pffpaeefeaehghftcnhn<drue/ietkaaitt0caag)gatt.a(th0-h8d.annle8e3eeaMtlrf)vper/htfa3toervaeiownt0e0lceaane0.rtle0daafe)e3oooenvpIdrofmeonpgnanrmarofcoatteeoehtt/taaktduheata0dagfesel.aefectr1neaadonp2acetoaw8actatxtatlr,oshdcretaaoOaetrdeppealtteaaaiedatmT,f.nyaerfFCyafedetenennedDtay<otdtadMaDaoattleo)gllt2e3odnhttah2xoiptpedt0lfxeaaioggoktgktnp//ntnkhktwOheentoggtrtydoJst-.. Table 13 Intestinal Hemorrhages In Offspring __________ of Sprague-Pawlev Hats Fed TCDD*7. I Dose iFetuses Affected/-!Litters Affeoted/-! 1(ug/kg JLFatuses Examined [Litters Examined 1 1dp dav) * I I# [t 1 10 (oon- 0/2 46 I 0 I 0/24 I 0 1 Itrol). I !I 1 ! 0,03 0/115 1 0 I 0/10 1 0 1 1 0.125 18/127 I 14 1 7/10 1 70 1 I 0.5 36/99- I 36 I 10/12 1 83 1 I 2.0 4/7 I.57 1 2 / 4 1 50 1 i-JLa.Q____ --- I ----- f -- 1 | A/ Data from Sparsohu et al* (129)* ueodVwatt0eaxfn.an2eiafKlpsydtrt8tcpaanee,,heerafara80farubtaeUl.atnrao8clgtteovd.htalaaaetrasoac4;ooeatodhfaeauTdefmnltBmgrCirT.gha1snaDPhC.dew0tloOotdDaiesrpfdorOtlnawoineeflcfaeladovtTyr(raht0nenteCaaa)eaWmnalaeaDa*etretltnnfveoDntftdtatHeod^ita/dlrcakleortietbdaRnsdftertb*epe(oatOtdTryhartfaeaoerJeaapld.aeSbldri6rIlloeedpan0eenwdhy.gis1ag1ou/im2bnkot4nhra8n)ygge-t-,l. lowvmbaMpoibitfrogerIbatfad/gnieaUtkglyfaerlletgh.yra,aytw.nttob,aawuatetoaanatloiitodlgdtncxothythnrdnlhcetp.d1weatrTph.etoeeCmepf2edxifrgr.Duapenohdcc4neDguttea.rteamdiyt8nrmwra.byowviteeeataninrwharanlat,tcddea,m0eraarntJnenyr1abHta8tdtaotaarmbn8*plrer!edegtaeetefdalphtenrTd1urrrten.cuoC0eoaaeddteuDpdtrougtegaaaO0fchat/eftikptt/iltkve2e81egader088gr.l nogoA i t m n n , v o c s, u r%--n ta x i, amo. i i , m &369T MOQ NOTICCS lpcrpienaoeevcbmrrieclcdelpeesean.nntrttDocee(d(oH4tsot4he)of)saosntoofkoffetInhnlt1eeehtt(apeh%1lg.e03/ak).np0cgIoognmmno/kttrahgrgloem/ikelfsesgcotoruwaenfsteateprtsauoarocsllalseodn.smuddT,cophe4asad3ees cWemd1of0afa0nylestccetploatrueenrnddracerdlardeaattnyostttsxhdwieae0cmvititttehybool;rory0a4p1.ol9m3pm0tgoereo/nfpkartg.ggttamel(oisotertyranm.tmtioToonorhefreeapp)drra/ovekudgegtruhnscopaeenlreydsrt Tibia H . Taratosenlo E ffecta.of.T C SD In Mister Rats*^ i! 11 i Fetuses with IFetuses with Mloro- lAvg. Fetal (Skeletal lnasal1.es/-laooplo V isceral I | 1 Dose 1 Avg. t Live | Height (T otal # Sxaslned ILeslons/Total t Examined1 l(u*/l)l ITest 1 | 11 1 11 1 Un- 1 10.7 1 4.82 1 5/107 5 1 0/13 1 0 1 1tre a te d 1 1co n tro l| 1I 1I I 11 I 11 1T r e a t e d 1 11.0 1 4.51 I 21/116 18 I 0/11 1 0 1 loontroll II I 11 1 0.125 1 10.6 I 4.64 I 3/121 2 I 0/38 1 0 1 1 0.25 1 10.9 I 4.79 1 6/109 1 0 .5 1 10.5 I 4.46 1 10/105 1 1.0 1 9.1 1 4.10 1 6/81 6 I 1/33 1 3 1 10 1 3/31 1 10 1 7 1 v io | | ITest 2 | 1I 1 1i 1 On- 1 11.5 1 4.68 I 8/116 7 1 0/10 1 0 1 1tr e a te d 1 loontroll 1 I I 11 11 1T r e a t e d 1 9.8 1 ' 4.77 I 9/89 10 I 0/10 1 0 1 loontroll 1 11 1 1.0 1 6.5 1 4.17 I 7/80 9 1 3/6 1 50 1 1 2.0 1 4.0 1 8.0 1 1 1 6.0 1 3.31 I 7/57 ,,J i 1 .(------------ 12 1 3/7 1 43 1 1 11 1 11 H 6 -0 1___________ Q______J ______________ I ! 1 1_ | 1 / Data fre a Khars and Euddlok (6 ); treated co n tro ls given ani so la-co rn o i l . StepfrloTtatmttwt9ehiehheeeqn)bpeoCvaCDrarrrreoousrrnIeesseotsDaenroomiildesfoduvtglr;(weDuai-vatan6ugaats0gthlrdyye7uo!lleiih.teeiegt9dmn.ts-fCeyfnonpDneaeoAscpa,he1itesnyionra1g9tfer.wCrofdw0inpiacmd/e0csfDk0aetortei.ttalUire0rnsi0egaenofocnecl1r.ydlrtpitn0alestotmg)asflle0epsdwny.oterMw1rrgsiatTcuscn,Ueirr/sthtonaneoCekei0aasauSgosmnudodpu.rgtDr0Ahisyriturvb.oce1pneItotDcioc,"nnh,agrvdDdeCune(ro(eoaduda1fe1ttMpt(rlloarhiimcd12Tendofnc0utie3Sa0eciuatnsro.evnr)or1O)rtblo0oln'eetwoyfol.cuipua0c1tfe,ltfrieatdgoisetoopartrpllemntvs8yyeanylpTfehsg.td)iftuar.diCeaae/wucnrfIlkdedSdceaenDceDisagaynmasdtdtitnisMdeetyDxttsufetd"idsanoesnctrtoS(/Ulhthioeelke0isauanIOsdynedtoeg9ane/l "nlb0udabIwqwTpnfganot.neueieigo0eChtAehcrrodee1n/taataeiDemknddhncAenstaagfdIihvDa,rarlocn.tgniayeoetdphnhnecetsdrpUrepwlgieossnlusuoru.e.esstfco0gorasntdoeIvry.seDfrated1nsefheidrnbtuv.cesiptd"ieptelelcehslvsotaraceocgurhdtIoaextyraiaaTnwome/veeldr,inktcmudthacileeutoolmoygahsiurentectmntrcehydriuatdapeaaadoaeirerpfaomvdnevpoleynafdlssrreuaaeayu,.teeeuclilccdfsgesrllotrDA0w>iitahmi;avpfhtmerc.bof0yyohanierdarevaw1les,loaoailecvotlnallbawtadlh.aptyilfaeacdslstu.trssgerraoiraedttoyodvwIn/aasnUteknuonenadttcsawcgsresteorlsteurg0seclaenettIUeaud.oporonnr1elamodaceeubogcscctsTaowvdlseeorepoeidmseeCt0zssdnstgentrlshe.tssDhog0v-ni/tadinrkfi0nevaooroaDneeifg1ygdgdetf-ttf, 17131 R 0O A 1 IM K IB , VOL. O , NO. 71-- NUDAY, A R K 31, 1*71 iI 17/ 12 2,, DOW169 5 9 8 NQTKV Bt(obnrMhcUohirooau(nam2yiotwsvcb11eoa)k*I.0ed)asned*aatanSatfflTttaehusthett;CtomeferegtharhQDsmabeatbHTeLoseDmaoeCtgaarseanetk(setaDnit2m/sctsint.eo3uD,diOolr7nclerStb)eryJsftettsxe(he.urfp4eatpssTfadurn*g,teovhfitrsda/cesnekeenutMsds0sysgVdrl.eL0ipfhaIne.fh3onefaereButcrvreemehnnhuetdrtdaiuoaotcm/syfrekak(drSbs2csohgmetnho2tanameo0ilbgircTrdn)bslemkeCiairssctyyaeeDwhtoomUsmnaeanDsLd4dd-.-.. ahpstsadftatohhreentatoaooxrreavdlsv0vmgaietecee.net2s0dedTon.aOoe1uiC-asifacrenaofnDpitlfe/t*otfdygkrceDdewa/trs(ockfksta7ratsilattgoJ-adne,osal0mnsegmitf<)mneveeoLTiyInte0cifonmc1Cl7eiasrcet30),oiDini1.lSc.t(ao0xonee7Dpn3almpf2rgedt.f(se*7/ep2atla)a/sohcJgl;kni6ratte/apgsidLkhmsnnrgaehdtishTrlsntatiaaimmevmanTvtrbersistCeicalor.n(eeabDtbg2aNs,tee2ef1rD.soeoeyn16nnC()rifdmo7leatilooa2etsneaoabbttfrfdays)-tt 1 A & 1 - 1 5 .____ g o - g f f e c t - L s v e l a f o g T s r a t o e e n s a l a f r o TCDD 1 I B o u t * d f i d - 1M o - g f f s o t - L e v e l | i I S o e o l e a 1e l n i a t r a t l o n 1u s / k s o e r- d a r A l1 1S u b o u t a n e o u s l <0"5 ` 1 1 O ra l I 0.1 2 5 1 1 Oral 1 0 .0 3 1 sfsreno# I C o u rtn e y and Moore (128) lE h e ra and R uddlok (6) iSp arsoh u e t a l . (129) l i i i 1 M ouse 1S u b c u t a n e o u s ) < 1 .0 i C o u rtn ey and Moor* (128) i J LI 1 1____OQeraaIl______ 1 < 0 .3 0-1 - li Ma i tu ab rt , t . nAd UD .lilml a t) n____( _1_2_7_) 1 l ntgu3ftomtasdgheor0uedseneeori(eanynnlmce31tmpdteiieedd5)ccep*,idaaintm2Iadnaduynos,naan3Insa4tfLntydrSTd,dl.h4a5lcs6pyeCf,i(tf-sl6el0rs2eteTioDae-tteg2tfTocsgoton<ti2DnottTutttu)aphiopooeC.1f1bddaeexxif-4T6DclD.ylseirie1aaccthvIDoi1atonncceeee3(tfwortiolTfcAdoafamnplgoeIaleepnKten3lcenybaygesd0tcspRtild*/trnatreikroaecacpeiomtmgaty1rnihtpdiddssosi6bmieseu.nectrnau)oi*oceSac)f.pbdw",--tditupircytkiaeTnawnbso(runinsaowtdchntatd)aCxutnaeseaehnrivtdde8iTmata3eegCiyam7endeo.nhyBsLaroreeguliat1stanan6ou1Leistrtndi-c1uorlIle/osTyyt6n0egs- tWh"e"eIRlDfnaeresaepur(al2etrs2ctm2eo)nfeatntnhrtediopsbfosyHtrutCdeolaeyngltwgsht,(eu2rde2l2ep)e.umbliesahseudrainnbdgy fmIpStcr1hnaer0opmTetou.rriaCoatrh,leostga3seaedrmuTnsdliieneBht4o-yiI6fDLfnirnenf.tI/c4caao6ntvriawldeieimlbmtaeslymoeonstgiiyefotccgii/hsceenkfaba.gstto.oortthtChrantfroh3astoecei,u4nlliaCeir4tslvtisf-SnteptaoTi7erDen-pyBodtfgdoadoiLie-locnuv/abot6yeentofesnedadmtdLmiwyacotincthurakaedawlkari.sldaitloedfnyOlietne4garirtey.nhetaa6dyos-tl,l HsridItnnneiTMeslrgncv.glidaedhRofll"emmoefgnpadoact2lmuhn*ek.ce4aeeootJlniftiffo-etnaT,ndt"eLucreisatyn(pfre4tsethhsStfaipoe>eoctatsrefaapkldttaltthirhrdteweaianabatneeanwtuiieysmgtedestehrr"adetdulinIaaetanmhnltstdfeotsoeeh.riiueannordetccbootrrsageefmerfeaardsvnssipeceee*rddadd- T>1 IS. I Im i - t ' V tSC-UttSC1*^ I II iI1s u t- Ii WISts. *i sUhnlUiIar.atriiiemsliIilaTh.irtist m ic m u t lirNtasrlu u trIIllSuiunwral III IIIlCCSaooonoontttrrnuooallttM^ll(1Mir-.M-i-t-m- wUMiiiI|1 IIfhr-orosttaodd Iti-mcm 1IsIuiiMhguituMmMoamilI1 Istmm tM.1 i|fpootod IstMM. m m Ii 1--ut1j.3^1|i|1 .1 3 0 ^ 1 iW ^I U37M22 1< 4 .3 1 1111 11 1 - . us97,...19i 0.5 4.1 1i1111 u 1112 wi** 11iI11 <<017 i*0 v ||11 \1 ii9iit..^ i1it lf ' ni 3 iii1 11 943*013t# /111111 1 37*1 2 1- 3 ^ 1 ' t i 100*' 1 1 TC^I * 1 T ^l lOC^ 1 99V1V4liifIILI/cBMCC//ti/5rraMoom7oMoo#oBDOTTTStttor'rLrrrrortooooooo*at/oloooloitt.-a4tTtttoooot/Srrrrr1tttttI01iIl1I1ltIfrma0nsrSlrrMuooMmuouroaCMtMa-l--ewo-uoe-uMottt-tdrrreMttM-o.too9oo.yyy.M0oio.Mt.ey.90<Tp.um.uttotoSo.fhhil11l1rl1t|1err11roo1to1uui--)u--*ucguu.t1of*bmfit(<,111i2|i7I|1911#3_ooo),11fffi971001_ppp022.rrrL1ooo11ji11111ct_nMaoo_nanSooa097700.yyy......J110179.,, __CIK_lllilll1111i111111lloo#rd*t 31I 111 00* 111 TT^I1 1 r^09# ' 11111i J<<S011^I1111. _ss!L 700 ` ^ <<01t i 111111 111 1 OO oo on d*F 4daojyr 111900 Of ooff ((lOotiOottttOUottlflOol*Oa.., 23n36 2K11-3903# 11111 111111, 7310 111 100*' 11 W2T1O099I*' 11111 1 tV11VpJ//or P2poOMoo,4s.uoo,ai9,0o0o-.l..T00o115t0ou0..roouadluhuoapoooooydoooodolluultaltoloooofc(faho2ooye,4o,yo5o-tlToutlMlooooto1r(0,h0o9o1oM:y13)0toploaMrotmoviro,mlo,1o:1s-)olfa 1a00vuollpco-rof 100 ul FSMRAL W H STO , VOC 43, NO. 26-- 10A V, A M R 31, 1926 17407 t NOTICES tttoodiLp1STsaswcItappkhoaamtemttrgnhhhhouinaiebm2pfiranxbooplekeoaghNoermeRClaisss6ogomnFdsowpnsmtes2netenixoeou)neeev/lrhgeltocWlmio5l.pe.keiesyie)rcruefrdereu2ofhnelsthpvlfvvfgAdBfli.tntewwa0e.ubmcitf)catoee4steetci4dslrt.esi(Iyoroteoagbdl0ifasl,rhaao1i9nedmatp5ecsf,wnrensx21oul9mte2nmcecst-iotrc3aorna5f0oitddn(sTdaemee5rcsoan,i5fl0Ttgttppaesrylrfarait)togotsncmeoeasannledpawanotscmtoma(oeaiwfrestdhsrfndTbootmoasd2nrosneasIde(eie2glrisogalsm21net,ast2duoddcreI4eaoies,er3/sbiw3/bnn4f,Dcxnpkogp./kted4p-act0ti5gN6sot,ilnacoh1r,icdr5hgoiico.geihaoeri-n)er5trnolo7dromanlMee-.Thtdrhrraneenll-T)dtoextoevot-lrtam1dTaa.stisweeaadeg(omduRosioetfr8ilseeddsneTeitfedee/ladfaac)nxeniwfcktIyeimmedb.,.favensinheedwr,diioflgintrdrcmnee2eic2teee(ooabyaenaws.trahiBst.Nvtg,(cchayderptr4odr4eitt1lfutheeoemyecttaeasd)t,m,ehrtelMs2i5Sforlreoceitolalotcut,etfeena827sro-o-vc0uxstcitneitnTRaacT.i0no)noinaauhem1.tlostacnopttcd01codhbxlgiiIgflreihletnlsngeaat5olrtmsSsealymeessi(teemeIclatr1owtmnefn<dsnrrntcnmrn5die2aworgo0sI0ilwienaei20oceftod0ipcnetccl./os.mp0ifunt(eii.e0ebdk0eactxI:ro1fAsssfrsetsrmn2ses,es5etegvrtitlattneetoeecocreiin)guopacfe<agugcntagsefrtrfmf(r-etrpddaplt0a0v1eaasanteseaafau/ols1irppihkibr.el2f.eeltclntitfaote0enel0s3elooloafaamamaseg5edsxltyrydsodd2n0i2geesssfl;l-.tr... ;..:'cswe(etpooc(mtgwspcpcaes0bkdrSwtct*h1iroeieidOoo.lsonxoonpbrirooag3ge%aTTTe2oirirsoagtmm,dmopnmdstlttnvsoanen5ufwxhl1aheuu/hehh9ywetltkteriu)i0b4lpirpt*rnyp0segoeeef.frntidedpvog4.%wsngi)aeiosiiat,s7tsdf/nchmcai.52ealirekrehf%oa(Iao.aeoeamaeode,alwnpnp(Scg4nwxgimveatdf21fndndI3nmgIiroe.1dipnain2r(t,eno50totTseIani4txherro5wngwlslH0ltwntraoh-.vanvmcyy.,etChsst1ulTfa/5tm.ufpyeeeiikiiioshm254igpsrd-tDtrttodn(stneh)oghfTh9e04tmh5wiiphAeent.gfe-etmgnst0ifDq%.ieIlads'eggmgagtpononrea)emn/ruehog0ts.ks8tgmheeadrinsuiruweebce(latgfeeef0shfgst/Je1udaamdsrnoiym(oknespg,/tcahc4raBedlddkaotscntrgd2osefl/has'tuDubsaoeitoshmkgiyyoot)to,)coinlno4ohnrdgser2iofgIiuotrgeaoxoyecttla.eoisbnidrn.a/.r5nlnnf4vxne.koIliflesysofoonns-sRnfo,idendh2eotngIT5tl.9soe2fashnlnhtr,iioftot-,d0aayt4t(rthvvcb(Fresr4TuhTceTlm*beClto..eeaeari.ilt5l"ree8eos5meg)taCeth'eladmele(fl)e-aeapsg,.t!-utnidtf.hbfTtesaDrTttdcisteglreofoeIptoeonoTetelelohanepde/tsetiDgrldferarakulocuicoew(a(prnwrfdo1tn(lgsApstots1otceloeoteC2sitthfaa(teadeI)si9nioffhuhdhnuB0)fonamtilbtsf)e)8,tghngwpeealree.ncntt)Tdy%ryamagfrshrpt;cnrpedolssTrareCnetn<erdibtltasooarnfyogtwceaswaRad(ha0oDute1mwl%low.sul/utttstemao.1eerekotehhaie0AenD9pInaayrptt%arbifldgdtn28hede0esse5sres-slt)t)l, ______ lftl 17._T f stasilo evaluation at 2 .4 .4 -T ^ ln lata^_______________________ I I I J___________ Var Llttar__________L II 11 1 lAvg. # Live{Abnormalil fetuses i 11 11 1 I Fetuses ifetuaee 1 with: i 11 11 1i i % Italar-ICystic i 11 1 1Route of 1last 1Idalnls- H"1 -- l__ 1tratlan 1i IDoaa If Llt-I 1(ac/ks)Iters 1 i Iged 1Kidney ifetal IAbnormali llenal 1 iHortalltylLltters 1 1 IPelvlil 1 t 1< S llat^ | iVontreatedt -- j {Control 1Stomach tubeI 4/ 1l 71 1 14 1 9.9 8.7 1 11 1 1 9 1 91 0 i i 12 1 12 1 <1 i ll h 1 43 1 i 1 57 1 (Treated (stomach tubeI 4.6^1 s 1 8.2 I 36*' 1 18 1 21 ! .2 1 88 | (Treated (stomaoh tubej 10.0*/'l 7 1 7.1 |Tra.tad 1stasset tutsi -JL.1 _ 2 * 7 y Contained approximately 30 ppa TCDD* I *8* ! H ! vt* 1 28^ 1 86 1 1 tJf. I. a 1 J__ 5S* J_63_l y Data fro Courtney et al. (123) y Treated fro day 10 through 15 of pregnancy. Killed on day 20 of geatatloo* y Dose, 200 ul honey solution (hooey to water, 1:1) per rat* 1 / 2,4,5-T waa suspended In a honey solution (honey to water, 1:1) In a volute of 200 ul yVper pPrat,o0..0o1sa. y The aaaple else was possibly too small to show a significant difference. Tabla 18. mbrratoxia Iffacta at V-4.S-T m HIST Mlaa^ II |Resorptions and/orIPetal ) rrtminn QiIDoae IImplantations! Peed Fetuses weight j Cleft Palate ili/imiBIT 1 * 11 1na./viRBie * 10 1 1 20 1 10.1 1 19/332 9.8 1 30/344 1 5.71 1.23 1 8.71 1.09 6/313 6/314 1 1.91 1 1.91 1 35 1 9.5 1 22/248 1 8.91 1.08 14/226 1 6.21 1 60 1 9.9 1 15/208 1 90 1 9.8 1 35/293 1130 1 _9.fi__ 1 141/316 1 7.21 1.05 111.91 0.86 160.41 0.73 19/193 1 9.81 fil/125.39/258 H5.1t ..Ufl.fil. y Data fro loll (125)* m77i8ceAmhlgtha/dkogub,geahennthIpnercerLveaiDos-ue5sd0lymfodaertetefrernmmalianmleedoNrttMoaliRbtyeI rwaats wdeasprseesesnedati1t30dmosge/skgabaonvdew8e0ighmt gg/akign (125). FBOAL IKMim. VOL 43, NO. 78--flUOAY, AFM. 21, 1978 66S69T MOQ 17133 OOdBSfJ 17134 O3 Mona* ITraafaat iT*>1 14_-__M_w__w_n_ti_ntm_w_l.r_, t_Ml_w_e-_tUL* Pa)f I2.4.4-T 1 IDicala I IS ListartiS U3/Iapla-l**3/31aglc IFctal I n . m relate (Cri ! _Utl_ J I 'with ct iwithICooteotIDoec Iwith 113 Itatloa 31taw ILittar v/KSIHeight IS LlttarsIS I* K m I Uaa/twM - w|QU ccatroll -- 1- 1 1 0.4 all 24 [ 32 1 * 4 1 0.6 1 0.9 1 l.28*t 6 I 0.6 1 1.30 t 6 I 0 .7 i 4- U)l <o.oa U o 1 33 1 I 119.0 1 38 1 3 5 1 0.4 1 . 0-5 1 1.27*1 <7 I <1 i ! 1,15*1 ft I , i I I. 130.0 1 St 1 7 1 o.s 1 1.0)4 11 i 1 ! I I 145.0 1 33 1 6 1 0.6 1 0.)8*l 16 I 3* ! iso.o ! 63 1 11 1 1.2* 1 1.01*1 20 ! 5 * i 190.0 1 S3 1 S 1 1.1* 1 1.02*1 35 I * ! 1120.0 j 54 ! 10 1 1.3* 1 0.93*! 54 I 12,4,5-T (B)I 0.03 bo.O 1 44 1 6 ! 0.6 1 1.11*1 22 ! 2 lto.o j 57 I' 7 1 0.4 1 1.11*1 71 I 9* : 1)0.0 1 71 1 a 1 1.0* ! 0.99*1 86 I 23* : V*/ il)a-P 1 71 ! 11 1 I-** --22_ t -28* i Oats froa Heubart and Dlllaaa (127); 2,4,5-T aaaple (b) received fra. Ball (123). P i 0.01. Tc(tp20tmftCwhe<eu..a043BCrcrgw1otle0.7oataS/ao.sdakB0nut-useapTgegoLetr,sportthfu/paeianmeuScnbnpri2te1soJnacmd,y4l,Da4ntay(uoLao,aotMa5tanganwftno-UdihdenTSangfdiinee3lOotiCeyhniorTIMxicsnDtngu)aiiat,ScnbaosnnicCOraln)rtoo0adayielDjr-omu)ated8eaoonnstc-aToinI(rd(tnpl1maAeTCirgpe2ldm1aaliDtse1myc1nbf.N1ai)eD0ecdl1ct,esetMoo0h(amttD2umwlaemRr0gdactdBao-)I/ightb.sekefaA6m/rnadgk0eai/atigdddc3hct2tt.ahamJe,o.my42l1ec)si..s0aLSnliuIceeSn&-iobteffsTOdo8rt-, ot82fndmeIUetlehn0,vfoofo4Bttfgeisntta,medgm5ee/oslkcecser-a,gtTits,nwgoshfcw/tcftnbekoaeeaose2.htugticandr.figb4itomFtodcIhee.eclSnnhtodtpilhd-.tt(er.sflTwahEueaeufApteCexts2socpiarapt,prntD4pemolo*fa2v,l1ra-5ae.o.leI0smpr4e-at3dset0uTlAtrdet)odauesai.sam-gtenciwTeNtcmnspaeorogedtaaronssoamo/psbakaocrdsdemotslpgfhifruregeteadpcmco'ofntoraoaoloeteafietrifsdnfdedcl,pfdeiddsamecdd4ewai;rt-cada0iyyeeartnei%welsealt:ftntrahedtteia8at,etropedh0tetUfadbw%wodtlto.th1tawuoehttI0ItieirhoSnnoen0eser- Tabi. 11 1 11 1 1 1 1 Doaa 1 CO-1 1 1 1 Hcuac 1 1 Itxpt. 11 DM30 1 -- 1 12,4,3-1 1 50 1 KTach.) 1 1 12,4,3-T 1 100 1 KTsoh.) 1 1 It fatal (CPUKAnalytic 1 1 ft ?m ata Fatal 1 Llttftrs t CP pari UlttftTftl Affected ratuaaai 1Mortality 1Haight llffaotad AffftotftdUffMtftd Im p Affftoc*d 11.1 1 11 1 1 11 | 6.6 1 1.33 1 0 01 01 0 1 6.6 1 1.26 1 0 0 1 0- 1 0 1 11 1 1 7.5 1 1.00 I 33 3.0 1 0I 0 I1 --- 1 8.S1 I2 ,4,5-1 1 150*f 51.7 1 KTaoh.) 1 llxpt. 21 DH30 1 1 1 0.91 1 100 11 1 1.02 1 0 5.3 1 0t 0f 1 33 1 0 1.0 ! l2,4,5-t I. 100 1 3.6 1 1(Inala. 11 1 llxpt. 31 DM80 1 8.4 1 12,4,3-1 1 100 1 10.7 1 KTaoh.) L 1 1 0.7**! 11 1 1-09 1 1 0.45*1 11 89 0 40 4.4 J 01 2.0 i !78 1 !63 1 80 1 1.7 2.0 2.4 i 1 1 12.4,5-T i 100 1 11.6 1 l(iaaly.)| 1 11 11 1 : 12.4,5-T 1 123 1 12. ! Iftoalw.U ! I gaa/* t dhso i -- ! 26.1 1 0.86*1 1r 1 0/1 I 0.71 1 11 1 0.65 1 40 78 0 2.0 1 5.4 1 0J 100* 67 13 1 1 1 1 l 1 4 ,2 4.3 1.0 1 1 I m . 2.4.3-T 1 u n j 27-0 QttSOi____ KTaoh.) 1 t IC3TB1/6I | _ 1 10.6 1 Monas 12.4,5-T I 1 1 0.67*1 11 1 0,99 1 11 27 0 1.0 1 0' ! 91 l 91 1 1.0 no J_____ l(Tach.) 1 100 ! 15.9 4. CD latiSuoraa* I 3.4 1 12,4,5-7 | 10 1 1.6 1 KTaoh.). 1 1 1 12,4,3-T 1 2 1 . 5 1 1.4 i KTaoh.) | 1 1 12,4,5-T 1 46.4 1 3-8 1 KTaoh.) | 1 1 C.T5*i 1 2.48 1 1 2.40 1 11 ! 2.34. | 11 1 2.20 1 11 40 0 0 0 0 1 . 1 0t 0I 01 0t o! 01 20 t 1 38 1 1 14 | 1 n 0 UO 1.3 2.0 j 1. |2,4,3-T ! 80.0*1 52.1 ! 2-30 ! 0 0 ! 50 1 a/ froa1 --KlifiB.I 1 _____ La -1______ L-______ _______ L _______ 1_ Data Courtney end Moor (128). 8/ Invcatlgatora thought this data to bs olosa to a oacci-nal toxlo doec. Sj Maternal LB-40. V p < 0.03. FBW U U 5M O T , VO L 43, N O . 70--flUOAY, A f U 21, 1*7 4.0 17409 NOTICES 17135 poc3gcsifo2a1tttcehrhia.l0afi,tb4g4eaovFcel0iersk,l,santesse%3eSee2iunctid2-trd-odef.uTovrwT.4inb4deowcsne.ltS.eessewSfidat(eyiradt-ursn-dtTetroontThibeavthasaolicprysmnmaiowe8fanuIltosb0olS(aiCacast0oo%mslOfaysorl1ie%Dnsnnete3drants,aadev-ge)a(lmhoIs.into1aemre'ooett4ddusmgshksw%s;:isa/eMien2iakldsectcty)h.-nhrgXd4noefneogwdeeaenaitfwtrtytndArdohetar4eeefcoeteral.ggehav3rdssntamatetrt.peeeeunieoawfrscnocAoosd,eusto,hneiemirtptmomttunsntwsdhhafe.ao1sioepleciile0aiTtftniaartcth0oseoneycerrollsfeaciaempat,d2adelhptfwnvey,mestcgn4acearnwtah,/oiipwlrol5kscccaiynamian-feagaattfTtiylhegassll. ecdarn2kbdpafcctaeeifno,leoioieud4oilfdbrtydrmdnnrue,esxinl5iygoetcnsni6ep-r(airentdTcgo31ynoawnwse)i%l3ru(ondasaei4Tevpptnttd)iehoaaehsai4gonanirfnwrb.ashtm0ilcibthdolldfnlrtloieriieateufmdnetshtn2pelatrs2todtii.etteeuite00irs1unerrrsos%des)sosidfetl.sTyieoaldrr"gnteiavsaafehrwanmvfCfliarryeelcpfneeailyteelctuolhedsethsnocmtesnrefettfospts0eotdaw3l.rcfr.dpiCxro2.4ootILeomtia,t5lnDdmrhn4asef5lesui,anta--r5cutr(urITct5otdnaZo-eebmhae0T;mtlxcd%aetwnsw1ltup,ieiu(h.e8cha0tat0eottgmfae0tes.sie.neffg0.ner3mcecrsbme5tsheCh)csioehet.noMe.taenmgorwespuTrsnti/utpi/kcspeliohkhroomilnIagratygtnenene-fl, n0bttmdhffpturhee0oyeriocsgtoae.aa0lesItldhdsn5fllscguieo)sgoalrcsmrateionhamntennfuntdoddctfdlapcyeorr/Ittepsoetnis3aoa.asaea7rdllnlssAi%lotert.ae.ewypfeAttsresetoie0Shoilnnanfi-lrit8gengddasbtfthdehotmefheaintesdesxneteMfcTtlpoeiytwlpclhemtie/.aeatkraeevtirllanrgeemlcaely.dlryewusse4ontwnhe8thbteshait%asivogiaggedteilhrhdneroctvniaeeinfoofdeonfcinffdvtctctoehoedeefaucadeetrdinlattsttdistuetclothtohsnehfobean(eisfenpsest, dgraeat"niinocMesdaa(1tne3bdr4yn)a.Irlnetcdoruxeciactsiieotydnswlaiivnsearml-stooa-tboeobrndseayrlvewwdee, iieggvQhhitt o111Vehicle 1|111o U :ia * |1111111(a00----D--M..o48e5/oTksaxb)ll11I11IDDe111110110o2a-----2sy1111e11s3355d-51111I1:f'1/at07889eo8b5689r/t////11181ar20201ol6722to*1x|1I111lc effa*fre.ucatsA41oI1SMf oF2r.et4at.1a1Sl-tvT111HFI(eneertieCgabelh-ett11(1_FHC_lel_toeu_fes_t*e_sP_elaItIe 9888786042 11111 111113674 11111 00001.....8908919574 11j11 _--176 IIIII (slavtxt.a r1s)1i1 _----1_64 1J111 % CC<ODO5 I 1 0.50 Ili-ta l 21/59 1 36 1 29* 1 0.87 ! 48 I 37 1 11 w ao* 11 --1.00*1Il122-1-i5sll 75/82' 152/171 1 I J_______ L i.afl 12-ISI 11/68 I 91 1 89 J i __ _ 11 a 7122* 1 0.46 | , | 1 1 1.03 1 0-70 I-- J____ ML_ I| -- ___67 I I I M/ Data froa Courtney (134). V Corn oll:Scetooe (9:1)-- oral. / Dlaathylaulfoxide -- subcutaneous. i/ This ooncentrstion exceeded the solubility ohareoteristica of the vehlole. 1SDfoJo/uunbdPPlianiigt00lt..o00bw05e1.ev.roldioasaeso. f vehicle resulted in effects acre consistent with those a h i - 22a__ Effecta of 2.4.5-T on Wiatar Rat Fatuaeaa/ CompundtDoae i# of iAvg. # per LitterjFetal Uvg. f Mai- | I I(mg/kg)|Litters!Viable Dead Height formed Fetuaeaj J_______ l_______ !_ J Fetuaea lFetuaea i(grama) ioer_Litter^__ L I T-1 1Treated ! 14 !Control1 ! 11.1 1 0.6 1l 1 I 4.65 1 II 15 1 1 I ! 50 1 7 1 12.9 1 1.3 ! 4.84 I 24 | l 100 ! 9 ! 11.3 ! 1.9 ! 4.60 I 29 ! | I T-2 1Treated 1 10 I 9.2 I 0.6 I 5.34 l 10 1 I 1Control| 1I I,I 1 I 1 25 1 13 1 10.5 I 0.8 I 5.06 I 15 11 1 50 1 12 ! 11.7 I 0.5 I 5.15 I 9 1 1 100 ! q 1 a.6 I 2.4 1 4.57 ! 32 1 1 | 1 1Treated 1 10 1 12.6 I 0.7 i 4.67 I 26 1 Control! I! 11 I 1 1 1 1 25 1 11 I 12.7 I 0.5 1 5.15 I 10 1 1 1 50 1 14 1 11.5 ! 1.4 1 4.91 1 28 1 1 100 ! 10 1 11.0 1 0.6 1 4.35 1 36 1 11 1 1 150 I 5 1 11.6 1 2.2 ! 3.98 1 56 _ _ | 1 T-3 1 11 ITreated! 10 !Controlj I 25 I 14 ! 11.8 1 0.7 11 11 ! 12.2 1 0.9 1 5.31 11 1 5.00 ! 1 1 17 11 ! 1 i 1 ! 50 | 2 ! 11.0 1 0.5 1 1 I 100 | 12 ! 12.6 ! 0.9 i 150___ L 1 i 11.0 1 1.0 1 oIT 1 a -Lllai.,, i 1.1 V Data from Khera and McKinley (130). ! 4.75 1 1 5.00 1 ! 3.00 ! 56 37 91 1 11 | ! 4.94 J_____ 13______ J/ One or more akeletal malformation (viable fetuaea). No treated control given. FCDOA1 U 0 U T O , VOL 43, NO. 78--HUOAY, ATM . 21, 1978 17410 DOV69602 m s * NOIK3B rcfawvcsnTtoruptftmspWnnfopH[maraaiorooerfTiaiblofornouoreheItrgfeintermoKoaliseitnrmdetamsrdmamueatnohnna.w4lmypino"tbrftespehmi.6ei,Tefooeba8eaiaefldat%saaoonrdmAoeadidCrtvrhe0dtrsenranclarmirantafoemreilDne*mitobmagratrm.yldIhodgrhos3Seitanenron,Z/laesoaX.rupn0admefekadgtppoctloli>as2ldannLlmAlrfngir/toue-(uctttaaid,.eddokmapfcdhocoepotdnlplnefee(geib1otuaTafTteesa3adnrhaopntda0n<o,twtstuueMcy8dlew-teocidh0otiad0d3rotcasrl%metangeeteuskoess,ey1hc.eeeornalo:guoifatgmis6Tl.isnaagcoeencnn,dsvbdolrhduthwwltTtthofywnhdaeftfestya)iuoialprdaootoemtepetrxestsme-oatneirfaeIiyUen1rriUrtcrknyogetntnlflvomelpdIear8,lsr*,*nsfearihfcrraeyara0taentea,lnalelatsUtdiaHtrwdseftoecourefoadirltmeenraau(eratwftisdeid1o>endaftnsdmganttdebayreIteorgrWmlvnlaedechagsf*Iaetdftp/-wpieban,oirtroa:eteksnvwnsl1latu.pocwnaecsteatfdgey"uiacuhipttIoebaraonnnaai,MbdaleaahelanstapresunftmrTtdavsyfeetethec<theeiuuhddmernyagtfsahe2srerwaewaaldtnwce!eaucvhen.aeurl2ra4tdoledirmrctelewv,iueites1elrAaevbsantntaldoell,daraonsemuftAgteegiaawnentn-uiiuvrwamdfrair,T/nrIeaiagottdsiUkttegnehraarelrnaeIheeahlesoygrao3toebdo1nexsrsgxddeyoieTdtt8ee,r)-ytlr-f.r, ufrsoi`nmSgtTath-t4iestwaicveareelrangoet vuaseludeInpetrhwidsoaasenedalleeyvteseirlsm..Dinaetda ' ` '. . '1' ; phkaleIcClrchi4tmeswatcssdIrt3fcIiUtiutnhhhnroeimaosdnag0lrrbainyan.irsoSl4eTsnechveefgamuaaua0env,detnn,.e,fAfblgdletogiadsla/gsnnnhcfeueoetcketsemrenoaItktselrda-odharedhmryteatugleodTnmaa3eosimnpsniniiIetdogdgpdtdf.unu0nnbdhInlidadapfowsel/nhbehneaiac8pgcckeukeeltbepredTIdcutaiilgyeiesrateaewongtmggoaedeteaplrets.y(t.rahsrabxchudcp,eexyrehthroehniuitalbbleheipnsPAcdtuenfaa,htfelaudochpn,eersreeeofaepcrcrtmvneyepaetreocsxodneho)eplrnsdeerloehtnsasoasnostimoafmdsntmnydo1rtomloyctte8osnicmstwefiee0detvrncerdee2n0dw,sroearcgn0tsenlorrosexomicaea.ialdrltrcsrt4oonmnsdaeaitbuhmyorooltfhloom.otaiouAclrtoteifnbapdsiaagenpnysuateefmcieferdebytrydudel-l.gsea3hvtlprtrsyparTrir1mdeypoaplep/se.Uvfatincsroo2h4os3kfhvadotssloa.hooeta.tonrtl,0atywagmetrtaaawsm8uutosordrmotTfht0elnailr,e,,lnlieo-fdcnuexomiooesntTadhioofrdwnrpwstmred2ys1niudronnfs8dmahtriecta,ert4o...isre0egmlw4ietJatgresrw.tIt,tsoebefhaotb,asnashthtahot/3a.ehataesfwbofs,ketbtreumoiysh--h-ef-rcuiatnretAnergTmgenl.*idtaedyttreepeddomyKymgmsshec1ealedtrredptoane.itilptns/eeolfahetgvntoskrvrt4brte.fostowyrmipm1eonoTt.oiiaienry0gcoanrnehdnvr0aep3scenae0irmh,daorasbeea0t.ftuoTpeiamlr1t4dm,eiurteiartinrmthelmpnc8cothcmi.imeayaroacbaBcthttov3otooihaxrilnhohoanrveinneIlgesno0-oeboonavsnradeinsdTdreoteododgse0cs/gefsflr..t' I I af fetusesThl 27- te h rro tm la * ff e t ____ 2 .4 .3 -T lit Ha _J rstol Vis-11 ibnor- i BoorrOs(ssl 101ado ICantat Dos* __ |f TotalIIt* 4 Uvsllvg UBight^lbtllty par loslltlos pr Total l IINorul-lpsr tlttsrKi !ILlttw* Ipm* LIvs Lifa fatuaas I I 1.4 11.0 1.8 1 1 4.5 I* n.42 | 1l ! 20 i 32.3 7.3 1.7 1 88.1" 1 23.0" I 28.4 l 11 40 1 7L3 3.7 1.7 1, 23.8" 1 33.3" I 73.7 I 1 i 1g 1 1 1C 1 1 I i 2.9 ! | ! 0.5 1 SO ! 91.* 100 1100.0 40 I 7.2 80 I 9.8 100 I 11 4 20 ! 8.3 40 1 4.0 0.8 0 9.1 10.4 12.8 12.8 13.4 i 1^8 _ 1.7 1-7 l.T l." l.i" I ! 1 1 1 1 3.3" I100.0" ( <i" 1 _---- | 93.1 1 0 I 90.l " 1 1 2 .3 1 88.s" 1 TM . o " 1 90.8" 1 0 1 93.9 1 11.1 1 42.9 _ 0 2.4 11. 8.6 2.5 l 1 1 1 1 1 1 1 1 10 1 i i i 0.1 80 1 43.8 1 100 1 VI.I 40 l 2.4 8.6 1 l.rf" 1 i il 1 5.1 i_ 1.9 1 11.4 1.8 1 58.3" 1 40.0" 1 il 1 i/ 1 10 .2 1 40.0 1 97.8 1 0 ! 12.5 7.8 0 1 1 i 1 11 80 1 33.3 7.8 1.7 1 68.3" 1 0 1 2.1 1I 100 1 4r:r . 4.S 1 37.9". i A ! 3.6 1 1 1 I" 40 1 *%7 ; ^,11,2 1.3" 1 88.2" 1 0 i 1.3 11 80 ! t * r ` I.s" i 69.l" 1 0 1 1I 10 f te.t ___ 8-9 1,^ 1 1t 1 r I D 100 1 4l.f T.l l.s" 1 T 1 . ^ i 40.0" 1 L1 a JD__ 100 1 vn.fl ___ u __ , *4/ 1 M . - & I 0 ! 4a// Borealil Data fro. Caillas *nt Vlllime (121). V Ipparwtly mlgftta ror BsaplM t as > attrteutaS ta . lot dstsataS. p < 0.0S. 4*2 0 6.8 16-7 sfscpwgrecedag3tmscoosUgmttMt"nsdsdUw(dctwt2ddotdbfndlod1bacpcaealerheaaoiditoiamir4ppupofea8eeefue.uuueunnaOaaseioroieoifsedeT4CBehfbrmefcIotimteolaaeunuesanpmnnpliynfpmlnccl,cmllddtitsmerneanirnbaaArcatitbe--lnfpllheoxotorolttnoefemmihaeet4eshtctenansy'iciDytpspnssecyeacatacc.lmfroeirltaMtiedd-bneddde0atgeiaemybadcUittosaT('ourcin38allttTdl^a.nd*idaua*anaoederaeeiJelseeadl./uoororlrtwT.alsfodnoyCloyetuoklcl.oowC4eec,nhsssntbrib-rfoitasaarcT8taeonfpwneiaeolnnondgce.anfe,o2eoslAogrftafooDdtbsoeoaoidsroanedtaahlieardPeboietopnewerft.ta.teidaneaxteherlm.fdeben4ffsay-fntofaoaoornatdBe1aDwsdeygsflges,nmyclar1TisldyooIeTce.tnntlalitlBee0brbdls1eounotmgaiorr8melenooaicain0eittatm.eewcmmemtaebre1veoddmaveasAnenhphax-fvdcdaQsstcurxorntbaapfmwtdrdwenavl0wdTtas.iembettieitndttomsohteieliereleednlooobsAwfenhtnhi3aueea8arnctnienferg.Dthaowoireahsrtnas.a.tWenfomLinrwsahy0bfyia0lfvrsclrgtee1amicmr-rsiseee,dIneirisnsf4tetteeiLevtocltnWiTyU<rensarlohmn0agfshnatiahseaitaivTnxhaoci0cetdgysamsedft(orUeedlgtlileeuga0raeinuo0nidothvnfai38aa1hnmerloUlefeasmtgnttoesrnd(ehsdtlatn.myeelsisiesea.r0irgfren.tevie4lUatyslia1ndl1tgcni4TsfiseltaeoIaeitreeVststamaqfsc1AhtlsAtednf1oeosa4bvlaeeliodtatmgAomayoriotIiaendUslrltmmIteeeat0e3t1eupslffa)trtongre-0msalaienbnimirtmwgeddr/ryoadvdrils0biadt1.p0rn,g-etUapotptUesp)aytcockllhna4otnoshafdilTe/in..Ieee8nx0dualnIaneypagaanohneomkolfaaittUl.gnrelopmfmA.ndoevelod3endpo1TuitlhlrosUtimlon(trnIremoruntglnicocaeroIfobedlf2aecaa-Aoaleanat)aeiedemoolnjgmeltstUnhfn.ter3yTrb,sddfse2dr.rsloobml)htwmrdhnfnttolgsiete4tt0nTofh/iesef4desteedeybxooIrgsi4i.wte,otssaneoatktuddaarAeUod(6i/olnncceipfaor.do,y,etoCetexncro)elywekUTdmgsdgsAfvfeecl.cbnehIoxesnifomsmcmls-u47nnesi(ietrA^enetgehniaDoaanMrn<teoTvtran1sdamtri3aoottpheotra5tStpcoigg.vndcasbceenyiycedtoedeyhautieib.1soraenet.ntebDox8teg,etfttrchOrt4yiwoerosar1septsrt.pfn:cndlmeaciilsrnotaeirw;fwd8eilnvipbaore,oeae<Igdatolr0s5ecddao,ahpoetged8nstdrtbn8pseoeaa.w3niisetesptei0tind3f0ahontusoeryeIret7lvat-tdamrnfvo3vntaiseattdiI,h.ocfdeedZnnhhuTes:madtnrrt4t,l.aiwh1rnnantgee3ea1ne:nti0itimeodooeoeIt,cmoeamwmals"t.l.d:eet.nantlntde1y0leareeran5not4sec8yealeeyamnyicnexhehp'stfsaSDaoece.eyygh)bgptdestl-:seoaet1n)etnrgiidswesmo.puleeTnecxtoTaitaexnatIan/phap,p8iva1mrtni8aanaw/vtttphnfRkeroagrcbeltduml0aekroIhifonhtrhe3rnereboeoaolrnieIneesdicdgtreotenerIoneorhltlbeeaolAdenaIile.fnnsaxgrehrrdoeesdeoniyen"eidotdda6dsnsn--r-,,fs--rft-)-,,t. ' ' itbektxruyocwoneanpoitmoefsotmlorfmiaretnmotltoenfnsrf<r.evwacsnntesid*nUaratsttitsMrniicnbtgdumwltemawbftefileletfuMotsfolwdoXeirltahOygIfeTnldk- m u i MMSTBL VOL 48, N a 7g--D A T , A fth 3 t, 1*7 1 NOTICES 17137 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UOtSTfft. VOL 43, NO. 7--HUOAY, A m 21, 197 17138 - A AoOV<aoC3lmpcmpmksaCBeddlmlUacfptsfd3k(smmdCtkkCtweeohobohiaugnaunggIaolaeggnaqo.e/anvv5SoTuTBDrfo(TTe4g3lgeoarscexdaaeeal/rllr:.sapfljawmo3b4igeemlaaolole/Jrr/.hdOhsutelhoxhsyyd-0ekl)ukllXwtyeSgeelk,oul-fgtmetftraerlaoee4ebna),iT-rgflgsneeIs.eoie0deofudfbrr1oo,ALarnOnfoyetin*ad)fitn:oar)fft0aridan0ismi0Wtkifi,detqn.l5eeortnneTuenrioornh0o,Iyt3la.fwostacofo-suao0eeolntdnt2assaogdpe23adeTfkodnroanr6lafntadntar.dlea.ta,dphoorulasimoyM4denr0hurmfn:npddqIteiItaatEkrrac(11lil1(1IlrIbsg.v!I1sehh11I1dmWtanohefod0tdptuektanbwfeitEgxt:IolfteilA-iileeouAfayfst2engheb-edstamdsti/mttydgTaproettm/TPideoxamoytaohoevsvgbTeutar-eia,wrleakTocEtfeWnxayteoisrihrmarta-opfealeTotgcvem-esadhgasa(aot,-shntraaOmevo0hsfom0erdTGttothrvdaelkon:Cfteromrmbaeoonte,tnriil(waahbiod.o.neanmitdfcCle00bJirlttsnadleauoallDrrlrud5ydSMesioleeenWfkwowuaure0oeko3meOnpDpnpoleoutiTagegexe-e2vfiialrDa0waltnoetalttt.aanpcogeiatikeaItpvfrh.OeeiCt,T7tafothatekeotetipaf0osaLpvfftithugiemurwehri)hpah.loeomxeeedrp.oagoctluuyDeta,mresosl(2sl50rnmliLeatspeafdn.b.aearer-tyendneaoLa3-iphwI3ddsruwwlcGDoaBe6xetffarTngTni^eod(:eittn.oaraa3gtedeteffb-pgIntmaaeeoodenphh/etplreBduulokD0hloktenoFoJoorvieegIensa-fOubWtltedteebikpIororngsS1ggKay)efgbHnausearautoeodnryhntpme,.aegowhfbta4g/erhutxultapSkfiplfo0puraftlMnta2hetswddfatex2-arroodklIascarniieoeltUOrtmtmit0hvaJeaenfrtLrhia4iBu,i*flhrldhvhT-aktsertemetiaQoyole&learoNceOt-dekJg-tpeaefoieseonftaoaefsrCuVnno6faMnuwbd%rsWri.TrlgwaottItafktioe,ldoIof.aonttnmgIp%rdhgsythenaae3kgxD-laeratemsonIetnema5sf->o0>hy3itucee.epCsd0admvtevsmtiPianIvaf-esODd)yn-tgd6ote-unOt0aereok0soOamlsTedmelo.mtgdeegf.TArynroiTt0atveEalf0JcawarifbtautarfhotJ//e(seou*0hnaebeDaeb0oii6*go3gMsioieovoperxtirlla1aplndSlts4lrtsn0oekyeg60ses]eeOWfffe,tt-fpeto0r02h11hara.c.e0o.9oa1TlaksmlnwagdpigtIi/l05l.yuaII[1lftnh2tIjsillntsv0nmgurrayahk0e6nahagIawtOXllaiinDoAs,ase-)ui,rtbsesir,tod01easeopbrgkoafe3xsacoaautieosataatHsuoeorf5fhhg/sanDMvniepn-ootcg,mthessioednnsoiseoctkeoeliinepaooexuAale5piur.tckotriiseplognslorplo*raoDqlrknVaWda-tewooreepTaobcowkelbatuouulilitdvTnisoiarto(rsfsterofaaluetreantaieltiefeo*wietrerxfnrt3nneditttrdedeveelakfuoro*nspnehehh.wdItu4msrtwieidaodTMretaf.detmednnihetu,cmo5rsoidla0e20eeglsegait1arelblauf-3snetrdet0l..Tsoe.IaApn.l-oydtoaeoor!rcorGtn.ntetn2l50e06vt/fnaeolugtfeinwTnhrethtMtorflatehg|0flea-attayftr-loae3*oeeactrmoloaTolaf0dlalgueepk.featula(hdroaocf4oirnfndM2pavogr/mprentaBetoatJoodotcdirnerlhstnm-dkaleolegortauwBhnapaTdsJaeegllane*ginat-dserneiaseae-hsnl(lr-ieeeaesa^kTly(piposnrtetudaibrn1cto-sdfsnoxee,k.ni4wgihefa)_eiprana4sao-rr111et111111rLbt111I1enOrmoafont.orvoansupdafnuedeuowi1nnablsfmndae;l)rda6/srtiideeclitorlycy6trndaetlaeetsXrnydiahpbladdn<e2shTooa.aalra3dieygliJrnoSnClatc7navbgm,alturati)w062t(h23fe32(1Phntouunfslo1hcraoe.0o*a.y2001I,edDoreasIrlhnJesi-rr|se8l.91t.p41,'68eia,p.-ar5ngai5TpwmspavattttpwaTocorptefUTitifslseoIGwf-gtg/enp=hhlapaaorrloanapnfoaproeilfqrCenotyer(iWlalTfnboaer/(ae0kt1roontllyrAglterbpumpeluf1rmtramoupDtemahomeshtt.)deegp>crkvsgehuH)nmada0nisastaJuieeoelwrptneltauDirpmecrd6ksUgawenullmitnceptdtDl.rdtham-yaoodatoatcufnosiiSehelU'e.dhiepAigunntnes3alatp,nfirneemtlwbfa6rnekqeaapiilltngssta,SoBr0raMeen3uoolaoy4,3daen.Uaesmuwoletao1hdtrcp4tot.traepsbandyd-snf.4tdtn6idhn1isLcmoioiaucuT)rekaveeftae(es-cldaidee.7oVmaoonheLdeamdueTsam3eedncklahptsnrefd.efgoeeihnod0-sutna-attripoegarlmdiitsT(Ideg,onhna.daeoLtenrodta.w11nirAxasossbhpaect/ablqlnni-fetedgntb6bscahpnpatebaneoeftpeefaeeinudttthwmtu6beertookrprgtielraruecnonihsqsardhircga)eecaetasravemWTrkapiltafda(iueUhthWewcrildtmetputseaadrys60rrya-estpiC'hledatitaoaeip0aeyoerereepvlpJu.nonnwmprucoenmmeeDnarmtesaduntat30.Tppw00ard(oload1ngioWreplxcrnohcfdaunmoneltaiseDikdriptf1eeoa..C.miil00iIgeklapgatspflsoiami4ohext/ttanti'binaurtphaahnsirp8u0mt0*MohDcs1.rn0~lgdogfratusoeoLtoyutayxtfiouptbaa3rsttg/ihpn0e3nsr0eDiratic)noda.c-Brbsrdapurowrt)efeettti,rorgeakd0rnniGoetp030se.nJaapCaefwporrpa6parnrsain;f4da,.a-tpetrrM.tts7e9ot2s,.ni0nuyeLe-iedrprShfoanpiaminpowobcnenwobpouetretwgay3n0tsag3rDa.rdrooshueohstgftaowaurosf-r3ec-eaaagn-sot0aTl/upUiuteetpCn1afsnekrTpulttleyhoIb(u0aoyaa(ne0Crnnh0hekgidai1tngwnaoeEodleo.IlrdpmnesnadtWd0saDd1yode6g/nsxr<pdtfapgedoeaocpaodiO6eg*saatsp'Dp*6nitsuaktspirutgtsbroea4.kiniwoob.)snw)aoumb)satuvnSisirlea6.gselnntgrsht(Uwtdfcovdstyaeovageat,Tsk0eTrTaUntohe4uootvaaatdsrie/ltaep-tiiilSnaxInnhoehrb3e>hpankohraortsevnSoreheoncoI|1eIIhIII111ntytfero43ggdesedeggere-sff--ge-.t-ttf-t-f.t,tr. IKiBUa vol 3, no. 7--m oA r, a m 3t, n n vftTfCdt8etphihioexg-iClpoTelyherrpuulDtnoyhomrtdtvuepeDehstatedraouehil)rbstlrfwrtihymocetysomteoflehlifeamrnogftiicexkthoglwtueolaiperuinrdrngitoaienrigiavrbcbeswlgaluuessdbo;mbe)ortraytcit(yeihryow4gsabtt.n)lholtheic,o2la0tdmleur,mn04;aolg2ua0dd,ttf5i,aectv4lai-(tnreo,tTiifb5othpldonoyy-gtleTrhsyarg<dan2e1a3r(omet,d,a}shp40rdremsm,pi0a5ed:TTs0li-saiilCC(T,;fvcyT03li)aiDD(0g)add2dtt0ubDoDemoo)erlrsr:mee(cuemtpfhfol(ouboe3to1ainiylr7srrlf) MarpplfCmld1dleeeeon6ruiivvrvbTfofggr2roffeee/ud/s.heekaTu1llkluutrrmge1pCtgeefoac)oa(o)nnpfaDntbftWsrXccalhatlTDeeene2ne32coC,ddr),4omr(4(eDk0U.bbpn,t5f5tia.hDeeort0n-Xht-raeTtoti0TrggwiwisBses0nfiune7o)ec(fiG.m6roneeacre.Mnngrralo8cpcotl4foectugutm0i3rmeu/ottlpsak.hahr4lngitgmaatefeo.e/)3tctek.ogeed-otagTndgedynnCngd)dnoe.soo,eaFsnieia--cdrniaTRxiaannmIcseoddpsdhserstvavotwsef/eulfoeecsfaeerurofetrpWnlscsherixnSeeectecTasps-oas-eetetetotCssrcil(iffkcoes0ttfDfiuttuiive(.feohhnd03tDrcecn3geeeaee0ltt TfeCtvpt8dftsLcbp(o(dppsrtttulhhoie2eheaxiul-pheiCeofouglocomTylrh4eq(erirnepmriilusutwUrucminDnw7lyotuhgeioaditmnasrtnvdc)e-g)lueapeeDhlieska,tbbadostigenatdolruleathiotrioesofta)riSeeesnftrwbrtrhtultiaonnohhadoemeydrcptstoyswerh)omtfnwdloeqmeereifh.lifhtaianm4eoranfugodithosWceakoiobtBefxgehgwyiuStu,leuooppaipaolrirrapuelnapdrriQlginotdrptmvangdeiaorsniagrrsmiAahuvcbbeelerarlin1wgskaggikglubeatpsbnddeslo0ucd;eu-iybyein()mehtoperyndanhatr2cily(ttpshttioreloya.sgtwa4o.csaEgsiibto40ettnts.bbnc-)hl1lTuohhioet.i.Gqroer,c2aoS0s,uloecrtad0meflhaefuutro,t4tnm-tre4-hn0a;oorxeTgolirw2o8w2iun0d.adtapebrdp5linf,tu,eabvct4:latWop4oame-(aoiigtpnWredeTil.oyfit,ordi5ttoslbu5phdokneoyin3.ofTua-tdgy-ftbl(noi4ert2ThTsirayfr2nTrtsreorkdrgt6(eehana2e4gukt8pphani0r1ep(roemtoc.d5enaiss)F4hespo-eir.rdnfet,0drkngmehmto.mnapiuopr5uag0raed1dTgsst;Trtlnerla-ss0dGy4aaiiii-1lCGTo(;svfCnlcfdt.yT8mhml,i030ueeitntore)aD,i(esireghD)0oadmdt2otcfsdeot/dtg1rehu0eD'bogueoo)muiIbeDeu8addw-aresuplraspnirit:m3lpeelcepectuhsmtllr(tema)hpo)hooeiffiad(u.luaa1btndo3ooon1etendoadipeea.Ilsrtiy9gnse6r-f)srsrrl,,fr MOTKM 17139 T allin 21 1 2.4.5-T I . TCDD I D 1.6 pounds/32 pt Z 454 g/- I D 0.00000016 pounds/- 1 pound a 22.70 g/pt; I 32 pt Z 454 g/pound a 1 0.00000227 g/pt; 12) 22.70 g/pt Z 1,000 ag/g a I2) 0.00000227 g/pt Z 1 22,700 ng/pt; I 1,000,000 Ug/g a 1 I 2.27 ug/pt; 13) 22.700 ng/pt I 0.1S pt = I3) 2.27 ug/pt Z 0.18 pt a 1 4,086 ng; I 0.41 ug; 14) 4,086 ng Z 105 a 408.6 ng I4) 0.41 ug Z 105 a 1 I 0.041 ug; 15) 408.6 mg / 60 kg a I5) 0.041 ug / 60 kg a J___ .nar ,da.Y___________ J___ 0.0007 ug/ka oer day | | j I I | | j I I j I I Table 28. Dermal Exposure Data (Tractor I Use Dilution rate 2 JI^5t I 3 pints I (1.6 pounds 1 2,4,5-T) per 1 32 pints 1 water | Mounted Equipment) TCDD 3 pints (0.00000016 pounds TCDD) per 32 pints water 1Amount of diluted Inaterial gotten Ion skin dally 0.048 pint 0.048 pint 15 Diluted naterlal labsorbed 1 (Exposure level 1 (Dose level l 1N o - A d v e r s e - E f f e c t UllfelBvelSl ..ffolfrf0ftite.ar_a_t_o_- 105 109 ng 1.8 ag/kg 20 ag/kg 105 0.0109 ug 0.00018 ug/kg 0.03 ug/kg 1 I TCDD I D 1.6 pounds/32 pt Z 454 g/- I D 0 . 0 0 0 0 0 0 1 6 pounds/- I I 1 pound a 22.70 g/pt; I 32 pt Z 454 g/pound = I 1 I 0.00000227 g/pt; I 1 2 ) 22.70 g/pt Z 1,000 ag/g a I2 ) 0.00000227 g/pt X j 1 22,700 ng/pt; I 1 ,0 0 0 , 0 0 0 ug/g a 1 1 I 2.27 ug/pt; 1 13) 22,700 og/pt Z 0.048 pt a I3) 2.27 ug/pt X 0 . 0 48 pt a | 1 1 ,0 8 9 . 6 mg; I 0.109 ug; 1 14) 1,089.6 mg Z 105 3 I4) 0.109 ug X 105 = 1 1 108.96 ng; I . 0.0 11 ug; I 15) 108.96 ng / 60 kg a I5) 0.011 ug / 60 kg a i J___ 1.8 nn/kg per day___________ | 0.00018 ug/kg nar -day__ L 1cc( FBXftAL U O U T tft, V O L 43, N O . 7g --HUDAT, A TM . 21. 197t 17414 `j-* 17140 dl(ldllmeeee0iivvvvTffg.0ffeeee/heek3llllrragmfeefo>oonno1W/rrcckfeeTe3gn3o,C)d7.r44kCbbD4tJieieen--DDtnTttTlgwwedD(ee(0nfG1oee.te0.hrnnr3ft.0oooi0sutmire1tltperhh8gantetete/ctelokdirorggsnninafedi/loesafknesit-j*drfggaamteddiwirivwvadsleer'elotferrterefsalnhexxleeaocpepe*eetftoao!fffcsfsfettuoeeu(chh3nccrtreee0ett N one sTWaplStneCi3cstoD.ute1rikctD1eiio(ndafgeXaanGp3XrrporoaleudlmuXburpuspBcuttlt)tseah.aniebwmtrlee*faopr*rireietnosTMrue' ocmof3mp,1ts4mia^o0f-eneTntdyaa.gnCaIdTsiF/nshouRsert etito(InallL)DA<ire.1er6ci7ta)l,lywABpoeprnkleiinacagthtiwoSnpit:rhaSyaxepProilaeaelnldya PaCopapppullilaeand mpmbnaectahqannoeeaiincuundnglknaeieehbTv,tqddaesahCut)lahdteDsioveophndtnDathfatoeelre.r3eruUmIman.sln04edtp..aUiTrSnerlidSo-araeeTe*Oydlxmrls-.ympppa,geofllaatao/rsrapdlnrua-1npaeeery0sylaexifsre.gpotwmdoaWorlaasaslbpop,tutieeatnprh4rrresls/ehiapoewtaafcohndnokruaesdeirtsnnda.seed,3irt(drs/h,dea4ee0cacatac.etnrt4-ldamerTyd4,,. exposure Data (Aerial XnnllaatlonJ_____ 1Bernal exposure to 3.556 ag/0.46 pounds nalathion 1 o (aerially applied 1n a l a t h i o n O 1I pr or 1 | 1 TCDD ( lose Dilution rate 4 pounds 0.0000004 1 M1 2,4,5-T per pounds TCDD I C5 1 10 gallons of per 10 gal- 1 0C3D 1 1 water/aore Ions of waterl pr or I | O il Diluted naterlal 101 10$ 1 0 3 Iabsorbed 1 11 (Exposure level. 3.1 ng 0.0003 ug 1 I1 00'.7 loose level 0.051 wg/kg 5 X IO*6 1 1 |1 tM o - A d v * r 9 - E f f a c t 20 ag/kg ug/kg 0.03 ug/kg 1 1 V ? (level for terato- I 1genio effects efDoxTiprvohidseeurfteohlelfoodwreirnbmgoatlchwaelxi3clpl.u4ogl,a5sivtu-iTeorentahstone(dsdeaTeiClyTDadDbel;rem(b31a1y)l ttbmohyeuotlhmtbieptaalaliyanptphtthlthioicesnatfdaiioegpnrpumrlrieaacltabeteyiooxnfp1,0o3r0s,a4u0t4ere-tT:aonfadconormdnTvTuCelCtrDitDpDltDyo. mbewpxyeolprartcokhcesigennurgtwraemdehaitsgyoe;h.a(trf3toel)f>dmt;1hTuaenltadioppr(lpy3lTi)ctChdaitiDvosiDrdfifegoputrhertreihseB81f-iydghatouhlurlyeer 1 2 - 4 . 5-T -- i TCDD 11) 3.556 ng/0.46 pounds X I D 3-556 ag/0.46 pounds X 1 ( 4 pounds > 31 s ; 0.0000004 pounds a 1 1 1 0.000003 ag. I 1,000 a . I 1 1 0.003 ug; 1 * 12) 31 ng X 101 12) 0.003 ug X 101 a 1 1 1 0.0003 ug; 1 I3> 3.1 ag/ 60 kg a 13) 0.0003 ug / 60 kg^ a 1 0.051 ag/kg lpldmldtileeeenuigivvvvTfgfgt/ffeeeeek/heeGlllklgrreifgfeeorno)oo)nonffWraruccaanTTee33pnmodC,,Cd44rapDkD,,bbtl55tlhiseheeDn--DoittTTigwswmscf((ecBeofoc0Gaeoaen.arr0nxlnrgrslcBo-tciieudnu1IlurSltntepaalhhmo~rgittseoefee*cgt,dget>mo/nhkMeinnudgojSfnsoU/aeweXkiitrtdcnarseymsde)davtr.eorvdaaewsfTeieorlflfe,erhmcfteestcnhueexxhetiorpapcsWaleuooottstf(fssno0fofuutt<esaa.hhr4trrcn3ctie3eeeh0t-t pWaplemstaeaintreno(tt,crsostietnoleustr)si.tkenctotdTveihoiIndeen4alfhgoxer0hayeapnaGanrpCloelsrrPa(sroto1aeauuRtd4urimbrdeoue7pu1inp.ceno8tttlts1oh3sefaX4.eoh13-scx8rn1t,mlop)4eue(no,aXfIdwa5onXtrpri-auehhTrg3r-ierseinia.XcneslTirah:Uaunevhtcmg5oAXiaCoeofieBp3rElmnareIt,)Dsi4ib.meaoaa4lxlrenfeu-1peeTnsaA,to0ayednhps~pdgs.uopIu6aiwrnlasTireinshsscehuutusvaaosete /km(ccTrm0ante1ieoa.pio4ho4gqctnpn4ied4tuocmllne)iyeppen.acle,aneoauCtrtlrtotuftaairishaonoatdphbordtdndlilerasofoasottnnAnihyemrc,q/eiImotst1uwe/fthngoi*avsoepa2rLiaf.llds4hlurluoepo(Jetos1n5rhnrnmue4a-ptetTd7wryprsa>ctoeootreoaethdr1erfuxheieatcarpaeot"vtsceloresueerwrsaaderrmudompas.augfrppiTrptenredtlehilhhie,rnicelndeseaoangrogntefscaaniaapaoo0nctsplefrn.lyt0plltucseresd4lohaaiiciri7srf-l. H9SRA1 BMttTBU VOL. 43, NO. 78--flUDAT, AM I. 21, 1*73 j OOPQT AAOn NOTIGES 17141 d6aweeCaUw0gmsxraaoooteppaimnrempoklmtalise1tecabnuh3retrty.rsreodeeoopdAnitwaures(kang.arvhtLechSmmhiaceailahdnnouottctuhr"ncetnt)eoohhatw3unleen,aladr4dotva,hsr3Tsaeib1(eta-irpa--Tel0efatolatevbaiirsponmaol.tephelltUkuTydlalimtrp3hleohote3idlherocngd)aa.aImmlwCmn.itlnymBhetEahahdasaiDakaeiliaptaauthe<hpantnidiwv1li>odiwdoeewnne4idnrni)r) al(ptpf37toouhos,ela4nenerrta.tce3bdisianes-aemeTmwnhra(etaIpoodf6dnloup6u0arihfuoll4tndiaimm)pemtol.bdelnoiea3edco)ftalr.sa,rapsomtovsen.Acahnamroaalccif)oalalcaieaarnnolwnts"blherewtlddoleeosrsuiononoppfnlfordogprrsuaa3rdltbeygy,tcri4oteh,no,as,5tshpwlhtse-AealoTme"ehslktasibsbaeslpteepaliatealoahsrmrvieoanicansannye.nahi(onlolaaduaattlrbrhnegtoohlMdedhefvSthOide"epTvsemhrtchedeesnvitmtaoeodtafalintshdvteoShlOuvamoptleeudrmrcooefepnClltearbtoeipnslosiawdienroiwtph.*hailcfa.hboLdvei.e, (ft1iooT)rnhmMeeaxuftplhotoileplsmoluwyareitnitchgfsoe)rcwaabliicrollutchlgaoitvn2ieo,c4net.Shsn-etT(rsadetaaieonllndTy aTionbCfh'sDmalD3aa3-: __ IAPI3- 32..__ Inhalation Exposure Data (Aerial Application) iaa/ iaerlraitacbolllnoycneanptrpaliteiodn of . - --- -0rpa.e0rt6e7goaafllgo0/na.436pewrpoituahncrdeas popalliac athtiioonn l1Use D ilu tio n ra4te vt241L0a,>4pt4geo>,ru5a5=/-nlaTXldoasnrpeser o f 0ppplToC.oee0nDrru0Dsn0ad100ocs0rf0egT4CwaDlaDter H1Huantge Absorption 100* 1004 (Breathing Rate 1Exposure le v e l loose level 1Mle vo-eAl dfvoerrset-eErfafteoe-t gania effects 1.8 a 3/hr p0 e. 3r4 2aghr 0p.e0r238 ahgr /k g 20 ag/kg 1.8 a 3/hr 0ug.00p0e0r322 hr 2perX 810h-6r ug/kg 0 . 0 3 ug/kg M) I2 ) I3) I1i 4) J__ paaOggo.Ou//oon6uu7dsaaa2;gX.X4/c4.uS1p-/T6aounp>de0rs .00*9.4706.58 11I11D hOO0a1ar....03O1r7692*76aaaa0gaagr.1_gg/_h7///_kcr_uga6_0Xg__ae/h_kx8_rgpX_;o_*s1_u_1.8_r.3_e_8o_u_a_ga__;/_-_J1111111I_234_)))1 ,0a000pp0080210g....oo...00000080uusI/000o006nn00000u7c0add100001u0.ss001102aa0T-0066698CagXa.000DX//0ch10Duuuu/00u029r..ggg100086/////0l0a06hha0a3t00u9grrgu00;p/lgaeo00;Xaungeu00rag04rX3/5ca08ud.4Xe6va; 11111I1111111I1 Ttpehldlplst1ttaW(tesnTIpasn(stGaiteeahhih3hstxnuwo,pdlifhgoCgoeouo0vvhitTsyf0ifee(aprcrpvhetoot/ausnfu0streoeDetedoukeahreretoiselrwmtil0lralcwne)iiunholkgcfrotDusesrsWevntteielaiefoganpsiolrnu)ghneargedecoenxa;slnCittlfltr/nWveinseh,udemioxheeagohrpkgcepbfnakuvfeTstrrnaptoeaodagihyedtTnhkotemleogctItlCfodhTifssl)sttrGooainlirrCetoororutfusftnubeeuoDkathootdaiapfbonoTtxnufrarDira4glcyhetbmilfnmioeooeoaeefDlmrvtrenCs0ilvrnDlloeddmt:untfsGotteeeg3abiwatDh-.Chs3patdetpdanroat.feTymtaoiur43,cehtlec(ueohbniDnF4*cooGepl3eo.4olaateeea5l.rdeoitRnuxoaa5..erxbbnb3ilsnrril-aupcotl.xpgpp-oaTtmeTilosrbE.m(asmTenmecu1cn4lbdbeio4upbhodiehydxrastu8alnottJafue1)spultupetyahiahepeloir-(3wmuci0vtlocxclttlc0tdtIgnTeohnr3ce.rterohebeSrttWfu1epca.ieisorigsa7ougei0dpvglnu)dt1nueotle2org,banlme3oacoiloeor(rfanng,tnsdferdylrs4ae4todtoornp3rtrtuuaiefesoahoxaei:Xiegok.entird8rmieiv5rfdttr-pfhgtgremcdeaiTen/eoo.t3tegsa-hemnTkoauheeests.TdtXrdgCrippgeriesigi;a3gas.srhntrieecsenaveasore;fnDie,ts.na)Ta(/teGrxlci4lehfniefdk3Xhosdmnd(dnofeoD.epsdhfrebeist35)ih-greedicscfugBmhtgWooiaxoeyga)I-tosyeb"mt3mhiTdneuas)p8Tsuleus3-pwnmm).ri.1suvrco(eratlo-fpeue,rC4ehpcoi)4(ehefrefrrefdexcsstuT0loreefektaD.raeyvuttoauuno6oifpe.liahsucbanbitho0lelogptur-dnneDclyo8aesstotrilyyrde3Tetneosrdhrlst-eso-ge,s.fy cdlp(mstaalItGrpCewainseuonnigirovFeTfttrabonrddeSei/foneeeRrpkhedusedgluiTii0rgeunttls1dpie1utoT.ecC)nc0aen6tvafuWt(a3bDhart3csotesmmhsbTinl.eeelD,pfo1eeocsldCseaus1ghnrrnosrlfektD<o/astagTonopakbfihwaft3nDitorr1ragieeXnaaee4vge.brtdt,tiTs)wleyeven3flcXvureCo,en.GoiaeeeemrndlrrarsDletTfelx,r3coXgao.pnncoppthD4uetgeeodButhso)3elicremaeacpots)aa3i.tfdhnf.t4unoWintftmeevoaoeirJnectdceentS-gyeoocshnTldaeen.yittrclnn.etioekgfndu)utoTslfvupietaisimd-eTnaaCcedvaituccitgnnelIhdeefuiDrstsoeofdsrvlsselsGesfstnDfanueufar(o,ttsersoar3eaihntrtosvWpic0nhnnfine3euette2cctaus-3msopaeS.eecate4,tttmr4s(eaifnogix.k0coaf5.tltd5/ppeuicb.ilhf,k0nads--4oculeaTTe3ogneg3e0at rekbstaoheapxgaroxvke"arpjywi"iafeJeeonposodnwhssgirh.ou*eoiosnraarannebnnsr7ttodtcidaa0otcnohcd-fslkltpteeeule(ugeh,e0mrace.3csaltanm)etaTdpaodal(hecputxiaerurelleyitlicaemanaohanTtuSetfeodihdtroenthbewWacnioaitntoccoirtaaoiahdrdslnildyaehncewilsisugdLlsnehylaogGdaednmfotiaoa.inft(n0opo-tt3h.agnl0r)easrs)3dspolo.p5auewwwfhItrcmniieieaeoinnfnrrrinayggeer/ H M SA i M O O T , VOL 43, NO. 73-- HUDAY, AM R 31, 1973 80969tV\og .r^ J 17142 N ono 1 Situation H i __ 2.4. 5-T (Oral- 0.0007 Bg/kg 1Deraal- 6.8 a g /k g 1 Situation 91t TCDD- 1O r a l - ----- . lDeraal-0.0007 ug/kg l l iInhal.- 0.2 Bg/ltj(M'=_ ICuB w a 7.0 B g/kg : 1 Ilnhal.- negligible*^ tCua* * 0*0007 ug/kg j 1 1 I 1 Situation #2: '2.3.5-T iOral- 0,0007 ag/kg 1Dorsal- 1.8 ng/kg 1 Situation #2: TCDD IGril" lOeraal- 0.00018 ug/kg 1 1 llnhgl.- 0.05A/ |Cua. 1.85 ag/kg 1 Ilnhal.- negligible*^ 1C u b . * 0.00018 ug/kg | 1 1 1 Situation 9V.__ 2.4.5-T- 1 Situation #V. TCDD 1Oral- 0.0007 ag/kg 1O r a l - ----- 1 1 lOeraal- 0.051 ag/kg 1Deraal- 5 X 10~6 ug/kg 1 ilnhal.- 0.026, ag/kg Ilnhal.- 2 X 10'6 ug/kg 1Cilia .9__ 0.0777 a g/kg______ Icua. 8 . 7 X 1Q~6 ug/kg 11 i / Calculations were u<ii on a wo r st-oase basis as 34 of dorsal exposure based on Wolfe (179) who states, "over 974 of the pestloide to whiGh the body is subjected during oat exposure situations, and especially to applicators of - 6liquid sprays, is deposited on the skin." Tci)D inhalation exposure values were negligible: Situation #1, 21 X 10 tu f / k g Situation #2, 54 X 10-7 ug/kg. rv. mouse iBaxsM t o roeaxau abvm m m m vbTaoWfmpofpt2qbilenaei,nglrluareCcrT(eciegaeodarmlneiar4DtlKnretdhsiest.iepepUGUntti.etuDilsAdnirsrse5tsnceeroievf-rseXsesesglraTfdfeeauluuenovslnalJinebc)mbGmimta5tX(dtetthm(yt-stoiireTphiptbn)eIlovbsr7nmi.itnt--ednresJXiuit5ecosofaugmtoup)ee(o3iuanitAncoaifvno6lrfsdte.eet)nhme0iue)tisddxtrttdA1aTdoahmheaoeoraipsbmsehsaennwmtfrrtusiftoltosedctsosirlaitsea1ceeloveefannitAl,vifatmsitga0oepltsde5yeiiraK0negdeosr-eisoD0ninsmdTeeta.s)tSnUeteneni,drhptcodiiiocnctusdtnfepoihytiesstadefibhearmiri.totafargmdeitesapftoetdll.oyerohd5nstwaeMpclapwhani-iiiadgntloTecheaasl,vrarrstixsi,SaKteteelcaestamisudirneaobbthrnIncouemsaacnecdfuuidedsdfttdtostriittortada/iurhooettteemeoexkdaeaaeff'nndeessrr-) sbtrbwargfma(u2aattv2thureoaopin5b,rnrrstioePfc(reroooatteira0d4qobgefnanreltocouut:e,(1e))atsislag't2ddpnJh8,w,3sir5npiN5vinwssimwe.-ttwfavdode04eaeuTierwoneiaroveflmt,amgytepye1fiydrl(eheows5laeiempp,.spteo0rtob0-ndllta.mPesTllT0aeifseu.agoo.dTav0<af0,aitnrlh)TtLyesgehl5eethlaofpedwpiiaiosn.shv0lnSenntari(nprlfiee.aae0cygistgcf0m1snod(sulos4.i.tft10epuwx3cogitl,9dnIt)v2riow.aean.mgh7e.a)etivN8antrtfrc0oTsrnreeehcEi,gtorutoelotirdd.Sleeu,aloreietutyaptnnaahpdfpTonnnhndpvbelglsteyodried.dsmsheacyrceoe2edl.lirrcyietneofa,snwctaofa0eET0fa1emttcrfeitneo0hmmnw.aece,deehhrf5d0r0egd.rcstrerae00eueuaeB.oeeletcen0yrshtrgltfmtpnn*hxedeeaepchoaooietrpdopgteenranrovhntstapsoeseeriflntmeitolscexclcmronretefloohili.-ne-ohivossmswrblasmcnidnAit.uelesmemruai4eetneoelttol,tmcaTrk-ydfttdanmdoouodohooteirheaeetnnadreootlannedaas!osddgyee-ssfflll,,-.. bAlcscfsscb2mgacocc2efwteao(cpmrwtttUoattdpwI1erhihhlhmeeotuoymtihay0efnnraonfoaf.pvt.iauvoaDDe4tifa4sireeomgie-elcmtpnmattntnmfeet52easdlnweeoruomlbehhaJ2hch/>iranset~eaaxe0l.cslskagnxy-bm5sgakrl2r4eduo,ewaajg3-vvnTTttactylia0egwugoigot,mxesn.usuemanCsTeer5brnl4thpen(aoetvmesswnmfnaiispmsddfliat-Cbfarrc4snnawanefgditteoi.faeeT5focesseo3ayf(vrsfwai0orretngrg-3seortornotcn-9inrieaareeerrg5scotTif.iieadcgXmnt7geTdioefemrtVencctkcaarmii0iehUmlptoyIla9aauenrav)eerwldeXnssts1srshe,nneaepyeeVenssrnrurbserntitsta,pevwIoe5reosdcltroneuarefomaddldnwocsrtcfsrIaraeno0tftraadtnr.m4slgBbodnTfeoneeeedaehaettdwrmnltptntfeemud.hsisswiCtiydleHrjSducuictaorefnecaoigglchoreecd.oftmeceen.mbstiVafcssuueecxufhfHaorhcntetRsnolurotrna5iieiorfMslvoricDoediitnrTnfnTrmstonlceecrlknev0ecdcoeaeoirr*ectftfiIyonggboycdsen-r*s.c0ehaimaosgdeilepfdsthmetnMlt5bo(feiene.vtrotsgcoyeldrfr.hwlhneranewemwdecsenm0uyre(stmeeoosscmDoa7wsd^uoTeoesrtoaenhi,ertvelUhddtSrJhsmov1eich9raue(rmpinsinargfrooXethreetiauondiicweca5oautfwe9lholhhbstgc/tonx(wririae7tiehtcdyfbth-Ska0s)nWt1otmseiiaehsoeipuegwtttpbic3ttoalo.ftenbge7.wsiiansnfidoraloseodootse)(ronivornpifdn1iegu25lnscf2egsienasntgseeerb"nwifstsehsw)udp7-a55odlesdnmauete"odfehoctdstsuif9onoiim4o0lctdtnfekashsaennwienilil,frotmawuegVhslesafhseio,rircannemtsradettye3stfsteathahentpr.lvrieoacmctacatepydidhen.ted6aaeorioatpaihiporemp2onhtnwnodth.n.oncceaT0Tlim-wnoicmdr,iuengdorroeoirf-cbiBogi.tumhwgNol1ruhd.aortnscoea2sgsd4odtrmha.sooememi0srleeenmetehepnyf,,oaooe.mrseetoecer4ld"rrnfcfTnTatmiesoaraTotrvcfdD5teau--em.'snoatvetsd5n5chmitttatmeofhihsh-ercrInlh-aimeeehtegtv0ioeaM-otioTaueoxlnuanaoiitratiifTordnieyddiioedc0ceessssfrrfr-.-.lsl pctptaceehmparer"""aatm.dTeoTsTcetuCthtbIiNdhocnnDe-sea.tYtbfclD2holreoifo-.fimi4snmlecTeJclaifoed-CtoenTsnEonrDducmtfatsheur-Dsseaunascte.tmeconltinarTdoonarat0nnhiittnitoa.icnie1ooivnenKnfaplntetwhuTpyotdwritmhC.dahsiaatDconisskiohrnDotnuslCwetsdwdahmoayosoeaa*erawnttpaRlehgoosarsauoowuattneacrdieapdhnrurbau0de.canl.strt1e-t. ,v-- FEMftAL KEOtSTO, VOi. 43, MO. 73--NUDAI/, A ft*. 21, 197 17417 NOTICES 17143 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O n flT S * * t t t i f c 0 A s ili M il H | D a tis i 19)l ** M it * 1 0 M f i l i M I* n T13 M f 3 U l t i ttMoo; o tkiM MS9HI jHisititts mi* Hlni|i latavitn t*foo I|II'I9NP3 IrO m >0 | imi 1|IM1M3>MP3 l |Mitl m o ) ali e/|i> a l i l i * N tA M lt * * 1 M O I* l a t i l* IH utili* MtftMl II Mini* lai ftaita* tilt ini j aia m *oi a n ifin tr*jf<orw|t*o 1jlM|N3i*9 >a3 j m ta olia * 1 vi imimmao o n t moimi tuie* Minia HCOal It/Ot *1 Min) all faioa u n t i *Aaa i a | 0 1 * *,fi iaaer 9 1 1 1 Minai fi m JOI ali tAO" a s a i i v i r m tt *n oavium i l f lM ls O l t u l i MC3 i> < iM t N M A M ifn r | f a n * M O It lM O %HtH9 ll A lir > 3 is 9 < * m 3 lln M H ia 0*af|P il* t* |M fn Sa a ia * ia * tll|9 j - t ' i ' r * o .* n t i nin*M m t k w jij i* f i l*l<f *1Ut?U)? 9! liimS ioMrsariJimJii () H I H *3 riS a ta l} t trvm ok f t **) ri*JlMp3 fHMI toit/tsiit) 4o***r-#M)siviso3 iuni m n m s nuet< Il Hi Mi HUIP HMflt l3no*M IfiU I iintnx tn/ia fi t*X 3U O N namsm usneo*# otstittnm irnsma* filtri 3wt lansrvsi <m)/n 8 1 9 6 9 1 ^ 17153 N o n e ' Mutucr u m n ulna* m m m n ;; ir . ia / a w ? MMMAU.I UtllM WOllU UMTAINCMC!>-* MN/IHTI; iO n r ia u t AtUMVOtfaT A A II t CO ) r ,|a f Mruoucr h k n ljitioo m * n * t* t t o t n t u i m i n u t o M Mucn (uariaM.)4;m (iTtHyuui caariauv *t8llrAr m in A A tifa A l l* N om ^a IU 1 I iijiriut* is iw * Mac mi iiinwiu mD i n i w <4i cmi At twatAMX.ll m liAil NJIuCI alai 17 l|X0 1*M MWHAAlIl ilula itUU . iC flia riA H r ab* amo m i m m i AAIIOI LiMWl*tA C/0 ine. Q H IM ) ixta M itflM t i i m i a MjoCTa*at **1 A IA * IU.CO U H I I M M a llU ' * tniiiiit mi m u n ti u . l t*6 u f in e . *,0 10 UAA. 1 M*A\ UI * ujBwCt 4 3 * C * n if BUM l i u 2.4 V * l AOLOI ItAa A k A lllB A n la ffA liii % ABO A I M ( 11 l 0 ta 4 4 M WttlAU I O U h 1 4i tu n a iriM a u i r |N W |iaJL|A t 4*2* * M j f c X t AMf * A cju* k O n c in iN a ftu 2 * * l- f AAA L j n t C iu la in a f X A I I U ?UU0 iO IM O M o t a B U I A * M U llllU lf AlJ M X 4M M M I U l . J N I t l M H C t t i l l A m i l INC * 0 0 A l* A lllA B C f UN M I * * ituO uC i * a #44204 I M M H U ( a AAAAA* U n ic o L u -a M M H 4 |L U 0 CuaVA|J|S 2 * 4 * 0 AMA 2 .4 ,0 * u h . A lili I l A M u n ic o * a * t - i c o m t o l t a WIM M S lk k C t AIA* UnfCO Lo OuM l u t i 1*2 i la /a i/rr M M M gO uC r HAMCN U t i l i M| 1A u x - A t t f t n iir t o t o i o u u c i| c o n ? A |a iM 1 , 4 , s*T e iT t M / t A i i i 1 4 /4 1 /7 7 ikgOMll AlAMkM limali ll<l 2 to C a A U r t b l A l t M t t i-O oUCIO C im i Al a i A / . ( M T i M / * i r > ifitlM a f* *1241 ia n Ano i a li| * Ojl.IiMn C u ta iC A C I cannounun i 2A ione a |0m a(Ma a fA n fO n o* C I a m a * a IH IJ O X I amo < A i ! l a t l i e n a i AauAn l u f N # 4 I 7 * l t i l t Al Aun lu e Ai a Im U I M i u l t i ( i r t a H nuan U L t a 49I* a A iia U M M A u fT ( i r t a ia nuon l iu n A A A lliA A ai* a IB I2A A * a i ( Ane AOOOAUa u C lf 1 C n tn lC A A . COnOAMY OB ) 4 i TCAMlA A4 M M A MJDWCT hMf n n a 4 4 4 1 1 * H b | I T * ? / CAO * M | 0 AAIA4B 0 A a |? l aO. 17 * a A I l U U a c s io io a m * a i2 7 t aia amoAuontto* 0 2*1i t i ANO c o a i riA a U . a i t * i .iajOuci NAn< . la i ! n liu B in i n a iira A n i IA U M AAaA A M U fi A ll il AniitOa `aviAIATA C * ta iC A l a#A Cp Ta 44114 HfOouCI ab * * a a a a i o n a u iA a ua*m i i m t c r i a c A ia m w u a m i u a m # F im a m * *0 # uam h t u t e l i C K i t a n v tn b l ia A IA * 700*114 iiA * A lUu4a-Jl A ffiiitO A n ia m a b AaO i m a I I I a 4 4 I7 M ' a i i i u a c n tn o tin c ** 01 ntACHCa in e 72? CMC$tACH AtaO lA V in 1A ?AAA 4414* IJOUCT 4 A a f * CMfnotAMH C n ta tA fka M i H S IO rO ia i* *aAaC ano auO A III A A I7 7 .M * CuW " t 1421 M i t a 4*C , o a tin A IX I 27A4 a HiuCT An * 7 2 * C a in ijn a a* UIO at U t a R l t a a K O ttA i UOISTM* VOI. 43, HO. 73--MIDAY, A ffli 31, 1973 DOW 169619- MOTKS3. 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MID. NO. 12>93 NTC. NO. WARSAW PANSTWOWY ZAKLAO HIGIENY. ROCZNIK'I. WARSAW. V.31(6)611-14 (19802-- , ______ s k i nA.bsorption o^r-T--l--.---r--4------d--i---c--t-i---1--a---r--O---p--h---e--n-o--i---c--y--s--c--e---t---i--c-----s---c--i- o tnroush the AUTHOR; Sencsuk > Witold TRANSLATORt Lilienheim DATEJ November 1981 REQUESTED BY*. L. Griswold 1303 TRANSLATION NO.I 31-11-7 CoZJ =E -- cn CpD- ao CO DOHZ I56f>64 Witold Senczuk, Halina Poeorzelska, Monika Debska ABSORPTION 0? 2.*+-DICHL0RPHEN0XYACETIC ACID THROUGH THE SKIN Texicoloey Department of the Institute of Bicanalysis and medium analysis of the Medical Academy of Poznan Director: Prof. Dr. W. Senczuk Trans. ? / - K ~ 7 Record / 9 o // MID. t r < . G* V ^ CODEN & P z -H A W Percutaneous absorption of 2-.1*-- dichlorphenoxyacetic acid by indirect method was investigated, determining the amount of 2 A - D in the urine of rats. The production of pesticides and their application ive rise to vide possibilities of poisoning with these compounds (1,2,3,5), and this prompted the determination of the decree of percutaneous absorption of one of most frequently used pro tective agents, namely 2.1+-dichlorphenoxyacetic acid (2.^-0). Experimental Part Material and Method The tests were carried out on 28 rats of the Wistar species, vei?hinf* each 200 p- ICe. The animals were divided into seven eroups of four rats each eroup. Commercial preparation "Pielik"(2.1+-dichlorphenoxyacetic acid: translator; containing about 85 % of sodium salt of 2.*+dichlorphenoxyacetic acid was used for the tests. The prepar ation was used in the form of aqueous solutions of different 2 A - D concentrations. Results of Determinations 1. Determination of 2 A - D acid in the urine dependine on the concentration of the tested compound in the solution The tests were carried out with the use of aqueous solutions of "Pielik" containing 0.5j 1> 2, and 5% of 2.*+-D acid. After six hours there was detercined the amount of 2.*+-D acid excreted with urine. The results are shown in table 1 and in F i ? . 1. 2. Determination of 2.W-D acid in urine dependine on the period of exposure The influence of the exposure period (2, '*+ and 6 hou^s) on the excretion of 2 A - D with urine was determined by using1 aqueous solution of "Pielik" containine b % of the tested acid. The results of the determination of 2.*+-D acid in the collected portions of urine are shown in table II. Fie. 2 graphically 17435 2 illustrates the results Table 1. Results of the determination of 2 A - D acid in u^ine depending on the concentration of the compound in the solution COM2 156465 Amount of 2.*+-D acid in urine (n?) Solution % Animal 1st day 2nd 3rd jointing after ______________ No (2*+ hours) day day_____ three davs________ a.r, av erage 1 . av erage -M l av erage .( av era ge av era ge i :i 4 Sn*(lniii i i Sn iln u i i - S hm Iihji i . i SoM itij i _* 4 0/3 1.0 l.ll 1.11 o/.iT :i.4 mi ;,ii .I.',* 1.7 7.0 Mi I.*7 li.il fl.ll I.X i.o 4.1.*. I. i i.i -1.10 1.4 I.S 7.X l.li 1.77 " -.4 l.ii Ml 1,MO ..j x.7 I.S 1. '..in 4..4 :.s 2.1 :i :i 4 .(HI 1.7 7. it .'.X (i.M Ml? 1.2 1.1 l.lt 1.1 1,117 i.it 1.2 0.11 o .ll o..v l.M 17 7.1 l.l l.s o 7.2 -Mi 2.7 2.7 :i.so 4.! 2.1 li.X 7.1* i.i'j n .;j n..- 4.1 :i.i! " :i.x l li.S :i.s I.X ;.!7 N .l 12.4 !MI r,4 M.72 IS .11 1-.I.I i.a x .o 17.7. 1.7.1 7.1 10.1* I s .ii 14..'12 Table II. Results of the determination of 2.V-D acid in urine depending on the exposure period .-mount of 2.^-D acid in u^ine (mg) Period of Animal Istday 2nd -3rd ;jointing after Rxrosure____ No (2*+ hour^day day ' three days________ 1 t .1 4 av era ge i * 4 :I 4 In iliiu i average i j r average * 4 . r. . i llUl Mi 4,7 -V* n .o I.S 1.4 1.1 :j .7 -*.07 li.o .7,(1 4 .S 7,0 4.1.7 O.X :i.s IJ l.li 1/17 t :i -..4 in .;* :.!:* I.S .7.X 7.1 |/N> o/i 1.7 ll.H O .S 1/ I.* 1.1 i.: 7.7 4,0 --7 7. 7 7.7 l . s 'i 3.:j 10.7 fi/i f>,4 :,:i7 7,a X.7 ft.li 17.7 *.!, :o IS. i:i.l `Mi M,0 I7 ,7 i D0H2156.66 - 3- Discussion of* the Results It has been determined that the amount of the substance excreted with urine is proportional to the 2 A - D concentration in the tested solutionsCFie.1). As the 2 A - D concentration increased, the amount of this compound excreted with urine, as compared with the precedine sroup, i.e. of lower 2.4-- D con centration of 2 A - D increased by about 50$. This related to 0.5 to b% concentrations, but after exposure to 5$ concentration, in comparison with the eroup of animals exposed to b% solution, 17$ less 2.^-D acid were excreted with urine. Also the period of exposure influenced the amount of 2.1*-- D acid absorbed by skin. This relation wa_s. proportional for 2, *+ and 6 hour exposure (Fie. 2). This can provide a basis for further research in determinine the biochemical absorption index. Fieurel. Excretion with urine of 2.^-D acid dependine on the con centration of the compound in the solution Fieure 2. Excretion with urine of 2.^-D acid depending on the period of exposure. wr 17437- - - -V - A Russian summary corresponds to the followin? English summary. 4D0H2156467 VV. S e n c z u k , I I . P o c o r z c 1 s k a, M . D q b s k a A D S O R P T IO N O F 2 ,4 -D IC IIL O H P IIK N O X Y A C E T IC A C ID T H U O U C .il T H U S K IN S ii m m :i r y T h e d e g r e e o f p c r c u t u n u u u s i i h s i i i p u i i i i o f ( m e o f i h o i h o .nI f r e q u e n t l y u s e d h erb icid e s - - 2,4-<iichlnr|>hcnn\y;iceti<: ;u-id -- w :is in v e s tig a te d . T h e in v e s tig a W i s t a rt i o n s w e r e c u r r i e d n u t w i t h d i f f e r e n t i - o n c c n t r a t i u n s o f t h i s a c i d i n a q u e o u s s o lutions o f ..P ic lik a " an d in relation to the d u ra tio n o f expo sure. rats w ere used in these experim ents. T h e d erm a l e\|>nsiire w as done hy the tail m e th o d . T h e u rin a ry e xcre tio n of the acid w a s d eteniiiiicil liy pas c h ro m a to g r a p h y a fte r p reviou s e x tra ctio n o f the acid from u rin e and its cslrifii-ation. P ISM IK N N ICT W O 1. l l o b i u g i n D. A ., S g r k i n A . L u p i u o s o t u J . V f Z a j c c w a L . A . : D i e j s l w i j e organizm czielow ieka i ziw otnych gicrbicidow -proizw odnych chlnriicnoksiuksusnoj J i r a x c k L ., K a l e n x k g J., K . ,k i s l o t y . F a r i n a k o l . i T o k s i k o l . . iniill. 32. 747. -- 2. Kubec Acn 48, e chlo 3(10. -- r in 3. a I l aa i lpi aonrnpvh yAr i.a cu M.. tCa hn ue an i utrahr cd na k np r iA .v yt ir. o, bKc u rhiel re bnikcoi d ,I . C s . d c r m a t o l .. 1973, Sanitary -- tu- xieologic features of a herbicide of sodium , am m u niuin and dim etliylaiiiinonium W ,,s a l t s o f 2 . 4 - d I c h l n r o p h i - n o x y a c o l i c a c i d . G i g . S u n i l - 1967, 32, 100. -- 4. .` e a c c u k I'o g o rzelxka II.: U u d o w a chemic/.na a tok syk od ynam ic/.nc w lasriw ieici poch od nych C 7 . q i ik w a s b w f c n o k s y k a r b o k s y l o w y c h . If. M elo d y oznnezania pochodnych kvyasu fenoksyoctow cgo oddana do druku. 1 -- f en 5. oZkasnykpireowpiico:n owe W ., glol u lwk o wms ok eaz uN . :i krwi. Roczniki P Z H . Praca Zatrucie Pielikiem , M cd ycyn a P r a c y , 1967, 18, 446. _______________________________ nn Literature 1. Influence on the organism of humans and animals of herbicides 1969, 32, 7*+7.on the basis of chlorphenoxyacetic acid, Pharmacology and Toxicology, 2. Percutaneous absorption in the production of herbicides 3. see above in Enelish H. Chemical structure and toxidynamic properties of derivatives of phenoxycaboxylic acids. Part II. . Method for determination of derivatives of phenoxyacetic and phenoxypropionic acid in urine and blood. PZH Annuals. Paper remitted to printing. 5. Poisoning with 'Pielik1, Occupational Medicine July 17, 1980 60-780 Poznan, Grunvaldzka street 6 17438 Ni 6 D i. -.a. ... :i.il.bgrui uin- ..-.u n in o i' M a r m a c . -, i" i l p - .. T;:o0x!ihc.o00l. ::: ne, d o 197 J . .ic acid 1949, ' :'iiuncncwlii\gc. - .ll:--Jlud.n:D1.ui0.-s:. . : Ni-li-1C2-. : a dru- n>: iv .ln e j - 14. .-' I. 57. Itoc/ii. rv.il. uw T. XXXI. mi 7 WITOLD SENCZUK, HALIS A POCOKZELSKA, M OSIKA DBSKA W C H L A N IA N IE KWASU P2 .R4Z-DEWZ UCH sko LO re R; O F E N O K S Y O C T O \V E C O Znklnd Toksyknlugii Instytulu Binan.iliiy i Badaniu Srodow iska S e n c z t i kA k a d c m n M o d v c z n c j sv I' u / . n a m u K icrow n ik : prof, dr hub. W . 'boriano well ama m e vr:vz skuri; k:cu su metoriq ponrediuq o za a cr a iq c los J.4 -D '1 ,1 - w u c h l o r o j e 'i o k s y o e t w e y a iu Tioczit s - c u r w . wrtroucsPchlirilnoaa,dntuiayakmncmijiaaiazpnwproezviesavtzziykccsiaeykmdkireww[,1a,jseu2d,inc2e3h,,g4o-s5dt|,ozwssucotz.cwjvhda^lnocciirceeojlfniswu,ntzwyoymkawsrzyubaonycylldcoouhwzoeeskgrrooemdskol(e2znl,w4iiwe-Doos)ci.tchoirponznaiya- 7.AC Z S C D O S W I A D C LN A Material i metodvka W i s t a r ,B a d a n i a w y k o n a n o n a 28 s u M u r a c h . s z c z i - p u <i m a . s i e c a l a 200 g r 10 g . Z w i c r z t i pk Jz .c Iuiim n a 7 g r u p p u 4 s / i v . u r y . D u b ailan u .:y tu p r e p a r a li ! hnii<Jlmvi*go ,,P t i* lik " a v v ie n ij^cefto u k olu 8^% Mili sodovw j kw asu l!.4-dw iK.hlorufenok>yncltnvcUu. P re p a ra i u zy w an u w pusiaci ru u vu- r o w w u d n y e h r o z n y c h s t i * z c m a c h 2 . 4 - D . Ofny zw icrzq l pu d u k la d n y m m uyera nblic/.eniu p ow iorzehni. zu n urznn o w pru- k a r h / . a i v i i T a j ; j r y e h ukul 20 i m J I v u l . m i i ; " r n / l w n e u u ti * m p . ->7- 40 C . P u u k p 1- A l o n y m e z a s i e e k s p n z y e j i <p. m/. ej > v e ie t v -v l a p i / r i n u / . u n u d u k l a l e k t u e l u h u l u ,, n y t li 4 ht y p u ,, S i m a s " , p u e / .y iu piv.e/. 72 u u d / .m v / l i i r r a i i " d zien m e p u d aw an u zw ie rz iu m M*nd du lubpika pu p uivji* mue/.ti. D m r./v u n * w u d y . Z u w a r t u m * k \v u * u 111 112 . 4 - D \v *h .*h *k i r ^ l .i nt : **tMI.i i hi i ..i l u j p . f t*i )*. *-j. pu upr/ubniiii ivyrk *ira h n v v u n i u b a d u r . r g u w : ; | / . k u i i h k /.u i jeu r ' U y f k . u ji H | . W V M K J U /N A C /.K N w z a l1e. zOn oz ns ca ic zoadn iset v kz we na isau b2a,4. -dDa nwe gma o zcwz iui j z k u w r o z I w o r z i- rwoaryjaBqdzcaadynloaacnnhrciyagco.iw5n,izyek1,on1-in2un,rnz4ocmipr.Vkz`ywii akusw/u.yasc2ui,u4-2Dw,4.o-dDWn.vycPn-hoikifriozpgirowzdeozdmi.nswatacwh,,ioPonikeorlcikswala"nlaozbacwilloiiis--cI 2. O z n a c z a n i e o dk wcazsaus u2,4c-Dk swp omzuycczj ui vv z a 1e z n n s c i okWrcsplloynwu csztaossuujcqkcspwoznydcnjyi (2ro, z4twi Gr go,,dPziienl)iknaa" wzaywdaiclaranjiuccyz m4'oHci zbcmada2n,4e-gDo OC 3 ccnfnf C0O5l m& MiM Si , \>>: k 17439 DOW2I561(69 (il 2 W. Scnczuk i inni v;r g T a li * I il | . W'\ li ikj k u u * i i 2 4- 1> w m u t a l i \v ih| iivriim /.uu |/.ku \v r u /tu n r/.u ih) Ku/.i ivr /Su ir r / r .u \ `r ii. *' k u i i - i i 2 !() u "* iniM /.ii (m-2) 1 dolili i i *i. *i.i 111 ilnlui mi lr/.i*i*ii illtluil'll i 0,0 .n 1.4 1.5 1.2 l . o :i .a 0.5 4 i ,ii 1.0 l.li l.o 1.1 4 .li :Ui Sn-tJnNi o.ilT 1.77 1.07 :i.si J.O '" " iM -1.0 i :: 4 S n i ii~i i u *" i :: 4 .Sp m Jiii.i i 2 :i 4 :i.4 1.0 7. l -V* - .. i j.o * I.IS I.>2 ii.ll Cx.i 4.* J.l 4. 4: 2A 1-l*i 1.11 1.MI 5.1 S.7 4.S l.H VI 4.s :.s .. \ :i :i 4 . >t> 1.0 1.2 o.o 0.0 (..-Vi - - l.M 17 idi l.l uso -.7 'j * :i . mi G.S :s.s .1.5 .i7 - s.l 12.4 'J.O 5.4 *.72 l.s.o la. t !M s.o 12.25 i ... 4.7 4.0 15.1 - 7 2. 1 2.1 7.4 .`.o :i 4 ;i.u 4. li .H ti.K .H Ili.2 7.2 lS.li Sn-i Itiiu -4. Il 4.*7 j.j.i I4.:U' Nr 1 k w ax u . W y n ik i nziinczanin k w a su 2 ,4-D \v z c b ra n y c h p o re ja c h m o czu p r z i d s t a w i o n a w ta b u li l i . 11u.s( r n c jq g r a f i c z n q v v y n ik w ju s t r y d n a 2. \ o .m O w i k m e w y n i k o w S lw ie rd z o n o , ze ilosc su b sta n c ji w y d a lo n e j z m o c z e m je s t p ro p o rc jo n a l n a d o s t q z e n ia 2 ,4 -D w b a d a n y c h r o z t w o r a c h (ry c . 1). W m iarc; w z r a stu st^zen ia 2,4-D ilosc te g o z w ia z k u w y d a lo n e g o z m o czem , w p o r w n a niu z g ru p q p o p rz ed n iq , tzn . o n izszv m st^ z e n iu 2,4-D w z ra sta la o ok. 50%. D o ty c z y lo to stq z e n o d 0,5 do 4% ; n a to m ia s t p o e k sp o z y c ji n a ro z tw r 5%, w p o r w n a n iu z g ru p q z w ie rz q t e k sp o n o w a n y c h na ro z tw r 4% , z m o c z e m w y d a lilo si$ o o k . 17% m n ie j k w a su 2,4-D . Nr 6 \V d ila n ia rn e kw asu 2 . l-<i'*uchlro icno ksyo cto \vego 613 R v c . 1. W y c la L .n ic l m u t c m kw a .u 2 .4 -D w /.nW v.nnsci od .tijy.enia / \ v i : | k u w roztw urze. upp oor zCwzeyazcanjssiiekm(errkty,s*bcp..icoZ2cz)hay.lcceMmjzi niouozwzsencpctloytgaows tbawaylnsloakrwapzwicnr oni kpipeaoozrdwesjntcoaahwnlaa.U;lnnoidaasone eidalkl.aawls2az,.ysu4c hi2b6,4a-gdDondz\vinncnnhdeloj oncpirkr;astq-- T u i i M. \\ y n ik C7J)*U !. I | l w iuihv.ii tv <*J ( /jks k /.vi-ji (lo /.H I11/I Nr I ilitln i* kuti.- u 11 w IIHM'Ztt III (** i '1 J :t 4 -- <1111, J 1 : \ hua l I 4 'f.-.ma l.t 4.7 J ..7 :i.o I..S l.-i t. -J7 ti.i 7,U 4,.S :.\0 4, r . i.* :i.s >? i.t; 1.')7 i :t -. 1"..7 .7 i.7 i.> *,.s -M i .i i ll.lt 1.7 (I .N H,.N 1 H.\ 1. 1 i.;# 1,0 7j LM j" -.7 :t,:i I .j .`.O 7,4 .7.1*7 7, .7 K.i 17,7 11.41 IV i::,i ` M'. >.o 1-, - J cn % ~% <=> m r , *-.c. `. i/i 1- r 'K SK s.->l-'V 1 T- i 17441 4Vs *`VV;'fX_vVi*-^* W j&NSf-li-* *1 Ht ~- c.;;.*.: :' '. C z2as ek sp o zy4c ji (godz) R ye. 2. W ydaU m te c irm k\va<; ' .4 -D Ic7.uu>ct ni z y cji. wi m ov.u- t*k>p>- B C e h u 'I y k , X . n o r o * e . n . C K , i , M. J c m G c k j P E 3 0 P E L 1J H E P E 3 K O > K y 2 .4 -lllX .T C > P < [< E H O K C n y K C y C H O V J K it C .IO T b l P (* i in p 1 i-.ip c a e .lu .ia C L , c t c iic j i1> p c m p l i iu i ii ' iv p e i k o , y o .m u ro i n :i:i , i(7u.*ici I ISpil- mi* i h <*m i .*x r c p G iin n .io n , 2 .4 -.iiix .io p < b e n o K C iiy K c y c iio ii k i i c .i o t m (2 .4 - O i. llc v .ic .iu iiu im x n p o o o .n i.m c i, n i.'iiiiie iiM u cT ii u t K O im c u T p a m n i jt o u k ih u o t i.i h iio .i. iom paCTDope n p cu a p a T a ..lle .n iK " a T .iK jK e o t upe.MCim D K C iio m m n i x u o c ra llp lIM C l 11ICM1.IX /KJ1 KOT1 I 1.1 X IK p i.lC .1 1 1 1 1 1 ( 1 1 U llC T a p l na JCl'lCTU PC 2 .4 -0 . K o iie ie c r o o m .i;ic.i> tcM o ro c m om oii 2 .4 -D 0 n p e 4 e.1 x .1 1 1 m c t o p c m r a jo t o r t x p o M a - to i p a c jiiu i iio c . ic c r o v K C T p a m n i n j m o*ih n jT c p ii( t > i( K n m iii. W. S e n c z u k, H . P o g o r z c l s k a , M. D q b s k a A B S O R P T IO N O F 2 ,4 -D IC M LO H P l IE N U X Y A C H T 1C A C ID T IIH O U C .l! T H E SK IN ' S u m n i ;; r y Tlu* degree of p e rcutan e o u s ab so rp tio n of o i.c of the m ost f :\ q u c u tly used 11.r 1 1iiid e > -- 2 .4 -d ic h J o r p lie iin x y a c e lu * a c id -- w ax in v e s t ig a t e d . T h e in v e s t ig a tio n - w ere ca rrie d out w ith d iffe re n t n n ii d u ra t io n s uf th is acid in aqueous so lu tio n s of ..P ic lik a " a n d in re la tio n to the d u r a t io n of e x p o su re . U 'is t a r ra ts w e re used .n these exp e rim e nts. T h e d erm al exp o sure w as done hy Ihe ta il m ethod. T h e u rin a ry e xcre tio n of the a c id w a s d e t e r m in e d h y g as c liio m a io m ..p liv a f t e r p r e v io u s e x t r a c t io n <>f t ile acn i from u rin e .n u i its e strifie atio n . P 1S M IE N N 1C T W O 1. U o ijiu p m O . A . , i' y r k n i .4. 11.. E a p u io s o u ' J . W Z a jc c w a l_ a .: D ie js t w ije na o rgan ism c z ie lo w ic k a i ziw o tn ych k is lo t y . F . in n a k n l. i T o k s ik o l.. HIGH, g ie :I2. rb ici 747. dow -- -p 2. rJoiirznws cokd nLy. c. hK aclhe lro. xr kf iye nJo. . k si K u u k b sus ec nKo. .j A cne ch lo rin a a p o rp h y ria cutanea tard a p ri vyrc.be h crb icid . C s. d erm ato l., 1973, 48, '.',(16 . -- 3. R u t l i o n n v A . !).. C h u m n r h v u k n .4. .V.. K u r ile n k o J. S a n ita ry -- to xico lo gic featu res of a h erb icid e of so d iu m , am m o n iu m an d d im c th y lu u u u o n iu m salt o f 2 .4 -d ic h ln r o p h e r .o x y a ie t ic a c id . G ig . .S u n il., 1967, 32, 100. -- 4. S c ii c r u k IV .. I 'o y o r z e l s k a //.: B udow a chennc/.na a to lp .yk n d yiia m ic/.iie w la sciw n sci poclm dnych kw a>6 w fe n o k syk arb n k sylo w yc h . C z q ii II. M elo d y oznaczr.nia pochodnych kw asu fe n o k s y o c to w e g o i fe n n k s y p ro p io n o w e g o *.v tiio c z u i k r w i. R o c z n ik i P '/ I I . P r a c a oddnna do d r u k u . -- 5. Z a iik ic - w i c : IV., R u ik o a -s k a N .: Z a t r u c ic P ie lik ie m , M e d y c y n a P ra c v , 1967. 18, 446. D n . 17.07.1980 r. 60-730 Po zn an , u l. G ru n w a ld z k a 6 AA9 C h lu .-i m n n n n ii Pp m I.i m iari,* i. w Ice111;: Ocee rv ok m ill* . I ij>P!1l17..i /. n Apy.mt1i-e;rt i'i i u n ie.* m n\Yii i.I.,' n siln;. > t.4 lli-n U 'irk s/' U '.itru li iskery k ;iNj ; nn_'-k tv i< j i r.y/.u* n v >k>' n i c k t* o \Y 7: na u*. ch ln rk PCW n>m i ni/>/n-j. \< ba ue' t o m cl U UHL 120 riiSTicim : iir.sinur.s a n d r x i 'nstmr. or ste r is ed .1o c: ra r. *! ! / i t a -i Ch i n '.>6 Co !*6 h o u r s , a t 5 mg p e r kg body w e i g h t . when each was adm ini til r a t s and dogs, 2 . 6 . 5 - T a d m in is te r e d by I n tu b a ti o n r e s u l t e d in r a p id unchanged 2 .6 .5 - T u rin ary e x c re tio n by r a t s , but much slower e x c re tio n in dogs with s:~.e metabolism o c c u rrin g . E x c re tio n o ccurred hy f i r s t o r d e r p r e n e - ' i s a w i t h an I f e l i m i n a t i o n v a l u e s ( E ( / v ) f o r ".inn, ra t:! , and dogs : f *6, and ')/ h, r e s p e c t i v e l y . [n man, b u u e r ii u lL ec a l . ( 2 ) f o u n t i ' / a v a l u e s of 13 h f o r 2 , 6 - 0 . Koh 11 e t a 1. ( 5 , 6 ) and S a u e r 1" ' " : o for 2, i -. . - -,~_-z_, j 5 /i - . r , (2) found E|^-> plasm a 2,6-0 respectively. valui-.s m naueritnff >2 , 12 .'L a ! . and (7) 12 o bserved th a t r l n n r y e x c r e t i o n was even more r a p id ( E | / . - II h ) lien 2 , 6 , 1 - 7 an d e Lira t r . s : i tin\ i administered :: 2 ,6 , 5-T was intravenously to markedly altered r;its. when h i s t r i b u t i on larger doses we r e admi r. i ; : e r ne. Exposara =:ud ie.s by Lavy ,vi. (1 ) on f o r e s t a p p l i c a t o r s allowed a e-cuy "pan e x c r e t i o n of '1.013 mg/kg body w eight from s in g le day r s o r e s . \ c o n sid e ra b le range of 2 ,6 ,5 -T was monsilt ed in the u rin e : cr d i f f e re n t crew members, w ith a mixer e x c re tin g the highest livei (0.096 mg/kg) and a flagman the lowest level (0.U01 m g r e r exposure. in a subsequent 2 ,6 -0 study on f o re s t r y w o r k e r s , 7. 2. Lav y, J . I). W a i s t .u l , R. R. t ' l y n n , and 0. `l a t t i c e ( 1 9 n ', cnoub) , found mean v alu es of le ss than M0.02, 0 .0 7 , U.OOb, 17.02 2 . ,,nd 0 .0 0 1 mg/kg bodv '. e i g h t , ."espoc t iv c I v , to r hate linen, : 'i i : t s , mechanics, >uperv iv i r : . md n;v..'rvers. 1'ne s e l e c t i v e ot t h e c u r r e n t s t u d y was to o b t a i n m e a s u r e m e n t s o f 2 , 6 - 0 l e v e l s in u r i n e from w o r k e r s i n v o l v e d Ln t h e a p p l i c a t i o n of the h erb ic id e under normal use c o n d itio n s. S p e c i f i c n i 1v , 2 .6 - 0 levels were measured in urine samples co llected prior to, d urin g, and a f te r ac tu al sprav operation!', from workers involved in g r o u n d and n o r i n i a p p l i c a t i o n s of .'.mine and e s t e r f o r m u l a t i o n s o r 2 . 6 - ii t o . h e a t . ."he r e s u l t a n t d a t a w e r e u s e d t o c a l c u l a t e e x p o s u r e dos-t-s .;r.c u r i n a r y e x c r e t i o n r e l a t i o n s h i p s . M aterials art Methods Protocol. Volunteers for the 2,6-0 exposure studv consisted o r 26 workers i.v.'olved in th e ground a p p l i c a t i o n In E a s t e r n N orth D ak o ta and 1. w o r k e r s i n v o l v e d in th e a e r i a l a p p l i c a t i o n in E a s t e r n W a s h i n g t o n d u r i n g t h e s p r i n g o f 1 9 8 0. No s u g g e s t i o n o r a t tempt was r.ada to a l t e r work h a b its or c l o t h i n g worn by th e work ers. In stru ction s were given for the taking, handLlng, and s to r ing urine samples and recording dates of 2,6-0 a p p lic a tio n and u rin e c o lle c tio n , equipment used, liouru and acres spraved, formu la tio n , wfnd condition, and job. \ summary of the experim ental conditions and laraneturs is given in Table i. Prior to the ex periments most p articip an ts completed an information sheet which liste d age, sex, weight, job, years of experience with 2,6-0, and applicator equipment type. During the experiments most p a rtic i pants Listed type of clothing and weather conditions. 10. n a m i i; r m I /'ip o w n r nj* Samp l i n t ; . ,r i:rI tv i dun L w o r k e r s rroin aor i a ; vi dr . d r A - h o u r u r i n e s a m p l e s nn a p p r o t i n . it'! a I ; c o n t i n u o u s l , --Ii a pp I l e a t i o n . T h i s repri st! n t . e r e d .1 t y p i c a l ; l t u . i t i on d u r i n g t In- hei i 11L ->1 t o wheat /in P. n s t o r n W.i s h i nn t nn . I nd i v i dun 1 ;r - ;pp I i on C non.1: p r o v i d e d s i x -. on s e c s t : ve -.i.i y tor n onerwusk period follow ing n sin g le 2,^-1 p a r t i c i p a n t in both g r o u p s worn m o n e s r o d to s i n g l e voi\!r>(.i .no. . nnni e p r i o r : o . -gpor imen: | Ta h i e i .'iigi'r . ir v or i.'onn j t i o n s and i'' r n n e t >rs i g r i r . u l t u r n 1 .. up L i e n Cor s_ Acri a j f ~r tern r , . ' . p f r l i c : t u>n . l e t l i o i ; in d Si i.Wn: h t n g ^ o n ) r* Sample h a n d l i n g . A t l u r i n e samples were each .subji/ct u n t i l c o l l e c t e d and transp orted to on r e c e i p t o f t h e f r o z e n u n i n o s a m p l e s , t h e y we: ( i n t h e r a s e o f t h e N o r t h D . r k n t i w o r k e r s t h e y we t h e P l an e M e t a b o l i s m l.nborn t oVv , I' .i reo, No r th ha p r i o r t n s h i p p i n g r.u he l t.sv i l I'c , Mare l and ) , i ss i rcturnylil to a re i r i gera tor iS'V.S pending . " l i l v s i - Ana i vs i s . file N.ish inj; t on t . M o : r t n e samp a t t h e ARS Yakima A g r i c u l t u r a l R e s e a r c h U i b o r a t n Dak ot a s a m p l e s a t the ARS P e s t i c i d e D e g r a d a t i o n B e L t s v t l l e , M a r y l a n d . The method used by both l s i m i l a r pro ce d ur e based on a method dev el op ed at and S e l l , u n p u b .). Several randomly s e le c te d ur: U Mi...,wu.., a u l a IiasuiuU 4. ** t a c o n j u g a t e w i t h i n '^6 t > - - - c o u r s , when e a c h was a d m i n i - d o r a l l m a t 5 mg p e r kg body oight. in r a t s an d d o g s , -T a d m in is te re d by In tu b a tio n re s u lte d in rapid unchanged i-T u r i n a r y e x c r e t i o n by r a t s , bat -such slower e x c r e t i o n in w it h some m e ta b o lis m o c c u r r i n g . E x c r e t i o n o c c u r r e d by f i r s t processes with h alf elim in atio n values (E j/ j ) for man, ra ts , ors of 23, 2) found 14, and 7 h, values or re id = h r. uo to : r .v o1v _,4-U. in nan, .".nuerhuff t Kohli a t a 1. (5,6 ) te r h o f f a l . ( 2 ) fo und p l a s m a v a l u e s o f 3 3 , 19 and 12 ,4-0, 2 ^ 5 - r, resp ectiv ely . Sauerhoff uc aj.. (7) ved t h a t u r i n a r y e x c r e t i o n - is - v i n more r a p i d ( E | //,' II h) 2 , 4 , 5 - T was a d m i n i s t e r e d i n t r a y e - v o u s Lv t o r a t s . J j . i s f r i h u t i o n L im in atlo n of 2 \ , 5 - f was " i r e e c l y a lte r e d w h e n /la rg e r doses a d m i n i s t e r e d . xk E x p o s u r e s t u d i e s b v ' k a v y e_^ _u_-. ) on f o r e s/t a p p l i c a t o r s d a 6-day mean ex crctuh v o: .113 .".i/kg hddv weight from e d a y e x p o s u r e s . A c o n s iMur a ; ft_- r a n g e >n 2 , 4 , S - T was m cn s iir - i the urine for different ere,: a;:roers/ with a mixer excreting l i g h e s t l e v e l ( 0 . 0 9 6 mg,'kg) aVd - : Logman th e lo w e s t le v e l l m g / k g ) p e r e x p o s u r e . Fn : V e r s o ' f u e n t 2 , 'i - D s t u d y on f o r e s - ' o r k e r s , T. L. h a v v , .1. 0. \ L s z . y i , '1. R. i 'l y n n , an d J . 0. ce (1980, unpub) , found near, vagues of less than <0.02, 0.02, , 0.003, and 0.001 m;/kg b o d y -e ig h t, respectively, for men, p ilo ts , mechanics, s u p o r v is jr s , and observers. The o b j e c t i v e ol th-> c u r r e n t s t u d " was to o b t a i n m e a s u r e m e n ts 4-0 levels In urine from porkers involved in the application a herbicide under normal/use conditions. Specifically, levels were measured In urine samples collected prior to, g, and a f t e r a c tu a l spray o perations from porkers involved in i and a e r i a l a p p l i c a t i o n s : p.-i-.e and e s te r fo rm u la tio n s of to wheat. The resuioam: ..a:a -ere used to Va leu la te ire doses and urinary, excret ion relationships. Lais and Methods 'rotocol. Volunteers for the 2,4-0 exposure study consisted workers Involved In the gr'ur.'i application in Eastern North an8 1/ workers involved in the a e ria l application in F.asts h l n g t o n d u r i n g t h e s p r i n g o f 1 980 . No s u g g e s t i o n o r a t was made to alte jr work h a b its or c lo th in g worn by the workin stru ctio n s weie given for the taking, handling, and s to rine samples and/recording Fates of 2,4-0 a p p lic a tio n and c o ll e c tio n , equipment used, hours and acres sprayed, formu, wind .' condition, and job. V summary of the experim ents I i o n s an d p a r a m J t e r s i s v.I.ve-i T a b l e I. P r i o r Lo t h e n ts most p a r t i d i p a a t s eornpieccil in in fo rm a tio n s h e e t which age, sex, w eight, job, years of experience with 2,4-0, and itor equipment type. During the experiments most p a rtic i" H M type of clothing and weather conditions. `t viti) x'.ll I I \l. .1l'i'hftilorx I'.l[untilr to 2.J-D I i.unn l i iv,!. ' i i d i v i d u a l w o r k e r ) r i e r ; . ' ini' ;'--n ro- v . d c c . - H o u r u r i n e samples on approx. in a t e a l t e r n a t e davs or Che c o n t i n u o u s 2 . A - D app l l e a c i o n . T i l l s r e p r e s e n t e d uh. i t -nay ho c o n s i d ered j typic.il s it u a t io n during the height o f 2,A-D l p p U m t l o n s t o uhe. it til E a s t e r n W a s h i n g t o n . I n d i v i d u a l w o r k e r s i r o n g r o u nd a p p l i c a t i o n s p r o v i d e d s i x r . o n s e c n t t ve da v 1'i-hnr.i rine. :n.r.nler, : or i w i . j - j ' i f k p e r i o d f o l l o w i n g i xi ngl . u l . ' i - o i n p !, : i a r i :>e. p a r t i c i p a n t In both gr o u ps were requ es te d to pro v id e l o n e - t i m e s i n g l e v o i d e d u r i n e s a m p l e p r i o r t o o x i u r i ment iL -i: * a t i T a h l e !.. Summary o t ( C o n d i t i o n s and I'.t r u n e t e rs oi ' .:iK, .-u.:t .' h" ______________________ a g r i r.ii l t u r a i App i i c a t o r Sj_______________________________ A p p l i c a t i o n Met h oil and S l a t e ! tern Aerial < S r n mu _____ ___________( W a s h i n g t o n )______________ hquipnent A Thrush Commanders \ Or iiminan A g - O a t s , ..nrt;. ' ' i x u .i ) S 'H 1. 1 *[' l.1 >1 So 1t - a - , . . , , . , ! ! \ Pipers it! ii;ib 1 Snow H in ' 1 Cessna O c c u p a t i o n |A Pi l o t s '> 'jpra v 1 Mixer/loaders i '1i x e v/ ! o. ino r s Clothing R a t e s Ih/.A Various -- Various 1., Z:i - -, S i kg/ha -- 2S - 3o Formulai lion -- 2A A m i n e , A e s t e r S e x 18 M a l e s , 1 F e m a l e 25 M a l e s , 1 Fe ma l e C e o m e t r i c mean Range C e o m e t r i c mean Range Age 33 21-ftA SQ I S - A l Wot i: t KDur i enee / 1- 20 !0 Spr ived acres r,a ROOD 3ft SO 2 5 0 0 - A 0 , . 100 1000-1 f t , 00 :oo JM;) " J - ' O l Hours per djv 5" 3-1 ft -- 'nvn nr v e a r '5 1A- nO ''' ." lots , i . A h and m i x e r / l o a d e r s , 5 .6 h. Sampl e h a n d l i n g . .Nil u r i n e s a m pl e s were s t o r e d f r o z e n by each s u b j e c t u n t i l c o l l e c t e d and tran sp orted to a l a b o r a t o r y . Sp oil r e c e i p t o f t h e f r o z e n u r i n e s a m p l e s , t h e y were w e i g h e d , thawed ( i n the case of the North Dakota workers they were subsampled at l lie Plan t Metabolism L a b o r a t o r y , Fa rg o , North D a k o ta , and r e f r o z e n p r i o r t o s h i p p i n g t o lie 1.1s v t I I e , M a r y l a n d ) , e:,-: i nod a r o d e , in.i returned to a re frig e ra to r (3"0) pending m .iiv sls. \n 1 I vs i s . The W a s h i n g t o n S t a t e u r i n e i . i mp l e i . e r e in.i I-.'/.e a it i lie -\KS Vaki ma \gr i r.u l t u r n l R e s o a r r n L a b o r a ' o r y ...id Lh e w i r 'd , Da k ot a s am pl es a t the ARS P e s t i c i d e D e g r a d a t i o n L a b o r a t o r y at B e l t s v l l l e , M a r y l a n d . The met hod used by bo t h l a b o r a t o r i e s was a s i m i l a r procedure based on a method d e v e lop e d at Yakima ( M a i t l e n and S e l l , unpub. ) . S e v e r a l randomly s e l e c t e d u r i n e samples were <J0 ft. oc O o UDM2 Ib b 3 ^ r s iir m i' im'.siolt.s ano f.xposurf. sxc.-.anged bet wee n the two L a b o r a t o r i e s f o r c o m p a r a t i v e a n a l y s i s , d e v i a t i o n s from t h i s method used a t B c l t s v i l l e a r e shown in t he :':llo w ing p a r e n t h e s i s . ) B r i e f l y the method Involved p l a c in g 1; mb u r i n e (25 mb ) , 2 mb 37% KOII (5 mb I N KOH) , 5 mb m e t h a n o l , .-.1 c l a s s beads (s an d) in a b o i l i n g flask, and r e f l u x i n g the c.on- : i - . t s f o r l h. -U t o r c o o l i n g , t he c o n t e n t s were i ra ns r e r r e d to a 111 mb s e p a r a t o r y f u n n e L , t h e f l a s k r i n s e d w i t h 25 mb w a t e r (50 mb l . i C l ) and 25 mb J l c h l o r o m c r b a n e ( I N " ' ' a d d e d . The f u n n e l ' o n - . : - . : i wore s h a k e n , a l l o w e d to s e p a r a t e , and t he '-octom layer - i t i r d e d . The u pp er l a y e r was a c i d i f i e d w i t h 3 nl. 11-jl'O.j ( 10 -.1 - . ' I :tgr,').i1) and 20 mL DCM (15 mb) was added t o che f u n n e l . fe nnel concents were shaken and allowed to s e p a r a t e . The ' DCM L a y e r i s c o l l e c t e d l a a b o i i u i c c l a s k . two a d d i t i o n a l . . .tractions w i t h DCM were c o l l e c t e d and t h e f u n n e l c o n t e n t s ; rsrded. ~he i)CM s o l u t i o n i n t h e h o l i i n t f l a s k was r r a n s t e r r e d t o a f .: t j r a c o r y f u a n e L t h e b o i l i n g f l a s k was r i n s e d w i t h 60 mb 3% N i . - . l c j ( t w i c e w i t h 25 mL 3.6% N a H C O . ) , ind tlie r i n s e s t r a n s f e r r e d t : tee f u n n e l . The f u n n e l content.", were shaken v i g o r o u s l y tor l -nd a l l o w e d t o s e p a r a t e and t h e b o t t o m l a y e r was d i s c a r d e d . 2 . r =e mb Hj I'O i. (15 mb 20% H-^I'O-.) was c a r e c u l l y added t o t h e s e p - - .r ttir y funnel and g e n t l y swirLed u n t i l e f f e r v e s c e n c e d im in is h e d . ~ a c i d i f i e d s o l u t i o n s were e x t r a c t e d t h r e e timer, w i t h 20 mb DCM . ~L) and e a c h DCM e x t r a c t d r i e d t h r o n g s a n h y d r o u s in a . . 5 i b Er l e me y e r f l a s k ( 1 0 0 mb b e a k e r ) . The DCM s o l u t i o n was Carefully evaporated to dryness. S a m p l e s were m e t h y l a t e d by one o f two p r o c e d u r e s . Ten m i l l i - 11: m e t h a n o l and I mb o f 16% P.F-j I n m e t h a n o l were added t o the r ; ; `. c u e In t h e f l a s k and t h e c o n t e n t s hoi l ed on a h ot p l a t e f o r . . . - . i n . E x c e s s m e t h a n o l was e v a p o r a t e d w i t h d r v a i r . About 0 . 5 > brown o i l y s u b s t a n c e r e m a i n e d . Two ml, o f 03% h e x a n e p l u s : Dintone were added to t he o i l r e s i d u e , mi x e d and p l a c e d I n t o re f r i ge. r a t o e u n t i l y. i s- I i g u i<i c h r o m a t o g r a p h i c . ( M i x ) a n a l v s i s . .-.r. a l t e r n a t e m e t h y i a t i o n p r o c e d u r e i n v o l v e d t r a n s f e r r i n g t he r c s l - i - i : o a 15 mb p o i n t e d t u b e w i t h f o u r 0 . 5 mb I n c r e m e n t s o f BF-j- i n m e t h a n o l ( 1 : 1 v / v j . The p o i n t e d t ub e was s t o p p e r e d a r c p l a c e d In an 8 0 C t ube h e a t e r . A f t e r L h the t ube was removed a r c a l i o w e d t o c o o l . F i v e m i l l i l i t e r s h e x a n e and 2 mb s a t u r a t e d .` a . l were add ed t o t h e t ub e and t h e c o n t e n t s mi x e d t h o r o u g h l y on a v e r t e x m i x e r . Fo u r mb o f t h e h e x a n e l a y e r were p l p o t e d from the '.tee and p l a c i d i n t o a v i a l . The c o n t e n t s of the v i a l were evapo r a t e d j u s t t o d r y n e s s w i t h d r y N-, i t room t emper a c u r e . Four ' . : . l r l i t e r s o f hexane were added to tlie v i a l and the c o n t e n t s 'c-'.rtii. A l i q u o t - ; trom t h e v i a l were t n k ` 'ii l o r Cb C asv.f. v. CbC c o n d i t i o n s . D i l u t i o n s f o r CbC a s s a y s were made when n e ce s sa ry . The CbC parameters were: ^ N 1 e l e c t r o n - c a p t u r e d e te c t o r ; g l a s s c o l u m n s were f i l l e d w i t h 3% OV 101 on G a s Chrom Q (6 mm . by 1 . 2 m ) , 11% ( Q F - L + 0 V - 1 7 ) on G a s Chrom Q (4 mm l . d . hy i n), and 5% OV 101 on C h r o m s o r b W (6 mm l . d . by 1 . 8 m) a l l 10. -'vmi l.T \r. Ipe/r, ifi'n f'\ >()/b 'O -svili; 3/'35 ' l i / , - 1. : .; > at 200 and 180 column temper alai res represents tlie a b s o lu r - values whereas the B e l L a v i l le lahnrator plu s i v a l u e 2.5 t i n e s ' he rycor . imp i tv . 'i n s u l t s and D i s c u s s i o n , re :le c o vi.-v ' i. veti i n ii-.. l'.-i L j I >: j , - -t.-i 1. :ompi : l a b o r a t o r y . - -u-haugpii a; ap I was n s e c as .-tn tot^i-cna I The n o l t s v i l l e i .'.jfiora t o : aOnUaI'Cr: l f.ih le I l i . ifn v e n .-; i t e r ) ane. .1-) .ideo ;uvc re-.! Ii'4 38 / 73 ! * ' 120 V\ ; / J 130 ; I 01 - O'J 960 2,600 \ . : '> - j \ . 86 + 3 83 -f 5 A 87 + <4 / \\vc '!) S'l.M i'l.'ir' ! 7 ir u < ; i* ' in ` :*r::! able f\ i l l l'. ; lampi, ra r i 1, . {' t ween 01le Y a k i ma anti Samp l e ___________ l a b o r a t o r y number j f a k i n:i \ he 11 s v i l 1c frfli Dakota i / Nl)a /2 0.17 0.01 4i ND fymp I c s ------V NI) \ 0.16 ' 0.003 \ O.i,! *. o . n '). id */ MD o' 0 . 0 3 >. IH ''if 0.0 1 0.66 0 . 38 ii 2.63 2.96 12 0 . 3 1 .033 '' None d e t e c t e d . y 3i ^ * i . , , . i . i**i i.....; . i r .it h .'s i .. ) !r i <_1 ! ( '> ni . ) , ! -il. I / " f i l l i ( i.i : i )Mil ) i il i l'ii i i 1 i r : : .; ' ..i.:- I!.,. I i 'it* ' i : . uu! j ch loro<noih n no :pf u r s m r r s ano rx ro su n n ir i; i . : i i .i re Jiiown : n c t I n v o l v e d p i n c i no >ff ) , r iL mol. h .m o l , . .O-M\l . !iI.!,k/';KVi..(m !I-Mi .!:n. i i { ` ) " V- r - i I ! i `I ;. ; :\:-ini!umz'i \ii.....v:>. : ^rI i ;i, V "I:.Jlis::*k; > . . ' t .m ioJ rtc^*iC - * r \ ;i f --ir;:.: r .............. r;u-rx*\.s,\r * v i p o r .11 f.. <Jr y in , s . .vero n>.*f. h v I n Led l'v ono ' n o i nul t -ni, o t 1U \ Kf-* j i : -. l:.h*->*.-!i I . iM!!'. .;ili*1I1th*' ij', u i'r;n\:ixi l.-r` . ;` ' i l V uU, I .i neo ;'M 11 i . iv k !'Ii !iI T) the ir: : K -W Mr L l . !^ - I : ce U . r . ; . * * i . C : on ..T ,i:e m r e n. p o i n t e d Cubi* f - ' i Z ' i i o u r . ; in v2 f^y)fl/vf )j\J-* iTCinu'i. poi".":;.T-:. co c o o l . (` Ivo/;ni I I i 1 i c e r s Mod to t he Cnbf nnd the r. F m i r .ni, o f /clic l i c i o n e l i - 1=: mm. mdI rol mu t-oss .1 vUi*. i l .drvTito cior n t e" . :-; he.'MM- wr / * Mjil'-d r o ; ii-.M o r r .'! i { n.l- i .i I -j rtii** nj^". -1i :>i v:echJ*r'e.M:cii!.'- r \ *: c o n / c * i n i ; ! : ;i . '/ *r iM t ` o m i i o n ^.1 : jceduro^ Ten ni I l i \nol wore .tddod to the hot I t t e r'.i N jr v ! : r . \ h o n L '. > V. 11 -'.u ^ .in t' ! Li. V>o ' L i c o c ! - r i t o ' 1 'n;i 1V - ; . i c r e n o n \ < o t J'-i" . :* iroiSncr.d . Lne Cube wVs rernuveri -.e nnd 2 nL s a p o r n t o d ? n i x o d t h o r o iii; h \v on a e r e p i p c c o d f r o i n \ r l i o : che v i . i l w.ro ev\i >o- " 'o r.t r.uro . Knnr . id rh o :i.wir.enCM r '!.(*. i'.w .'iv. J i t i v i u . 1 ijntU M i.'; l u i - " -.ip*, . - v r e " . i d o win n 'In* *d ,t ; p . t r . t n e t o r s w o r e : ' ' i lo c t ro ti-c-i p t u ro d e te c - " ! nnn'! *"<.* t i I li * d w i t h \ . \ o n (..tu r . h r o m '} ( h min "i , 11 ( 1 I * n V - I / ) mu , i . ; o n ( h mui 1. d . h V IJV l* l .m Ld ij` ui;iitH` h W t - r. by l . t f ni) o i l IO. '.'WM I T ,\l.. ,1 i>i'lictin>rv F.\pn\nrc in 2 A - D 12? 11/ l * wi'Mi: i Til/, ', r i * .it !>M, J O, ,,r 69 ml./'min ;ina 160, 2 0 0 uni LUO'' c o l u m n t e m p e r a t u r e s , r e s p e c t i v e l y . The d a t a r e p o r t e d r e p r e s e n t s t he a b s o l u t e v a l u e s me a s u r e d by t he Y a k i ma L a b o r a t o r y , wile re. i s t h e O u l L s v i l L u L a b o r a t o r y s u b t r a c t e d from a l l f i e l d sam -ani' Le` .pl e . ; a v a l u e 2 . 6 t i m e s t he r e c o r d e r peak h e i g h t o f c o n t r o l u r i n e Resu lts and D i s c u s s i o n i'. cover Les o f 2 , i - l ! (80.2) and 2 , 4 , 5 - T ( 0 2 ' .) a d d e d t o u r i n e n e ai von Ln T a b l e LI and c o m p a r a t i v e 2 , 4 - h i n i i l v s i ? i n s e v e r a l Ialvo-;; t o r y ..ccliangurt l a mp l es i s . ; l v e u in T a h l e i l l . The 2 , ' i , 3 - T - a s use,I as au i n t e r n a l s t a n d a r d at tile R e l t s v i l l e l a b o r a t o i y . he b..-1 t s v i l i e l a b o r a t o r y I'.iund h i g h e r 2 , A--IT a m o u n t s In manv u r i n e fable Li. Recoveries of 2,4-0 (propylene glycol butyl ether s t e r ) and --; *.'Ti 1,5 --T ( i s o o c t v i e s t e r ) Added t o 25 mL u r i n e . ! ..i -0 2 (, 4 , 5 - T V.lded OR ' 1\) Recovered y i 3 f I 4 '1 6 - 9 Added n?> 27 48 Kecovered 0-/ 98 . 10 48 J- / -Mt mow S3 L 4- 5 4 + 3 33 96 -f- 4 ; ; n 9? u. 6 540 100 + 4 2,400 83 + 5 1,350 95 + 4 4 , 800 87 + 4 2,700 97 + 6 '.^ ` 1i\ 90 7 " ' . La u da r . 1 e r r o r Ot mc/in fc'cwin i* r.o 12 t r i a l s . 92 fi. r.o" . a l : * : . piparne l ve 1 , 4 - 0 (ppm) An nJ v. ; i ? or U r i n e a amn lcs b e - Sami ' e vCi'n 1 be Y aki ma and B u l t s v i l l e L a b o r u t o r i e s . laboratorv Sample Laboratory nienhe r Yaki ma B o ltsv ille number Yaki ma Eeltsvllle - - - d u r t h Oak o c a S a m p l e s ------- ----------- W a s h i n g t o n S a m p l e s ----------- 1 NDa ) 0.17 NO 0 . 16 13 0 . 0 4 14 0 . 0 6 0.05 0.05 3 0.01 0.003 15 0 . 1 9 0.25 NO ND 16 0 . 3 2 0 . 5 1 '1 0. t>1 >1.24 ' j. 18 < .'ill 0 . 46 0.29 0.11! Ml) 17 : - 30 18 1. 05 19 1. 21 20 , 1.1)8 2.00 1.43 2.02 1.17 ) 0.03 0 . 01 21 1 . 25 1. 53 10 0 . 4 4 0 . 38' 22 1 . 88 2.24 11 2.h 1 12 o . 31 2.94 .033 23 0 . 8 3 24 0 . 2 0 0.93 0.23 `'None d e t e c t e d . rrt"**4 j i)Ufo L I o b *!0 ^ 12-1 I'liSIUIDI' Itl'SIDI'l N A N D r M 'OSUKI s a m p l e s , : s p e c i a 1 1 ' . h e Ii t.;; 11 3 , ' ' i - b n r i n u o n L e u i i; :i i n i ; C m sam ples . file procedure measures c o n j u g a te d 2,4-1), a l s o (j4). A e r i a l a p p l i c a t i o n w o r k e r s . The t o t a l amount o f 2 , ''i--D a p p l i e d t o ..'h e a t on a w e i g h t b a s i s , e x p o s u r e p e r i o d , and moan d a i l y e x c r e t i o n r ; : a e x n r c s s e d on a hudy wi*ie.hL h i s i s f o r tin: a e r i a l a p p l i . . j t i ; : . o r r . e r s i s siiown i n f a b l e I.V. A p r e e x p e r i me nt a l o n e - ' . i mu v o i d s a mpl e was c o l l e c t e d from most p a r t i c i p a n t s . T h e s e o n e - t i m e a.-.p'..-; c o n t a i n e d from 0 . I t o 1. 6 npm 2 , 'i - D , w i t h .a , i v c n : i of A . The mean d a i l y e x c r e t i o n r a t e t or a l l w o r k e r s was t) . !} 12 -.pay w i e c h c . i-rom an o c c u p a t i o n a l s t a n d p o i n t , rhe per day er. cre t _: :v r a t e was s u b s t a n t i a l l y h i g h e r l o r t h e v . i x e r / l o a d e r (mean 0 . 0 2 rz ag body w e i g h t ) as compared to p i l o t s (mean 0 . 0 0 6 mg/kg) , and rrrta.bly a s s o c i a t e d with t h e i r handlin g the 2,4-') c o n c e n t r a t e . The i-w number ot p a r t i e p a n t s r e p o r t i n g e x p o s u r e i n f o r m a t i o n r e l a t i v e to 2 , 4-f) amount handled and hour;; ot e x po su re negated ( T i b i a 1) an y v a l i d s t a t i s t i c a l a n a l y s i s ot t h e d a t a when worker number 1 m s not i n c l u d e d . t h e i n f o r m a t i o n p r o v i d e d by t he p a r t i c i p a n t s , we, . . ere. u n a b l e to f i n d any r e l a t i o n s h i p between c l o t h i n g worn and 2,4-1) e x c r e t i o n L e v e ls . The m ix e r / lo a d e r e x c r e t i o n 2 ,'i- p l e v e l s (Table TV) c o r r e s p o n d t o t h e 0 . 0 2 mg/kg 2 , 4 - 0 e x c r e t e d by bnrehmen o f T. i. . e a / v , i . U. W a l s c a d , If. if. F l v n n , ind .1. 13. . l a t t i c e . , ( 1 9 8 0 , i nraj l t ut . o n s i a' . j rah I y l ower ( 0 . 0 b n g / k g ) tli an r. he 2 , ' . , 5 - T m i x e r s j : L e v y ' s s l u d y and t he 0 . 0 / 7 mg/kg m p i l o t s to a low ot 0.01 cg/kg in supervisors of fo re s try workers in Sm ith's et a 1. (8_) s t u d y . L i k e w i s e , t h e wheat 2 , 4 - 0 p i l o t s e x c r e t e d 0 . 0 0 6 mg/kg compared t o t h e 0 . 0 2 mg/kg f o r e s t r y p i l o t s o f L a v y et^ a_l . ( u n p u b ) . irtu nd a p p l i c a t i o n w o r k e r s . L'rinary u x e r e t ion samples from gr"i:r.7. i p p l i e a t o r s and m i x e r / l o a d e r s from I Jorth Dakota wore taken >n u . ' j u s e c u t l v e . l avs a f t e r a s i n g l e 2, '-!) e x p o s u r e . `l os t p a r t i c i p a n t s provided one pre e.tperimentai urine .sample, which co ntained f r o ; " . u n d e t e c t a b l e i p i a n t i t i e s t o 0 . 6 ppm 2, 6- 1) . The t o t a l amount o f 2 , 4 - D a p p l i e d , h o u r s o t e x p o s u r e , and d a i l v and t o t a l e x c r e t i o n on a body we i gh t b a s i s Is shown in T a b l e V. ,`c.ree p a r a m e t e r s - o c c u p a t I o n , amount mi x ed o f a p p l i e d , and e x posure period were c o r r e l a t e d with the amount o f 2 ,4 - D e x c r e t e d in u r i n e . '.Then t h e o c c u p a t i o n a l s e r i e s i s c o mpa r e d t o t h e t o t a l amount (mg/kg) o f 2 , 4 - D e x c r e t e d , th re e sub groups are i d e n t i f i a b l e , (a) a p p l i c a t o r s , 0 .0 0 5 ; (b) m i x e r / l o a d e r s , 0 .0 0 7 ; and (c) mixer. Lvader/appl l c a t o r s , 0 .0 1 8 ; i . e . , the e x c r e t io n le v e ls in cr ea se d i c b < c . T h is r e f l e c t s , (n pa rt rhe long er av e ra g e exposure t i me f ; a) and t h e h a n d l i n g o f 2 , a - 1) c o n c e n t r a t e t o r the. m i x e r / l o a d e r , a p p l i c a t o r g r o u p whi ; co mpar ed l.o i.hc- m i x e r / l o a d e r ( 2 . '* h) and a p p l i c a t o r ( 3 . 5 h) g r o u p s ( f i g u r e 1 ) . . o r e x a m p l e , the c a l c u l a t e d 2 , 4 - D e x c r e t i o n r a t e fo r the m i x e r / l o a d e r s would be 0.002 mg/kg/hour of 2,4-D exposure. T o t a l 2 , 4 - D e x c r e t i o n was a l s o c o r r e l a t e d w i t h t h e amount o f 2,6-[) nix ed or a p p lie d ( F ig u r e 2 ). Assuming a one day exposure to |(). NASH I I AI ,-t/>/>/n'dii'/'V /. i h> ` // o' ^oi4 v*4 u/ Mlxor/Loinler/Pilot. b / l-'or 80 k y person, c/ Including No. 7. D U H 2 I56 4 5 5 it st ici df: s f s i d l t s a n d i'.x p o s u r p . a l l y t h e h i g h 2 , 4 - 0 u r i n e con t o " . '.,sn Lug t en ;oin:edure measures conjugated 2,4-0, also (). le n t Ion w o rk e rs. The t o t a l nnour.i of 2,4-D ap p lie d leighc b a s i s , exposure perio d, sad -can d a i l y excre- sseil on a body we ig ht b a s is *.-.e a c : i a 1 app 11- 13 shown i n T a b l e f '.'. A p r -:u : ..-.mi r .1 L m e - r i / i e c o l l e c t e d iro n most p a r t i c i p a n t s . These onertime ed f rom 0 . 1 i.o 1 . 6 ppm 1 , ' i - u , avernsy/ of s a n d a i l y e x c r e t i o n r a t e f o r . . . - /T-iors w<v4 ' J . 0 I 2 h t . \ From an o c c u p a t ioiuni s t a r . f j : . r . t , r h e / f '(J-r dav was V u b s t a n t i a l l y h i g h e r f o r cue .-.ixor.-' l e a d e r (mean w e i g h t ) a s c o mpa r e d t o n i l u c s : e = n 'Uj/iOf) m g / k g ) , socl at ped w i t h t h e i r n a n d l i n g v.w ... concentrate, of p a r t l c p a n t s re p ortin g exposure rr.siirnat ion - D amouno. h a n d l e d and hours o f x r f/u re n eg at e d s l i d s t a t r e t i c a L a n a l y s i s o f tr.a J L : a when wo r ke r t Included.N. / n f o r m a t i o n p r o v i d e d by t he p a r r 0 g i r a r . e s , we '. . ere i n y r e l a t i o n s h i p bet wee n c l o t h i i ' u : worn and 2 . 4 - 6 s. The m ixer/loader excretiocr 2 , - - J Levels (Fable t o t h e 0 . 0 2 mg/kfc 2 , ' i - l l e x c r / t v i ry bat ohmen ot T. V a i s t a d , R. R. F ] \ n u , and j / ). " a t : l e a , ( I 9 S 0 . j l d e r a b l y l ower (,0V.)6 ng/k^O t h . r : : v . .. . 4 , j - T i s t u d y and t h e 0 . 0 X 2 mg/jft; in p i l o t s t o a Low o f ipervisors of fo r e s tr y workers in Smith' s et i i . wise, the wheat 2 , 4-DWi. Iocs e x creted 0.QU6 mg'kg 0 .0 2 mg/kg f o r e s t r y p y r o t s o f l a v y e_c aJL. ( u n p u h) lc a t lo n worker from >rs and m i x e r / i u d u c i a ^t.e/m . . .ji-y........... -.u l . wei e t a k e n d a y s a f t e r a s i n g l e 2 , 4 - U e >: r \ i ; r . ' 'o s e p a r t i - . one preexp erim entdl urine s o r.:\ i, which contained l e q u a n t i t i e s t o 1/.4 ppm 2 , 4 - f . \ mount o f 2 , 4 - D a p p l i e d , hours o: e x p o s u r e , and e x c r e t i o n on a body weight b a s i s IsVrhnwn In Ta bl e t e r s - o c c u p a c i o n ,1 amount mi xed or a p p l i e d , and e x - re c o r r e l a t e d wyth the amount o: 2 , 4 - [ \ e x c r e t e d in o c c u p a t i o n a l s r i e s i s compared to t h e \ t o t .i l f 2,4-D e x c r e t a y , three subgroups are I d r W i f i - n t o r s , '\ 0 . 0 0 5 ; Lb) m i x e r / l o a d e r s , 0 . 0 0 7 ; atw. ( c ) l i c a t o r s , 0 .0 V 8 ; i . e . , the ex cr tio n levels\^n - Th ls r e f l e c t s ! ip. p a rt the lor-.ter av era ge ex posure he h a n d l i n g o f ^ 2 , 4 - D c o n c e n t r a : '- f o r t h e m i x e r / r g r o u p when c o mpa r e d t o Che - . i xer -' l o a d e r ( 2 . 4 ! I 3.5 h) g roups ( F ig u r e 1). For example, the c a i - c r e t l o n r a t e f o r the m i x e r / l o a d e r s would be 0.002 i-D exposure. e x c r e t i o n was a l s o c o r r e l a t e d '.. ith the amount o f ip L le d ( F i g u r e 2 ) . Assuming a one day exposure to 10. NASH l.|- At.. .I/i/./iiW o/w E.\i>o\itrc lo 2 .J-D 125 I ' jiI jI i; I V . l'.JIIU 3 , 4 - J 1 2 - U u y i 11 Lr; r I'.t 1 1l u n L l o M O I11111 OOUS l i x p n s o r u lo A e ria l A p p lic a to rs in W a s h in g to n . W orker lo ti 12 - I J n v a p p l i c a t i o n 2,4-W n .i . T iK '.r a n o m ic lb kg b o o r .lo a n ijni: '.x c re l ion o f 3. 4-W !i:it'/ k g X : 1 .v fi ** ' .'J 11 12 13 14 1 !i 17 l o a n Moan Mean lla tio .4/1. M /L :i/i. l/ l. M /L W /L./P 1t P P P P \i iJ O o v e ra ll .'1/1. / i' M /I.4-P 5U0 2 .2 0 0 1, 000 -- -- -- 860 I . 050 1.120 '150 -- 100 030 -- 740 -- -- 395 1,290 800 1.6 225 1.000 730 -- --- -- 390 17 5 510 130 -- 415 375 -- 335 -- -- 450 31)5 360 1.6 > 1 ---22 i M "n in 4 23 15 1M --16 30 M 1. 4 6.5 !y ;4.5 1 . 9 i.n 5 4 .0 in.5 I 3 .0 J .; 4.7 3.3 !i' 1.4 1.3 0.6 b / 10. 1 30.2 11.6 n .i. 6 .0 3 .3 M ix o r/L o a c lo r/P ilo t. b / F o r (10 k g p e r s o n , c / in c lu tlin g N o. 7. I .,n i .: V . I m i n 2 . i : j I -: j . ' >' L- M " ir. 111 i : h i 1 l l l n l ' 111 11 i n t i lli 1iO 1 111 11.11 <it i . Win ki:i Jiil. 1 l ) . , y . l j ) j i l U . . l l ;<>m . -1- 1 ) .1.1 . .icuiu nl T o k'd I'M hour s t 111 1y c: : :1 t .1 n l : . I n . 1 'i . 0 ii' i l 34 Hi T i il .i 1 t .. | h i i , m c l) ' k s, X 1 0 " J 1 3 4 5 6 7 8 9 10 1 12 13 14 15 16 17 13 19 20 21 22 23 24 25 26 : lean 9 /;! !lee aa nn n / M ean .lea n A li- A A A A A A A A A -1/ L 1/ L .1/L M /L .M/L M /L '1/ L M / L / ; `. M /L/A M/ L /A iI/ L / A M/L./ a M /L/ A M /L/A A. M / L / A M/ L/ o v e r a ll A A M /L M /L/A 23 -- -IU 1U0 120 1 00 ~~ 13 23 107 20 23 23 50 35 5B -f _ 112 2u0 14 3u 40 83 102 03 70 76 33 S3 10 "** 10 45 54 45 *~ 20 10 49 9 10 10 23 16 26 19 51 91 i3 -14 10 38 46 (29) (32) (34) (18) (30) 1 1. j 3 7 5 3 3 6 i i i 3 3. 5 4 3 15 n 3 3 9- 5 3 6 6 10 4. 7 3. 4 03 . , 5 4 7. 3 M IL'' 0 .0 9 N il MU ND N !J M l) M l) 0 . It. 0 .0 7 MD M l) MD M i) ID (J. 13 Ml) 0 .2 1 MU 0 .3 ft M l) MU 0 -1 . 0 .3 3 MD 0 .2 7 0 .0 5 0 .0 3 0 .0 2 0 .0 2 0 .2 1 0 .0 5 M l) 0 .0 7 ND 0 .4 8 1 .0 3 1 0 .4 1 0 .0 6 4 .0 0 4 .1 3 0 .9 3 U .88 0 .3 3 1 .7 4 3 .9 6 0 .7 5 0 .2 8 3 .3 6 5 .6 0 1 .2 9 2 .3 6 1 .3 5 1 .0 7 2 .0 7 0 .9 1 3 .7 4 1 .9 6 2 .0 2 1 .8 0 1 .2 7 2 .4 2 .1 i : i N ) U .07 MD 20 I 'j 12 5 .21 0 . -15 10 i 4 .40 0 83 0 .13 l 13 J1 . 6 7 19 U .711 0 84 8 .71 1 60 0 80 4 73 4 30 0 73 `i 50 I 04 i1 73 60 18 l 18 i 51 3 .37 0 . In ND 0 .0 7 ND 0 .0 7 1.71 1 .3 0 0 .5 2 2 4 .0 1.73 0 .5 0 0 .4 4 1 .1 3 1 .5 2 4 .2 2 2 .1 6 0 .6 2 8 .4 3 2 .3 3 6 .3 6 6 .0 7 4 .1 6 0 .3 3 2 .9 3 0 .7 3 5 . fi !i 3 .0 0 3 .2 5 0 .9 1 1 .5 1 4.11 Ml) 'll) xiU M l) 0 . 14 0 .68 0 .55 11 15 2>0 1 .4 (. 0 .07 'll) 0 1) . 347J 1 . 17 5 .64 0 .34 5 .79 ) 00 10 . 4 5.0 1 4 .78 1.1 3 1 6G 0 .37 5 .34 9 .47 l S3 .3 4 l . 17 4.02 i'i lj N IJ N 1) 0 .3 4 0 .2 7 0 .4 1 0 . 06 0 .3 7 1 .2 7 0 .0 7 0 .2 0 0 .3 3 0 .9 8 U .'Jl 4 .2 6 MD 0 .2 7 2 .5 0 1 .2 6 2 .3 2 0 .9 3 2 .7 9 0 .3 7 3 .3 7 1 .3 6 0 .2 7 0. 20 02 ,. 92 62 U . i)5 \ i) IS! I ) ND 0-34 11. 14 M l) 0 . 17 li. 39 1 .0 0 0 . 14 N 1) 0-20 0 .6 8 0 .9 7 0 .5 4 Ml) 2. 94 1 .2 0 u. 5 0 .9 3 2 . 53 i 07 0 . 18 1 .3 9 , 0 .9 0 " 0 .3 6 0 .1 9 0. 36 , 1. 49(1 0 .3 0 U . 0 lJ 0 .2 1 0. Q 1 .5 6 5 .9 5 1 7 .9 1 .4 5 7 6 .0 1 7 .0 '.5 4 3 .5 9 7 .1 2 1 6 .4 1 4 .3 2 .0 8 3 4 .7 1 3 .0 4 4 .2 2 1 .0 2u. 1 4 .3 1 1 5 .2 2 3 .6 1 2 .7 ,i/ 1 2 .0 4 .9 3 6 .8 1 7 .8 ii.' a / D a y 2 , 4 - J ./ j s a p p l i e d . e/ D ith o u t w ork er 9. L / M i:-:or L o.j d e : ./A p p l i c a t 'JI c / N e m o d e t e c t e d ' . . , ; L o u t . o r k e r 2 0 . i ,, w o r_v_a CD era cn - " 3 'f " - - i jj m r> .-H1 O '" o \ _K_ dour !a'/ a/ Day 2,4- as applied. e/ Tithout ..'ofke 9. b/ !li\er/l.o.i(!er/Applicatur. c/ Mime detected. X 10^ 000051 ...... 209305 19506 17.9 1.45 7(i.O 17.0 2.54 1.55 3.59 :1t!ha7261......1u1m7I2i 44.2 21.0 20. 1 1J45...3261 21 32 .6 .7 . l^.O 64 > 9U3>. 1 7 . 8S'' C3 O tv3 en a-Pn" en d/ l.ithuui worker io. r3 jowjuJiIi-- -IV j.i nsvM oi uaasoaxu usv s.idtiisaw :ianud > O II L. i ms I \j O r i si U 'iiii i'i s ii ii 'i : \ n i > i M ' i i s i m '.i 0 10 20 JO 4 0 5 0 EXPOSURE AMOUNT, kg Fillin ' 1. R : .,;ii'iiiv/ii/i bei invi amount of 2,-1-D applirtl miti cxtreiitnt ntl,- (ex cretion -- 1.12 0.21 mixet! nr applied Cr: 0 / i l " ) . M) .`AMI I I \I.. I[ ' ' h i n h / \ / y / ' l ' u n - ' : !) ^ 3 kg i LUC LI)) 't tli*1 Loc.i L mount wo ul d bo Q . 0 L 5 nig/kg hody w e i g h t . i t ihou 1d t h e .imotint oF J , 4 - U mi x e d mvt bo t h r most i m p o r t . m l uuj \i-lui*r*1 o'/r11rc;i1f1 ITiU or ip p li o d o t !1 . i f* I .11 i nish i p 0 11r \ :i i f h v i t i l i h> -'i O' ' ,f 1 >il I', i/i ; . or ;i1 . ,r: i ng t u l re l.i t ion".11i p . t h i s - M i i d y , boc:. i u f*t? f ;ni*r i Fi od, i nworn w.^s nor. t ho 7 ^ o t o ' o 1 , t h e *: Me i.M iv:orn w.-iK; tow i.Mr Lan lo r.o iiuouii L \ : h , - n u x r . r u i fid . / - n n o - i ' . i l r . 1 .,L1 -.rouri i mum da i l y \ o x e r a t i o n s .1 'Ml r,f j l z . r .ih i.- i b l y m o re isnej i r u t i v e - it r ; . 0 v i 1r ra t tie r th a n V he ;rotincl w orker Pa b i o V I . * .p.'^xv, ir.u:x i f t n i r u n i v o t / / * r '.vpit: IK'. 1 ;S r - i f 1 inii'.i / ' o r r ii l;,, '.ot.'i M o u r./ . n 'l r.n v '. - v i / h c -n-, ,~/y 3 10 7l 191.. 9i \ V24 !- 2 5 . 9 homuna r i : =-jnrJ i t h j t h \ f Mudi es. r "i > o r 2 ,4 -L l by .lerjici1 .ini] .roi'lnd 'is i w e i g h t , o r t v p e / o f , ; l o t l u m > \ <r>Ji.-vcr , - a d o l e d w i t h op f o r b n r h .1o t ^ : i uni r r v u i . i .ir.o f 2 , 'i-i.l a p l l u . i l .miJ w i t h u r n ! \ ; or. :;h i >i i i i '': : i r 1' r c s u m a b l y t h i s r e f l e c t s t h e \ m o u n t a t 2 , . - ! ) c i by a b s o r p t io iV th r o u g h the s k in ^ I n h a l a t i o n , one g e s t i o n . f le e r in g ej^ i l i ' J li.' ^r , ; > ( 7 ) observed^-' t h a t a l l i n g e s t e d l?r b o d i l v a b s o r ' b y man was a b s o r b e d i n t o t h e pl.rsm a and e x e r e : , th e r unchanged nr as a c o n ju g n t c \ in the case or a l. ( 5 ) , la d lc n te d 2 ,4 -0 would fo llo w n s im llj: ' t l i c v r e c o v e r e d 777. o f th e i m v s t u d 2 , i - l ) and a f t e r 9b l/ { l e h r i n g e t a l . l a ) , ind k o l i l i ec I . d / ' a l . f,2) yound n r i n a r v e x c r e t io n and n l. is m o l e ' !; t / 2 t i m e s o l 2 1 a n d 19 b , r e s i n ' e t i r e I y , f o r 2. 18 h , r e s p e c t l v e l v , f o r 2 , 4 - U . Tire l i j / a t i r e m i x e r / l o a d e r s , and m i x e r / l o a d e r / a p p l le a t o r s , r- 3 5 , 3 9 , and 48 h . An ^ \ / 2 1 f r f rc s l; 9,'-*. c a l c u l a t e d f r o m l . j v y ' s t a_u (_l) d a t a was b in lo n g e r iv [/2 tim e s a s s o c ia te d w ith the 2, 4-0 f t : e%o ivi DOHZ 156459 :. -.T i'.rsinurs \n o ixrosnitn. /I / / Iff SASH IT . Iftp lin irn rs ti.\i>(>Mirr 2. ' D 45 kg (100 l b ) o f 2 , 4 - D , t he t o t a l amount e x c r e t e d o ver 6 d a ys wo u l d be 0 . 0 1 5 ing/kg body w e i g h t . I t s h o u l d be p o i n t e d out- t h a t t h e amount o f 2 , 4 - 0 mi x e d or a p p l i e d or t h e e x p o s u r e p e r i o d may not be tlie most i m p o r t a n t r e l a t i o n s h i p to u r i n e e x c r e t i o n ' c v . The c a r e or c a r e l e s s n e s s w i t h w h i c h t he worker ;.'or t er ms h i s d o t y and t h e t y p e o f p r o t e c t i v e c l o t h i n g worn may p r o v i d e a more mean i n g f u l r e l a t i o n s h i p . In t h i s s t u d y , b e c a u s e H-,,-; ..van -,f 1 ;t h i n g worn was not s p e c i f i e d In t h e p r o t o c o l , rhe i c s ' i l t a n c c I o t a in.', worn was t oo v a r i a b l e t o make an y s t a t i s t . l - . i l c o r r e l a t i o n i l li a mo u n t s o f 1 1 , --0 e x c r e t e d . O n e -h a lf of a l l ground a p p l i c a t o r s exposed lo 2,4-!) had i.ixinum d a i l y e x c r e t i o n s o f < 0 . 0 0 2 nig/kg ( T a b l e V t ) , //hi eh i s p r o b a b l y more i n d i c a t i v e o f t he e x p o s u r e l e v c i t or an tverai'O ' o r t e r r a t h e r t h a n t h e / 0 . 0 0 3 mg/kg maxinium mean g i v e n in Tabl e Cor a I 1 round 'workers. T a b l e V I . I n d i v i d u a l f r e q u e n c i e s f o r `l a x i n u n 2 , -!.' O a i l v ' r i n a r v _______________ E x c r e t i o n s o f N o r t h D a k o t a ( r o u nd Ann I i c e i i o ns .___________ 2,4-0 Excretion __________ me I0~^, ' ke body w e i g h t ______________________ rt l|p' r __________ ________________ 0 - 1.9 V) 2 - 1.9 i a " 5.9 j 6 - 7.9 1 8 - 9.9 1 10 - 11 . 9 24 - 2 5 . 9 2 ! Comparisons with o th er s t u d i e s . The u r in a r y e x c r e t i o n 1 uc 2 , 4 --i) hv a e r i a l and g r o u n d w o r k e r s was noc a s s o c i a t e d ith . i , w e i g h t , or: t y p e o f c l o t h i n g . H o w e v e r , 2 , 4 - i ) oxer. " L i o n was i s s o - c i a c e d w i t h j o b Cor bo t h a e r i a l and g r o u n d w o r k e r s .mo w i t h na.Too: o f 2 ,4 - 0 a p i i e d and with hours of exposure for ground workers. Presumably t h i s r e f l e c t s the amount o f 2 ,4 - D taken in to the bodv ay a b s o r p t i o n t h r o u g h t he s k i n , i n h a l a t i o n , and p o s s i b l y some i n g e s t i o n . C e h r i n g e l . ( ) K o h l i ejt l . (6^), and S a u e r h o t f e ^ a l . (7_) o b s e r v e d t h a t a l l i n g e s t e d or b o d i l y a b s o r b e d 2 , 4 , 5 - T o r 2 , 4 - 0 by man was a b s o r b e d i n t o t h e p l a s m a and e x c r e t e d in t h e u r i n e c i ther unchanged or as a co nju g a te in the case of 2 ,4 - D . Kohli et u_l. ( 3 ) , i n d i c a t e d 2 , 4 - 0 would f o l l o w a s i m i l a r p a t t e r n hiu-.nise t h o v r e c o v e r e d 77Z o f t he i n g e s t e d 2 , 4 - 0 and found no met bo I I t es ' i t e r V1<> h. ' l e h r i n g e t a l . ( 4 ' , and K o h l i ^ t Jij [. ( ^ . j j ) . 1M<* E a u n r h o i f e_t a l . (J2) f ound u r i n a r y e x c r e t i o n and p l a s m a c l e a r a n c e s f o r nan w i t h E j / 2 t i m e s o f 23 and 19 l t v r e s p e c t i v e l y , f o r 2 , 4 , 5 - T , and 33 and 18 h , r e s p e c t i v e l y , f o r 2 , 4 - D . The &[ / 2 t i m e s f o r a p p l i c a t o r s , m i x e r / l o a d e r s , and mIxer/ Loader/ app l l c a t o r s , r e s p e c t i v e l y , were 35 , 3 9 , and 48 li. An ^\/>i t i m e f o r f o r e s t 2 , 4 , 5 - T a p p l i c a t o r s , c a l c u l a t e d from L a v y ' s e t a l . ( 1) d a t a was found to be 52 h . The longer E [/2 times a s s o c i a t e d with the 2 ,4 - 0 ( t h i s study) and - U U Ht. I J U 4 - U U | ' 0 l'I S II' IDI. KI.MIIIII , \ M ) I NI'ISUKI J , , 1 ; - o t h e r s wonpared Co d , ' i - U o r d , 4 , 5 - r i n g e s t i o n s t u d i e s C d , 4 , 5 , e ) a r o b a ily r e f l e c t s the sLower rote of plasma absorption of the h e r b i c i d e s , compared to i n g e s t i o n . The data suggests the w o r k e r s d i d ?. poor j o b o f s k i n p r o t e c t i o n and s u h s o t pi e n t w a s h i n g . 'n d_hi i nc n t a 1 ( 4) s t u d y , Hi e o n e - t i m o i n g e s t i o n -as " -g V d v w e i g h t . the Per dav x c r e t i o n was I.. V , i . 4, 0 . 7 L , and . ; j :sg/kg fo r days l to 4, r e s p e c t i v e l y . The Kohl l a ! . ' : , - a . f e r J . ' i - D tnd 3 , 4 , `--T '.bowed t ''e s a n e ' ' i vl . r .f wigni c ; c = - : * - //kg ' . u s a g e s , hui p r o n o r c ion. i t e I v l e s s r.ir md ! ig ! a t h i s e.xpe r i ne n t , ' h e nor day -.<c r e t ion 1or Ltie a i e . r f l . i c e r -,round w o r k e r s ( T a b l e Vi on d a y s i Lo ' i , r e s p e e - t i v c i y , :-tr 1 . 2 , 1 . 4 , I . ' i , 1 . 4 , and i . l mg :< 10 V k g , a b o u t o n e - thousa nd :': ; r.uch as the runner. l e : . r et a i . (4) a l s o c a l c u l a t e d the c o n c e n t r a t i o n of , 3 - 7 _r. SEia i r o n r e p e a t e d d o s e s . They found t h a t a matiruun j j nci ' r. t : " : 1 : - was r e a c n e d a f t e r 3 dav:; alien t h e r a i e or d, i , i --!' e i e a r i n e r :"r:.~. pl a s ma e o u a l e d t h e amount i n g e s t e d . T he a n a l o g y can b- s r - l l c c t o t he u r i n a r y e s c rer. i on a m o u n t s , -, i , o , b e c a u s e a l a s _ a c l i s r - n c e r a c e was e x a c t lv t he same a-; t h e u r i n a r y sc r a t i o n r a t ' .7he re t o r e , i t would a p p e a r tli.aC t he a e r i a l workers ' T a b l e ! . . -` I pure l ) had e s s e n t i-i l i v r e a c h e d I lie laximum i . - O .w:cre:i :nu. d o n c l a c l . . ^ . vc f . a t K s . an s e a <>n tin.- o v u i i s pro i.m eu h e r e , ->o'iie e s t i m a t e a : J , - --D e x p o s u r e can be c a l c u l a t e d . For e x a m p l e , t lie ground ?.?: 1i.c 11 ion workers exposure to 2 , 4 - D can be e x p r e s s e d as perc en t d a i l y e x c r e t i o n ( F i g u r e 4 ) . 3y knowing the t o t a l u r i n a r y ny. cre t i - r. t " T '.ne g i v e n day a f t e r e x p o s u r e , t h e t o t a l e x p o s u r e l e v e i . va. .-a 'a ! au ) a t ed . in a n o t h e r e x a m n l e , t h e a l l - j o b s per da v u ri n .- rv c i t r s : ion or the a e r i a l workers ( T a b l e IV) was 0 . U J 2 ng/k.7. : :r n0 v e a r - o l d oil kg worker w i t h 10 vear. s e x p e r i e n c e if 3 ) j c . ' ux-aosiire per year cou ld have abs orb ed and e x c r e t e d is -v.icn. a; E . . d . ' i - D In h i s l i f e t i m e , wh i c h i s a b o u t d o u b l e the S i n g l e i r . j e s t i o n d o s a g e s r e p o r t e d by C e i i r l n g <^t j i l . ( , K o h l i ^ t a l . ( 5 . 2 ) . and S a u e r l i o f f e t a l . ( 2) w i t h o u t any known i l l effects. Aknowledcements The a u t h. o r s t h a n k t h e 43 v o l u n t e e r 2, 4- 1) a p p l i c a t o r s who p a r t i c i p a t e d In t h i s s t u d y ; N o r t h Dak ot a S t a t e " n i v e r s l t v I'x t e n s i on p e r s o n n e l i t. : t he H u s h i n g t on S t a t e b' luiptor of N a t i o n a l \g r i c u l t i n a l V v i a t i c r : .'-.ssoc i.a t i on who c o n t a c t e d l he p a r t i c i p a n t ; -.: V. e . A l l e r , ' .. kina L a b o r a t o r y L o r c o l l e c t i o n o f u r i n e ...a m ple;; f r o m e a s t e r n . s l a g toil and a s s i s t a n c e in t he a n a l y s t s o f t h e s e sam p l e s ; and 3. S. F r e a r , P l a n t Metabolism L a b o r a t o r y , USDA, SEA-Alf, Fargo, North Dakota. I o. \M| i ! \t Il ' ( , h t , ; f t 'I \ / 't ' i < \ m /. 0 A V n: I \ % / o f T O T A L E ^ C R E P i O M ------- Figure 4. Fcrccnf of (LiHv 2.4-f) r.xrrction fn)in tfayy {rA- : 0 . 0 4 -f / i t I - /./ i f 1_l r ; . / i i f 1( r: t) W 00W2I56 6I r ; r:r-,Dr. ui sinurs \ no Hxrosi'RO 1) w o r ke r s compared to ' r _ , - , 3-T i hr e s c i on s t u d i e s probably r e f l e c t s the slower rote of plasma absorpe c b l c N e s , compared co I n g e s t i o n . The data su gg est the 3ra a p o o r j o b o f s k i n p r o t e c t i o n and s u b s e q u e n t w a s h i n g , lie C e h s l n g e t l . (4) s t u d v , the C i mn i nc. c J f i o o -./.is T/kg bouy w e i g h t . The ner : : .trstion was l / j , I , 0 . J 3 mj Vkg f o r d a y s 1 to , t e s t e r : t v e l y . TY\n K o h l i e_t , s t u d i e s * , f o r 2 , 4 - D and 2 , . 5--~ showed the r.c o r d e r o f t o r 5 mgXw: d o s a g e s , but r a r e r : ; n a t e i v l ii ss f o r T and osages. InNchis experiment. dav e/icrorion tor / l o a d e r g r o u n S . w o r k e r s (Tabl e- T' :r. d a y s / t o i , r e s o u c - e r e 1 . 2 , 1 . 4 , i \ 5 , 1 . 4 , and 1.', " IUy^/kg, about, nne- h a s much a s t h e n f o r mer . l n g t _ a l . (<4) a l s o , e a l e u l a t =c ojiy ie ncr a tio n of n plasma from repeaegd doses, bound Lliat a maxi nun d o n was r e a c h e d a f t e X 3 d a y s yhe rate o f .!, 4 , j - P f rom pl a s ma e q u a l e d t n X amour.: o u s t e d . The a n a l o g y p lie d to the u rinary exet / n i s , a lso , because e a r a n c e r a t e was e x a c t l y tVe is the urinary exr.ro- . T h e r e f o r e , It would uope\ tiie a e r i a l workers , f i g u r e 3) had e s s e n t i a l l y : the maximum 2 , 4 - 0 plateau. b ! Re m a r k s. J a s e d an the r e s e n t e d h e r e , some o s - 2 , 4 - D e x p o s u r e can be c a l c For example, the illc a t lo n workers exposure/ - \ c a n be e x p r e s s e d is l l y e x c r e tio n (F ig ure 4)/ snowing the t o t a l urinary f o r a n y g i v e n d a v o f t e r / ' e x p o s u r e . l'\ t o t a l e x c o s u r o be c a l c u l a t e d . in .mobi le: 1 1 - jobs par dav c r e t i t o n o f t h e a e r i a l /workers T a b l e [V\J was <>. 0 J 2 30 iW* 60 y e a r - o l d 00 g worker i t f ; J O v V a r s p e r l enev e x p o s u r e pe r y e a r cjou Id have ' S o r t e d anji e x c r e t e d as 9 j 2 , i - 0 In h is li/eci.ne, about d o u b l e tlu: e s t i o i i d o s a g e s r e p o r t e d by deb t a g e t a l . Kohli et , and S a u e r h o f f e t / a l . ( 2 ) w i t h o u t any known \ l l lents itlior*jjithank t)A 43 v o l u n t e e r 2 , 4 - o a p p l i c a t o r s w h u \ i r .n t h s t u d v ; / N o r t h D a k o t a S t a t e T n l v e r s l t y f':< t e n s i on nd t he W a s h i n g t o n S t a t e C h a n t e r i f N a t i o n a l A g r i c u 1to r- A s s o c i n t i o n / w h o c o n t a c t e d the p a r t i c i p a n t s ; W. C. ma L a b o r a t o r y l o r c o l l e c t i o n : : a r m e samp t e s from hin gton and a s s i s t a n c e in :he - a i l v s i s of these -mn. S. F r e a r , P l a n t Metabolism L a b o r a t o r y , USDA, SKA-AR, h Dakota. .'Ml I 'I . >i\ /.Mtr\urr to . ) 31 \D 1-0 r V' ' ijurc P e rm it of daily 2,4-1) e n retton lc v n \ mm ;r.''/vv</ c f ig ure 4 . P en cut o f daily 2 , 4 - f ) e x c r e ti o n f r o m <i v//i(,/<* iw ff osu rc fo r the first days ( rr : 0.04 f- 15 il -- /./ il1 | - 0./,?<.!'(r* O W ) hosed tin yrottnti x!f>f)lit atinn\) risiiiim. hisun'is w:t> i.\msiiHi Literature Cited 1. L a v y , T . L . , S h e p a r d , ' H . S . , M a t t i c e , d . D . J . A;, i l c . __ ! 'nod Chcm. 1 9 8 0 , 2 8 , f>2f>. 2- S a u c r h o f , M.W. , U r a i m , W . l l . , R l a u , C . i ; . , nn.j m-h r i nu T o x i c o l . 197 7 , 8 , 3. 3,, W o l f e , H . R . , A r m s t r o n g , J . P . , S l a i ("l , D. 0 . , and C'n A r c h . E n v i r o n . I l c a l t l i . 19 7 2 , 2Ji , 39. U . G e h r i n g , I' . J . , K r a m e r , C . G . , S c h w e i z , 15.A . , Rom. , J . 0 , ami Rowe, V . K . T o x i c o l . A p p l . P l i a r m a c o l . ' 97 3 , 2b^, 382. 5 . K o h l i , J . D . , K h a n n a , R . M . , G u p t a , l i . N . , S h . i r , I . M . , Tau.l,-.,. , J . S . and S i r c a r , K .P . Xcnobi ot i ca i 9 ' 9, A, 97. T.-. I ". ,6 . K o l i l i , J . O . , K h a n n a , R . M . , G u p t a , H . N . , S h a r , M . M . . ih u J . S . , and S i r c a r , K . P . A r c h , i n t . I' l i a r ma c o t i y n. 1979, in . 250. S a u e r l i o f i , M.W. , B l a u , G . r l . , B r a u n , i-.'. II. , and G-dii' iu T u x i c o i . Appl . P h a r m a c o l . I 9 7n , 3d , 9 9 1. 8 . S m i t h , P . A . , Rainsi-) , d . C . . I j r v t , ; . , , .` 1. 1; . , and . I r a n: : , T o x i c o l . 1981, I , 33. Rr.cTdVED August 12. 1981. D0H2156462 Rev iev. o! Studies: 5vii.i1 2In,4c.l5u-diinrgicAilpoprloi*cnahteonros\ t*\ijn!cdeeirr:f f /m . i., i r - . i . i c k \N is r v,. ii un ai I he I ) " '-'. C !:.'tiic.'l ( uiup nnv. :irn! I m if m ii: : I. i.. L A ' . ' . j ! ?nivi.,r - i ` \ . \ t ' i s . r . A ltl n tmi f I / .< I " .-." - :r :n 1i~t: :- \. i'):(j\W}<j'./lw-.N:<>lI'l_;'ilw.lr-r:r;'-J.h;i!C,'r -.vi', \::'.I I i .i,- im i i o . - . r : t) y oo r* ;c ' \' : , : -- . . 1. . , . . u ; . v : \ . j . I 'l'.TriC'-i' 1 : i ). Ti . f I ! 1Y.'-' ! j i'-L - '97? n a . : . ni \. .:.. : 'f-A ;- I -ate!: *j.*t nir: : ; i ~ , . nol i!., .-.r i r i . y ;r. t J.__V.'i i ' - ; '> ' * vr- ` ; - ' 0097-f.|5f. S2/01SZ-01.V<m I A n u ii ;'ti C'lu,,r . \ ' n p 9 f: i 7 w n n 5 ju i*C ~ oL 3 7 . -- i^i. The Lancet Saturday 26 June 1982 No. 8287 VOL. IFOR 1982 HERBICIDES, OCCUPATION; AND CANCER S ir , --In th eir review o f the ph en oxy herbicidc/cancer controversy D r C o g g o n and Professor A cb cso n ( M a y 8, p. 10571 ask for more inform ation. I have updated an occupational mortality stu dy1 w hich th e da further light on the m atter. T h ere ia conaiderable exposure in W ash in gton State to phenoxy herbicides and chlorophenola in agriculture and forestry and the w ood products in dustry . 2,4- D ia used extensively in wheat fa rm in g , roadside brush and weed control, management o f unwanted forest grow th, and in pulp m ills and sawmills fo r control o f bluestaining fiingi. T able l shows m ortality due to soft tissue sarcom as, H odgkin's I. MipISub,alic .tiieaO(cNrIuOpSjnH--){iml prnnMa nt lir ia CSiytM State. I ttS - lln . HEW table i- osserved/en fe c t e d deaths (and fairs) for se ib c t e d CANCERS* IN OCCUPATIONS WITH EXPOSURE TO PHENOXY HERBICIDES AND CHLORONlENOLi WASHINGTON STATE WHITE MALE DEATHS. AGE 20+ , 1950-79 Ocmpattoa SuerAcotirsasau*e Hdoidagcakainc*i Lnnueymricmicorpunmhioaoa-,- l)*mOpthheorau* WOSTFOXLPRFRpmUleaairorViarahwnncpceirbnirbimelhhdetnmdrmoclacoarafucechaftdc'awrrearprnena'ddldyfeornunammpm%mrmr(lrkeNptec-enctoOaina*criSnc)n 253//126 ((/MS2i)P 11//22 ((4U0)) 1/1 <w> 112 (39) 10V/S10 ((99911) 4/1 (20) i Vv Su (io7) (lit) 2SnH ((S2O9)) 2/3 (92) 4M (99) Z1V7i./7S*1 ((ll:ieittt))tr (a ) 711V23Ii2////7I*1IiO11 (IXt (((1//((Jo27Jf1nf/)))) 4V1/4i 0 (/AO (IF) vVsS (tu10s2)) 2/4 (19) 0/2 m VS (32) 5/4 (H i) 412V7//44153 (1(2M2) (22) 237V'224 (I(i9UH2)l) i n s U21 tin t/69) Total tirc<d0. 49/41 (120) 109/107 (102) ISB*192 i ; sot: rto---1; s j-jo i- r. 109/104 <;) {----- *----------* M tiM O a t PAtRBO W ti| tea.L r n r t d n e k * k a x S e a a je - M - d a lk 4 w jc t7 - 4 e lS tp e n c p n ^ a u M a ta n a la r TABLE n-OCCl'PATlONS WITH HIGHEST PMRs FOR SOFT TISSUE sarcomas (7th icd 197) Wa sh in g t o n sta te w h it e m ale DEATHS. AGE 20 + , 1950- 79 Observed Expected P M R Marine engineer) - ASCNABTPCBLPB-toe?rrUuaeauioarauBurtcvid.cmoamnfkrrWhlcanmdfubroireMawsnrie/aarinybmThjtfani,ilu-eo,cW,sadoneappraanfiwryil*ugelrcnueamrlfgbfiecaiiioannncgunneetreeenerrdr)men Mechanic: (NCS) 3 <0-5 >400 5! 1 i >300 10 } 300 73 772 4 2 350 3 1 209 14 195 32 154 2 1 179 4 2 J77 21 m 2 l 175 2I 6< 154 156 disease, and the non-H cdpkin's lym poom as for men in occupations specified) Mendicantw hich have exposure in phenoxy herbicides and chloroohenois. O n ly firr-ten N O S (not otherwise have a notexcess e f sort tissue sarcom a, but the local proportional m ortality rale (P M R ) for these occupations is significantly increased. Sim ilarly, papermaliers have a significant excess o f H odgkin's disease while the F A IR for H odgkin's disease in these occupations is o n ly 102. T a b le t! shows the 15 occupations ( o f 2 18) w im the highest P M R s for soft tissue sarcomas. N on e o f them have an obvious exposure to the phenoxy herbicides or chlorophenola. T h e dry cleaners, printers, and m echanics heve solvent exposure. T h e mortality patterns seen here do net oifer convincing support fo r the phenoxy herbicide and ch lo ro ph rao l link iu soft in sue sarcomas, H odgkin's disease, and non-Hodgkin's lympnamas. coSnutrpapcot rntoed2i1n0p4aMn b0yHK. aiaooal Imiutur for Occupational Surry and Hcalib VWeikuial(alnad SHuamaihDStrctifvlMcnU, mi otrMVM.WaskoioMtatsoa.UAju S.umuelM'LH.u m .Jr This MATr, ^^fcG H ruw tK ~ iR 3 7 2 - - 0 c I? ? 2 _ 7^QC I 7wnfl P. K. Taskar, Y. T. Das, J. R. Trout. S. K. Chattopadhyay, and H. D. Brown New Jersey AgricultNuerawl BErxupnesrwimicekn,tNSJta0t8io9n03, Rutgers University, mhhhghw2aasf2sdc(Dahaaaueaci,ge,eeAesvsIatAnznnleeArenteraitd,,stieZec5crrirc5,sdcd-deao-byTiu-CTnopiaec,bilhOlsnaneuaboeritjeLwdnniyausceetrcdOhnctpiccnrhedoNdeeph2pcartsndloimde,o,ulroAovno&peo2(nbmrbeo2-atnu,aspotlADrhnnxsyB,r,bviypeAsodd.y-Oa.tioDrhhrvwVat-toteDenaEheiouoanenddAYbcorrxet)tmssbohno.o,seriycmas1eubxre-nabaaa9rtyinmCca7ssefatbOceor6iluta,secdahenr;oIOirtusedcriyndeetseuPrbtgoieSEsscc,uitiaeAecRxsrrielldenUhtist(thDchaus,Eaos,da(a1eosRIeccvtttuAmoi9hHaiaelfinZsdo7loepOflpg-tie4nagbh2rCFrlrt)ueeetFe,(iiOyAemscnchea2tsLonoeoacle,t,bO5ooxiosAtlnrenNm-ydf,ufsbrt,Tar5esiepio--ae2thopc8ftlafehd,Tv.caffieroaAedeeshB)rersld-eOpc.e1ribtitDeosaVau9actsiyvsnEc27t,phrteodYiie7i,BceenAndoa;rsromegevnbse2,a,1cnm5mPiose,9atc-vId,Alrlugur7aiTPaieaoceesti6evE-lnnseeegalsd)tiRsaga.t.slneinhweicboeptetngdiherafelrseeogaMoUlttsriconinero2eaetsaoirhwdea,rxndanoAngehsytsllt-iptea.aeloa-,ltiyhDehnmrnsfoaefeaeaigft.1lfsanftr9tafmneohoeuf7tiradhoesxH3sgee)ryeemohpiuthnansleeevsilrcyseacp,rsmeAhtatocieetegDrtmetaeacongirwwt.ectni)lraoiyCtlnhiethnombxefcetpmeohedooareninescmstduauepcuralrreoucatmimrtbboeetillmonndpeiseoehu2irrrenec,nttAdhigdae-saoelDernr(rLdq2uEic,FiumAnVsooagY-nnrDaaedtnhv1siidutft9taymoir8ioyural0nmanor)sAibf.un(lplebeceapNo..h.tdlgiaooiyc.rnnT,aaeshtctuoagihtnsrareedfsrrladseicteetssuhexntsdeip,ecycorqiossno,ruunefratepsatnmoacotctttiraotattlyusoll ,af2aof,lAnaaf p-rD MATERIALS AND METHODS wwaa0tthhnt-oetd4eerra4kecwnbhEosspeoedqexlerdyel.ktrev.ioceottfehntdntem.rE,d)ehcapeahceenwhaeardndlaadtsbasthuuasyywciubrsmkes.jeeyeridooaeclnunaStdnerttogwxtehaecarmemcxhsiolaeiaednemvslaxeeetidyagrnmoa(aabouftithgynzifoeeeeenwadsthcshpohefae1row9dakvUdrs,et.ornobbe(lioulsvom3itnezoh1atrededsybeeit0peery.e.afr6over7sprese)Asrhyusyqhaprsmnue.aimdc,poifaeraanptrnn.fui)nvtclegpasopewrrluifeootrn(rhaearrtecereeetoars vpeerrisoidTtyhefroosrmtundMeyaayrwt1ah9se31ccaatrmoripeAudsugoiunusttNee1wi9t8hB1e.rrunoTsnwheitchlkoe, cNacaetmiwopnJuesrwsoaefsy Rcoduvutgerirenergds Uwthnietih 0007-4361/ 82'0029-0586 SO1.20 re) 1982 S p rin g c r-V e ria g N ew Y o rk Inc. S Z m I 7H0Q weeds and grass. Each area was roughly between one-half to one acre. : Acid (2,4-D) grfaaunisrgtleiyndWgectoaabtlehmt1ew0rethmecrnooinlue6dgs5ihtipooaeunnrtsdhthd7o8iuusrr.inwsgtuitdhtyhhiseuxmscitedupidttyyonwfroeormneem59oocdctoearsa8ito9en2, ,. tewmWhepinnedriatwtuasre and H. D. Brown U n iv e r sity , rs0:.esdnegesntE1a.tasi.slRe.gnhcniweptboetenhdgiaeerfsereloglMtatiUorsocinreo2neecoasairvarexhdn,aodnngisythelistl-p-teaa.telao,Dlihhmynfrnoseafeeeai.af1tlgafsntrf9tnmfaohoeue7tafirheds-sHx3o-g--ee)eyer-- mgaeaitnosqaiagrlutlaueoisstlvnhyaeTgameshileaf1epnsitnlnpdgsetprfra/ragartlohywa/bam3yeioaln0isungDr2tgemao,4wsottith-munpaDCrlecaetb.hrhiteyaneeetmgrdihTaioaoihcnmhetluaoa.rlinhsc,xdotethTaUurnessbhrs.epeSiicspar.Aawtaipeedyrrap.dee)selalriascwwoabahpfahwetsepiocDlleldhmriMreeiAindxcaa-nseco4tddotanrhcvttuwawoeipciarnainetcsceidhlroedekannvbtettaey.3perpa.tl8so.tepwrfurlabanAa(tynopeiaDibrpnnctruggapioPdirxonsdinieoiutxdrr bficnyiolltmmleeeecrTcttohheaaadabnnssoocoillm.erwbrmteaaFesnidtinsnieavatwbaelolpleyydorye,raaisatfetutlsderowfraCacwsocehaedeshexrywxetdrnpoaeorckmsstsueardnmaedn,ewdcwghiattaahhusnezhoneenld-.hpteraienxdRaasentmseeaidedntdu(hYewacIniPacsophelsp1. a19w5r7ZAae5tr)ieeB.rdF^ | !; wdaafttwhofale.rrtryieeeec'eser(1Btthrwma9tleheo7ooaoed7rrdwtak)ney..toidrsnreak,fgamTostae.rhmpnxrldeeect rOeshnaettvhcmw.eetneoerernrdeTedxightabdaheynrnl4t'oadswoptthdonacoenoobsa7llaeleplymdedfozocaopeutryllideeersodis.nnbthesywueBrewiscrlnawoehemeoeordderpkmrslaamseewmesaatnhnrdpadoweldoeensdaarneout dwfcrchitenheuoSrgeAerl liUfneoeacEcenlRnoldtHdolelsO/wdeaooFcmifFrntbpegeecldhet es xnuhset idep,ecycor qsoisn,ourunefrateapscnamcooccttritaotttalyusollfa,2oafl,4naaf-prD-- Ij;1Ij cea(1vno9eallr7leyy8czV)et.2eed4gdebhtyboaeutitfrohosnerefomsaaremntdhtpholedeimssnmoaenefxddtDiastAthoeVrliIeyDleOasNadfImStaeypresle.tsthaefSlr.aomtmr(ep1al9ceth8sme0we) nteratreneadatnterdOdeLaSthOtaeeNrdneaeoatwnndaceerle. mdsueaptteoegcl2rctao,o4prp-hDoarn(tdr)Te.sraaidcsuoixre MefoxootdrtealcgNtleaods.s i5n6co0nl,u-mheenqxuapipnapecekwdedawswiatihnthaley3lze2ecdOtrVoo-nn101acagopnatus r8ec0h/1ro00 .iyusyqaphrsmneuai.mdc,poifearaanptrnn.fiu)nvctlegaspopewrrlufieoort(rnhaearrterteeeteoars o_sfyRcoduvutegrirenergds wUthinecih- !I!,i | Gas chromatographic conditions used were as follows: DGFCSlaoaoemlswut:epmclnretaMocvmreoe,talhutEtamehnlrreeeio:cauitlgnrohAjenrcgctocheneadpctoulruemnNi 63 tem perature: CLIl.noeDlnjue.gmcthontifootnefCmhptephoeecrrotalctuoutmelrumenmpnerature 32(5550:9mC5l)/min 632121120801007f1mOt1CCmSVu-1p0e1lcoonpo8r0t / 587 '81 0029-0586 SO 1.20 ;rla g New Y ork Inc. j ; 97. 9 I 7HHO tthorroyuC.glhintihcealaudteotmeramteidnaptirooncsedounresblooofdasecroummmaenrcdiaul rdinieagwnoerseticmaldaebora RESULTS ANT) DISCUSSION surfacDeisitsribpuretisoennteodf i2n,4-TDabolen h1u.man volunteers (applicators) body Table 1. D istribution of 2,4-D Residue on Body Surface A ppNloi.cator ygH/seqad. f t . 1110923456871 2131721111484667289471...........5290151280852965620600 yCg/hseqs.t f t. 1196131711134871141341...........8356439555517836590680 ygH/seqad. f t. 9441711153491601084...........7461166826273466006933 raensdid2uA9e.t67othfey5ge2/ns.4qd1. oyff tg.a/sqdon.ayft'hste. wboonarckkt,h. etheheaadp,pl4ic9a.3t9orsygh/asdq. anf t .avoenragthee 2c,4h-eDs in Ta2b,l4e-sD2reansiddu3e, dreastapeocntivveelgye.tation and so il surface are summarized Table 2. 2,4-D Residue on Vegetation (yg/g) Treated Area 213 0 X X+l X+2 X+3 01004...507940 222895...683055 21726...741035 1416...369722 2023...114346 Table 3. Amount of 2,4-D on Soil Surface (yg/g) Treated Area 231 0 X X+l X+2 X+3 031...502840 034...217130 001...719205 021...285790 077...823050 0X+2 pre2trdeaaytsm aenftte;r Xtreaptomsettnrte;atXm+3ent; 3Xd+aly-s a1fdteayr atrfetaetrmterneta.tm ent; Twf iharess at2v7de.9raa3yg)ey. gv/gTahlueoef reopsfliadn2u,t4e-tDidsesrcuereseiadsauetde thotoen ve8ne.5dg7eotyfagtit/ohgne inwinoprtlkhainengt trdteiasaystue(dei.eoanr.e, a 8S 1'74CI niaegwnoerseticD aldaebora- plicators) body dy Surface esaqd. ft.0469430151..........24636276119646337006. ' q .63 sadq. anf t .avoenragthee 2c,4h-eDst face are summarized g/g) X+3 2302...411436 (Ug/g) X+3 077...323050 yr atrfetaetrm terneta.tm ent; no~rk<thilanengt trdteiasaystue(dei .eoanr.e, a ditnhuecerewfaoasuserdt2h.6t8odaU5y..g1/2gOUsnogt/ihgleaonot thtthheeer hefonadnudrot,hf thdtheaeya. vf ierrasgt edvayaluwehiochf , shooiwl erveesr,i ddcuaeeltcewucAtlaaasnbtea4llde3y.s1rtioes stoibodefu6e205.,.641.-6DTphtaoerretsta8am4ip.on9eue6rndtltirbotiyfellratihsoie,rn .daanriadrwnmthoethnrimtooeuragshfuirelthtdeer2f,4ri-elDtveerarelewsdais usseurqibnuseetLnrawtecvamtseilnemagosefuatrshe2uem,r4ee-mdDn.te.arseTushrieeddutaebbapsleelus s(bineinltortwirninspsirciecsepDnhtehnevonaloliulciesc)ss cifrnaolmcseureluaamctehdansdubby Table 4. Amount of 2,4-D Measured as Phenolics in Serum A ppNloic. ator 2,4-D Residue (ng/ml) X X+l X+2 X+3 1110456892371 24112876812------9155028.......9624404 -- * 46715754537111--5402484264..........6868620313 119986..71 11----3.6 143251--07904.....19280 431116479381.10---96684874-........93118833 Xa fte rpotsrtetaretmatemnet;ntX; +X3+l 3 d1aydasyaaftfeter r trtereaatmtmeennt.t; X+2 " 2 days Table 5. 2,4-D Measured as Phenolics Excreted in the Urine A ppNloic. ator 1 10234685971 003031711--.........199739043105945003 12 1055713_--......563142774577 1--.73 24 36 48 60 72 84 06--..0623 1------.28 021...876753 120213----.....7964489745 221...483634 222333221----........5243942914327068 1316------...207406 622--...587743 143337711----........9420949428847856 24453751----.......0323202--1950627 1 - posttreatment Tdhiaetealvyerabgeefobreaseexvpaolsuueref.o r Imphmeendoilaitcesly ina fsteerrumthwe adsa7y0's.7wnogr/km, lthimemvealue 589 <r: I Z WS I2M0d wTacCoghhemeeanitpnvfoiuaufwplncudehenscoc, draauh1nypo0gw6eit.eno6dv3e1f1rrn2,3og0mh/c.m5aom13ule.r8sna1ngddoo/mwpfganlpgooca(zonoinelerc7odht0oe.9ule5f2rovi0nune3ergl.0c./mh3exlndpgoaon/ysm.uCrlehA)oenvcceoChrahigr5ede.0s5epdcahoypengndaonoldndicay. aapcbnblllodailnoecdeiucTclreahichncaleeenla.agelnnefdfsa(eWlcwmyBcsaeCnir)seyo, fnmoheo2tahmd,t4ieeoc-rDgeoldnbole.bobxionlpodHoocsodpouwanresercveaeremonurn,mcertsareoecr(md1sio9enwbpcleoha(roHeardanGmgs)tec,eusetdhelwielresmed(raRw.ecBeoorCcNebr)aos,csetwaruvp(hdeHpidicCreeeTdic)n),i Lbdavhpblriafitrpihnezteiaonuriaiaihycgeeevklehyrltssausaahdie.eaeemsuotnvwwaslllilemneThsiasiiottaidnngodw,sutIhaslieaeertonbem(eonnwabp,a.tlfriyhndniwevfc-toodie0dei.ctactlasichheAhdpi.chslti0nayuehaurseton1msin)eeaietilsvhagci)ualtoinlseehwanatnftruyooreinliceclnaiasovnydafehhsitilmeegidssxaryracwelehocnnentsyaemseorcgfogtteiihnenisrrtefegrdohenseoccst.raduiawehfatotdtehhsetoeili(larulnaehveaTmatbrsshdete-eafetshei0eanlalreCticidyahwd.necrscrtoa0hvtvhdestale5woewehwacusiodd)dnsrrotellaieheesuptcettsiraihrowv,ggecanrnonuthseaahhtrtttmsigaceailteitletihahufnctohs.tleryiotegasevfcrvediwmWepdtsarodheve.a2claarhpnuelnilhos,aateya4lndawenepttin-smPiessrDoindheewcittpttrrohhnehheesiroaeiendddineeeeczrcrrdeenvaeaoacriulnmpeuohbteptnsheidnyeedclaa.ricoeaanialtirentnektavdoBssctieendeenTtuhtirUdidrtisaerchtbourceniohshteNamtnnhadswehprcitt/gigeiaalephecdiolahcssrrlt(racyuhneideuecltritmiyriesatpbhafunitsaitiraserimidghncewnbenscornsuycdeyqitriatfgoneegutsurcahrebeaon,eihrcetldnmeaieahfnislinevr-cetidk . Tbewnairtf(t(hnhceomoopfhiehedfhctrheoeehyessaeuncmpftetlnnruoRastltetoeoiirutfrccoenlaniiooeriaoinsnotgfcfffslueandv))itdlccie2er2ttnieesacbr,r,m4g4htnsaeie-nooasa-.verdD0nndensffi/ddogsaatieCehcierstronhenhsxpa.tlnovectpioihsnencetoshrApoos,tissoieebcsnnturimuertbeoacsruugdeaeoealhltmdyhnes.pnaiyapritapnb,fobephnrooonbicyertnmdovhrostcsewynedeeitiooraert,iievhllcsb2itteodnhhewuai,lcg4sdeerctu-yefaitDlahnnhcqviencedtahduetsoehvme.agaeismartenoosaett(ttmlhiOdpsaeiceetoeteeotcatyheirhclurlommneas.atelneuroiprainenonfblpeoW)otafajhldwn2erteiaeLdpa,cca4nEdhrssbsta-ooVsusesDtmnYaatorroohomese(irrueTlcelp'iasncaaposatnccsirebondoeeuba,lflrsedioneurtlindidfbd.cn.oayiau5oeccncdo(tr)tna1eniLav.tsoh9hlbeeinr8aocnrlsoev0shftgueee)eotghnfhyt ACKNOWLEDGEMENT No1ef-w82thJ,eerssuUep.ySp.oArDtgeedrpicabruytlmtSuenrtaat tleoEf fxuApnegdrrsiimcauennldtturSbeyt/aPGteiornannnstPyNluvoba.lniUciaaStDiSoAcn-aTrPNeSoUU.-RnDUi-v-00e4-r15s90i12ty- . vnecthorcaihgre5de.0s5epdcahoypengndaonoldndicay. teseadr(cRew. o3ecorCeNrb)aos,csetwaruvp(hdHepidiCtreeeTdicn)),icuideJaiaTr.cidd.earrscNibhiauoenihcsotecmcndh/snwpheaictcriiggeeapahelodriahlssrt(lrceacunyhdeeuircilttaimreysabithpfutniisiiaciersardmnncgneewnhbsosrcuqydcfceyiiSjatrenagouegsrtuthhleabederionettrtndhferneaasifiiSlnfneervtl-ci-ed-k-- , trriiaana3a{hseaeo(rireTeplcuil'assaapnotatneirccsbonodee,ubfallrsednueiortlindidfbcd.n.oayai5uoeccncdot()rtnae1inLa.tvsoh9lhbeeinr8aotnslrohev0sftgueeee)otghnfhyt i1So-cnTaPcNSeUoU.-RnDUi-v-00e4-r15s90i12ty- . REFERENCES COOPER, P. : Food Cosmee. Toxicol. 1_2:418 (1974). DAVID9O4NI(S1,98G0)..H., HAMILTON, R.H. and MUMMA, R.O.: Plant Physiol. 65: DIAZ-C(10L907N6,). J.D. and BOVEY, R.W. -.Texas Agric. Expt. Stn. MP 1303 LEVY, T.L. : Dow Chemical, U.S.A. Report. October (1980) OLSON6,40B.A(1.9, 7S8N).EATH, T.C. and JAIN, T.C.: J . Agric. Fd. Chem. 26: PIPERA, pUp.iN. .P, hRaOrmSEa,coJl..Q2.,6:3L3A9NG(,1M97.L3.). and GEHRING, P .J.-. Toxicol. SAUER.8H:O3FF(,1M97.W7).., BRAUN, W.H., BLAU, G.E. and GEHRING, P .J. T oxicol. YIP, G. : J. Chromatographic 5-ti. 13.:225 (1975). Accepted August 29, 1982 r \ lr- I u 591 Vc -; DOM2 1 5 6 4 2 9 11M OA i UOH: 5 Ur\ O m j .1 1 i \ VONocultmuombbeeerr-s1N04o-v5ember 1982 JTEHD6 10(4-5) 521-857 (1932) \ ISSN : 0098-4108 K. - ' X 'b H 'j L [i q g t ALLERG IC H YPER SEN SITIVITY TO THE HERBICIDE 2,4-D IN BALB/c MICE Janette R. Cushman, Joseph C. Street Toxicology Program, Utah State University, Logan, Utah Following several reports of human allergic hypersensitivity, the ability of 2,4-0 (2,4-dlchlorophenoxyacetic acid) to elicit 2,4-D-specific lg antibodies and delayedtype hypersensitivity in BALB/c mice was studied. 2,4-O-specific IgE antibodies were delected in mouse sera following the second intraperitoneal immunization with I, 10, or 100 pg 2,4-O-keyhold limpet hemocyanin conjugate with aluminum hydroxide adjuvant. Specific IgE was determined with the rat passive cutaneous anaphylaxis test using a conjugate of 2,4-D with bovine serum albumin for challenge. The highest antibody titers and a measurable response in all mice were seen in the group that received 1 pg of 2,4-0 conjugate. Dinitrophenyl-specific IgE was measured at all intervals examined in mice immunized with a dinitrophenyl-keyhole limpet hemo cyanin conjugate. 2,4-0 applied epicutaneously on 2 d or over 4 wk failed to elicit delayed-type hypersensitivity as measured by change in ear thickness, incorporation of 5-f'1,l/iodo-2`-deoxyuridine, or histology following challenge on the ear. No 2,4-D-specific IgE antibodies were detected in serum during the 4-wk sensitization period. Similar treatment with a known sensitizer, dinitrofluorobenzene, produced delayed hypersensitivity. Following 4 wk of dosing, low titers of dinitrophenyl-specific IgEantibodies were elicited. IN T R O D U C T IO N 2,4-Dichlorophenoxyacetic acid (2,4-D) in its ester and sodium, amine, and lithium salt formulations is the most commonly used phenoxy herbicide, w ith, for example, 18.3 million kg used in the United States in 1974 by agriculture, government, and industry (Keil et al., 1977). Human health hazards associated with the use o f 2,4-D have been relatively insignificant (Bovey and Young, 1980). However, 2,4-D has been impli cated in occasional reports o f hypersensitivity reactions in humans. Baio-Bango et al. (1973) described a case involving severe bullous dermatitis in a man following exposure to a cornfield sprayed with 2,4-D. In another report, a female orchard worker in contact with the herbicide This research was supported in part by Cooperative A greem ent C R -807295 from the Environmental Protection A gen cy, a National Institute o f Environm ental and Health Sciences training grant in to x ic o lo g y ( E S -0 7 0 9 7 ), and the U ta h A g ricu ltu ra l E x p e rim e n t S ta tio n , Project 6 0 3 . We thank Rita M . Nelson for her valuable technical assistance. Requests for reprints should be sent to Janette R . Cushm an, T oxicology Program, U M C 4 6 , Utah State University, Logan, Utah 84322. 729 Journal of Toxicology and Environm ental Health, 10:729-741, 1932 C o p y rig h t <0 1982 by H em isphere P u blish ing C o rp o ratio n 0 0 9 8 -4 1 0 8 / 8 2 /0 9 0 7 2 3 -13 $ 2 .2 5 ALLERGIC H YPER SEN SITIVITY TO 2 ,4 -0 731 purchased from Amersham, Arlington Heights, III. Keyhole limpet hemocyanin (K L H ) was obtained from Pacific Bio- Marine Supply Co., Venice, Calif., and purified according to Garvey et al. M M(1977). The final purified KLH was dissolved in phosphate buffered saline (0.15 phosphate, 0.15 NaCl, pH 7.2) and sterilized by filtration. The protein concentration was calculated from Kjeldahl nitrogen determination performed in duplicate based on a nitrogen content of 15.4% (Fairless et al., 1967). Aluminum hydroxide adjuvant was prepared according to the method of Levine and Vaz (1970). Animals BALB/c female mice, 9 wk old, and Sprague-Dawley rats, 4 0 0 -680 g, were obtained from Simonsen Laboratories, Inc., Gilroy, Calif. Preparation of Conjugates 2.4- D -K LH EEDQ was used to couple 2,4-D and KLH using a method modified from that of Fatori and Hunter (1980). The reaction was performed in an ice bath and the pH was monitored continually. 2,4-D (0.48 g) was dissolved in 2 ml of acetone and water (2:1) at pH 4.0. NEEDQ (0.108 g) in 0.7 ml acetone was added to the 2,4-D and allowed to react for 10 min. The pH was maintained at 4.0 with 2 HC1. The 2,4-D and EEDQ mixture was added drop-by-drop to a stirred solution o f KLH M(0.168 g in 1.5 ml of phosphate buffered saline (0.15 phosphate, 0.15 M NNaCl, pH 7.2) over 3 min. The pH was raised to 8.0 with 0.5 NaOH M Mand maintained for 2 h. The preparation was extensively dialyzed against phosphate buffered saline (PBS, 0.01 phosphate, 0.15 NaCl, pH 7.2), sterilized by filtration, and analyzed. To determine conjugated 2,4-D , the protein complex was acid hydrolyzed, extracted with benzene, and the extract taken to dryness and redissolved in methanol. The sample was analyzed for 2,4-D using a Varian Model 5000 high-performance liquid chromatograph using 35% acetonitrile and 65% water (pH 3.0) at a flow rate of 2.0 ml per min through a reversed-phase C-18 column. Absorbance at 285 nm was recorded. All analyses were performed in duplicate. Protein concentration was estimated by Kjeldahl nitrogen determinations. 2.4- D-BSA The conjugation of, 2,4-D and BSA was performed using the coupling agent EDC at room temperature. 2,4-D (0.221 g) was dissolved in 2 ml dioxane, and the 2,4-D solution was rapidly added to a Msolution o f EDC (0.192 g dissolved in 2 ml water) with the pH maintained at 4.75 with 0.5 NaOH. This mixture was slowly added to a solution of BSA (0.168 g in 10 ml water) at pH 6.0 with rapid stirring. The time from the addition o f the water to the EDC to the completion of the addition to the protein solution was found to be critical and was kept at cxcr>rv CJ cr c. ALLER G IC H YPER SEN SITIVITY TO 2 .4 -0 733 of approximately 2 cm2. 2,4-D was administered at 11.8 and 118.4 mg/ml and DNFB at 5 mg/ml in acetone and ethyl alcohol (4:1). The doses of 2 ,4 -0 were equivalent to 2 and 20 times the dose of DNFB on a molar basis. Control mice were treated similarly with the solvent alone. Six days after the second sensitization (d 8), the mice were challenged on the right ear with 20 pi of solvent and the left ear with 20 pi of 2,4-0 (11.9 mg/ml) or DNFB (2 mg/ml). Following challenge, DTH was evaluated by measurements of ear thickness, ear histology, and the radioisotopic method of Vadas et al. (1975). A t 10 h after challenge, each mouse received 2 pCi of [ ,2Sl|-U dR in 0.1 ml o f sterile saline intravenously. Ear thickness was measured 18 h later, with a Mitutoyo engineer's micrometer, in units of 10-2 mm. The pinnae were cut o ff at the hair line, placed in buffered formalin in individual tubes, and counted on a Beckman gamma counter. The ratios of the thicknesses of the left ear to the right ear and o f the counts per 5 min of the left ear to the right ear were calculated. For histology, the ears were cut and stained with hematoxylin and eosin and also toluidine blue for mast cells and basophils. Other groups of 10 mice received sensitizing applications of the test materials or solvent on the abdomen on d 1, 2, 8, 15, 22, and 29. On d 8, 15, 22, and 29, a blood sample was taken from each mouse as described previously. The sera were tested for 2,4-D- and DNP-specific IgE anti bodies using the PCA test. Ten 2,4-D- or DNFB-treated mice and 6 solvent-treated mice were challenged on the ears 6 d after the final sensitization (d 35). Ear thickness was measured 24 h after challenge. The means of the test and appropriate control groups were compared Fusing the r-tes't for equal and unequal variances, as determined by ratios (Brownless, 1960). RESULTS The degrees of conjugation of the 2,4-D and DNP haptens with KLH and BSA are presented in Table 1. The K LH preparations did not achieve as high a degree of conjugation as the BSA preparations, but the conjugates were considered adequate for sensitization. 2,4-D -K LH injected intraperitoneally elicited IgE antibodies specific for 2,4-D following the second immunization, as demonstrated by positive PCA reactions using 2,4-D-BSA as the challenge antigen (Fig. 1). The specificity o f the response for 2,4-D was ensured by the use o f the BSA conjugate rather than the KLH conjugate for challenge. The highest titers were produced 7 d after secondary immunization in the mice that were sensitized with 1 pg o f 2,4-D-KLH. All the mice in that group produced detectable 2,4-D-specific IgE. Fewer mice responded to the 10 pg and 100 pg doses of 2,4-D-KLH. The geometric mean of the titers for the group receiving 10 pg was lower than for the 1 pg group. The single responding rv; ccTr (V ... rp irm n ES r 07 s' V,$ rXi'>- A LLE R G IC H YPER SEN SITIVITY TO 2,4 -0 735 study investigated the sensitizing potential of 2,4-D in the BALB/c mouse when applied epicutaneously and when coupled to a protein to simulate an allergic conjugate that might form upon coupling to body proteins in the exposed human. IgE antibodies specific for 2,4-D were elicited by sensitization with 2,4-D -K LH . Epicutaneous applications o f 2,4-D did not produce either DTH or detectable circulating specific IgE. " 1 iT- *T i 0 (1lC0%) 2 (100%)jjjjjj (0%) (0%) (0%) I ISgi-<-1--:-8 r<1:8i -<-1--:8-------l+ i mWm/y-/' 7 14 21 2 8 3 6 4 3 Oay of Sludy (1 I0 > jg v 64 (60S) O0<. 32 16 8 i 1<0.) |0.| <1:8 <1 8 (0% ) 0a (40%) t _____ L 0 7 14 21 2 8 3 6 4 3 Oay of Sludy Id) c c r. r^ Cr cr -p p - F I G U R E 1. IgE a n tib o d y response sp e cific for 2 ,4 -0 in fe m ale B A L B / m ic e . D oses o f 2 ,4 -D -K L H administered intraperitoneally at primary (1) and secondary (2) im m un izations were (a) I p g . (b) 10 p g , and (r) 100 p g per m o u se. T h e bars reprt-sent the ge o m etric m ean z the standard error o f the PC A liter for m ice producing detectable circulating IgE antibodies. The percentage of mice that produced detectable antibodies is shown at the tup o f each bar. A LLE R G IC H YPER SEN SITIVITY TO 2.4 -0 737 The lowest dose of conjugate, 1 pg, elicited the highest igE titers with the highest proportion of mice responding as compared to the 10- and 100-jug doses. This pattern of response was reported first by Levine and Vaz (1 9 7 0 ), who noted that high doses of benzylpenicilloyl and DNP conjugates elicited little or no IgE antibody production while eliciting good levels of IgG antibody. Tamura and Ishizaka (1978) showed that immunization with relatively large doses of ovalbumin resulted in the generation o f antigen-specific suppressor T-lymphocytes that were not demonstrated in mice that were immunized with small doses. These researchers concluded that the IgE response in relation to dose depended on the elicitation of suppressor T-lymphocytes and not solely on the activity of helper T-lymphocytes or B memory cells. Other studies in mice and rats indicated that the size of the primary dose of antigen is important in determining the primary response as well as the secondary response (Hamaoka et al., 1974; Jarrett, 1978; Lee and Sehon, 1978). In this study, the 10- and 100-pg doses seemed unable to elicit a primary IgE response but did generate a dose-related decrease of the secondary response both in terms of a decrease in the percentage of mice with Sensitization: . Challenge: Soteont 2.4-0 2.4-0 Sotoont ONFB (Contra* <11.8 mg/ml)(1 IS.4 mQ/mlt (Controq (3 mg/m* 2.4-0 2.4-0 2,40 u> onfb dnfb F IG U R E 3. D clayed'type hypersensitivity f o l i o e p i c u t a n c o u s sensitization on two consecutive d a ys. (0 ) Ear th ickn ess. ALLERG IC HYPERSENSITIVITY TO 2 ,4 -0 739 Sensitization: Challenge; s(Colovnetnrotl) (11.9.m-og/ml) (1128..44-0mg/ml) s(oClovnetnrotl) 2 .4-0 2 . 4-0 2.4-d dnfb (5omn fgb/ml) onfb F IG U R E 4. Delayed-type hypersensitivity follow ing m ultiple epicutancous sensitizations over 4 wk. The left ear was challenged w ith test co m p o u n d , and the right ear w ith solvent. T he bars represent the mean fro m 10 2 ,4 -0 - or D N F B -tr e a te d or 6 solven t-treated fem ale B A L B / c m ice + standard error. The asterisks in dicate th at the m ean is s ig n ific a n tly greater than the com p arable con trol m ean (p < 0 .0 1 ) acco rdin g to the r-:cst fo r unequal variances. to dinitrochlorobenzene reported by Chase (1947). Cyclophosphamide pretreatment appeared to increase the number o f mice producing detectable IgE toward DNP but not the titers. Based on these experiments, it appears that 2,4-D carboxylate-coupled to protein is capable o f eliciting a specific IgE response, albeit a relatively low response compared to that o f a strong sensitizer like a ONP conjugate. Although 2,4-D acid administered epicutaneously did not cause delayed- need betype hypersensitivity, other formulations o f 2,4-D such as esters, amines, and other sajts to tested to determine their sensitizing potential. REFERENCES ._ W.A sh erson, G . L , and P ta k , 1 9 6 8 . C o n ta ct and d e lay ed hyp ersen sitivity in the m ou se. I. A ctiv e sensitization and passive transfer. Immunology 1 5 :4 0 5 -4 1 6 . M. A. AAsherson, G . L ., Pertra, C C , and Thom as, W. R . 1979. C on tact sensitivity and the O N response in m ice to high and lo w doses o f o x a z o lo n e : L o w dose unresponsivencss fo llo w in g painting and feeding and its prevention by p retreatm ent w ith cy clo p h o sp h a m id e . Immunology 3 6 :4 4 9 -4 5 9 . `QUHZ Ibb'Uli anriiJtii a. A L L E R G IC H Y P E R S E N S IT IV IT Y TO 2 ,4 -D 741 Levine, B. B. and V a z, N . M . 1970. E ffect o f com bination o f inbred strain, antigen, and antigen dose on im m une responsiveness and reagin prod u ction in the m ouse. Int. Arch. Allergy 3 9 :1 5 6 -1 7 1 . L ittle , J . R . and Eisen, H . N . 1967. A n tigen . In Methods in Immunology and Immunochemistry, eds. C A . W illiams and M . W. Chase, vol. 1, p p . 1 -1 9 6 . New Y o r k : A ca d em ic Press. M ota, I. and W ong, O . 1969. H om ologous and heterologous passive cutaneous anaphylactic activity o f m ouse antisera during the course o f im m u n iz a tio n . Life Sci. 8 :8 1 3 -8 2 0 . O kudaira, H ., Su zu k i, T ., and O g ita , T . 1980. A study o f the rat passive cutaneous anaphylaxis (PCA) reaction fo r the assay o f m ouse IgE an tib o d y . /. Immunol. Methods 3 3 :3 6 9 -3 7 7 . Z.Q u ija d a , L ., K im , Y . T . , K isk in d , G . W ., and O v a r y , 1974. Im m u n o g e n iciiy o f low ly and highly d erivatized d in itro p h en yl-b o vin e 7 -glob u lin in d ifferen t strains o f guinea pigs. J. Immurol. 1 1 3 :1 2 9 6 -1 3 0 1 . Rinder, 0 . F. and Fleeker, J. R . 1981. A radioim m unoassay 10 screen for 2,4-dichlorophenaxy- acetic acid and 2 ,4 ,5 -trich lo ro p h e n o x y acetic acid in surface w ater. 8ull. Environm. Conturn. Toxicol. 2 2 6 :3 7 5 -3 8 0 . Tam ura, S .- l. and Ishizak a, K . 1978. R eaginic an tib o d y form ation in the m ouse. X . Possible role o f suppressor T cells in the transient IgE a n tib o d y responses. /. Immunol. 1 2 0 :8 3 7 -8 4 3 . T h o m a s, W . R ., A sh e rso n , G . W ., and W atkin s, M . C . l ? 7 o . R eagin ic an tibodies produced in mice w ith co n ta c t s e n s itiv ity ./ . Exp. Med. 144:1 3 8 6 -1 3 9 0 . Thom as, W. R ,, W atkins, M . C ,, W ood, P. J ., and Asherson, G L . 1978a. A n tibody responses to co n ta c t sensitizing agents. E ffe cts o f sensitized cells. Immunology 3 4 :4 1 1 -4 1 7 . Thom as, W. R ., W atkins, M . C ., and A slteison, G . L . 1978b. R eaginic antibody to contact sensitizing agents. O ccu rren ce o f cells w hich suppress Ig E and n o t reagin responses, immunol ogy 3 5 :4 1 -4 7 . U .5 . E nvironm ental Protection A gen cy. 1980. Summary of reported pesticide incidents involving 2,4-D. Pesticide In cid en t M o n ito rin g Service R ep o rt N o . 2 8 3 . Vadas, M . A ., M iller, J. F . A . P ., G am b le, J ., and W hitelaw , A . 1975. A radioisotopic m ethod to m easure d e lay ed -ty p e hyp ersen sitivity in the m o u se. I. Stu d ies in sensitized and norm al m ice. Int. Arch. Allergy Appl. Immunol. 4 9 :6 7 0 -6 9 2 . Received February 10, 1982 Accepted April 3, 1932 , -VC. - .. V :V - (2,4-Dich]orophenoxy)acetic J ~ gnc. fo o d C ftem . 1982, 3 0 . 375-381 Acid Exposure Received by AT- Aerial Application C r e ,3 7 w7sf 5.L during Forest Spray Operations Terry L. Lavy,* John D. Walstad, Rinda R. Flynn, and John D. Mattice 505 D0H2 15 6362 In three helicopter spray operations, forest workers were monitored for exposure to and interna! dose of (2,4-dichiorophenoxy)acetic acid (2,4-D). Levels of 2,4-D were measured in air near the breathing zone, on denim patches to estimate dermal exposure, and in the urine excreted for 2 days before and 5 days after the spraying to determine internal dose. Each crew made two applications about 1 week apart to compare exposure from crew members wearing customary clothing and following normal precautions (T-l) with that of the same crew members wearing protective apparel and following special hygienic practices (T-2). External exposure was low with the highest level at 0.0911 mg/kg of body weight for a batchman in T-l. The total internal dose determined by urine analyses ranged from nondetectable to 0.0557 (in T-l) or 0.0237 (in T-2) mg/kg of body weight. Those crewmen working most cioseiy with the spray concentrate or handling spray equipment (pilots, mechanics, and batchman-loadersj showed the highest doses. Protective clothing and good hygienic practices limited exposure. On the basis of analyses of toxic levels of 2,4-D in laboratory animals, human exposure levels in these tests were well below that which might endanger health. Considerable research has shown the effectiveness, The objectives of this study were (1) to measure both economic importance, toxicological effects, and environ external exposure and internal dose received by helicopter mental behavior of herbicides. However, only a limited crews spraying 2,4-D in the forest, (2) to determine whether number of studies have measured amounts and disposition protective clothing significantly altered these measure of herbicide actually absorbed by applicators (Sauerhoff ments, and (3) to evaluate the relationship between ex et al., 1977; Kolmodin-Hedman et al-, 1979). Such posure or dose and the worker's duties. knowledge is important for the safety of those whose use herbicides and for the understanding of those who regulate MATERIALS AND METHODS their use [e.g., U.S. Environmental Protection Agency Measurements Taken. Tests were designed to de (1978)]. This kind of information was recently acquired termine the quantity of 2,4-D in the ambient air of the for the herbicide (2,4,5-trichlorophenoxy)acetic acid worker's breathing zone, the quantity of 2,4-D that came (2,4,5-T) (Lavy, 1978; Lavy et al., 1980a,b; Ramsey et al., into contact with denim patches attached to the worker's 1978). The purpose of this study was to provide similar information for (2,4-dichlorophenoxy)acetic acid (2,4-D). The rapid degradation of 2,4-D makes itone of the least clothing, and the quantity and rate of 2,4-D that was subsequently excreted in the urine of each worker. A i r S a m p l e s . Battery-powered air sampling monitors persistent herbicides in the environment (Norris, 1966, 1970; Lavy et al., 1973; W S S A Herbicide Handbook C o m mittee, 1979). Furthermore, the long history of 2,4-D use with no reports of illeffects to applicators suggested that harmful levels were probably not being absorbed. Nev ertheless, scientific data were needed to document the extent of exposure occurring to workers under actual field conditions. The results of this study, when used in con junction with toxicological data, provide a meaningful evaluation of applicator safety during use of 2,4-D under various conditions. Techniques have been developed in recent years to measure external exposure to pesticides (Durham and Wolfe, 1962) and internal phenoxy herbicide dose as measured in the urine excreted (Sauerhoff et al., 1977; Lavy et al., 1980a). The 2,4,5-T present in the urine has been shown to be a reliable indicator of the dose received during application of 2,4,5-T spray (Lavy, 1978; Gehring et al., 1973). Since 2,4-D is quite similar structurally, and since it is metabolized in a similar fashion (Sauerhoff et al., 1977), the same technique has been used to ascertain the dose of 2,4-D absorbed by workers during application (Kolmodin-Hedman et al., 1979). were attached to all workers involved in the spraying program to provide an estimate of respiratory exposure to 2,4-D ester. The monitors contained amberlite XAD-2 resin, which is effective in trapping airborne vapors and spray droplets of 2,4-D esters (Johnson et aL, 1977). .After the air monitors were exposed during the treatment period, the tubes containing the resin were removed and placed in small, airtight containers until analysis. For these analyses, the total volume of air inhaled was estimated by multiplying the rate (1740 L/h) at which a person doing this kind of work breathes (Durham and Wolfe, 1962) by the total time of the exposure period (148 min). The total volume of air inhaled multiplied by the concentration of 2,4-D (micrograms per liter) from the resin of the air monitors gives the total amount of 2,4-D inhaled. This amount is expressed on a basis of micrograms per kilogram of body weight. P a t c h e s . Before the spray operation, denim patches were attached to crew members'clothing near bare skin areas. For estimation of exposure to the wrist area, a 2.5 x 15 c m strip was stapled to each shin cuff. So that exposure to the bare skin of the head and neck could be estimated, one 2.5 X 40 c m strip was stapled to the back of the collar of the shirt, extending to the points of the collar on each side, and another 2.5 x 40 cm strip was Department of Agronomy, Altbeimer Laboratory, similarly attached to the hat band, extending from the University of Arkansas, Fayetteville, Arkansas 72701 front and around both sides toward the back. The patches (T.Li., R.FLF., and J-D-M.), and Forest Science Depart were attached to and removed from workers by persona ment, Oregon State University, Corvallis, Oregon 97331 not exposed to the spray material and were then shipped (J.D.W.). to the analytical laboratory in individual glass containers FOOD 1982,30.R e p rin te d fro m J O U R N A L O F A G R I C U L T U R A L A N D C H E M IST R Y , 375. C o p y r ig h t <6 1982 b y th e A m e r ic a n C h e m ic a l S o c ie ty an d r e p rin te d by p e rm issio n </t th e c o p y r ig h t ow ner Jt. '7 i' VC ^o O V* 376 A gric. Food Chem.. Vol. 30, No. 2, 1982 Lavy el al. T ab le I. S u m m ary o f B a tch in g , L o a d in g , and Sp r ayin g In fo rm a tio n crew ] T -l crew 2 crew 3 crew 1 T -2 crew 2 crev, 3 b atch in g operation lim e required (a p p ro x .), m in volu m e m ix e d , gal lo ad in g o peration n u m b er o f loads volum e/ioad (a p p ro x .), gal tim e req u ired /load (a p p ro x .), m in to tal lim e lo a d in g , m in sprayin g op eratio n lim e req u ired /load (a p p ro x .), m in to tal tim e fly in g ,* m in 15 1000 13 80 0 .5 9 3 43 5 1000 14 70 1 14 2 29 60 1000 17 60 1 IS 3 .5 60 6 1000 13 SO 0- .5 2 .5 34 5 1000 14 70 1 14 0 27 c T h e tran sfer p u m p failed to o p e ra te , so th e b a tch in g o p e ra tio n w as co n d u cte d m an u ally b y using pails. "trigger tim e " for spraying was ab o u t h a lf o f the fly in g tim es. IS 0 0 0 17 60 1 2 .5 -15 * The actual immediately after the spray operation. In addition to height and weight measurements, a photograph was taken of each worker in spray attire to determine the area of bare skin exposed, based on values provided by Durham and Wolfe (1962). The area of bare skin, in conjunction with the amount of 2,4-D deposited on the denim patches (known area), was used to estimate dermal exposure. U r i n e C o l l e c t i o n . The pharmacokinetic behavior of 2.4- D and 2,4,5-T in humans has been established for a 6-day period (Sauerhoff et al., 1977; Gehring et al., 1973). The total collection period in this study covered 2 days before the spraying occurred, the spray day, and at least 5 days after each spray application. Polyethylene-lined containers (2.5-L capacity) were used by each crew member to collect tillurine excreted over consecutive 12-h intervals throughout the test The urine samples collected prior to spraying were used to detect background levels, ifany, of 2.4- D present in the urine and to check for interferences that might confound analysis. Workers were instructed to avoid contaminating the urine. The urine was kept in a cool location before being transported at 3-4-day in tervals to the laboratory for analysis. Crew Description. Three different helicopter crews (designated crews 1, 2, and 3) participated in the study. Each crew was comprised of a helicopter pilot, mechanic, batchman-loader, supervisor, and two observers. O b servers were included in the study to provide an estimate of the 2,4-D dose received by individuals who were not directly involved in the spray application but were 25-175 yards from the helicopter loading zone at the time the spraying was done. Test Description. Each crew performed two applica tions, which were approximately 1 week apart In the first treatment (T-l), crew members made use of conventional spray techniques and performed their normal duties using ordinary precautions ( L a v y , 1980). They followed label instructions and other legal regulations but received no additional guidance from research personnel. A second treatment (T-2), in which additional precau tions were used, was conducted following the conclusion of the T-l phase of the study. During T-2 the workers wore special protective clothing consisting of disposable Tyvek coveralls. (Tyvek is the trade name for D u Pont's spun-bonded olefin fabric, consisting of a lightweight paper covered with a durable plastic film.) In addition, pilots wore normal flying gloves and headgear, mechanics, batchman-loaders, and supervisors wore chemically im pervious gloves and boots, clean hats, and goggles, and observers wore cotton or rubber gloves, clean hats, and goggles. During T-2 itwas permissible for research perr sonnel to suggest to crew members how to m inim ize ex- T a b le II. R eco v ery D ata for A ir, P atch , and U rine A n aly ses analyses o f no. of 2 ,4 -D acid fo rtified sam ples replicates eq uiv ad ded* air* lab o rato ry fie ld p a tch e s* la b o ra to ry fie ld u rined lab o rato ry fie ld 4 4 4 4 4 3 4 4 4 4 S 8 8 8 16 20 12 6 12 12 12 FS 0 .0 6 8 0 .3 6 0 .7 2 3 .5 1 8 .0 8 3 .0 mg 0 .0 0 3 7 0 .0 0 7 4 0 .0 1 5 0 .0 3 0 0 .0 3 8 0 .0 7 5 0 .3 7 5 0 P. 7P5m0 0 .0 3 8 6 0 .5 6 5 2 .3 0 0 0 .0 3 2 8 0 .0 6 4 5 0 .2 4 6 0 .8 4 2 av T r e c o v e r y - SD 87 -. 19 S I : 0 .8 7S : 3 SO : 6 115 : 13 71 ; 2 156 : 17 122 : 4 95 : 12 101 : 9 116 : 9 104 : 13 105 : 9 112 : 13 98 i 54 74 : 7 73 : 7 98 i 48 86 r 26 7 0 : 11 73 : 10 T h e so lu tio n used to fo rtify sam ples w as a d ilu tio n o f (S/N = it-E s t e r o n 9 9 C o n c e n t r a t e in h e x a n e . * T h e lim it o f d e t e c tio n 2) fo r air m o n ito rs w as e sta b lish e d as 0 .0 5 O n ly one air m o n ito r co llected fro m th e w orkers in dicated the presence o f 2 ,4 -D , and it w as w ith in the range o f 0 .0 6 8 - 0 .3 6 tig s h o w n a b o v e . T h e a v e r a g e r e c o v e r y v a lu e , w hich in clu d es trap pin g e ffic ie n c y , fo r fo rtifie d standards in th is ra n g e w as 84% [(8 7 + 8 1 ) / 2 ] . T h u s , an 84% re co v ery fig u re w as used to co rre c t th e v al'je fro m the air S/Nm o n it o r w o r n b y w o r k e r 3 3 as s h o w n in T a b le I I I . * T h e lim it o f d e tectio n ( = 2) w as esta b lish ed as 0 .0 0 3 7 m g. M o s t o f th e 2 ,4 - D v a lu e s f o r p a t c h s a m p le s w o r n by- w orkers fell w ith in th e range sh ow n ab o v e w here 100% re covery (w ith in exp erim en tal error) w as o b ta in e d . T h u s, there w as n o need to co rrect the v alu es fo r p atch sam ples co llected fro m w orkers for p ercen t reco very. d The lim it o f d e te c tio n (S / N = 2) w as esta b lish e d as 0 .0 4 p p m . U rin e sam p les sh o w n in T a b le V c o lle c te d fr o m w orkers du ring the stu d y w ere corrected fo r p ercen t recovery by using a slid in g scale as co n stru cted fro m the ab ove recov ery data. aa posure. For example, crew members were instructed wash their hands before rest stops and meals and also take showers and change into dean dothing soon after the spray operation. Both treatments were designed with the intent that the only exposure to phenoxy herbicides would occur on the actual spray day of T-l and T-2. All selected crew mem- cca: ri- <_ cc cc  *-D Exposure Received by Aerial A pplication Crews J. A g 'ic . F ood .`.C Iffi; 377 T ab le H I. E stim atio n o f R e sp ira to ry E x p o su re to 2 ,4 -D A s D ete rm in e d fro m A n aly ses o f A ir M o n ito rs W orn by W orkers0 T -l (ord inary precaution s) T -2 (special precau tion C 1 w orker no. w t, kg 2 ,4 -D on air voi re sin ,6 ug sa m p le d . L concn, Mg/L estim ated r e s p ira to ry exposure/ body w t, ug/kg 2 ,4 -D o n air vol resin .6 Mg s a m p le d , L concn, *g/L r e s p ir a to ry ex posure/ body w t, n gikg 11 8 9 .0 nd I2 7 4 .9 nd 13 7 9 .5 nd 14 9 7 .6 nd 15 7 2 .6 nd 16 7 2 .6 nd 21 6 8 .6 nd no 9 5 .3 c 23 9 0 .8 nd 24 1 0 2 .2 nd 25 8 4 .0 nd 26 7 2 .6 nd 31 8 8 .5 nd 32 8 9 .9 nd 33 7 9 .5 0 .1 3 34 9 0 .8 c 35 7 9 .5 nd 36 7 4 .9 nd 1 6 .8 1 9 .9 2 4 .0 1 7 .9 1 5 .4 1 4 .1 1 8 .2 c 2 C .0 1 8 .6 2 4 .1 1 7 .2 3 0 .S 2 3 .8 2 3 .1 c 3 2 .1 2 1 .9 nd nd nd nd nd nd nd c nd nd nd nd nd nd 0 .0 0 5 6 c nd nd nd nd nd nd nd nd nd c nd nd nd nd nd nd 0 .3 0 d c nd nd n H 7 .5 9 nd nd nd 1 1 .0 0 nd nd nd 2 3 .3 4 nd nd nd 2 0 .5 2 nd nd nd 1 5 .1 9 nd nd nd 1 0 .7 0 nd nd nd 14.41 nd nd nd 1 8 .5 0 nd nd nd 1 9 .4 5 nd nd nd 2 0 .7 5 nd nd nd 9 .7 6 nd nd nd 1 2 .1 7 nd nd nd 8 .2 7 nd nd nd 1 7 .0 3 nd nd cc cc nd 1 8 .9 4 nd nd nd 1 4 .6 0 nd nd nd 1 5 .3 1 nd nd (S/N0 T h e lim it o f d e t e c t io n = 2) w as 0 .0 5 u g . V a lu e s w hich w ere below the lim it o f d e te c tio n are represented by nd (n o t d e te c te d ). 6 A ll v alu es h a v e b e e n c o r r e c te d fo r p e rc e n t re co v e ry (8 4 % ) a c c o r d in g to d a ta p re se n te d in T a b le II. c P u m p fa ilu re p reclu d ed m e a n in g fu l an alyses o f these sam p les. d R e sp ira to ry ex p o su re p er b o d y w eigh t for w o rk er 33 w as d e term in ed as fo llo w s: (0 .1 3 u g o f 2 ,4 -D / 2 3 .1 L o f air x 1740 L o f air/ha X 148 m in X 1 h /60 m in )/ 7 9 .5 kg o f b o d y w eigh t = 0 .3 0 u g o f 2 .4 -D / k g o f b o d y w eig h t. C c s-: t-v: c c c bers claimed to have had no known exposure to 2,4-D for one exception, batching of the 1000 gal of spray mixture at least 2 weeks prior to the study. As a precautionary took from 5 to 18 min, depending on the pumping system measure, however, urine samples were collected for the 2 employed. The exception occurred during T-l when crew days preceding T-I. Seven days elapsed between the spray 3 required nearly 1 h to transfer the concentrate manually days in T-l and T-2 for crew 1,and 6 days elapsed between from the drum to the batch truck via 2-gal pails because the 2 spray days for crews 2 and 3. the pumping system failed to operate. Treatment Description. Personnel engaged in su Loading the spray mixture from the batch truck into the pervising and applying the herbicide treatment were helicopter tanks took 30-60 s/load. The volume per load trained, licensed, and certified by the appropriate state and varied from 60 to 80 gal, depending on payload capacity federal agencies. The spray applications complied with of the helicopter. The spraying operation took 2-4 state and federal regulations and were representative of min/load, depending on ferry distance. Actual "trigger routine aerial treatments in forestry. time" was 1-2 min/load. Total time required for loading The application areas, typical of the Pacific Northwest, and spraying the 1000 gal ranged from 41 to 78 min/ were located near Raymond, W A , Cottage Grove, OR, and treatment. These spray periods were comparable to those Gardiner, OR, for crews 1, 2, and 3, respectively. At each in routine forestry operations (American Paper Insti- geographic location, two sites were selected within 10 miles tute/National Forest Products Association, 1978). of each other for the respective T-l and T-2 applications. Chemical Recovery Data. Laboratory procedures used Each site consisted of an approximate 100-acre tract within to analyze air monitors, patches, and urine were similar a larger forested area. These tracts contained Douglas fir to those used by Johnson et al. (1977) or Lavy et al. [ P s e u d o t s u g a m e n z i e s i i (Mirb.) Franco] in need of release (1980a). T o ensure that no 2,4-D was broken down prior from competing vegetation. to analysis and to establish the percent recovery for the Treatments were applied by helicopter at each location analytical techniques, we prepared a series of samples in late February and early March of 1980. The formulation fortified with known 2,4-D amounts for each sample type used was Esteron 99 Concentrate, which contains 4 lb of (air; patches; urine) in the field shortly after collection. acid equivalent (a.e.) of 2,4-D/gal as the propylene glycol These were compared to samples fortified similarly at the butyl ether ester. The herbicide was mixed with diesel oil laboratory just prior to analysis. Limits of detection were and water at the rate of 0.5:0.5:9 gal, and the resulting established by a signal-to-noise ratio of two ( S / N = 2). mixture was applied at the rate of 10 gal/acre, which Recovery data are shown in Table II. Reported values provided a 2,4-D application rate of approximately 2 lb of for experimental samples shown in Tables IIT-V have been a.e./acre. Therefore, each 100-acre tract received about corrected for percent recovery as discussed in Table 0. In 1000 gal of this mixture. all cases, the 2,4-D values are reported as the acid form. Treatments were applied in the early morning hours. Phenoxy esters are converted in the body to the acid form, Temperatures ranged from 4 to 13 C, and relative hu which is then excreted in urine (Gehring et al., 1973). midities were usually in excess of 80%. Winds were gen The Amberlite XAD-2 resin from the air monitors and erally calm, with occasional gusts up to 5 mph. Weacher conditions were typical for the season and were well within the denim patches used'to intercept 2,4-D spray mist were analyzed by gas chromatographic techniques (Lavy et al., the regulatory restrictions for spraying. I980a,b;Johnson etaL, 1977). The limits of detection were Treatment Logistics. Table I displays the information established as 0.05 Mg for the air monitors and 0.0037 mg collected during the treatment phase of the study. With for the patches. ii ( l/J;l a M 3TS J. Agric. Food Cr>em.. Vol. 30, No. 2. 1982 Urine samples used to measure the dose of 2,4-D re ceived by crew members were analyzed by a modification > g: a gas chromatographic technique used by Lavy et al. 1 (i^SOa). When the methyl ester of 2,4-D was prepared, i: was found to elute at a retention time similar to those cf interfering peaks from the urine. The method was codified by preparing the butyl ester of 2,4-D with B7--butanol. The limit of detection was established as ' G.C-4 mg/kg in the urine. T w o different columns were used routinely in the N;igas chromatographs to confirm results obtained from air, patch, and urine sample analyses. RESULTS A N D DISCUSSION Air Samples. Thirty-two of the 33 air monitors which remained functional during the test did not contain any 2.4-D at the limit of detection of 0.05 t i g (Table III). The only air monitor containing a detectable amount of 2.4-D was worn during T-I by the batchman-loader (worker 33), one of the crew members who manually transferred the 2.4-D concentrate from the drum to the batch truck due to a malfunction of the normal pumping system. Subse quent conversations with this worker revealed that odors associated with the concentrate were discernible during the transfer process. Therefore, it is possible that his activity may have accounted for the 2,4-D detected by that particular monitor. The amount detected during the test was equivalent to 0.30 t i g of 2,4-D/kg of body weight. Patch Samples. The amount of 2,4-D deposited on the denim patches attached to each crew member's clothing isshown in Table IV. Levels detected were generally very low, and in many instances no detectable exposure oc curred. The exposure that did occur appeared directly related to workers'duties. Batchman-loaders and m e chanics usually showed some degree of dermal exposure; observers showed almost none. Observers in crews 2 and 3 were stationed outside the spray areas during the 2,4-D application. However, worker 15, an observer in crew 1, was inadvertently in the spray area during T-2. Table IV shows that his patches received slight amounts of 2,4-D. Since all patches were placed on the outside of the clothing in both T-I and T-2, no major differences in patch exposure between the two tests would have been expected. An exception occurred in T-l for crew 3 (particularly the mechanic, worker 32, and the batchman-loader, worker 33), who manually transferred the concentrate from the drum to the batch truck when the transfer pump did not work. This operation increased the opportunities for ex posure to the concentrate, and visual observations of these workers'clothing revealed that certain portions did indeed become contaminated during the transfer process. The transfer p u m p worked properly for this crew during T-2. This fact probably accounts for the reduced amounts of 2.4- D detected on the patches of the mechanic and baichman-loader in T-2 (Table IV). Five of the six patches on the headbands of batchmanloaders contained higher amounts of 2,4-D than their other patches (Table IV). These workers attached the quickcouple batch truck hose to the helicopter during reloading. The wind generated by the whirling helicopter blades often prompted the batchman-loaders to hold their hats in place. Although these individuals often wore gloves (always in T-2), the gloves were sometimes contaminated with 2,4-D which could have been easily transferred to the patch on the headbands as they held onto their hats. Urine Samples. Whether intake of 2,4-D was through dermal, respiratory, or other exposure, the actual dose can be determined by analyzing for 2,4-D in the urine excreted. The total quantity of 2,4-D excreted during T-I and T-2 (spray day plus 5 days thereafter) was determined by i S. ~ XL X ~ 1C in in cm -d C C - .C - . --CC C OO -T -- -- CM d c d c c d d co c CM 6 : o : : c c e: al CM -- c*.cn c _____ cm o c ccc r co CM O q oc -- c oc cd rrr- rr-~ c-- bb a c jc cI* ^^ Cx >. M V Cl n co CM CM oo oo oc OcHfotlC)oM^ ooc oc cn T r Cfi "c3 to roo c CM E o c 90a--s90aCMs- 3c "3C "3C in q0 0 "3c Cdi--n 0 Q 4Tr- o r^ Ocm" P-4 9 -o -a -c -a 9 o o co c c c co oo 3c G as r- o co cn oo -c,oooo *3 c ca *c0c*c ^ o o -- o o CM o ow3 0(A *.u uE t x uz CCM a 0l cq i0(fOl0Pr0iJoO0uOs0of0Wic0rC-0vr ti0'of a ah x a a c r CO E * uE 0000000 oo O U3 CO CM CO CO CO o to to co r - r - 00 V Q 0 *2 0a e0 O r-coo0oOcC-Oc0-5tColci-- S 4> I g ^^ m h CM CM CM r; cn COCT > cn 2,-t-O E xposure R ece iv ed Dy A e r a i Application Crew s 24 102 25 84 26 73 31 89 32 90 33 80 34 91 35 80 36 75 800 1580 760 800 1580 800 1680 1620 1680 540 510 540 800 540 640 640 640 640 nd nd nd 0 .0 1 2 0 .9 6 2 0 .3 5 6 nd nd nd nd nd nd nd 0 .0 5 5 0 .3 7 6 0 .0 0 8 nd nd nd nd nd nd 0 .0 0 8 0 .0 1 0 nd nd nd nd nd nd 0.0 1 1 0 .0 1 0 0 .4 5 8 nd nd 0 .0 0 7 nd nd nd 0 .0 0 0 7 0 .0 6 1 7 0 .0 4 09 0 .0 0 0 5 nd 0 .0 0 0 5 nd nd nd 0 .0 0 4 0 .0 1 4 0 .0 4 8 nd 0 .1 7 0 nd nd nd nd nd 0 .0 0 7 0 .3 4 8 0 .1 3 4 nd nd nd nd nd nd nd 0 .0 0 5 nd nd nd nil nd nd nd 0 .0 0 8 0 .0 4 2 ml ml nd nil nd nd 0 .0 0 0 1 0 .0 0 0 6 0 .0 1 0 2 0 .0 0 2 7 0 .0 0 3 9 nd (S/N b T h e li m i t o f d e t e c t i o n 2 ) vyas 0 .0 0 3 7 m g . W here a v a lu e o f n d (n o t d e te c te d ) w as o b ta in e d , a z e ro w as u sed fo r a v e ra g in g p u rp o se s. The. d e rm a l e x p o su re area w as cc a lc u la t e d a f t e r v ie w in g p h o t o g r a p h s o f e a c h w o r k e r , r e v ie w in g t r e a t m e n t n o t e s , a n d u s in g v a lu e s o b t a i n e d b y D u r h a m a n d W o lfe ( 1 9 6 2 ) . T h e e s t im a t e d d e r m a l e x p o s u r e p e r b o d y w e ig h t (m illig ra m s per k ilo g r a m ) rep re sen ts th e a m o u n t o f 2 ,4 -D th a t m a y be d e p o s ite d on a w o rk e r's sk in in re la tio n to his size an d a p p a re l, as c a lc u la te d fro m ( 2 ,4 -D on f o u r p a t c h e s ( m g ) X d e r m a l e x p o s u r e a r e a ( c m ' J l / l t o t a l p a t c h a r e a ( 2 9 5 c m 1) X b o d y w e ig h t ( k g ) ) . j Agnc Fooc C .ie-n . Vo< j C. No i . l e i j i 379 >--* kT* cn T a b le V . D a lly Q u a n titie s o f 2 ,4 -D E x c r e te d in th e U rin e an d E s tim a tio n o f T o ta l D o se R e ce iv e d b y E ach W o rk er" w orker no. duty day w t, kg 1 2 ,4 -D e x cre te d d a ily ( T - l) , m e dav day day day day day 2 3 4 6 fi 7 T -l6 to tal 2 ,4 -D / day 2 ,4 -D , b o d y w t, day 8 m g mg/li: 9 2,4-L) e x c re te d tla ilj (T -2 ), m g (lav day (lav d av day II) 11 12 in 14 ' (lav dav 16 16 T - 2 ,< 9 2. I D . lindv w l, m e m g/tig l i p ilot 8 9 .0 n d c nd nd nd 0 .1 13 nd 0 .0 4 8 n d 0. IC1 0 .0 0 1 7 9 ml ml ml ml m l nd ml nd nd nd 12 m ech an ic 7 4 .9 nd nd 0 .0 2 6 nd nd 0 .0 0 8 nd nd 0 .0 3 3 0 .0 0 0 14 n il ml nd ml nd nd nd mi mi nd 13 b a tch m an 7 9 .5 nd 0 .0 2 2 0 .0 1 9 0 .1 2 0 0 .0 3 2 nd nd nd 0 .1 7 1 0 .0 0 2 1 6 nd nd 0 .0 1 6 m l nd 0 .0 2 0 nd nd 0 .0 4 2 0 .0 0 0 5 3 14 su p erv iso r 8 7 .6 nd nd nd nd nd nd nd nd nd nd n d n d n d 11(1 0 .0 3 7 m l m i 0 .0 2 9 0 .0 3 7 0 .0 0 0 3 8 16 observer 7 2 .6 nd nd nd nd nd nd nd nd nd nd nd 0 .0 4 1 nd lid nd nd m l nd 0 .0 4 1 0 .0 0 0 5 6 16 observer 7 2 .6 nd nd 0 .0 4 0 nd nd nd nd nd 0 .0 4 0 0 .0 0 0 5 5 nd nd nd nd nd nd n d m l nd nd m ean (crew 1) 0 .0 6 8 0 .0 0 0 8 2 0 .2 0 0 .0 0 0 2 4 21 p ilo t 6 8 .6 0 .3 7 2 0 .4 4 6 0 .6 1 9 0 .5 3 6 1 .1 6 6 0 .7 6 0 0 .4 0 2 0 .4 4 6 3 .8 1 9 0 .0 5 5 7 0 .1 9 3 0 .5 2 5 0 .3 8 9 0 .1 1 9 0 .0 6 0 0 .3 3 9 1 .6 2 5 0 .0 2 3 7 22 m ech anic 9 5 .3 nd 0 .1 8 9 0 .0 5 7 0 .0 9 0 0 .0 7 4 nd nd nd 0 .2 2 1 0 .0 0 2 3 2 0 .0 3 4 0 .1 9 1 0 .1 0 9 0 .0 4 3 0 .0 8 0 0 .0 3 5 0.4 92 0 .0 0 6 1 6 23 b atch m an 9 0 .8 0 .2 4 3 0 .2 5 3 0 .3 4 7 0 .1 6 6 0 .6 6 4 0 .1 8 0 0 .1 6 0 0 .3 0 6 1 .7 1 8 0 .0 1 8 9 0 .2 8 4 0 .5 2 7 0 .3 6 4 0 .3 3 0 0 .1 2 1 0. 163 1 .779 0 .0 1 9 6 24 supervisor 1 0 2 .2 nd nd nd nd nd nd n d nd nd nd n d nd nd nd nd nd nd nd 26 observer 8 4 .0 nd nd n d nd nd nd nd nd nd nd nd nd nd nd nd nd ml nd 26 observer 7 2 .6 nd nd nd nd nd nd nd nd nd nd nd nd nd ud nd nd ml ml m ean (crew 2) 0 .9 6 0 0 .0 1 2 8 0 .0 4 9 0 .0 0 8 | 31 p ilo t 8 8 .6 nd nd 0 .0 4 6 nd 0 .0 6 3 nd nd 0 .0 7 3 0 .1 8 2 0 .0 0 2 0 6 0 .1 0 3 0 .0 4 2 0 .0 2 5 m l nd 0 .1 7 0 0 .0 0 1 9 2 32 m ech an ic 8 9 .9 nd 0 .0 7 3 0 .2 2 8 0 .4 3 4 0 .1 8 0 0 .1 3 3 0 .1 4 8 0 .0 9 8 1.221 0 .0 1 3 6 0 .0 2 6 nd 0 .0 8 3 ml 0 .0 7 0 0. 170 0 .3 4 9 0 .0 0 3 8 8 33 batchm an 34 supervisor 36 observer 36 observer 7 9 .6 9 0 .8 7 9 .5 7 4 .9 0 .16 8 id nd nd 0 .2 3 8 nd nd nd 0 .5 4 2 0 .1 4 0 nd 0 .0 3 0 0 .7 7 3 0 .1 6 2 0 .0 8 8 nd 0 .6 6 7 0 .1 6 5 nd nd 0 .3 3 7 0 .0 9 3 nd 0 .0 6 4 0 .3 4 0 nd nd nd 0 .3 4 5 0 .0 7 8 nd nd 2 .994 0 .0 2 8 0 .0 8 8 0 .0 9 4 0 .0 3 7 7 0 .0 0 6 9 2 0 .0 0 )1 0 .0 0 1 3 0 .2 6 1 nd nd nd 0 .2 8 3 ml ml nd 0 .2 4 0 nd mi nd 0 .3 0 6 nd ml ml 0 .3 1 4 ml nd nd 0 .3 3 7 ml ml ml 1.74 ) ml 11(1 ml 0 .0 2 1 9 ml ml ml m ean (crew 3) 0 .8 6 8 0 .0 1 0 4 0 .3 7 7 i).0 0 lit b0 C r e w 1 w o r k e r s 1 1 - 1 6 ; c r e w 2 - w o r k e r s 2 1 - 2 6 ; c r e w 3 = w o r k e r s 3 1 - 3 6 . T r e a t m e n t 1 ( T - l ) " o r d i n a r y p r e c a u t io n s . T o t a ls i n c lu d e v a lu e s fr o m s p r a y d a y ( d a y 3 ) p lu s dth e n e x t 5 d a y s . c n d = n o t d e t e c t e d ; a z e r o w a s u s e d f o r a v e r a g in g p u r p o s e s . In tr e a tm e n t 2 ( T -2 ) s p e c ia l p r e c a u tio n s w ere o b s e r v e d . T o ta ls in c lu d e v alu es fro m sp ra y d a y (day 10 fo r crew 1; d ay 9 for crew s 2 and 3) plus th e n e x t 5 d a ys. 99 9 S I ZH00I jso J. Agnc. Food Cftorr., Vol 30. No. 2. 1982 --wy ei al. 1D0 N2 15636? T able V I. C o m p ariso n s o f R espiratory* E x p o su re , D e rm a l E x p o s u re , and T o ta l D ose o f 2 .4 -D R ece iv ed during Treatm ent 1 (T -l ) and T reatm en t 2 (T-2) for Sim ilar-D u ty W orkers estim ated respiratory exposure, vg/kg estim ated derm al exposure, m g/kg dose, m g/kg" w orkers T -l T-2 T -l T-2 T -l T-2 p ilots 11 21 31 m ean" m ech an ics 12 22 32 m ean6 b aich m en 13 23 33 m ean6 s u p e r v is o rs 14 24 34 m ean6 observers 15 16 25 26 35 36 m ean6 nd nd nd nd nd nd nd nd nd nd 0 .3 0 0 .1 0 nd nd nd nd nd nd nd nd nd nd nd nd nd nd 0 .0 0 1 0 nd Q .Q 007 nd 0 .0 0 0 5 nd 0 .0 0 2 3 nd 0 .0 0 5 9 nd 0 .0 6 1 7 nd 0 .0 2 3 3 nd 0 .0 0 2 3 nd 0 .0 9 1 1 nd 0 .0 4 0 9 nd 0 .0 4 4 8 nd nd nd nd nd 0 .0 0 0 5 nd 0 .0 0 0 2 nd nd nd nd nd nd nd nd nd nd nd 0 .0 0 0 5 nd 0 .0 0 0 1 nd nd 0 .0 0 0 1 nd 0 .0 0 0 5 0 .0 1 6 2 0 .0 0 0 6 0 .0 0 5 8 0 .0 0 6 0 .0 2 1 6 0 .0 1 0 2 0 .0 1 1 1 nd 0 .0 0 0 4 0 .0 0 2 7 0 .0 0 1 0 0 .0 0 4 5 nd nd nd 0 .0 0 3 9 nd 0 .0 0 1 4 0 .0 0 1 7 9 0 .0 5 5 7 0 .0 0 2 0 6 0 .0 1 9 S 0 .0 0 0 4 4 0 .0 0 2 3 2 0 .0 1 3 6 0 .0 0 5 4 5 0 .0 0 2 1 5 0 .0 1 S9 0 .0 3 7 7 0 .0 1 9 6 nd nd 0 .0 0 6 9 2 0 .0 0 2 3 1 nd 0 .0 0 0 5 5 nd nd 0 .0 0 1 1 0 .0 0 1 3 0 .0 0 0 4 9 nd 0 .0237 0 .0 0 1 9 2 0.0 0 8 5 4 nd 0 .0 0 5 1 6 0 ,0 0 3 6 6 0 .0 0 3 0 1 0 .0 0 0 5 3 0 .0 1 9 6 0 .0 2 1 9 0 .0 1 4 0 0 .0 0 0 3 8 nd nd 0 .0 0 0 1 3 0 .0 0 5 6 nd nd nd nd nd 0 .0 0 0 0 9 c V alu es in clu d e 2 ,4 -D e x cre ted on the spray day plus 5 d ays fo llo w in g . 6 W here a value o f nd (n o t d etected ) was o b ta in ed , a zero w as used for averaging purposes. multiplying the 2,4-D concentration detected in each sample by the volume of urine in that sample and then summing the values to give a total amount of 2,4-D for each treatment period. When divided by the body weight of the individual involved, the result was an estimate of the 2,4-D dose received over each treatment period. Pharmacokinetic analysis indicated that greater than 9 5% of the absorbed dose of 2,4-D was excreted in the urine by the end of each treatment period (Ramsey et al., 1980). Less than 3 0 % of the 524 urine samples analyzed con tained levels of 2,4-D above the 0.04-ppm detection limit (Table V). Table VI reveals that most of the positive samples were from the crew members most closelyinvolved with the actual spraying-- batchman-loaders, pilots, and mechanics. Thus, there was a relationship between worker duties and levels of 2,4-D detected in the urine. Except for one pilot (worker 21), who had assisted in cleaning spray nozzles, batchman-loaders and mechanics showed the highest levels of 2,4-D in the urine, while observers received the lowest levels. Urine samples from observers standing near the heliport rarely contained any 2,4-D and then in only negligible amounts approaching the limit of detection. The only supervisor excreting 2,4-D (worker 34) was probably exposed when he helped manually transfer the chemical during the T-l application. Similar exposure did not occur during T-2, and no 2,4-D was detected in his urine in T-2 (Table V). Ifone assumes a no-observable-effect level of 24 mg/kg of body weight, as determined from toxicology tests with laboratory animals, then safety factors for the categories ofworkers involved in this testare substantial (Hall, 1980). At least a thousand times the actual dose received would be necessary to correspond to the toxiclevelsfound to show an effect in the laboratory tests. Members of crew 1 generally received smaller doses of 2,4-D than did members of the other two crews (Table VI). On the basis of milligrams of 2,4-D per kilogram of body weight over a 6-day period, 2,4-D excretions in urine from crew 1 members ranged from not detectable to 0.00215, while members for crew 2 and crew 3 showed maximum doses of 0.0557 and 0.0377, respectively, for T-l (Table V). Analysis of variance showed that the amounts of 2,4-D excreted in urine following T-l were significantly greater (p < 0.014) than those following T-2. However, when crew 3 was eliminated from the comparisons (because of the different procedure used to transfer the concentrate from the drum to the batch truck), the level of difference be tween T-l and T-2 decreased (p 0.15). The differences between T-l and T-2 might have been greater ifall the 2,4-D absorbed during T-l had been ex creted before T-2 began. Nevertheless, if 2,4-D in this study was excreted in a manner similar to the data pres ented by Sauerhoff et al. (1977), then over 95% of the 2.4- D dose from T-l would have been excreted in the week prior to initiating T-2. Five workers in crews 2 and 3, with duties as pilot, mechanics, and batchman-loaders, came into T-l with low levels of 2,4-D in their urine (Table VI). These findings were contained by using two gas chrometographic columns and two different methylating agents. The presence of 2.4-D in the prespray samples was surprising in view of the facts that (1) the worker information sheets filled out by the workers indicated that r.cne of them recalled applying phenoxy herbicides for at least 2 weeks before the study was conducted and (2) human exfreticn rates for 2,4-D and 2,4,5-T indicated that over 9 5% of the material absorbed before that time should have been excreted in the 2-week period. Conversations held with these five workers after the study, revealed that they cleaned, assembled, and tested their spray equipment before the study was con ducted. Exposure to 2,4-D may have occurred during these activities. Although certain members of crew 1 also per- -t /' *-? 1 I I 'i t ( 2,4-0 Exposed necevtd by Aerial Application Crews formed these tasks, they apparently followed more hygienic practices, since they exhibited little, ifany, presprav dose of 2,4-D. CONCLUSION This study found that some crew members involved in the aerial application of 2.4-D for forestry purposes ab sorbed low levels of 2,4-D, but the doses as indicated by urine analyses were several orders of magnitude below the no-observable-effect level determined in toxicology studies. These results are in agreement with those of Nash et al. (1981). The doses were comparable to those found in an earlier test involving aerial application of 2,4,5-T but were substantially lower than those found for ground application of that herbicide (Lavy et al., 1980a). Nevertheless, this study established that, if desired, exposure to 2,4-D can be reduced by wearing standard protective apparel and following good hygienic practices. This is particularly true for mechanics, batchman-ioaders, and pilots, since they are closely involved with the mixing and application of the herbicide. For example, wearing chemically impervious rubber gloves and using modern siphon pumps and drip-free coupling systems on transfer hoses virtually eliminated dermal exposure (the primary route of entry). Supervisors and observers rarely exhibited any tangible exposure to 2,4-D, even when in close proximity to the spray operation. Those who handled equipment and re ceived detectable doses of 2,4-D did not show levels which would appear to constitute health hazards (Hall, 1980). ACKNOWLEDGMENT W e are indebted to Dr. Logan Norris, Pacific Northwest Forest and Range Experiment Station of the U.S. De partment of Agriculture Forest Service at Corvallis, OR, for the patch design and choice of patch location on workers. Also, we appreciate the assistance of M. Davis in preparing this manuscript. LITERATURE CITED GDAemuVoIDRmPhrnefhr.rCeasreiaPbiKnniscmtuegaui.a1tsg,tm,n9uTttePai7wtpPocme8l.tixa/'i.JdoeNiop.cfenF;neaot.EKr;.PtlAiP.IWrrognAAaoSnasmodupa'itslunbilpeftsceemrFult,x,t.otsRipeHCPrt/otCee.h.NegssaGodRutiarns.rPt.;mteitirnraoBSaoaainctundrncihaeoliouawlnlsnl.lcpgyF.etaWossot1nz2inr9As,d,esJ74BIsefs3,Cos.t5O.,orto-PA2ocT.n2ri6^.oa1t,E,4itd9nRi3,PAo6u5u5oA2n-cem2sT,:tde'-ss2e3WuRJ6rA6Rsi.,ce1esaeQ7ags.sbion5ih.n;suc-itnR9iPtrfatago1oaattti.rwpbiooeoelnnesner,,.t J. Agric. fo o d Own.. Vol. 30. No. 2. 19S2 381 NRSW4LNRULNJLKLLHotaaaaaaa.aoohaao'SShAuSEpaicv1SFHTCvv2mmCtvCWFsF1Aiv1rsVlrnlo.Snilune7,yruyley.oroym99hoooxyooopa.,esgesipgiAErd,1,sb,8cboo8,,sx,1npntnresrNJeptthtotpo.i01i,TTeeNd0nimmi,re"oy.3o;ytotoRflTeTocod.THkln6aDssiasan.va2.LnF..s,tnL.ni,Wocf.tn.tiii.t,e-y,ci.u-mJms..,erfnt',iLJie:La1.3l"r1tr:hnG2at.oy,Porr.AEeoL"Ttet-LDsR7.er.D3..eAbLtc8eo.;CnD;Hegr.'ndMdC..Wod1A.;r7;lC;ieWr.d,oTrCT.aRS.Syomuec,e5rem;T..sRpPdKl"6p;k.,ooJs,fidSthtntao7"dS1'LraDeoedoo1.M2u'r.pSrxxisi;eFFe.d1;e;Whme9c1sonrann9er6ihciilmpt9eamei6Fh9sooeftvccNiLNjt7YghaL-eteiat8rtc.aHea88poioorsyr6n7s;tn,eiaGsinannaia0ulacare0eRitnra,ull,3ngeavrcvdesFhort,;.tg.,t;1AtsBs.PraTm0birneto8eiyouyvt,t.,9ntdoCoBpTotCp11r..r1semd,o.,rw,i,r7JSiWoWF,nanPp9snp9os..9onhenbonL30.1;TPootutT.a7',i86narmtJ;meofae,,9-.hCtSEcrl7coo1;.1n06A.;l..t1Dmct7oyP2o3iDi,e..p-,-bdri,erBFFC1a;;t9Fe.kLF16Lo,f9kCSrd;ni,ilu1Cn4C6tt,.oeoceaoo.WM4.Mn7.i2oe.y.eL;,7-2c4C,;t,onraut,jonr.1t,-rDr,.ie4t4.ao,elMn.1on4sasno7oeoEsEo1Boc-,vKA3stS'9:4t1f,,snsnRmD;H9efEdNttdtfy69a7ooi7At1AW.i2tg8rLd..e;9,gci8x0.Cm5uiRW.2aP.;;3eE1;ts2Pemlse;a-oTp-.-Hlntc.s.-oCrs3ixer,i49e4Pvi.rPm2Booda,h4cpHoae.tomp7po.a-n67ytJrr4syPrsutd.acpDelnLok2.oed5oo,.i6.iRh.uapirreuocers.aFa.ra-u.jjdiuJo(TD.rl;"s1yauctneTenlnteeEe.c"E.Mc,:Ji-P.,trc.csgtssdoHiFt.3sne.iCx;tntsGusaJRLDt.MonCe2EgoNopoeEA..rbRA.aRCn.:eC;..lrHr.hAoknxno.nmisAcemebesosaSos.,p.EErCuRvcseusLgsighWummtimeeoescC.riid.toMDmth.ie;rrrvelroiitss.c.plespvPippoidaeC;emBtcu.B.accGiuAeal:Nos.dlnderaiP.a.rneueCduimehaoRmretEe.1ng.tFtrlittnHl.i1;thbdi9iloTeoinlQbnnomoo..ot9o.y7CsrBu>Rncaoj,ggion7iuFnu8oneseNc:nanEfhE.r8tqIFd,aoFb;fcs;iotarLdg.ennvvaRouRs4lrtyom2unFFW,m.bC,Wetv.i3vre,r!Ce,niesAeo4o.dehi1ie1iSosPitppr,t(rra.aosroDs9ss9,eon5t7.toooeostattsaWem77ikmbi8-arrCrAhnoghnrsnlr3d9JTyyy'y)lst,tt-..,...,.d.. swoOptRhufeeiceprtctthiproemaaoibuvdpreeetteernehdrdto2mnfS1raobis,mtsry1asor9tetieirh8osov1enoinde.rN,owogAUeafasMtncnitochiniazveneorapeacttrtlDhiesioFmdii1ntroy0peOsr,cleo1yscts9futotoe8AprPbn1prroed.koorfoadrR2rtnAuise1sncevr,at1kgmisss9a,etAen8hFdn1ssiaatsm.syosoeTacrfeAtinhtastuetigheisvsoraiciisrnrlcrcel.iupehsp.lerP.ttoauurTrderbchauclhileecsitwhvEuebeasxddyse D0H2156368 < n i.m Im kv I 1 2. 71 '<> i QoK ' ^ 3 7 2 - NOtl/`CCc-:'>T*hiOs'4MATC--A." *-= J ^'_ ^ c _1iljriir Environmenial ' Coriiamination and Toxicology 506 qRRlZMOOi aLnadunAdmeriinneg HPerrobciecdiduersesfrfoomr RCeomnotvaamlinoaft2ed,4-FDaicbhrIicosr1ophenoxvacetic Acid Ester Carol Bryan Easley, Joan M. Laughlin, Roger E. Gold, and Duane R. Tupy D e p a n m e m ot T e x tile s . C lo t h in g , an d D e s ig n . 234 H om e E co n o m ics B ld g ., U n i'e r s ity o f N e b r a s k a - L in c o ln . L in co ln . N eb raska 685S3-OS02 Abstract. Denim fabrics were contaminated with 2.4 -dichlorophenoxvacetic acid (2.4-D) ester and 2,4-D amine formulations and laundered. The vari ables examined were pesticide formulations, tem peratures, pre-rinse conditions, detergents, a m monia additive, and number of washings. A clean fabric, designated the "transfer fabric", was laun dered with the contaminated denim to assess amounts of herbicide transferred during laundering. Solubility of the formulation was a major factor in ease of removal and transfer during laundering. The amine is water-soluble and was readily removed during tite laundry process. Generally. 60C water temperature and heavy-duty liquid detergent with out ammonia additive provided better pesticide re moval chan other :e->ted conditions. Pre-rinse was not a contributing factor in herbicide removal, but resulted in significantly less amounts of 2.4-D transferred to concomitant laundry. A second washing cvcie removed significantly greater amounts of the heroicide than a single washing. Emphasis on reducing accidental exposure to pes ticides is paramount as pesticide use has increased dramatically in the last four decades (Deichmann I972). Concern has increased for the safe handling and usage, environmental contamination, and ef fects of pesticides on non-target species. The three natural routes for a compound to enter the human body are oral, respiratory, and dermal. Wolfe e t i l l . (1967) showed that the major route of 1 Published as paper n u m b er b~l>'4. Journal Series. Nebraska A g ricultural Experim ent Station. Research was conducted under Project Nebraska 94-tllu and North Central Regiun Pesticide Im pact Assessm ent Program Project N o. 144 pesticide exposure and absorption was through the skin and not the respiratory system. This was ex plained by the fact that only small particles enter the lungs, but larger, more numerous particles settle on surfaces such as skin, clothing, and soil. Concern for dermal pesticide exposure is highest among ag ricultural workers, farmers, aerial sprayers, and formulators because of the duration of the applica tion season. Since the skin is the main site of pes ticide exposure and route of absorption, attention has focused on clothing items which cover and protect skin surfaces. There is evidence that such clothing can be contaminated by pesticide (Finley e t t t l . 1969. 1977, and 1979). Metcalfe 1 1972) found biologically active methyl parathion it).O-dimethyl 6>-/?-nitrophenyl phosphorotliioate) (MeP) residue in fabrics after three washings. She also recorded M e P transfer from contaminated fabrics to clean fabrics during concomitant laundering. Recent work by Easley e t t i l . (19ol) indicated varied success in the removal of M e P from fabrics by laundering. M e P enuilsitlable concentrate formulation was more difficult to remove from cotton and cottoa' polyester denim fabrics than encapsulated or wettable powder formulations. Fiber content was not a contributing factor in the removal of M e P regardless of formulation. Of the laundering procedures inves tigated. pre-rinsing followed by a wash anti two rinses resulted in overall increased levels of pes ticide removal. Laundry additives of ammonia or bleach were relatively ineffective in assisting the detergent in removal of MeP. Additionally. Laugh lin e t u l . (I9SI) found that washing equipment re tained and provided for possible transterence to subsequent laundry. The majority of pesticide laundering studies have investigated insecticides: however, the largest por- Springer- New0090 - 4341/83/0012 - 0 0 7 1 S 0 i .2 0 C) 1983 V erlag Y ork Inc. C II Easley ii/. lion of peslicitlo active inurcilicnl (a.i.) applied to crops and. or pa.slurclant.1 in the U.S. arc herbicides pended from a drying rack while pipetting was pcrlorm cd. and remained suspended to air dry. (El'A 19S0. U S D A 1981). Certain herbicides, includinu 2.4-13. are under scrutiny by the U.S. Envi L iu n u lrrin v C iiiid itio n s ronmental Protection Agency (EPA) because of potential adverse health effects. Approximately A contaminated denim swatch was individually laundered along I.5U0 products containing 2.4-D are registered with the EPA, and over 60 million pounds a.i. were used in 1980. This herbicide is used in the control of broadleaf weeds in small grains, field crops, rangeland, and turf. Interest concerning the impact of 2,4-D on human with an uncontaminated transfer swatch m 150 ml detergent so lution calculated proportionally to a standard 45 L washing m achine volume. Laundering of each swatch was done in stain less steel canisters of an Atlas Launder-Ometer (Model B5). A water bath maintained the water temperature for a 12 min deter gent wash and two rinse cycles o f five and three min. respec tively. health surfaced following the EPA's emergency suspension of 2,4.5-T [(2,4,5-trichlorophenoxy) acetic acid] and Silvex (2-(2,4,5-trichlorophenoxy) propionic acid] on February 28, 1979. This interest T e m p e r a tu r e if L a u n d e r in g : Fabrics were laundered in either a 60"C (hot) water wash and 4 yC (warm) water rinses or a 30C (cold) water wash and 30C water rinses. Although previous studies for laundering contaminated clothing (Easley e t u l. 1982) cc was due to the chemical similarities of 2,4-D and had recommended 60"C or above wash lemperature. current 2.4J-T and the concern that 2,4-D could be con energy costs have caused lower temperatures for fam ily laun taminated with dioxin [2,3,7,8 tetrachlorodibenzop-dioxin (TCDD)| which had been linked to fetotoxic and carcinogenic effects. E P A initiated a review to determine if2,4-D should be investigated under the Rebuttable Presumption Against Registration dering (Lovedav 1979). P r e - R in s e : Fabrics were subjected to either a "p re -rin se " or " no p re -rinse " treatment. Th e pre-rinse was the first step in a fourstep process in which each contaminated swatch was pre-rinsed in 150 ml distilled water for two min prior to laundering. A 49'C c. cr cc (RPAR) process. E P A concluded that scientific tox water pre-rinse was selected for the 60C water wash: a 30"C icology studies on 2,4-D did not indicate that con tinued use of the herbicide posed significant health hazards; however, additional studies were sug gested. pre-rinse was used with the 30 C water wash. Contaminated fab rics which were not pre-rinsed were laundered in the standard three-step process o f a wash and two rinses. Transfer fabrics were not subjected to the pre-rinse cycle; these swatches were introduced at the washing cycle . The purpose of the present study was to investi gate laundry procedures required to remove 2,4-D D e te r g e n t: Since previous work had identified heavy duty liquid from contaminated fabrics and evaluate the poten ( H D D detergents and high phosphate Jetergents as elVective for mv-my1 '-ar.ithion rem oval (E a sle y e t u l. 1982). these two Jeter tial tor dermal exposure following laundering. gents were used. The non-phosphate H D L was D ynam o- a nonionic liquid detergent manufactured hy the Colgate-Palm olive 4 C o . The 12Cr phosphate detergent was American Association of M aterials and M ethodsr Textile Chemists and Colorists (A A T C C ) Standard Detergent i h 'u b rn v; Tw o ly r e 1' `>1' fabrics were uscii: I) denim fabrics repre sented pesticide-contaminated clothing laundered in a home 124. widely used in textiles research. Detergent solutions were proportionally prepared using 0.2 ml H D L deiergent/150 ml water [0.137c solution (m anufacturer's recommendation) | and 0.3 laundry situation: and 2) transfer fabrics represented textile g A A T C C dclergent/150 ml water [0 .20 solution IA A T C C stan items laundered in flic same load with contaminated fabrics. An dard method) |. St/.r e o llo n O lK r polyester blend (2/1 (w ill denitn greige goods) was chosen for the contam inated fabric. A 5tK cotton-iOCvpolyester double kn it, sim ilar In weight to an infant's T -sh irt (5.7 g m ; >. was the selected transfer fabric. Th e transfer fabric was laundered concomitantly with a contaminated denim fabric. L a u n d r y A d d itiv e : Am m onia (N H ,) additives are used in the home laundering process to assist detergents in cleaning. Com m ercial pesticide applicators nse amm onia-water solutions lo de contaminate spray equipment. Therefore, contaminated fabrics were laundered with sudsy household ammonia as a laundry ad C h e m ie a ls: Either 2.4-D ester or 2.4 -0 amine solution was used to cnntaiTiinatc denim sw atches. A l.25bi. solution, commonly used lor agricultural application, was prepared from field formu lations [amine furm ulation: alkunoi amine salts. 2.4 -D acid equivalent lb.5'4 (1.7 kg/3.79 L ): ester formulation: propylene glycol butyl ether ester. 2 .4 -D a ciJ equivalent 44.V r (1.8 kg/ }.79 l.l|. F u lir if C o H iiim in iiin m : Denim swatches. 8 x 8 cm . were con taminated h> pipetting two ml of 2 .4 -D formulation unto the fab ric A magnetic stirrer provided um foim agitation of the 1.2 5 % solution during the contam ination process. Swatches were sus- ditive or without ammonia in the washing solution. The ammonia (3 .5 T --i'vt- ammonia concentration) was added on a basis of 11.4 m i/150 ml water, equivalent to 250 ml ammonia additive per 45 L washing machine volume. R e p e a te d W a s h in g : Th e effect of repealed washings on pesticide rem oval had received lim ited investigation (M etcalfe 1972). Contam inated fabrics were laundered through one complete cycle or two complete laundry cycles in this investigation. Using 3 2 x 2 * 2 x 2 x 2 x 2 kl'X-'k design (pesticide formulation. ' The use of tradenames docs not signify product endorsement 17480 i'l '.4-0 ( iunpiMnulN tiom (A'nt.imifuicJ l.ihncN prc rm>c. determent. am monia jiU liiu e . repealed A .i'lurv.:'. :hc c o n ia n u n a ic d denim lahric*y were laundered along u iih utKOMinminaied iran-d'er fab ric*. U nlnm ulcrcd c o n ta m i nated lubric> (c o n tro l*) were analysed a* an in d ic a to r o f in itia l c o n tam ina tion and as a baseline ttKY >fo r ca lcu la tin g percent pes ticide rem oved and percent transferred. A ll variables tested in tins Mud> w eie re plicated three times. Extraction Procedures c w ilh a 10-ml iliquot o f C H C I ,. follow ing 'c p tir.iiio n . C I I C I , ;id d o J lo Ihe com bined extruclv in the round bottom lliivk . C o r jS E tents in the flu-k Mere con centrated to to e ml by r o i.m v .tc u u ilN i evap oration. The chloroform extract wy transferred to a ie-i tube and further evaporated to 0.10 ml using a N . stream . low ing addition o f R F.-tn ethan ol. the procedures were the as described for 2.4-D ester extraction. The 2 .4 -0 am ine transfer fabric extractio n s did not result in an em ulsion form ulism fojlow ing the addition o f C H C I ,: th erefore, only tw o 55 ml ehloroT/ lornt extractions were performed. Procedure d e xclo p m e n t in d icated an a ly sis was m ore e ffe ctiv e in the 2.4-D m ethyl ester state. T h erefore, techniques were d e vel oped io convert 2.4 -0 ester and am ine to 2.4-0 m ethyl ester. 2 .4 - f) Eitcr: 2 .4 -D ester is essentially insoluble ill w ater, but soluble in most organ ic so lv e n ts. E x p erim e n ta tio n with ap p ro priate solvents for extraction was undertaken during procedure developm ent. M axim um recovery was obtained with aceto n e. Fabric sw atch es were e x tracted tw ice w ith tw o -150 ml aliq u ots ol aceto n e in a tw o hr m e ch an ica l sh akin g p ro ce s s , as d e scrib ed by E asley et til. (19X1). A liq u o ts o f 2 .4 -D ester extract were saponified by adding 2 ml o f a solution made from 6.4 g potas sium h ydro xide (K O F I) in 10 ml H .O plus 90 ml eth y len e g ly co l lE G ) tA ly and F au st 1963). T h e resultant solu tion w as e v a p o rated to 2 ml under an N ; gas stream w hich rem oved the aceto n e. An udditix'nal 8 ml K O H -F .G were added. The solution was vor tex stirred and h ea led in a 70*0 w ater bath for 10 m in . poured into a 60 ml sep arato ry fu n n e l, an d acid ified w ilh 4 ml 6 iV su l furic acid ( H .S O ,) . Salt form ed during neutralization and was redissolved by ad ding 25 ml distilled w ale r. T w o 8-m l a liq u o ts o f chloroform ( C H C I,) were used lo extract the 2 .4 -D acid . T h e com bined C H C I , extracts were evaporated to approxim ately 0.10 ml with a N~ stream ev a p o ra to r, after w hich 2 ml boron trttlaonde tl) F > in m ethanol were added lo ach ieve esterification o f the 2 .4 -0 ,.c:d . r hc -olution was healed to 7 0 'C or ill mm and q u cn cn cu in an ivc o .iin . F ive ml o f a saturated salt so lu tio n and 0 nn issi-"C i;.n c w ere ad ded and vigorously v o rte x eu for three nun io ettcct pu:'.m ooing o f 2.4 -D m ethyl ester into iso -o ctau e. M tir phase sep aratio n , a 2-nil aliquot o f the iso -o cta n e lay er w as pipetted iiito a vial tor gas chrom atographic analysis. The 2 .4 -0 ester transfer fabric extractions were prepared tor analysis m the sam e m anner, with the exception that the entire acetone extract was concentrated by vacuum rotary evaporation :n approxim ately live ml prior to saponification with K O H - E G . Amine: 2 .4 -0 am in e is extrem ely so lu b le in w ater l3i)f) a 1lull g 11 -0) an d d e te c ta b ility o f resid u es a fte r la u n d e rin g needed to he thoroughly explored. Am ine-contam inated laun dered denim sw atches w ere extracted in two-150 ml aliquots o f 0.15 V sodium h yd roxid e solution during two hr o f m echanical sh ak in g. T h e en u re e x tr a c t w as poured into a 5<H) ml sep arato ry funnel and a c iu iiic d wrth 10 ml 6 Af H - S O , (B u e h o llz IV X I). T h e 2.4- 0 acid was extracted with a 35 ml aliquut ol CHCI,. A severe em ulsion problem during phase separation was reduced hy the addition o f three ml absulule ethanol. Follow ing two mm vigor ous shaking, the phases were ailuwcd to separate. The chloro form phase and em u ls io n w ere drained in to a 125 ml sep aratory Afu n n e l. secon d c h lo ro fo rm extractio n w as m ade and c o m b in e d with the first using the sam e procedures. Follow ing phase sep aration in the 125 ml sep arato ry fu n n e l, (he ch lo ro fo rm e x tra c t was drained into a 250 ml round bottom llask . R em aining w ater and em ulsio n in Ihe 125 ml separatory funnel w ere re -e x ira ete d G a s C h ro m a to g ra p h y P ro c e d u re s A Hew lett-Packard gas chrom atograph lM o d el 5840A) with a flam e ionization detector was used for analysis. The separation colu m n w as 1.83 m x 3 mm I .D . packed with J'T O V -2 5 on I C O - 120 mesh C h ro m o so rb W H P . The identical co lu m n tem perature w as 1S 5 C . and tem perature w as program m ed to in crease at a rate o f 5C/min to I89*C. Tem perature o f the inlet was 195C and the detector was 300*0. Nitrogen earner gas flow was 1,290 ml/hr. air w as 13,200 ml/hr, and hydrogen w as 1,320 ml/hr. External stanJard quantification was performed using a standard solution o f 2.4-D m ethyl ester l Dow Chem ical C o ., 99.989* purily) with recalibration every fifth sam ple. Peak area m easure ment was electronically calculated by a dedicated m icroproces sor. T w o injections were made for each sample and averaged per replication. The amount o f 2.4-D extracted from unlaundered co n tro ls and laundered sw atch es was ex p re sse d in nanogram s (ng)/cm*. S ta tis tic a l A n a ly s is D ifferences in the am ount o f 2.4-D ester o r am ine (n g c m : ) be tween controls and laundered vwatchov were expressed in per centages o f 2.4-D removed anJ transferred, ano subjected to arc sin transform ation. A factorial analysis o f variance ana a D un can 's m u ltip le range test were used fo r Jata analysis. In d ica tio n po f significance was at the a .1)5 level. Results Due to the complexity of the research design, the findings are discussed separately for 2.4-D ester and 2,4-D amine formulations. The treatments of pre rinse, water temperature, detergent, ammonia ad ditive, and repeated washing arc presented for each formulation. Furthermore, the amount of herbicide transferred during laundering is discussed for each formulation. 2 .4 - D E s t e r F o r m u la t io n The mean percents of 2,4-D herbicide removed from contaminated fabrics ranged from 2S.67c to 44.99%. Amounts transferred ranged from 1.05% to 2.05% of the initial contamination (Table I). The 74 C . R. t'fill. Table 1. M e m percent 2 .4 -D evter rc n io 'e d by lanniJeriMi: from con tum inn ied denim Ijb r ic and transferred to v im eiin m a m h I.Hindered labnc Treatm en ts M ean removed Mc:m *r transferred1 P rc -ririiC Pre-rinse- wash W ash fonlv) Tem perature M TC wash/4yJC rinse 30 C wash/3l)cC rinse Detergent H D I. A A T C C 124 Repeated wash/ndditive Detergent Detergent + N H , Detergent ,. - washes Deieruent + NH-, 36.52*34.503 44.99* 2 6 .0 3 3 39.80* 31.22'* 32.08* 28.86* 40.59'* 40.5 r if 14 14.99 -1 1 .8 8 - 7.40 -1 3 .6 7 -1 2 .3 2 10.56 4:13.35 13.09 13.53 1.48* i.:r 2.14* 1.05 3 1.61* 1.58* I.S 9 * 2.05* 1.231 1.16" 0.78 0.80 0.75 0.34 0.85 0.75 0.89 0.82 0.48 0.52 (T' M ean transferred co m p a re s the am oun t (ng/cm 1) o f 2 ,4 -D ester on co n tro l with am ount (ng/cm: ) in transfer fabric : M ean follow ed by the sam e letter w ithin treatm en ts are not sign ifican tly d ifferen t at p .05 level * Standard deviation J UJJa low residue removal is attributable to the insolubil ity of 2,4-D ester in water, yet this insoluble formu lation apparently was carried to and retained in the transfer fabric even though the transfer fabric was taken through a complete laundry cycle. P r e - r i n s e : N o significant difference was found be tween pre-rinsed samples and non-pre-rinsed sam ples, although removal was slightly greater for 2.4-D ester contaminated denim fabrics which had been pre-rinsed. Fur the transfer fabrics, pre-rinse plus laundry resulted in significantly less 2,4-D transferred to concomitantly laundered fabric than those that were not pre-rinsed. T e m p e r a t u r e : A significant difference was found between the hot (60C wash/49C rinse) and the cold |30=C wash/30'C rinse) laundry procedures for both the contaminated denim and transfer fabrics. The higher water temperatures (Table I) were more ef fective in removing the ester formulation from the fabric, but also resulted in increased transfer of the pesticide to concomitantly laundered fabric. This may be due to increased solubility of the ester for mulation at higher temperatures. D e t e r g e n t : The use of H D L detergent resulted in significantly better removal than that of A A T C C Standard Detergent 124 for the contaminated denim, regardless of temperature or laundry proce dure. However, the amount of 2.4-D ester in the transfer fabric was not significantly different when a comparison was made between the two detergents. This indicated that the amount of 2,4-D transferred was similar regardless of detergent type. A m m o n i a A d d i t i v e : For both the contaminated denim and transfer samples, detergent washing alone was generally more efficient than detergent plus ammonia additive in removing residues from the fabrics. The use of ammonia at the concentra tion tested appeared to inhibit removal of 2.4-D ester. R e p e a t e d W a s h i n t ; : Repeated washing was signifi cantly better than single washing in the removal of 2,4-D ester from the initially contaminated denim fabric. Repeated washing also resulted in less 2.4-D ester being sorbed by the transfer fabric. 2 ,4 - D A m in e F o r m u la t io n Laundering procedures removed 99.17% to 99.6?% of 2,4-D amine from the contaminated denim fabric (Table 2). These levels of removal were due in part to the extreme solubility of the amine formulation in water solutions. Differences found in the removal of the 2,4-D amine formulation, though statistically significant, were not meaningful in a practical sense because of the nearly complete elimination by the laundering procedures tested and low toxicity of this herbicide to humans. Minute amounts (0.02% to 0.26%) of 2,4-D amine were retained by the transfer fabric after concomitant laundering. : . mi ^ I,: u:i:i.i11J | . - I) .nric l>\ l.u!Tnjcr:.-.a rom ctm iam inicil Jen in i r.ibr:,.' .m J n .in si'crreJ 10 .'uncum icintly la iin jo rcd M ean ' re m in e J Mean O iransierred1 99.37- ^VO 54 99.36- = 0.49* =0.7? =0.55 = 0.71 0.080 .2 1 ' 0.170.12- = 0.11 =0.15 = 0.16 -0 .1 6 99.65* 9 9 .2 4 6 == 0 .2 9 0.81 0.180.11- =0.14 = 0.17 9 9 .3 9 -1' 99.1799.63' 99.61*' =0.38 = 0 .4 9 = 0 .4 2 =0.37 0.26- 00..0225*** 0.04' =0.11 = 0.19 = 0 14 =0.08 s p a r e s the am oun t (n g;cm 3) o f 2.4-D am ine on con trol with am ount in gcm -') in transfer fabric ante ietier w ithin treatm ents are not sign ifican tly different at p s. .05 level C c *r* c c c c cr '<> ' jr.illcani difference in herbicide > between the four-step washing '"- 't.'dcd a pre-rinse cycle and the rcc - ; `p treatm en t. H o w ev er, pre w.t?:-.-, reduced the am ount of 2.4-D -- rrcit ns com pared to the three-step ' `Mtcant d ifferen ces w ere not Tn '"e ntt ihO'C wash/49C rinse) and . : i f , s e;t:;el aun tra d n e s ring fer proce fabrics . icPic. it apparently toc fabric regardless c huween HDL rd Detergent 124 ' ': : f 0i0; c1 1s:1.1 1 co n tam in ated the detergen fabrics. ts were stat isticaily compared. These "ins.*ns wore similar to those of the ttatt.i.on t fable I). '* ' findings from the 2.4-D ttmine iitiitsfor fabrics indicated that * |.. `-1t may !m\e Detergent inhibited residue reiilonc was generally ?= -...'n!iN1;'e Utidteeiteenrgceenwt iptslunsotam.simgnoinfiicaanatd.- 1 V>,: second washing significantly :iln' tabi ic2.a4n-dD daemcrineaesefdromamiohuentcsono-f residue transferred to concomitantly laundered fab rics. Conclusions General conclusions and recommendations result ing from this study include: 1) 2,4-D form ulations which are water-soluble are more effectively re moved through the laundering process than insolu ble form ulations: 2) 60''C wasn/49"C rinse w ater tem peratures resuit in better residue removal than 3h(e)aCvy tdemutypelriaqutuidredsetfeorrgetnhte perostveirdefsofromr uglraetaiotenr: r3e) moval of 2.4-D during laundry than does a high phosphate detergent: 4) 2.4-D can be transferred from contaminated clothing to textile items laun dered in the same wash load: thereiore, it is im perative that contaminated clothing be laundered separately: 3) pre-rinsing is helpful when laundering contam inated fabrics, and does result in signifi cantly less 2.4-D being iransfeircd to other tabrics in the same wash: 6) am monia as a laundry additive offered no advantage in the removal of 2.4-D resi dues during laundering: and 7) two launderings ot contam inated fabrics result in greater removal than one laundering: however, the effects ot more than two washings needs further investigation. Differences in the am ount of 2,4-D herbicide re moved from contaminated denim fabrics and trans finegrreisd dtoepoetnhdeernftaburpiocsn dpuersitnicgidceonfcoormmuitlaantitolna.unSdoelur boiflirteymoofvtahietnfroorumguhlaltaiounndweraisnga. mBaejcoarusfaecotot rthine erealsae- *7) :a C . B Easley ri ni. lively low loxiciiy of this herbicide. transfer in laundering is not a m ajor co n cern . It could be cnlrv and laundering. Bull. Environ. Contam . T o xico l. 22. 59X ( 10791. anticipated that exposure due to prolonged dermal Finley. E . L .. and J . R. B. Rogollio: D D T and methyl parathion contact could be minimized through proper laun residues found in co tto n and co tton -p olyester fah rics w orn dering of clothing contaminated with 2,4-D. in cotton fie ld s . B a li. E n v iro n . C o n ta m . T o x ic o l. 4 343 (1969). Laughlin, J. M ., C . B. Easley. R . E. G old, and D . R. Tupy: References M elhvl parathion transfer from contam inated fabrics to sub sequent laundry and to laundry equipm ent. Bull. E nviron. C o n ta m . T o x ic o l. 27, 518 (1981). A ly . Osm an M .. ami Sam uel D . Faust. D eterm ination o f 2,4- L o ved ay . R . M .T .: Textile consum ers' laundry m aintenance d ic h lo ro p h e n o x y a c e tic ac iil in su rface w aters. J . A m c r . h a b its , p r a ctice s and p ro b lem s in L in c o ln -L a n c a s t e r W ater W o rk s A s s o c . 55, 639 11963). Bucholtz. D .: Purdue U niversity. West Lafayette. IN . Personal C o u n ty , N ebraska. M aster's Thesis. University o f N ebras k a , L in c o ln . N E 11979). cum m unicntion. M arch (1931). M etcalfe, G . L: T he absorption and retention o f selected ch lo ri D e ich m a n n . W . B .: H ealth h aza rd s in farm ing and ga rd en in g . I nated h yd rocarbon s and organ ic phosphate residu es in c o t ed. C h ic a g o . I t ..: A m erican M ed ical A ssociation (1972). ton and cotton polyester fabrics. M aster's T hesis. Lou isian a Easley. C . B .. J. M . Laughlin. R . E . C o ld , and D . R . Tupy: Methyl paralhion rem oval from denim fabrics by selected State U n iv e rsity . Baton R o u ge. L A (1972). U.S. Department of Auriculaire: Im plications o f pesticide regu laundry procedures. Bull. E nviron. Contam . T o x ico l. 27, lations. Econ. Research Serv. Staff Report N o. A G E S S - 101 119811. E asle y, C . 6 .. J . M . Lau gh lin . R . E . G o ld , and K . L . Schm idt: 810730. W ashington. D C (1981). U.S. Environmental Protection A g e n cy : Pesticide industry sales D etergents and w ater tem perature as facto rs in m ethyl and usage 1980 m arket estim ate. O ffic e P esticide P ro g ra m s. parathion rem oval from denim fabrics. B ull. E nviron. Con- W ashin gton. D C (1980). tarn. T o x ic o l. 28, 239 (1982). W olfe, H . R .. W . F. Durham , and J . F. Arm strong: Exposure o f F in le y . E . L . . J. M . B c llo n , J. B . G r a v e s , and K . L . K o o n e : - Pesticide co n tam in a tio n o f clo th in g in co tto n fie ld s. L a . A g r . 4 20. 3 (1977). w orkers to p e sticid e s. A rch . E n v iro n . H e a lth . 14, 622 (1967). : Finley. E. L .. J . B . G ra ve s, and F . W . Hewitt: Reduction of m ethyl parathion residues on clothin g by d elayed Held re- Manuscript received March IS. 1932: acceptedJune 28, 1982. i ; iaa & " ^ 'j *'* *. ;\ The Science o f the Total Environment, 31 (1983) 203--218 Elsevier Science Publishers B.V., Amsterdam --Printed in The Netherlands ^ar j- -^29 HS'S. ' CACAERTCIICNOAGCEIDNICITY AND TOXICITY OF 2,4-DICHLOROPHENOXY- MELVIN DWAINE REUBER 11014 Swansfield Road, Columbia, AID 21044 (U.S.A.) (Received February 9th, 1983;accepted May 4th, 1983) ABSTRACT JAN 1 1914 U B *A K t/X m ,A M sapnoeinnknenrefoidoodn2f2bpmpoe,,hal4l4mciaaaubn-r-slsDmaiDlimmnymgleaiensscaainachllmoossneolborofo.tifegcrtiMiaeohnitnnsn.hpgeeasmesohl2m.el.pe,ui4muc2lnnma-et,ogaDas4.ix.mmgc-MyDeeasmanan.gciladiiecesrvLtyoea2iyaocnn,nm4gcdd2atl-pyadfd,hn4eltideocdm-reDhsaasa(litto2lnroeiec,rsgr4ooorfe-emapwpDnmthrasai)oescasipnlniecyosiwgnallerrceacseaaartitslenrinsstnci.oeomigirngnMwao2edclgn,arees4eleivre-caenDaesinlrfepcoaodddrptroesiencvmtidaahnelumolesaostornaepeallsryehtesisdmnapadcoipoonnrfhiefcdcsaonarosebrrenfeecaooeidstinmptniehcglodiaaunmlssiilcemnnaeiarcxdrssaiaeesdnstonoyes,icffsmnetaactteannhheomlddaessf INTRODUCTION dTcaeichgreTeettashictiaenicvaieadcoui,tdtxhritiaen(scr2lti,sk4apo-ellDtf,asn,)ap,tnalahinmsnadptsaeilctbsgsireeaoeesnnws. tdetTuhressh-xpeecadrrroeecmfthoeueordsmteimnbdicgyaatyoltchhykieeseimlaklrriiedscdaainacdlseo,iyltayy.2l,pAe4ald-bacdousnionttcreohhbulaeeosnrdrbdowifpcesrihueodedbmensaoc[axut1nhyt]dee-. to"x2ic,4it-yD tiesstwsidhaevlye suhseodwnasthaahte2r,b4i-cDidceantocacuonsetrpoolicseorntianign itnypaensimoaf lvs.egetation. lgoapIiwkertrntuiarilhaddlirivszgepeeibarpnsoldrtypisgionrore.paoaesnulda2..yas-d,eednI24ldsdetti,-,4taDifcsv-lorphiDeponfiiedespmrsieeh.suvosoaesneIaliemgtnilrdnseptseoitepsliatsaneolut,nuacispoewispkeasnreodinledloiwlspzaonieanevnnadrrdemnagacdfltaeeeieainnntorrragineycemartsoasial,msoulsssnrscaoaipalrnlnlrcdagoiddaoodepyvanjsrisieatsnnaorcsrongeufeeafgtdntcnoeahatwpdicaalteoraronfraeeosodasardrrrtostaeipiouhocidualnenorkss,dmostteirulaodloeeldrnsaefeshgfks,osfarleusorhaursugrdnib,cagreedhpaershnstcnoweacrdunrlaseaassdnaybsneatspesdrdinroosaaaduanfnnnotcdaidoddresl to control ripening of bananas and citrus fruits, to delay preharvest dropping o f some fruits, and for the control of rot when lemons are stored. 2,4-D 0048-9697/83/J03.00 C 1933 Elsevier Stiene* Publish B.V. 17485 _ o o r-O CC0rCO"JOD31 D0 W2 1 5 6 3 2 7 204 ci ci o c h 2c o o h 2, 4-0 ioswmmpcaircpWlsauloiypoeiritxnanthatstgeinoontthcnfs.aieaavn2lcel,yrwl4cyei-osodDnsraeptssarbpfaaimyrnyeddiesanesdpdfarotiatletouiysagisgnneewagttrhaoidhenyferunVmtwstoih,aeiittnpshhnsluaah2pmmne,ut4ra.r,bnn5pis-ucotirsrdtseiheeclyrr,hioelopuosrog,rshoawspciabhdctliieeedrnreeocntaxottnyxadcalilcocynoe.etttDihafcfceretriacfctteaisdiartfehataoeersnrer. dacwoiRtU2o1wB[noavu4f,0naeo.i4traStcTTS]astue-cbhmietii,.nDltnhhtndihAraeanwiiietg.uibmlts.FoshleiRi3elisspgiceealoTs--rsetaloerlnehixhstcancoua3Amv.eaeorakndi0nSirTemrcnealgdu'ttciwFsyshr.utmfichiyBoineteIddteieedniriiapioeysrlonsxoneltsoratniJtaaircfcoseovawhoadaclhdfnnu2neaptlvadd,dno.aw2ek4ynRaadtnefr,Tg-eedeFs4tstDe.saasphe,-DuptstDrtnK,ereIsairutAngtoeroioano1ablIcnndyrddznn9lho2eiuietldnf7ca,Elofihhbic4ote5scvsseuite-2rtsaost.ieaDero,oetencf4breoeoAspns2rc-ntnpDetltGehD,neoses4ceataoegetrEo-mlengfrsicDw.bwuocuso,moaoyantSMrhrefnlaiualMottremnMenuopntoerpsodrhoauetdeuoyenoeeuetcssyrpdauldeaeatisiytditnsemn[koimteSin1v(dobnnna2waptue--eSenuosn7ratta5twfdd3uoahlswul1eomi]bbifensldp1oeeeaRetaoiesyrrsdacidlUbtlaamlteotni,hgifirt.ui[todmdKolreaoe6rvinuSer,t,ttu]e.aetryvecthrsekgt2e2udi)ataaesvegneei,,rd.rdn4oe4wtdebverwiar-nd-Te'eeedaybtDtaesdscohaklhiwlrluucae,nssegee[fahsleutobd.5ootu,ssulslsemrro]iadesednm,rataelytosiecteeorhtdjtaebhplssseoipeouanmtstearihbnateddnrFtsdadaiepethantDnttasuttadrenahehehettorroA.ddndadaeeeesl from linear trend. FDA 2,4-D RAT STUDY 6m2a5Ole,ssboaronm1d2e2-5M50 efpenpmdmealleorsfaat2st,,4et-ahDcrheiendotwsheee.ekTdshieeot frfaoatrsgew1,0ei4rnegwienesedtekivdsid[e1uit,ahl3ley]r;cT0a,ghee5dr,ea2nw5de, rw1e2e2r55e, wheeaSigruhtr,evdilvivwoerres,ekwslpeylr.eeeHnke,imllkeaidtdonlaoefgtyeiscr, s1at0un4ddiewtseeswetkeesrs,.e adOnodrngeaonrpgsearnwioewdrieeciagalhllystos. wweerieghtaedkenfrofomr mcluodriebdunfrdomrartaetsktihllaedt daieftde.r 52 weeks; however, no organ weights were in 17i86 ;N2I 563 28 205 TABLE 1 (NFUDMABREARTOSFTMUDAYLE) RATS INGESTING 2,4-D WITH CARCINOMAS AND SARCOMAS (Dpopsme ) Carcinomas P Sarcomas P Both* P 6105251--522255510250 25320662///////22222125553425((2((((122(2083114%4%%%8%%))%)))) ) 000...000112112 0.012 0.057* 27364241///////22122224355525(2(((((34(811201%7%64%9%%%))%)))) ) 0.049 000...000152821b 39699631///////222212253542552((((((433213(%965263%%%%%0)%))))) ) 0000000.......000000034000034333559*3833b b*c SDToeemsptaefrotruarrtpesohfsraiodtimvbeolittnrheenacrdar.tcreinnodm. a and sarcoma and are counted only once. Detailed histologic examination was made of tissues from six male rats and six female rats from the 1250 ppm 2,4-D groups and the control groups. Lleisvieorn,s,kwidenreeys,ecsptiloenened, ahnisdtoolovagricyalolry ftreosmtest,haes rwatesllonasaltluomthoerrs danodsesotohfe2r,g4r,-oDss. At the end of 104 weeks the following rats were alive: 12 males, 6 females a(f8OenmdpBfeapomlmtdeeasys)l;t(ee1ws8s2e5mi(wg10ahe2pltr5espesp,mapr4n)em.dpf)eo;tmrhtea1edl0eosrmag(sa5anlpse--hpsb,omow9)d;inyf9gewmmneaaiolgleehssdt,i(fr96fae2tfrie5eomnpscpafeomlsers);al(imv2ae5norndp, gpk5mitdh)nm;eea9yvl,emashr,aeiolae1urs1st, groups. These results have little meaning, however, since the rats that died with the most chance of being abnormal were not included. The spleenbody weight ratio was slightly elevated in rats given 625 ppm or 125 ppm jp2,p4mT-Der2m(,4pi-nD<als0lhy.0,o5wt)he.de mreadcrbolcoyotdosicse,lslsligohft rpaotlsycghivroenma5spiap,man,d6s2li5ghppt mto,moord1er2a5t0e hypochromasia. These changes were not present, or were of a minor degree in control rats. Malignant neoplasms at all sites in male rats There were increased incidences of malignant neoplasms in male rats given all doses of 2,4-D (Table 1). Nine of 25 rats (36%) given 25 or 125 ppm (p =0.0053) and 9 of 23 (39%) given 1250 ppm of 2,4-D (p = 0.0033) dwceeeivrveeinlogdpoe6sd2e5crpaeprlacmtien,do6m(opafs=2a40n.d0(2359s%a)r.)c,Fohmoaradss.foemTwheeeruminneacxliipdglenanaincneetsdnoerofeaptslhaoesnms,esthnteheaornpaltamssmarlees 206 TABLE 2 NNUEUMRBOESRAROCFOMMAASLE(FDRAATRSATINSGTEUSDTYIN) G 2,4-D WITH LYMPHOSARCOMAS AND (Dpopsme ) Lymphosarcoma P Sneuubrcoustaarnceoomuass 05216155222- 551502 5 0 20603245///////22221224555325(2(((((22(0811610%%63%6%%%))%)))) ) 00..005255 000...000310488*2 0001131///////222212255552342((((((440(0042%%%%%%%)))))) ) * Test for positive trend. rmaatsle irnatsohthaedrcagrrcoiunposma(ps a=nd0.s0a4r3c)o.mTashi(rpty=-si0x.0o03f 81).22 (30%) 2,4-D-treated Sarcomas in male rats howTheveers,arthcoemreasweirne 2a,4s-mDa-ltlrenautmedbemr aolfe sruabtscuwtaenreeomusainnelyurloysmarpchoomsaasrc(oTmabalse, rr21aa),2tt. ss5Sg0(ai2vrp4ecp%nomm)2a,o4isnf-Dgw2e,es4hrta-ieDndgpsr(ape1rs2ce=o5nmt0pa.pi0nsm1(48p)(op=(fT=02a.5b00l5.er02a41t)s9). .)(,T16wa%nedn)tyi7n-tghoersfetien2g3o f2(15320p2%p(m)19,r%e6c)eoimfvia2nl5ge Carcinomas in male rats sm5yasoCstfeam(2rTc4.ianSbroialxmetsao1s(f2).1i2n%5Twm)megaanillveteeynr-ratawt6tss2o5t(r2ope4fap%tm1e)d22i(npwg(i=e1ts8ht%0in.20)g,24m2-2D5)alooewrfer12ra2e,t4s5-sDgpeiepvnmdeneiv(npe2l,to4=hp-eDe0de.0'nhc1daa1odr)ccriacniannorde cinomas (p = 0.012). Malignant neoplasms at all sites in female rats Eight of 20 (40%) female rats given 5 ppm (p = 0.019), 11 of 22 (50%) g2i4ven(752%5 )pprmece(ipvin=g0.602558p),pm13 (opf=230.0(5070%47) )o,na1n2d5 1p7pmof(p25= 0(6.08%22)),fe1m8aolef rpsaelartsvsmeidnsgineast6ti7naglolf1s1,i21te54s0fe(pTmpamablele(rpa3t--)s. (05A.90l%0to2)g2ei)nthgoeefsrt,i2n,mg4-a2Dl,i4gn-dDaenv(etplon=peeo0dp.l0am0s1mal8isg).nwaenrtenoebo Lesions o f the lymphoreticular system in female rats The highest incidence of lymphosarcomas was 12 of 24 (50%) female rats given 625 ppm of 2,4-D (p = 0.00007) (Table 4). Female rats in the other CccnOn ^ 17488 ' D0M215 6330 207 TABLE 3 CNOUMMABSER(FDOAF RFAEMT ASTLUEDRYA) TS INGESTING 2.4-D WITH CARCINOMAS AND SAR (Dpopsme ) Carcinomas p Sarcomas P Both* P 51605212522-15550250 51112473048///////122222214205324((((((545341(2384208%%%6%%%%)))))) ) 00000.....0000011106377559 1148823051///////222122242130524(((((3(45532(50%0653%%%%%6)%))))) ) 0000000.......000000080012019141043*4707 111168583717///////222222145322014(((((((65457258700539%%%%%%%)))))) ) 0000000.......0000000000520982021204282s7b b1c SDToeemaptaefrortuarUrpeohfsraiodtimvbeolittnrheenacrdar.tcreinnodm. a* and sarcoma* and are counted only once. 2,4-D treatment groups had 24--27% lymphosarcomas (p = 0.011--0.018). Thirty-one percent of all females (p = 0.00073) developed lymphosarcomas. The findings are even more significant if hyperplasia o f the lymphoreticular system is considered along with lymphosarcomas, i.e., 39% (p = 0.00005) of female rats ingesting 2 ,4 -0 . Female rats also had sarcomas o f the uterus. Carcinomas at all sites in female rats Carcinomas at all sites were seen in 43% (10 of 23) (p = 0.065) o f female rats on 125 ppm, 58% (14 of 24) (p = 0.0059) given 625 ppm, 52% (13 of 25) (p = 0.017) receiving 1250 ppm and 46% (52/114) (p = 0.013) of female rats given 2,4-D (Table 3). Carcinomas were found in the repro ductive system, particularly the mammary gland, and occasionally in endo crine organs. Neoplasms o f the mammary gland in female rats The incidence o f mammary gland tumors was higher in treated female rats, particularly on gross examination, which is generally quite reliable. The number o f rats with such tumors was less in all but one group after histologic examination (Table 5). On gross examination, 18 o f 21 female rats (86%) ingesting 25 ppm (p = 0.0064), 20 o f 24 rats (83%) ingesting 625 ppm (p = 0.0080) and 16 o f 23 rats (?0%) given 1250 ppm o f 2,4-D had neoplasms o f the mammary gland, compared to 10 o f 22 (45%) control female rats. The findings are quite different for the numbers or rats with histological sections examined by pathologists at F D A and sections available for this examination. 208 TNAUBMLBEE,R4 OF FEMALE RATS INGESTING 2,4-D WITH LESIONS OF THE LYMPHORETICULAR SYSTEM (FDA RAT STUDY) Doaa (ppm) Hyparplaaia P Lymphosarcoma P lHyymppehrpoltaasricaoamnad P 02S16166222-166602 6 0 0022421//////0222222/2286241(1(((((10998407%%%%%(%9)))))%) ) 0.066( 0666361////6/222222//223601214(((((042222(6%6674(30%%%%)1%)))%) ) 000000......0000001110101826007037 0888461////6/622222//23612204(1((((330243(6%25(66%3%%%7)9%))))%) ) < 00000000..0......000000003000010090231800*0348415b b* TDaaaptafroturrpaofariotlmvallbnraaanrd.trand. I"' J' X) o I 9 S IZHOQ TABLE 6 INNUAMTBIOENR*O(FFDFAEMRAATLESTRUADTYS) INGESTING 2,4-D WITH NEOPLASMS OF THE MAMMARY GLAND AND HISTOLOGIC EXAM Dose (ppm) 06621616222- 165602 6 0 Gross* 87812110/8/00622/////1202322114((23431((((064788(%%60636%%%%3))%)))) ) P 0.0064 00..0090180 00..00203038*' Histologic* 7161111/4710602//////2120222114(33231(((((664466(%636286%%%%%2)%))))) ) P 0.0334* Histologicd 687191131///61222////2122032114(((33331(((6594(664%5%%037%%%)))%))) ) P 0.070 *4**1* TCHHGeoDiriassorttlersooepsfllcoooantrrggeetiipducccroraaofesllopieeftrsirxxvyosaauemammrtvtriitieFnnrvneaDaandttlAiid.otoi..nnmbbeyy, i.e., time RFDeuAb.er. of appearance of first neoplasms of the mammary ginnd. D0W2 f56332 UOM> D0N2 I56333 210 Comments It is worth noting that histological examination of tissues from this study was inadequate. Microscopic neoplasms would have been overlooked at the 5 to 625 ppm doses of 2,4-D (only gross neoplasms were sectioned histologi cally) ana also even at the highest dose because only six rats of each sex were examined in detail. Also histological sections were not available for 19 mammary gland neoplasms described at the time of necropsy, and no explanation was given for this discrepancy. Despite the shortcomings of this study, it must be considered as an acceptable study. The largest numbers of rats alive were in the 25 to 1250 ppm doses; and the smallest number o f rats alive was in the lowest dose, 5 ppm. These results suggest that rats in at least some o f the 25 to 1250 ppm groups were not ingesting their diets because of toxicity. The differences in the incidences of neoplasms, therefore, would not be great. Tumors were analyzed, on the basis o f 25 rats per group, and the following conclusions were made by the authors: " There is a statistically significant (p < 0.05) linear relationship between the proportion of female rats with tumors and the level o f the log dose, but not the arithmetic dose, indicating that there is a tendency for the proportion of female rats with tumors to increase with the log dosage. There is also a statistically significant (p < 0.05) linear relationship between the proportion of male rats with malignant tumors and the level o f arithmetic and log dose. A comparison was made of the control group with each treatment group. Statistically significant (p < 0.05) differences were found only between the control group and the 1250 ppm dose level with respect to male rats with malignant tumors." The authors also believed that the raw data and the pathologic interpre tation did not support the statistical' analyses and that " a carcinogenic effect of 2,4-D has not been shown" . They also stated that " additional support for this interpretation has been given by the long-term study in mice" . --i*- Summary Male and female rats ingesting 2,4-D developed increased incidences o f malignant neoplasms. Lymphosarcomas were increased in rats o f both sexes, and neoplasms o f the mammary gland in female rats. Conclusions 2,4-D is carcinogenic for male and female rats. FDA 2,4-D DOG STUDY Beagle dogs, 6 to 8 months old (3 males and 3 females per group) ingested 0 ,'1 0 , 50, 100, or 500 ppm 2,4-D in the diet for 104 weeks [1 , 2 ] . Organ weights were taken for brain, heart, liver, kidneys, spleen, thyroid, adrenals, and testes. Tissues from all dogs were studied grossly and microscopically. 1743.2 D0N21 56334 211 Many of the dogs ingesting 2,4 -D lost weight. There were scattered lesions such as atrophy of the testes and prostate, interstitial nephritis, hemangioma of the adrenal, atrophic or cystic pituitary, atrophy of the thyroid, and hypoplasia o f the bone marrow. Most of the lesions were seen in the endocrine organs. Control dogs generally did not have lesions. Comments Previous experience at F D A has shown that long-term chronic dog studies should be carried out for six years or longer in order for neoplasms to develop. Since they occurred predominantly in 2,4-D treated dogs, lesions may have progressed to neoplasms had the dogs been treated for a longer period of time. Summary A two-year feeding study in dogs cannot be considered a carcinogenicity study. INNES et 1. 2,4-D, OR ITS ESTERS, ORAL MOUSE STUDIES 1. 2,4-D The maximum tolerated dose o f 2,4-D was given to two hybrid strains of mice, (C57BL/6 x C3H /Anf)F, designated as " strain A " and (C57BL/6 x A K R )F ! designated as "strain B " mice [4, 7 ]. There were 18 treated mice and 18 untreated controls o f each strain and each sex. 46.4mg/kg was given in 0.5% gelatin daily by stomach tube beginning at 7 days of age. After the mice were weaned at 28 days o f age, 149 ppm o f 2,4-D was mixed directly in the diet and provided ad libitum. " Strain B" male and female mice were also given 100 mg/kg, followed by 323 ppm. Treatment was continued approximately 18 months. Postmortem included thorough external examination and internal examination o f the neck glands and the thoracic and abdominal cavities, with histologic examination o f major organs and o f all grossly visible lesions. T-fhTyrhoeirde glands were not was no increase examined. in neoplasms in the 2,4-D-treated mice. 2. 2,4-D isopropyl ester " Strain A " and " strain B " male and female midfe were given 46.6 mg/kg o f 2,4-dichlorophenoxyacetic acid, isopropyl ester in 0.5% gelatin daily by stomach tube. A t 28 days o f age the mice received 111 ppm in the diet for approximately 18 months. There were neoplasms in the lungs o f 4 o f 18 " strain A " male mice (22%) ingesting 2,4-D isopropyl ester compared to 2 o f 17 matched controls (12%) and 5 o f 79 pooled m de control mice (6%) (p --0.0584) (Table 6). In this study, " strain A " male mice receiving 2,4-D isopropyl ester de veloped an increased incidence o f neoplasms o f the lung. 1 7433 212 TABLE 6 NWUITMHBNEEROOPLFAMSMASLEOFATNHDE FLEUMNAGL(EINMNEICSEetIN*1G. |E4S,T7INJ.GMO2,U4-SDE SISTOUPDRYO)PYL ESTER Strain """"""BBABAA"""""" PMoaotlcehded PMoaotlcehded Doae (jjpm) 0000111111 Male 225924//////111971878098((((((112611102%12%%%%%) ))))) P 0.0584 Female 003113//////118118777882 ((((((040663%%%%%%)))))) .D0H2156335 3. 2,4-D butyl ester " Strain A " and " strain B " male and female mice received 46.4 mg/kg o f 2,4-dichlorophenoxyacetic acid, butyl ester in 0.5% gelatin daily by stomach tube. At 28 days o f age the mice received 149 ppm in the diet for approximately 18 months. Three of 18 " strain A " female mice (17%) and 4 o f 87 pooled controls (5%) had reticulum cell sarcomas (p = 0.0955) (Table 7). In this study, there was an increased incidence of reticulum cell sarcoma in 2,4-D butyl ester-treated " strain A " female mice. 4. 2,4-D isooctyl ester " Strain A " and " strain B" male and female mice received 46.4 mg/kg o f 2,4-dichlorophenoxyacetic acid, isooctyl ester in 0.5% gelatin by stomach tube. After 28 days they ingested 130ppm in the diet for approximately 18 months. Neoplasms in treated mice were found mainly in the liver and lung. One " strain A " treated male mouse had an " angioma" of the liver and another an " angioma" o f the spleen. In this study, neoplasms o f the liver were slightly increased in 2,4-D TABLE 7 NREUTMICBUERLUS MOFCEMLALLSEAARNCDOMFAEMS (AINLENEMSICetEalI.N[G4E, 7ST],INMGOU2S,4E-DSTBUUDTYY)L ESTER WITH Strain """"""BABAAB"""""" MFoaottcehded FMoaottcehded Doae (ppm) 0000114499 Mate 052111//////171191789808((((((1660161%%%%%%))))) ) p 0.0714 Female 423230//////811181787826((((((1051141%%27%%%%))) ))) p 0.0956 DOW215S336 213 isooctyl ester-treated " strain A " male mice and tumors of the lung in " strain A " female mice. Two male mice had rare tumors; " angiomas" of the liver and spleen. INNES et ai. 2,4-D, GR ITS ESTERS, SUBCUTANEOUS MOUSE STUDY A single subcutaneous injection of 2,4-D, or its esters, was given in the nape of the neck to two hybrid strains of mice, (C57BL/6 x C3H/Anf)F, designated as " strain A " and (C57BL/6 x A K R )F j designated as " strain B " at approximately ihe 28th day o f age {7 ], There were 18 treated mice and 18 untreated controls of each strain and each sex. They were killed after approximately 18 months. Mice received the following doses: 215mg/kg or 464 mg/kg o f 2,4-D in D M SO ; 100 mg/kg o f 2,4-D isopropyl ester, 25.5 mg/kg of 2,4-D butyl ester, or 21.5 mg/kg of 2,4-D isooctyl ester in com oil. Necropsy included thorough external examination and internal exam ination o f the neck glands and the thoracic and abdominal cavities. Histo logical examination was done on all major organs and o f all grossly visible lesions. R eticu lu m cell sarcomas in "strain B " fem ale m ice Five o f 17 " strain B" female mice (29%) given 2,4-D isooctyl ester had reticulum cell sarcomas, compared to 5 of 157 control female mice (3%) (p = 0.0009) (Table 8). Summary 2,4-D isooctyl ester was carcinogenic for the lymphoreticular system (reticulum cell sarcomas) in "strain B" female mice. ARCfflPOV AND KOZLOVA MOUSE AND RAT STUDIES Three groups, 100 each, o f CBA x C57/BL hybrid mice were used [5 ]. Two groups o f mice received one drop of a 0.5% solution o f 3-methylcholanthrene TABLE 8 NCSAUURTMCABONEMEROAOUSPS(I"INNSNTJEERCSATIeNItOaBNL"[OM4F,A72L],4,E-MDAONIUSDOSFEOECSMTTUAYDLLEYE)MSTICEER GWIIVTEHNRAETSIICNUGLLUEMSUCBELL Dom (mg/kg) 01 Males 00//11861(0(%0%) ) Females 55//11757(2(93%%)) p1* 0.0009 / c p n r ! 7mnn 214 in benzene on the skin for 3 weeks. Later the skin of one group of mice was painted with a 10% solution o f the amine salt of 2,4-D in acetone. The skin of the third group of mice was painted with a 10% solution of the herbicide. Mice were observed for 20 months. Neoplasms o f the skin Papillomas developed on the skin o f 17.7% of the mice treated with 3methylcholanthrene followed by 2,4-D, and none for the mice receiving 3-methylcholanthrene only or 2,4-D only. Comments Groups of rats also ingested l/10th the LD 50 of the amine salt of 2,4-D [5 ]. The dose was not given. Summary 2,4-D is a promoter o f neoplasms o f the skin in mice. BOUTWELL AND BOSCH 2,4-DICHLOROPHENOL MOUSE SKIN STUDY Female Sutter mice, 2--3 months o f age, were used [6 ]. Mice were painted on the skin with a single initiating dose of 0.3% dimethylbenzanthracene in acetone followed by 20% 2,4-dichlorophenol in benzene, benzene only, or no treatment. 2,4-Dichlorophenol was applied twice weekly. One group o f mice was observed for 15 weeks and a second for 24 weeks. Neoplasms o f the skin Mice treated with both chemicals developed an increased incidence of neoplasms of the skin. Thirteen o f 27 treated mice (48%) (p --0.00607) had papillomas and 3 o f 27 treated mice (11%) had carcinomas of the skin, compared to 1 o f 15 untreated mice (7%) with papillomas and 0 ooobff set1hr5veeudsknitinnreian1te2d10omfoi1fce616(t0rte%rae)taetdaefdtmemricice1e5((76w52%e%e)k)s((.ppP--<ap00i.l0.l0o00m000a0s41))o;fawntdhheecraesrakcsiin,npowampearilse lomas were seen in 3 o f 27 mice (11%) and carcinomas in 0 of 27 mice (0%) receiving benzene only after 24 weeks. Conclusion 2,4-Dichlorophenol prompted the incidence o f neoplasms o f the skin in mice when administered after a single initiating dose o f dimethylbenz anthracene. DISCUSSION 2,4-D was found to be carcinogenic for rats in the original publication by 17436 0W 2 ?5535a 215 Hansen et al. [1 ], It was also concluded that " 2,4-dichIorophenoxyacetic acid is carcinogenic in rats" in a preliminary review of the raw data, but not the histological sections, requested by Senator Edward M. Kennedy's Subcommittee on Administrative Practice and Procedure o f the Committee on the Judiciary, United States Senate [8 ], The examination and diagnoses of the histological sections, which was done for this review further strength ened the findings and conclusion that 2,4-D is carcinogenic in rats. Experience has shown that it is necessary to review the raw data and histological sections of old chronic toxicity and carcinogenicity studies in animals [9, 10, 1 1]. The data from studies often is not adequately analyzed and the conclusions are suspect. It also is not unusual for results of such studies, which are statistically significant, to be ignored because they are described as not biologically significant. The pathology report for the FD A 2.4- D study in rats was completed in 1964; however, the results were not published until 1971 [1, 3 ]. 2.4- D is mutagenic and teratogenic as well as carcinogenic [12]. 2,4-D and its derivatives are teratogenic in mice, rats and hamsters. 2,4-D induces skeletal malformations, cleft palats, eye malformations, subcutaneous edema and hemorrhages in the snout, abdominal cavity, liver and soft tissues in rats when administered during early pregnancy [7, 13--17], 2,4-D is embryotoxic [1 8 ]. 2,4-D penetrates the placenta and the fetuses [1 9 ]. 2.4- D caused point mutations in animal cells without liver activation, damages D N A in a manner similar to ionizing radiation and stimulates mitosis [20--22]. Endothel-treated fruit flies developed an increase of recessive lethal mutations [2 3 ]. 2.4- Dichlorophenol is a major product o f the breakdown o f 2,4-D by microorganisms [2 4 ], The compound is also teratogenic in rats and carcino genic in mice. [6 ,1 4 ]. 2.4- D is rapidly absorbed from the human gastrointestinal tract and distributed widely throughout the body in animals and in human beings [25--2 8 ]. It is fat soluble and rapidly absorbed through the skin and lungs [2 9 ]. Acute effects of 2,4-D poisoning in humans include headache, weakness, dizziness, nausea and vomiting, sore throat, irritation of nasal mucosa, impared sense o f taste and smell, substemal chest pain and loss o f consciousness [3 0 ]. Peripheral neuropathy, which begins with tingling and numbness in the extremeties, has been reported in humans hours or days after exposure to 2,4-D on the skin. The symptoms in some people increased through several weeks until pain, paresthesia, and paralysis were severe. Disability was protracted and recovery was incomplete even after a lapse o f years [31, 3 2 ]. These symptoms resemble those o f multiple sclerosis, and this has been confirmed b y the finding o f plaques o f acute demyelination in all parts o f the brain o f a man who died after ingestion o f 2,4-D [3 3 ]. The formation and occurrence o f tumors in man and other mammals, such as rats and mice, is quite similar [1 1 ]. In tests undertaken to date, it has been demonstrated that virtually every chemical which has been found to be carcinogenic in man is also carcinogenic in one or ruoze !D0H2I 56339 226 mammalian test animals. It has been shown that if these compounds will produce tumors in one species, they will very likely produce tumors in more than one; thus adding weight to any finding of carcinogenicity in tests using any mammalian species. Sufficient documentation is available on qualitative extrapolation o f animal data that one must conclude that a finding of carcinogenicity in one mammalian species should be deemed to have relevance for other mammalian species -- including man. This threat may not be manifested for up to 30 or 40 years, given the long latent period of many known human carcinogens. Given the state of carcinogenicity testing and knowledge, there can be only one safe tolerance for a carcinogen -- an absolute zero tolerance -- and the only way a substance shown to be carcinogenic in test animals will not be a threat -to human health is simply to prevent that substance from entering the environment. To the extent that it does enter man's environment, it will constitute a very real threat to his health. Recent reports have described an increase o f malignant neoplasms in human beings exposed to phenoxyacetic acids. Humans exposed to phenoxyacetic acids or chlorophenols showed an increased risk for the development of soft-tissue sarcomas [34, 3 5 ]. Results also have indicated that humans in contact with phenoxy acids may also develop malignant lymphomas [36]. ACKNOWLEDGEMENT Statistical analyses were done by C . A . Riggs, Information Systems Department, Frederick Cancer Research Center. English translations were kindly supplied by Ruth M. Shearer, Issaquah Health Research Institute, Issaquah, Washington. REFERENCES 1 2 WTd1i2.c.2hHH-loa1.br9oe2Hprm.haneansneo,nx,FyDaRcA.etTiMc.eamHcoiadrbaenirndmuarmantaeannatdnitdlOedd.:ogGPs.a, tFhToiotlzxohigcuiocglah.l, ACphprlo.nPicbatnonx.i,ci2ty0 o(1f 927,14)Changes in Dogs Fed 2,4- 3 4 .6 .TDAPJAihOh.ae.i..cpctrRehHJbhrNre..lliaao.oldbi,MPrrmdAeooaBe.rplirpmilncIohhoahnaaaetemrinasnnnpyae,,ioooaannRxvxy,Feoyy.DBtaoseAARAn.fa,dl.cdMJptiM.dBdeL.oNsaeffUftotamNoieldtr2rls.load.,,TT4rnKeCawHw-dsnDoa,o.odnz,aMulcyLnYoVeme.d.vreaoaOFaIri,pennnas.nrS,sl,doVkttAtuAia.,uta,syl..dltJe4eJrJy.dP2ir..ai:iJoLLt(lo.a1,Peefnc9LahGhhit6tmmy.hhea9amPoreaa),telnn,io1ctc6ndgGdaa1iialra0(c.csdt1t1eaeeUn9U--flddoo7.lC1NrgM,41Khe)Lot1aanulv.rne48miceigF.d3nhmei--ot,adyb2rl8Liie0gpb4irn,eer1M5oi(n9nREp,ii1,6dtanec94ttrBghayt6.l.ieie3slFRilshn.e.oadmtHnfrd2aiatcn,hr4eJste-:., lation from Russian). OOW2I56340 217 11111112221112411293568700239786-'STMTooTJpnepoSBRatmtaSZRKLFpDtRrDM1pMRtpMaNBRchhreo.fsnr.cxheh1feo.p...t..c.h.oa.Cu.e.fge.s.e.eip.aladioseeytx.oneemeseWg.MACtVn,ai(tEFattKWnnnAL,SirKscvninrssihDe1DD4untDciado.e.1c..a.piaoo.s.lt..2e.iro.a.9tla.o7oca..a.tiinm.niAt9ohxxatS9mAixdenAFXBan7HLeiotcCit1BKace7KHtuneyyi8cSehtcee)ylRtRhRd6eifRlalo.ess-hha7oin.sooaadheaencaoadAlec)4stcgenede(yTme,udtoccukandeeChtrRprcxnotu1huu7ruRodulptpu1eearrrorptrsea.weeoor.asea,lfw9eebateb.bibe6cfrptt0cpaletrooStrttnnwmdnAliifg,reu7eeiereieEeahiosl2sS.l.eccdvofd,eec,,tdd.riursrtrhreg7ratnmnr--lRi.inniazray4,,hP,ee,lPncla.onisPn)tRi(pEs,vna,a.n,lm6daaicerhmHs1edhn2RaaeaenCPeRatc1Pcic.cacoa0n6r.A0iPnaarscn,nsensaGihohioseoe,iolr443ca--eodsd,dt5EnrtWddtWdctryoed.vvuulienivri.maS-n1Io,edhSi,clasncn4L(cisDadmnrpil(si..F..nte-d,Ri1DatcietaieaEmav7,(h.ahf2deLid1nwoalCn)Aei2w9aCtlcHoYoib..0)PnDet.ae,peso.soti5rvfiLn,.4ioo7nors.cn.tpags.lks.4,oTstaKeSfg.ecm8,.-oln0,ionmlap,lio-SwrnsPc..HBdoleoh.piinM.IfD,tr)mtBet2oSesPnfa.pUeenbinnaiteya.Br.unhB,l2cpcact.dsrfoa)Co1aimco4yrmascls.iCdahfe2ictWiltsmSrounKo.fdd-lvs.5id.etooEsrl,siail:o.aDcus.rEcdaondexuit(hcoeTc7xnieianMaaicvpnnyATnne1nlEvvitscn,,dhrnGncti-dlnhoitcsheSdidlioaac9iNotecvvpiu1ottudcee,saetsFiGoeo,tmii,phs7xacaaiopmwyflaP5m.treotrTrmn,.vanFeahldoyli22iefetv,s.o.9nuagcRaaJsteliedthy,entfostB)ilEnioun.4,UTo.aihn.iKlhrncotPsenoenedontoh.n.dentt-R1lndee,eokTsef.,nLr.inoaaiiD.gdretSmft,r4oe.vD,xnCsoxeaomst(ux9e,ebr.B.s---VintPifd1UsE6eibxewraamyoroirdo1cCi(..aauIn9c.anoninoooi.n,cG2anmao19.(oriefcSstcisonv7.otnsisf1emcnvMf8oJs4drft9ile.tio,edri(Ss9.esudJ.e.dr9i.tgce2lor7,-,pc1vmr.yuDic.t,r)tePiaoh2spP7eaohaf7in1r,.9e6oTltG(sn:CnecKen,Mlire1eotperne0)1r45nintsIois.mcbmti(pednlt)ooEdmeton-9.cc9t.tsi1imca1(ahaDamsimsirsAnEliov7eTs51)hcsT9necr3otcorhrritvsouonegai57nniine9iet.penoag57s)st4.yidndmgdlttbe9urmm)vn.ao.tlt7oo--x7uai1AaegesraerDnm--dnittvpM8onlieooa),1e-3iso,rlanai1cingcsaihn)fotupc6n--iwlv5peinn3poi4kavfe2ttTceitnPil1rosa6rioatodd13rldll8attii,fo42cesmas--ahlss.inyortc70ulnyf--(..,,nwtte,h2,ddotl,eet1fu4.5ceaeauet,t(1i49ustbm4c4sih9eir---,doEnCnneVtut.7encttDa6yip0dWaeeh(7incndkutseEnb4mottge.o11aafni3,tilodogm.rm(tsfmlvliaoraoD192tGNbsh)g.i1eol,tssne5oef7ifu,imirNceedb9nh,.sio4PcotsT.fy11gp1ptnhteori72nf,uAerJgAeonp)ihy50phriiro,6fer.lAadcciogngt4Cr0e-ooeaocnv8ntr)se,eTd2atLaf-eg--nretarrnaaat0on,adona4,lctieee,onert.41n,nna1Lmia2xsir1tnrcm2wlsWc1v,,iod--te,N0n,iic50,loaaha4af9sSneic4f1bfadyD-T--s.ol8nmagnenul-s6o-tatr,oadsder1eYidprdrCp8y4gdn2u(oheicraiatI7ieAi.Epoce1e.c,,oaitnncintnafnnr4s.atnhnivtho5elnnpAgencdits1or-ggiltlreifvr.lgieehdDo.co9ruonccaeroittlinalaeypoiooair7tsrtntir1tntcdeihonrosoteodimoan1pyi7sitodoycdhne1ec-s-s-f.,,f-,,,. 24 25- 26 27 JDpASKa4.e.d..b(sDd1stEKFio9.cir.r7hnniKpda4ePrteon),iaasohstrD9snhiis,7nia,sJ-naaaRt.1ndrnq.Ai0ddub.N0SgaueDr.t..t.xiic.oKFcCnrsohL.eyoa.tasinFdntoLenadnCmenaw,ghesol,ei,BifsmmR,.M2.eiNC,n,es4.h1ati-adte4Gdibumoio(eucn1ilphciR9satloa6moelf,6vraoc.)M,noph54d.fhl0o5MeCr0mn(i.--n11oi4cDa9x6-rtly70heaoa33bdabc).reie,apl1etlJhid0c.ed7nSe.a2og.d,x4Trda-yaddaniiacncdtehiootmlinoncaraoanonpd,fdhdXteKeenin.nnoPoxas.byneSilaioemicrtceciatcateliasrdc,,, Acta Vet. Scand., 7 (1966) 240-256. I 218 28 29 30 31 JArNp(tRMha1.hu..et.9AesP07lWnsu..i7ho.na.Be)GxngRSruy)3.oba.araAl-iutddcc1oeriise1ndocrtthehein,.cio.oTnfvE2,.fa,,,ncP4HviWA.-d.i0.r.HGo,(H.Nn2aH..J.,r4odByHCn-igrne0eh.aae)suulrSnmtahfa,anoa,nnGdlc2idltoh.9.Jwe,EL.(m..i13RnBk9S2g.ol7.aB4(Suo1a)rcrno9aah3dwnl6a1d7nn--aL)k,Pd3e.PmI13rJ.e,1.i.rnKSAiGpi--isbhreti1srehlao1rerati8rninlpokgtnno(i,Eoe,TnuntTohgrhooeliefpsmfhahatateothnerxtby.rioaiccfTanifpso2dtlrx,eea4orsit-pcideofoerxinlrocopthmigoelfyossrtou,rhoomre8e-f 32 33 MshAt1cae3..lr0tabCW9oni..c.fieBd2Dsee,tu4er. kd-rA0lleoer,yycfAh,da.rJincPcrdh.ha.tlKahIonnor. dotlR..p,M.Nh9eM.e4ndTao(.g1,.xe9IyTe7la,hl2cNae)(pte12iauc9r7r,60oa3cFp-)i2aad7tt3,ah55lJy.1. hf-Aou3mlm5loe2awrn..inMignegedex.spAtioosssnuorcoe.,fto127,a14-dD(i1m,9e5at9hc)yol1ma3mm0i6on--ne 34 35 36 smctLtMLiotad.a.a.lnnplHHEicsihgnuaeerengir.sbndkda,esoesenntLslalxt,]loany,7nkmcaaM7,aencersdeL.(stt1i.eEeidA9ncsHrn.8cpiaikahe0nScrsyc)gidasidmeonea2snllnda0ll,o,ysl8atr7Nr-nto6oc2ud.rhmm1g(0l1aP0o,o.n9.r.rCiBo7Lscpae9esrhso)ngeoe3fn,-ln8cveToot7erh.tn,n2seMtMt,--rsoBo,sa3lUorlc8i.sfheg7ttJrl-nu5.otaaid.rCsnnoysdtapu:nlhe0Syceme.onarfA,nopt d3lhxtsieo9slemass(xuno1apedi9roa,s7psnaC9uhdrar;ceesoen7exmo1tpcxo1aooy--ssncua7tharnr1ceoedi7mld.tseisoc,xtuacpLldhoayesskmuuaorbrnie- '*9Sl? *r,n A rch . "Environ. C o n ia m . To xicol. U . 4 2 7 -4 3 5 (ISM5I J1V | A rc h lv of C *no7--vIr-*-ir1rIocoa.xannnimdcmoi ne l rartti oa ogy rl rvj C I98S Sonn(cr.vrlif New York lie ~cn cn rvj GCOO AFocirdes(t2ry,4-WD)o:rkEexrpsoIsnuvroelvaendd iUn rAinearriayl EAxpcprleitciaotnion of 2,4-Dichlorophenoxyaeetic R. Frank*, R. A. Campbell**, and G. J. Sirons* 'A gricultural Laboratory Services Branch. O ntario M inistry o f Agriculture and F ood. % University o f G u elph . G u elph . O ntario. N I G 2 W I, and " P e s t Con trol Sectio n . O ntario M inistry o f Natural R esources, M aple. O ntario. LOJ IE0 Canada acadbT4lmstcbcttltteAtaalmt2mmeihoohuiheanp.areanysiov,nh7vae4errbaeaamaedytnlpdisdee5cetr2ellc-1rfnrsthtegeeyuDkrpltt88ratugr0ph11haaicrowr4ip8lann9l.weia9nwosilerfrrwf4tqgagn8dotaioeor8cspgefpn4e1/tuohieiaenee2tolr.dkpeiongr.%gudreanikr.tcif1gredwdghvk/n,t/sotrswee0os00hEihtt.etUeesporaowiwte..ebweotsrtaxons1dd1esmTelnrrshsotxarfuomvcpvuamaisriwfshekeu7disnggpattisooroenwt:iceile.r2y/airataiyoloryrs7v.dkivnpionrevlatetnu.oan3sesyhgiohgivrtntabweerreornu.on,hesilseTnedeixesagvnide-re,ctfo8Ocaosscanhhsfweheei.li.ifltogrriop1nd3terdeneonletwrebSha1wryhhtr7vwscbdenrstheea-wpelmttr,eiaoriapo.do.nidayeosraodleoslsndr2a0daaiepeshevfnsreepxFf2gabyd.mytabiritpec3spirria.ogl.siaostwn2adeleoaea0neiohslryeyhpwxgfsdnyrn,ns,gopToseeapeeiei2csudaidporfenoerwsptdr.0dtlet,aegckhaiuritdxgsnl4hip.igtoqoyo/eneue9ncci-ehkeoldhsuoddngorDat4titraganesechagpsetifernfafdn/pnb.evprtaiadueoitbdidiaidhlnn2mimyr2umetnrlriyroanoiIecuada,itn.rsoon4yldoa4dhnewhrsytilii,1oennint-anlyd-nei19snpeaDedsDxsfega1ob9f9t8sdgoeatuwuocspc98ynfu.1,sioriv5trfarrt8r2frln.exorihiatrf2iaeirpo9noe2nnihningaoaone-.n1tnslw.rgDamg4egceimgemv0dedelohpu-s2aeftl9u,yaopaD-ahctpnfrans.1wdrgstlst4oe0ir0oatrrswfi9ufeo/niighne-uanoca.k.oi8sns1oidn77nDeereoenlyasgg1te8f.rfl "Slt-Ite-tudb1dimc1ihe9as7ne|t)ab.anyald.nFdE(1rrS9an8nae4uk)(el,1irn9hN8oa0efs)ft.heLatealta.vlay.(l1.(e19t(981a729l7)8.),2(h)1.Ka9v8Po0eolm.lsa1hon9odd8wi2ne)n-.t dcsclte2tfrTohwoubswttiahoeootaheh,vufe.errm4eacutreTgaeaiirrWiaps-tntinrrrebrtochihsnDLlesgteaun.aioo.nhiaiehaeccear,roasnuitmnaqahyitiv(ltandhnsreslb1(dittuleynapcobowipoeoec9sandwtdel)nsrruo8oiirooteewaotaao.na4tesrnouyt-r(tyescpbnsa)drwcyhecdfercinheai)ediesntbdydroritocddlehnanhoeogeir.hunaenratoedcutnibtrninwons(gtitpitneasta1mtuhrdexhrtltetele9aemeanuesfoiylebdeeco8oovxttcdynsiai.tq0bonerephtoxhysnfeh)euohgnqsaoieto1dsenxdaairuwnor1srftcoegnnpbymuorigfalabapofyadto,ieurelsicteaonmnmdeesspntdewinndadlwuerddrhdyeow.dtyr.horepeeinos5dmeivsfIsneFatat0trlil,binheerarkroo:gotsye1eeda(ilvoeaxnrten2dnctieherdtyesnvd,teatetastler4iewodiiideinerlynnnv-crtlmmnpsiaDhagnygohetciatpesboeanauarmaasmnpewaebrlhtladlatsmledialdopeenaaeysiorytartimdrorlhculedsiirniblaaiooansruekaragoistafmlnffgnsf2neilmoo.affordua,rodLtrrace4ansToie2ertpnsciense,;pecwrx,fb5httts4dmtpoicatipi-ui(doh.otcoalbTnoot5aohasiiienhnhnrn)ff-)l,e Materials and Methods Field Operation efsmtIPIionrpqofoorruinmzqat1iseeyv9uer3iaodanr1li2epegs.gpbna4oelnyFt-inDfdeaieda2ltlwr1e.Es4a9lw,os-t3iaDtie2neanprgredeafnipsLecdo2telVoed.irr4strn6hp-o0ictDefeop0oean)emrssisrsuwteapfoepdotair-iptrnonohfercirneesoOtasstys.srnlcw.ltTocoea2eonhsrc0rmciteeaJoeestpr.meneLsedtCotromi(ananEiptnniegiestotaotrapKdnearllerataaoodid.ponnrfutTnuis6nsmshL0kvaeV0soanw.sl-dfgvei6on/ir0tLrneog0mgappuaacterlnnhioarddde 17501 -i:8 R. Frank et at. DON 2 1 5 6 2 8 4 During (he m ixing procedure, (he contents o f each drum were pum ped directly in io a m ixing tank together with w ater as (he diluent. D uring lo ad in g, the herbicide solution was pumped into tanks in (he aircraft em ploying a high cap acity pum p. To m ini m ize spillage during (he loading operations, a dry-break co n n ec tion was fitted betw een the end o f the hose and ne iniet port o f th e a ircra ft tank in 1981 an d a q u a r t c r turn ball valve w as in stalled at the end o f th e hose in 1982. U rin e sam p les w ere co lle c te d in 1981 from a crew o f three persons em ployed in m ixing and loading 2.4-D into fixed wing a irc ra ft (G ru m m a n A g -C A T ) in order to in vestigate e x p o su r e . T h e ir ag es and w eigh ts ap pear in Table I . W orkers F I . F T . and M I used new ly purchased m ixing and loading equipm ent. Two w o rk ers ( F I i M l) w ere em p lo y ed in m ix in g and loadin g spray so lu tio n s w hile a third (F2) w as in vo lv ed in reco rd in g, su p er v is in g , and assistin g in m ix in g and lo a d in g . A s added d u tie s, w orkers F I and M l rinsed em pty d ru m s, hosed dow n spray equipm ent and (he loading .file. cleaned spray nozzles on air c r a ft. and repaired leaks in (he loading and m ixing system . U rine s am p le s w ere c o lle c te d in 1982 from a s p ray crew using eq uip ment that had been used for several years. The crew included Sione m ix e r an d lo a d er (M 2) and tw o ba ilo o n m en I M3 M 4). T h e ir ag es an d w eigh ts a p p ea r in Table I. W o rk er M 2 w as em p lo y e d fo r du ties sim ilar to th o se o f w o rk ers F I and M l in 1981. W orkers M3 and M 4 were bailoon men m arking the swaths and giving the helicopters (Beil Long Ranger) ground guidance on each flight pass during (he spray operation. W orker M3 o cca s io n a lly a s s is te d M 2 in m ix in g the c o n c e n tr a te be fo re it w as loaded into the helicopter. Worker Protection W h ile m ix in g , lo a d in g an d clea n in g-u p in 1981. (he three w orkers w ore at ail tim es protective clothing including a disposable suit m ade o f " T y v e c " (a liquid repelling m aterial not com pletely im pervious to organics or solutions o f low surface tension, but w hich allow ed the exchange o f air) as well as neoprene glo ves, rubber boots, hard hats, face shields, and respirators (half face type). O v e r (he ll-d a y period, each em ployee was issued with 4 or 5 new disposable suits, and 2 or 3 new sets o f cartridges for (heir respirators. Show ers were taken within one hour after each w orking period (Table I). In 1982. w orker M 2 w ore (he follow ing pro tective gear: hard hat w ith flip-up v iso r, respirator (M S A C o m fo I I . h a lf face type #460968) with filter. (G M P Pesticide C om bination Filter. #448847). " n on-breathing" Stanley Kem W e f* W ear ja c k e t and pants (Ju ly 9 and 10). S ta n le y K em "n o n - breath in g" coveralls (Ju ly 1 1 -Ju ly 27). neoprene gloves, and rubber boots. T h e contents o f the cartridge filter between Ju ly 6 -2 3 worn by worker M 2 were analyzed for residues. Workers M3 and M 4 w ore (he follow ing protective clothing: a hard hat. " non-breathing" Stanley K em coveralls and rubber boots. W hen w orker M 3 assisted M 2 in m ixing 2 .4 -D he w ore the sam e apparel 4as w o rk e r M 2 . A ll three w ork ers-ch an ge d co v e r a lls after ev ery to' 3 spray operation s, every 2 to 3 d ays. A shower was taken by all three workers within one hour after each spray ses s io n . Bystander T h e U S E nvironm ental Protection A g e n cy (E P A ) has required the U S Forest Service to prepare a w orst case analysis (or for estry use o f herbicides. O u r study was designed to determine the worst case exposure for a bystander ( i.r .. being accidently directly sprayed). A t a forest site near K irkland L a k e . O ntario a bystander IB I Table I) wearing shorts, a T-shirt and sneakers, with bare arm s, legs and head w as sprayed b y a B ell G -2 h elico p te r (lying 90 km/ hr at a height o f 11 m a b o v e the grou n d . T h e helicopter had a 9.8 m rotor and spray boom o f the sam e length m ounted in front o f the sk id s. Flat fan n o zzle s (28#6520) orien ted back 43* below horizontal were fitted on the boom and a pressure o f 195 kPa w as u sed . To assist in d e term in in g the am oun t o f 2 .4 -D actu ally deposited on the bystander ( B l) . two subjects (B2 and B3) were positioned one on either side o f B l . E ach wore two disposable " T y v e c " suits (one on top o f the other to avoid possible con tamination from work clothes). The suits consisted o f hoods, sm ocks and pants giving full b ody co v erag e. The helicopter sprayed three parallel ad ja cen t sw a th s, ea ch 20 m w ide, and the three su b je cts were lo cated in th e ce n te r o f the second p a ss. The site ch osen for the test w as a clea rin g o f 20 m d iam eter on a road . A p p lica tio n w as m ade b e tw e en 2010 and 2017 h r on 17 A u g u s t. 1982 ( I8 * C . 5295 rela tiv e h u m idity, and no w ind). T h e 2 .4 -0 was applied at a rate o f 1.62 kg ae in a total spray volum e o f 55 L/ha. T h e outer disposable suits o f B2 and B3 were cut ofT and divided into four portions: hoods, arm s, torso, and legs. Each portion w as placed in 500 mi o f m ethanol and transported to the lab oratory fo r extraction and a n a ly s is . B y s ta n d e r 81 rem oved 'his clothes and show ered three hr after the even t. Deposit surface areas were com puted for the three bystanders. Since the clothing worn by B l w as skin tigh t, it was assum ed that the surface area presented fo r deposit was equal to his body surface area. The latter w as determ ined by constructing skin tight garm ents which w ere then cut up and m easured. Since the clothing (protective suits) worn by 82 and 83 were very baggy (he total surface area o f these garm ents did not represent the surface area presented for deposit. The deposit surfaces were com puted by measuring the surface areas o f the various p an s o f cloth in g on life size front view p h o to grap h s o f B 2 and B 3 . It was assum ed that the surfaces o f arm s, legs and torso were cylin drical so (hat three dim ensional surface areas could be calculated by m ultiplying the cross-sectional areas by pi. Cross-sectional areas were also measured on a life size photograph o f B l. The ratio o f m easured three dim ensional areas to measured cross sectional areas for B l were: arm s-- 3.12: torso-- 3.33: legs-- 3.37. Thus the m ethod for estim ating the surface areas o f B2 and B3 available for deposit is reasonable although confidence limits can not be placed on the calcu lated areas. B2 and B3 were as sumed to have the sam e size heads as B l but the surface area for deposit was reduced by (he area covered by goggles and respirator. Urine Sampling A ll urine excreted by the six w orkers and the bystander was co llected , beginning several d ays prior to com m encem ent o f spraying and continuing until a n um ber o f days after the end o f the spraying period. In all ca se s, there w as no guarantee that (here was no exposure to 2.4-D during the pre-spray period. A ll direct contact with 2.4-D w as avoided during the post spray pe riod. For each 24-hr period, the total urine per person was col lected in a 3 L plastic ju g w hich w as refrigerated until shipped to the laboratory for analysis. 17502 Exposure of Forestry Workers to 2.4-D 29 T a b le 1. In fo rm atio n o n six w o rk ers and a b y stan d er in vo lv ed in aircraft ap p licatio n o f 2 ,4 -D in co n ife r release program s during tw o successive years 1981 W orkers* 1982 W orkers* 1982 B y stan d er H im A ge (years) Body W eigh! (kg) Duration o f direct exp osure (hr) Urine: Specific gravity Mean SD Num ber o f showers (during spray period) FI (M + L) 21 51 65 1.013 0.005 22 Ml (Ni + L) 20 70 65 1.016 0.003 II F2 (S) ->2 57 65 1.015 0.005 15 M2 (M + L) 25 80 50 1.018 0.008 18 M3 (M + B) 23 82 51 1.013 0.005 18 M4 32 r ' 75 39 1.013 0.009 15 81 38 84 1.012 0.003 1 M + L -- m ixe r and lo a d er. S -- s u p e rv iso r. M +- 3 -- m ixer and balloon m a n . B -- b a llo o n m a n . F -- fe m ale, M -- male Surface Swabs F o llo w in g the 1982 an d 1983 sp ra y s e a s o n s , s e le c te d su rfa c e etoagchethpeerrswointh's mureianne.volumes and specific gravity of areas o f helicopters, vehicles, work p lace , and living and eating quarters were sw abbed with cotton balls wetted with m ethanol. A total o f 37 areas e a c h 0.1 m : w ere sw abbed at tw o sites in northeastern O ntario where aerial forestry spray programs using 2.4-0 were conducted . A clean pair o f disposable plastic gloves were used for the collection o f each sam ple. Cotton balls wetted with 7 m L o f m e th a n o l w ere used to sw ab the su rfaces in tw o directions. The areas were then sw abbed a second time using dry co tto n b alls. A ll sw abs from ea ch site w ere placed in v ia ls, sealed and retained for a n a ly sis. W ith h an d les, knobs and iatches. where the areas w ere less than 0.1 m : . a correction factor was used to give com p arable areas o f 0.1 m -. Analytical Procedure On receipt o f each 24-hr urine sam p le, the volume was measured and the sp e cific g r a v ity d e te rm in e d . S in g le 50 m L sam ples o f urine or swabs w ere h yd ro ly zed with 250 m L o f 0.1 N N a O H n-and w ashed tw ice w ith 25 m L o f 20% d ich lo ro m e th an e in h ex an e. T h e a q u e o u s p h ase w as a c id ifie d w ith 2.5 m L o f 1:1 H .S O , and e x tracted w ith 50 an d 30 m L o f eth yl eth er. T h e ether extracts were com bined and dried with N a ^ S O , and evaporated to d ry n e s s . T h e h erb icid e resid u es w ere este riiied w ith boron trifluoride in m ethanol (14% B F 3) at 80*C fo r 30 m in . T h e m ethyl esters o f the herbicide w ere extracted w ith benzene and water was added to the m ixture to rem ove the ex cess boron trifluoride. The benzene extracts were dried with anhydrous N a -S O , and the total volum e ad ju sted to 5 m L by ev ap oration . A Tracor 550 gas ch rom atograph equip ped with an electron capture (u Ni) d e te cto r an d an e le ctro n ca p tu re lin earizer w as used to quantitate herbicide residues. T h e colum n was packed with 5% O e x s il* 300 G C on C h r o m o s o r b W an d the co lu m n temperature was I60*C. For confirm ation purposes, a gas-liquid chrom atograph fitted w ith an ele ctro co n d u ctiv ity d etection system set in the chlorine m ode was u sed . U rine spiking teats show ed *^at 2 .4 -0 re co v e rie s v a rie d fro m 85% to 90% . Results sDtaentadilesr oanndagpeeraionddswoefigehxtpoosfuwreorakpepresaarnidn TthaebicbyI 1981 Operation fewsia2facglaoaiegscittpdwneLoepOow1nexfnoirnennrifaoosmioitetm1vearpveenlrrvedaeTdcntrntrron0teuevedrelaewbkcrrepieastdahlcdes.rfcnoanetlhrer3s9xl3iitoeeoetsoynodonwan3ne)h4btio)enr(iai.trhm.fyl)eeseftt.Tneyaphxefidotp.ereedexptc9mrTaevtauepA.sTheffApT.ae2ohop.bbgteuamohlr5b6ostT4wt,epiheanuoloiatak4erIose9ye.5ourb2teheccIfs5ltne-wosencodhelnar6,tu(Deet%pdo2--ep4smr2uha6sdhectdf.nmr.ku4b5g-)sgwt0aeraeeea2tp.tDi0-e7ipitee/0tm3tirroissnyn.ohaa2Lit.cmhrffexae2t/pW3nsnsgrnasi,oiikAaart3e4tanr0mgctew2pcdi2vrght6tpaahro-ovwaioeti.e,sa5ieDeey2espn4aeld4crnocsrbpntaal/rt..ktc-vioi-ohol/ohg4LhireioufndsDodvDtkuaemenonaoraonw/-hrrerdd)dlegkrrhDydcstir,fcc3eishi(yduge(naoiiaoxneTe2u2Fbaiabdcm2ilrnespefsdmtenn6p,hlloiawbio2lueu.o4dlxaemnne4ubtao(oa)rdieurpr-twreproceAsl1-tlnlaeDelsddavayafdrelihsD.rof6htbidgategixlutyiei(e-hlarn-faiadio/lsawtTllhuwwIitgeoriespoLneieededm)tienirtpnwaeup-onned.2nda)seonJ(gbgtsciuertt,nspdesoAFthricgw1/hlwctaohxhn(mLki7eJeoefar91hoeTIlrgyoanceei9oieler,drb0a)51vtmt2hta2fer9tderr/h9etth9stdiraab.)tdpke5olehn2e4xhahom8.e/bnmuolaMadaweetsdagrert.-1acaryadwyr4iey.reDrLeacb,i.rdirelosim-1nea2nnyTeoceqeoqDe(trT(oto)acetrshiodTnThokuahdwxuaw.cisa(ffhtteeoexfvceiiaTaaocaovf(adea7sLoon6rmibebtew2rtrrn-oa2tsm3sinrptet7ionlalrw,abotichhs.kee,e4eturt8odr4tcn8tuoliheanaeossorteraer-ercentet-9dhmerneDebsdtassrpyarfDsshLgd25ee2esell 175G3 430 R . Frank et al. T a b le 2. D aily excre tio n o f 2 .4 -D by the three w orkers w ho m ixed 7 .9 9 J L o f 2.4-D concentrate (4.797 kg o f 2 .4 -0 acid equivalent) and lo a d ed 73.895 L o f h erb icid e m ixtu re into aircraft (each load 678 L ) in an 11-day period in 1981 -W orker F I (M L) W orker M l (M -r L I W orker F2 (Si Period Pre-spray Spray Period Post Spray Date August noon-noon "lb 2 -3 3 -4 4 -5 5 -6 6 -7 7 -8 8 -9 9 -1 0 10-11 11-12 12-13 13-14 14-15 15-16 16-17 20-21 21-22 22-23 nifCidlt Loads4 o 0 H 15 18 15 13 10 4 5 3 4 11 0 2 .4 -D <Pg/L) < 0 .5 C < 0 .5 C 6. 10. 14. 44. 43. 152. 323. 227. 61. 191. 235. 326. 163. 43. 24. -- -- fug) 0.3 0.6 II. 18. 34. 75.4 69. 167. 339. 45. 98. 248. 413. 489. 179. 43. 17. -- -- 2 .4 -D (pg/L) < 0 .5 e < 0 .5 e 4. 5. It. 15. 18. 16. 22. 27. 15. 20. 24. 45. 16. 17. -- -- 23. (pg) 0.6 0.9 5.8 9.3 15. 12. 36. 30. 34. 26. 17. 15. 18. 66. 14. 15. -- -- 16. 2 .4 -D (pg/L) <0.5= < 0 .5 C 0.5 4. 9. 14. 5. 14. 16. 6 14. 3. 4. 7. 5. 0.5 -- 0.5 -- (pg) 0.3 0.3 0.4 3.8 9.5 15. 13. 17. 17. 8.4 17. 5.1 4.8 14. 7. 0.6 -- 0 .6 -- * M ixin g w as done during ea ch tim e-period in w hich loading took place * M id n ig h t to n o o n -- 12 h r 1Lim it o f detection w as 0.5 pg/L 4 G lo v e s to m -- direct contact with 2.4-D oblcecu4)r.red, that could account for these levels (Ta 1982 Operation ob3Aa4caoctsorc2asaIraa)bnnlprr.nnvrcn.i0.en4teamoddWstdrdeea1ay-ftaogkT1reDetn0ltly-reo965e3yohdhiebes8)),rn19pshefex..spek2s3egea0asodp2det5e,sh.rDeDn.elura2oriw8rutridot.idrurshu0oMidt2reiede(fmriurednc6arooaviid2rLnegprn0lethrneicsaea.gng0swtageuosxfwotgo(lphmgtoaitteTe2tfnoheoer/2nhrdxa.tLuandrein4.bhdeubsck4yldti-aeraltahrhc-DeesiihmstepcDt.aidnnrduiepsat/aeetvgue5iepkc.e.trrmexor)e)tdcageieO.ienafo3eyrwetesrdwenih5ndAebsop1otxed6ad,hoopm24idarcpbtri.erde5tewv6nlapkoaeoroy,(i59e.tgf8tmiestogfTogiow9arum7rrrwaatrgilddsnsko7roexbgpaeteawo,eoefeelegxddyiLde2rndfigw,iu2tsmt7amiohh9Mrw.6womyo6a4itfa,Jw)unf4/rtn-oi.2uesdhwkam2tDg3hdkrlh1ane,eDyk0elhw4y0dorawneseheh-u.rana(LDarn0xaar(eMTa2sdnmTidd-cqM8tnaeao2o12(era5ebugdT8e0fzbr2bbJ0hlitazcu.welea.eriodia0teeblsasleoheenesaiay%xo5lrdnrnnedees3ys1.-I oasomrtewiwbtOeattbMcipwhmhnihaogvcvfarxaooaentarae3oeAretWleleWepuns2esiiblrmtladrrgrnouoe9akemn,one,s4awophoigiioxroeasde1hnxro-waertarnwdcnluacD.dhi/kinnkya0esosrdnsarroiweodssesexamsne4agmrLb1nerwirpr7tefacy9.s3yaeksltta.o1aus8M2raMyp7hde5oonnDse(ossrbt.3e2efrT4oii3.hff.4taJf4aarrstn.uii-auui8owitbnlpsnoDacerdouIrhblwl%mt.oceiioncosgnoyanrelannpaioseroioany,rn.vagdansia2r5fkdsntu(isgnreoes3sifehfas.3fTeact4tprtds)tegsuen8ee2prmaaahe.tn-iirfrgmmdd,elbDgtuptxeo(p4oeilaeges0ln1seaptas-rpath/enwdt,e8o.Dkssloas1li8.osatwc1tsosgfos5nsh8ot%cdlct(el.geiryre2)tehodmT-eoncs8aebh.kusded)asuasuangyt.Looiaeadpn.pe3(tHlb(drdtdxtyur2drisaar7rltuo(eioniai2ye.gweeshsTcdMs4mdrpgyop,do-ehatisa4p%a6s.wnel2euntup2b5.e-tp)bnuttgrerrhlmDr.)l3,elhh9afeiroye4pi/ays8iroanetTda7tf2g-yo)hid5oddyteD.awnthh,haim2e)wahri4yndagitai.ere%aiopew.sn-nberrvolvTswD9eyuaiicpcaderipcofarwhcrtsoltkiat/btaelieprletti.ekosofehohbronkiebxrauasngedrWiaoirelcepstitpona;1pygkbnhnneerri6pgdoobloeedaehnmdgolm,darJtsfvMolroiitietaskiuratecedhoneiwtaahbhixxelnox3earfilgdnyn*yeea-sltr.,f 17504 ID0H2156286 i Exposure of Forestry Workers to 2.4-0 431 I8Z9SIZMOO T a b le 3. R a te s an d am o u n ts o f urine and 2 .4 -D e x cre ted by the six w orkers in the pre-spray, sp ray , and post-spray periods 1981 and 1982 W orker Param eter Pre-spray period Spray period Posi spray period Total period F I. M l. F2* FI Ml F2 M 2. M 3. M4* M2 V.3 M4 P eriod <d) Total Urine (L) M ean 2 .4 -0 Ipg/L) Total 2 .4 -D (tig) M ean 2 ,4 -D (p.g/kg bw/d)b H ig h e st 2 .4 -D (iig/kg bw/d) Total Urine (L) M ean 2 .4 -D (p.g/L) Total 2.4-D (ug) M e a n 2 .4 -D (pg/kg bw/d) H ig h e st 2 .4 -D (tig/kg bw/d) Total U rine (L) M ean 2.4-D <|ig/U Total 2 .4 -D (pig) M e a n 2 .4 -D (pg/ltg bw/d) H ig h e s t 2 .4 -D (tig/kg bw/d) Period (d) Total Urine (L) M e a n 2 .4 -D (jxg/L) Total 2 .4 -D (tig) M ea n 2 .4 -D (pg/kg bw/d) H ig h e s t 2 .4 -D (pg/kg bw/d) Total U rine (L) M ean 2.4-D (pg/L) Total 2 .4 -D (|ig) M e a n 2 .4 -D (p-g/lcg bw/d) H ig h e s t 2 .4 -D (|ig/kg bw/d) Total Urine (L) M ean 2 .4 -D (|xg/L) Total 2.4-D lug) M e a n 2 .4 -D l/ig/kg bw/d) H ig h e st 2 .4 -D (pg/kg bw/d) 1.3 1.75 < 0 .5 0.9 0.012 2.91 < 0 .5 1.5 0.014 1-1 1 < 0 .5 0.6 0.007 3 2.3 69 156 0.65 3.5 7.6 26.5 0.11 2.9 4.7 13.6 0.060 II 16.81 123 1717 3.06 8.10 14.50 16.1 218 0.28 0.51 14.38 8.1 111 0.18 0.30 18 15.3 837 12659 8.79 IT t 22.0 261 5760 3.90 8.37 17.5 243 4289 3.18 ` 7.73 7. 9. 8 7.53 94 818 2.29 9.59 8.91 22.3 189 0.30 0.94 11.10 1.9 24.6 0.05 0.25 13. 10. 8 9.5 423 3617 3.48 9.83 10.9 159 1543 1.88 3.50 8.4 109 987 1.65 7.31 19.5, 21. 5. 20.5 26.09 103 2536 2.55 9.59 26.32 17.6 409 0.27 0.94 26.59 5.1 136 0.12 0.30 34. 31. 29 27.1 611 16432 6.04 22.2 36.4 203 7330 2.88 8.37 28.8 181 5290 2.43 7.73 * Post spray p e rio d s w ere 7d ( F l ) . 8d (F 2 ). 9d ( M l) . 13d (M 2 ), lOd (M 3) and 8d <M4) 6 n g 'k - body weight/d copatfnUt`tpaaaarplfapokecrammptristitteeaninhetiinyod-tenneaehsnaadrpfpaaaqtrtsentreeornpuafrdaadmacriryatlooiaeeylresmdyesltsqpteiexhevburqptrcsrairthisuenrehopycae.rageeumiotttoigTeiqwnoeofrdqhhuadennnoutiesautlrrihurerckepaatadildtvenemmntteuserredddtsestasoiinoln.c8ectaethftafosn'dotoinnodatslholtnlfeiobeeli1fdnssuq3wesuMcaurdletceneiiaua4dpvoxfaaylemnplfetftsydiitloocrenaasastlnicighietlfsnntotdtaoee2wwn(odcrrT,id4fdnoiitatnl-hbenhebsDglryetwloaccedwemoatoetl4nihbnnaxes)idesKr. f tlyHuniier carMIenrnhesdettithidotoeuuhnr1eivis7snoicieai(sninno2rdtieu,ht4fyte2l-pe3Duoucrtfttoieansodppe2fp.r4itenaOhaAyetrnhuscbe9griyeunptswosrtTteas,1-an1stbodhplareeernarsd7syp(u.r81aba16Fnyj)erdtooceamtpqn1ou(d7Bs9iApthltm)isuospgewreun1aaxs1tys,t, cea2owamda9t2dattDtoaixh.nehh)nen,a1hro.4l/eedpepTcdycc6iahv-TcrroooosuhDlasrietaBhthnnsmsemhlephflai3eeogseewtra*otdhtp)idaaretaud,aieedueyarphsdnvguspe1terntieobtahaeh6edacpodaeordriyb2esresonlnibeteiasrztsuiahdnsdhvcmetowobtonosisaeealitrlfntieiiogftdehsnbttn(xtoasthu/Taetedehrtfpnnauraheshledodaeeereelrbleuabeeye,ry.rrscjrslxtaigvepdttieoaAtoou(enbpciiahrelvnBfntnda4tesrooep<aoeaiayi)nsdaollon0drn.trptb)ehvhyosudt.epwlFedt1eieoesespeiheltaonneoii(posexcadctslptwpuskoolihsguacteTaoagolioitgsirtrdrdnmstwo/tanieifeeb.hLtotbtaa1esdiettdwaoAnlc8nhoemleleid(1toeagrnedsTphcdryees2fsrao8oiepaatncuB.r.twhcabn.4sp1rtetemglelelil5-tsaciTo/ltebcaDat.pLirtww8thsocnheitphrt7opoattgnehaaarm)aitwwnrsf.isnhnteywbantagaedgaeBhys1cci1avse2o(cta.ail6tshos6Tneep.ltrc4ue42orwfvbwaat2tvtast-uubmelehhhBeik.aDgellnadt4deyeedgsgenhe2lt- 00H2I 56 288 432 R. Frank et at. T b l* 4. R e s id u e s o f 2 .4 -D in sw abs tak en from tr u c k s , h e lic o p te rs , o ffic e s and liv in g q uarters asso ciate d w ith tw o fo r e str y spray programs R esidue o f 2 .4 -0 in jig/0.1 m: surface Living & eating quarters (after 1982 season)* Living eating quarters (after I983 season)* Supervisor's office (after 1983 season) Sink Counter top Door knobs R e frig e ra to r door handle Table tops Sam ple numbers Seats Steering wheel D oor handles Brake pedal Tools Sam ple numbers 6.4 3.9 * IS a 25 288 l . 04 = 0.73 I3 Seven trucks used I982 and l 983 0.8 = 0.9 34 = 30 45 = 6 8 184 I00 34 Floor Cou nter top Door knobs R e frig e ra to r door handle Table 'ops Freezer door handle 4.8 = .3 0.74 9.8 = 7.1 69 0.39 = 0.53 12 15 O ne truck not used on site 0.7 2.5 I3 -- -- 3 Seats Controls D oor latches Pilot's helm et Passenger headsets Chair arms D esk -- right D e sk -- left Two helicopters 1983 2.2 = 3.1 72 = 12 6.7 = 7.1 12 7.3 = 5.4 14 15 12 1.3 3 Control Sw abs < 0 .1 3 * N in e m o n ths a fte r 1982 s e a s o n , im m ediately fo llo w in g 1983 season T a b le 5. W o rk p e rfo rm a n ce by three w orkers in 1982 Date W orker M2 (M 1- L ) W orker M3 (M -i- B) Ju ly -A u g . n o o n -n o o n M ixed (U . Aero* loads M ixed <L) Sw aths* (no.) 9 -1 0 10-11 11-12 12-13 13-14 14-13 13-16 19-20 20-21 21-22 22-23 2 3 -2 * 24-25 23-26 T2 o6t-a2l7 7328 2452 -- 6461 2797 -- 6151 3664 2474 --* 1203 6083 -- 7264 --45877 3` 0 I 19 22 6 9 I3 3 0 I5 I2 0 22 I0 I33 2452 -- 6461 -- -- 3677 -- -- -- -- -- -- -- -- 12590 72 0 4 46 89 25 30 52 6 -- 40 454 73 32 338 * E ach aircraft load 340 L . *`* HSEpaoicslhleedspwu2na.4ctht-u04re0odnmwlewhgiildeeloading * Con tain ed 9.430 L o f 2 .4 -D concentrate. Rate (kg ae/ha) 1.1 -- 'i 2 ) ? *i > U U U -- U i.i i.i u --1.7 A ccid. sprayed 2 -- 0 0 5 0 0 -- 0 -- 6 0 0 0 0 13 W orker M4 (B) Sw aths* (no.) 70 ---- 72 8 79 48 96 -- 196 33 -- 30 33 493 Rate (kg ae/ha) > -- -- 11 7 * 1 1.7 1.7 -- 1.7 1.7 1.1 --I.I 1.7 -- A ccid. sprayed 1 -- -- 0 0 l 0 1 -- 0 0 1 -- 0 0 4 octwhlnoaeAlstyhhs7is0en1u.ag64md4,nai%nngwgdo(hTtsfihckatahbihntlee.wli17att6)sl.4ecTm2oh.vg4ies-orDmefd2ew,aw4an-sisDthatbhdhsaeoatpirorBbse(libtdeaedbathsrodroonrubahgneiddhs asttmiokboruisnsnsootwraobwcofheuhedlildceahbghsyswawvaaBeesnllhdlcalraodeastprhtmorseecdsoas,.lceptcnhTutehhsrnaeti4hrm).r75,oo1%sun6tgohoropffgttthhhterhoeoeefuaxgb22phs..o44ostr--ehpDDde i .7501 DOH2I56289 Exposure of Forestry Workers to 2.4-D 433 Table 6. D a ily e x c re tio n o f urine and 2 .4 -D by the three w orkers loadin g aircraft and d irectin g spraying in 1982 Period Pre-spray Spray Post-spray Date Ju lyAug. 6 -7 7 -8 8 -9 9 -1 0 1110--1112 12131415161718- 2109- -21 21-22 222324252627-23 2829303 1- 1-2 2345678- 13 14 13 16 17 18 19 20 23 24 25 26 27 29 30 31 1 3 4 5 6 7 8 9 W orker M2 (M + U * 2 .4 -D (p.g/'L) (pg) 105 70 33 55 1289 963 651 1151 845 2153 2219 569 363 190 231 945 375 659 1821 434 152 984 586 943 625 1090 318 88 89 170 242 136 164 70 74 56 26 44 902 770 521 921 761 1722 1775 398 290 171 208 1134 450 527 1639 304 122 787 293 377 500 654 286 70 53 204 97 95 131 70 ICdO W orker M3 (M + B) 2.4-D (pg/L) (pg) 10.1 4.1 8.6 10.8 191 181 163 526 202 542 556 237 75 105 141 276 344 429 255 193 263 288 105 261 347 63 57 75 45 65 12 4.5 10 13 210 199 1% 631 222 596 667 284 90 126 169 331 482 686 77 386 395 230 74 287 261 278 107 91 98 32 85 Worker M4 (B) 2.4-D (pg/L) (pg) 4.3 4.1 5.6 23 137 146 211 255 214 286 417 192 89 84 401 368 527 507 191 113 211 274 237 24 136 40 73 47 39 4.3 3.7 5.6 23 123 146 211 281 214 286 375 ' 192 98 34 401 368 580 456 172 68 211 548 119 19 82 40 73 47 59 ---- * T h e ch a rco a l and paper air filter taken from the respirator o f M 2 yielded 356 p g 2.4 -D d8(ewhftDcMaOThi6axnar-thgeayt.lcFdo9iecawbosrnocs)runle)lfagieelce.ldtnl(s2auigoygocl7t.rswofe4lplnr).oeogd.=ei-rTlnto0ddlehFYgohbtexeiorowoicanxpeesrlnbg=pexcohiilndrrptsasydehweeuv2oaatesda.reiosya7eeoumrb3wnffdnnroiIsttaeerio,osl--tsxopbl,hrot8isfyobt-mwu.hoa0se52beiiru.Bd.t4hndj4pmeeh4gal4.e-dg.tcliDX.rhfg7vte2T-roh5lair.oB(iognh4eelnurughjss-eIigDteiatb.gpdh,reae/gduikbxrxstaeeghoitcac0nyhmdrnr.dscbes9eeydkeie,o4ttcciiidtwonoxtlshahyienoneinneqonmi=edwg*uofo,2ehafofeaFtt,ttii42ifr2i7gmgmfo-,.1h41oh=4Dne66st-rt- Surface Swabs 1982 and 1983 oInpesrpaitteioonf, htahveinbgyssttaanydederalwivaeydfraonmd tahtee ainctuthael ssparmaye eohibqirbstctqw1hnnehereneiur9iiualrtonseesnnF8aeenati1ytrgttc2rodourerahk9eten,ttrurrdl8eedeerwsisaw3eratrnruwlshsssse2siiewurainlorw.atsvfetr4epiefaassouefnreTer-r.sseharrsroDyronaiftce2mranhsmatboeleh.ulogecloti4ssscepenpefc-oitophtdDsophoae4nrpsvailfeltdefpninoriseerei-megrsiedfdhnlssdta1-iislhpdiinvi9yeviitcnfeinraiidek8renoncalng2aduscethagyradhb,.resirtues2ceelw,sepRcatypwl,.pmhe4eonfahrceoiRros-sdaueoseoliDsahrooyleinnlttdsnadiisd-w.eetntcndusueaaoltgpT(doeielromtapTvtirrsephrsnewiaatihcxenteognrtbyooeoaecghasplanfrlrne)retatqsipsqeie8dicno,s,u7iote7uuounewnl)ranaanip.ascdtismrrnahowenttTt1tobdodexeid92aaharftsrsspr8.elebess4esr1laldsst,eaowi-lawt(uvDflihcpmakanrahsiaoerinrnenineeegeobnxelinddddgdn-ne iJr U'T /7 T 4)4 T able 7. U rin e excretion o f bystander ( B l) and am ounts o f 2.4D v o id e d fo llo w in g a sin gle overspray at a rate o f 162 mg 2 .4 -D aeim - o n 17 A u g u s t I9S2 (Su b ject 38 yr o ld . w eighed 84 kg and 196 c m (all) Date-* Aug.,-82 LShnc <L) 2 .4 -D tig/L Ag 15-16 16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 M eans & Totals 1.3 10.7 13.9 1.9 64.7 123 1.9 129 ** 181 245 399 1.6 16.0 25.6 1.4 16.6 23.2 2.0 5.6 11.2 2.1 3.3 6.93 1.6 0.3 0.48 1.8 0.3 0.54 1.7 < 0 .1 0.17 1.7 < 0 .1 0.17 1.5 1.0 1.50 1.3 1.0 1.80 I J < 0 .1 0.13 1.8 < 0 .1 0.18 p.g/kg bw/d AS Pre-spray (15-17) Post spray 117-31) 3.2 24.4 0.82 0.61 137 716 * S a m p lin g period c o m m e n c e d 0620 ea ch d ay A ro u n d spray equipm ent c 399 p.g/d = 4.75 p.g/kg bw/d oottcwtopsimwrr2Ihehdeeetobfa.rreoee:4uacsfrTu)sn2)erir-ttie;esladieneh.Drkrsda4gireidlrgeuetnvts.-eseoherDgerissaoestnsedcabduuhffxotuwfotuirpewoptneisfmoenhtpchrarluensteeslanbceprrtpit.iuoheeoeeahwbronesetlscTitrerfsrogheekafa.vshrbtowdopksb1aehtitAsrrfeh9lsmheoeuet8soehlyovrsvops2pensarveeiwepurenadehtdspa2drbwphndedepiye.aaeecerd4drlf-iln.irsyloaons-nevisaDlynsT,rgdfesginpioe,ash,fntstsdurotoshkpiareaaorsorleisrawhoppcnsfglascahrnsoopdahayhote,onashlesaictvunsndtsdnhohiano-oesestgiosfraddaneadnsep,ondlmhdlutiglederadriedaert.avsdiiretesdenhnyriukstiTanudaageonci(rngdhpctn.d1kre(idike1eeud.osum8qIr2arsiuelnnrsedieu,thspsioisejpsundaeiaoiridcr,.geewodedenglfsobh/sars/vue0.e0meeienoeero.nr.ooiss1d1nsdestftff Discussion whsspWuoariedrptohbcerealkrtodvuehwitresisleoiocnrnwihgnsuevrltmwieohnvelieevcerewalelsdleo.votrTaiekfnklhs2aeem.nno4d1if-x9Dt2aoi8nc1.4igtgni-cnrDraesgenapwttdaihltsyae(lnbFooraaeItflhd.dloteiuFhnoc2egn1e9afam8anc2icodretcnncrMrttaaheafbwcalt)tt, D0H215 6290 R. Frank et at. eipmmB(snMreeaiaaqroxsy2tiueire,odednwbnnMeceasocre3,senadotfaholroaeneefibnsnfdsldfstceehorMcrelechlvtoaio4eafoswn)natni.iccncionteTgeongnhtfpdhditbtosiaruhyrastetedstictteieihhbtffdsafeeleeycwxrta(1eep6mu9tnr.oh8te5coh1sae%ruoctecrromtesrnhcveaseaotwsyioufd1te1iwbws9or8p0eeoau1r-dsrsa2akys0itepocno%rrooresabnpx:)yie.t 1. 4532.... CSouLMSlonrplouieaidaxpoladledivensinrinreingonvg3rgsgricposoaliurfeinnapraacgyckieriwrsnancaofgrntdtrarduakfoortt.iefrhsnieawgtalcenpotddiiarnunkngdtgdeiierlasuiwsnpealenbistsrtahhftleoeilndorgmominnidinxrmg2uinmaadgnnsudatine3ds, ooafcdhfpeosccKoaoobww1uvdeeileaotDrrabnrxnoulaafothfnerf1roxopxoorfoaezeefaPsnesmcaesei7NBmuppeplmsBhatiik11nnbeotntderd2vrg6igmtbh0oopao0laaaeysaoeeaarbyoem.ei-hhrloess4npsursbttsfavm"srnaernedemtiottyeiuoeyh-efersbeo1rti/ohtfn-nDdvlohgddoru2bdwdte9a6ojgstadnbetaoaiteeohxe..ut5ca.yeehx0nc/lf2eovni4atckysdlai3otststxbteutwTo.umnioeeiten2lhg-rgtaa)o4nidaymcto.Dfgaar.hhxnnra,nefas-aseea4roa/an.pflesiiaptDtbtOwaa(oesneTtr.tntgsi-dwneuft1tdoholeoietr-DectdLoy/t(eeohewscdar9dsioeg(lMlokdcseibxxerdoosas1layrlsut7ieebgrt2y{oofseb-vkceciii9tv3n-e4dsmtdasmicso,e3Hiabbrsesoaere8i,ynbdn)cue1ikwde.raepneoslarr;2daiti7dao2ogtr'dtuwt-refmsyhlttbtnpdo)r'syivneetidaoeewfSearenboevsydi(lrihoedtsrMtityrisdrntrsti.guaeawn(wionneec2digrrcietd2eagcuohmrtrM.nkeGtiewI.2/aeppexu2ohea4mklbnktnee5fnde,Fit.eood/eTpec.ea4etue-gyefgria5dr2a2aexrDrrfMoihtlhd0oottthhb(.lanfgslttmed.opb71b.rin,wosyhneoftMey.ypai1c3hniee/o9uyndmsgfratnIfdttlp18rhatirp8sm2rnfAr.hosustna//ohagat8uLiluea2daktpatehawrlnregtc2myeeh-leagb1el)ricahgnwsrtnhevd1iert/..ntaede9nahlaymekhdata4aolbrrde9isrn7e.hsbyoodgFceUnstiax-el8iMse1dhgiwiiDohutoweicFe82Oli2panxxchs;(bn2tah.msiddewgnr4w.,lhnNoiohecdei70olptueDndwyB)hwsdfoe(au1rruarrie9idswthreOg1tnetrhls9leawptmtatihwyciietydi9siwltsmhpme8ssnie.Ehlswttimiodgusts7saaleth1hreeoafabhwaogaiLo/eeiaiab7esaio,ers'neetapnsxnipko/bgaxrdtbe)shj,)1hekrsngohekg;eFcnprhsN(racmefs6eigaaoldMir1nbtaacoeogowetrleoIwren6lesuO/9mbnfttaeerltsrhdrnfbdar-dln.3soiaHb7toftgolbdemta2waorsolEiaitei.otaosooM8ienreaidoihaienoi.diysfxbltinudailsL4)dsarddgsydendenoyde-nayy);-tslttl-t 7t) ^' u Q Exposure of Forestry Workers to 2.4-D D0M2156291 435 Table 8. Su rfa ce areas o f clothin g w orm by two su bjects acco m p an yin g the bystander B l and deposits o f 2 .4 -D on the clothing Bystander B2 Bystander B3 Average Part ot` clothing Surface area m* 2.4-D deposits mg mg/ixE Surface area wr 2.4-D deposits mg mg/m: 2.4-D deposit mg/nr Hood Arms Torso Legs Total 0.170 0.429 0.999 0.373 2.47 2.08 9.04 104 15.5 131 I2 .J 21.1 104 17.8 52.9 0.170 0.453 0.684 0.862 2.17 18.5 10.0 134 20.0 183 109 22.1 196 23.2 84.3 60.7 21.6 150 20.5 68.6 Table 9. Surface areas o f the p an s o f bystander B l's body and estimated 2.4-D deposits on each part Surface-area 2,4-D deposits Part o f body Total nr Bare skin m2 Total mg Bare skin mg Head Arm s Torso Less Total 0.206 0.399 0.859 0.695 2.16 0.251 0.510 0.761 12.5 8.61 129 14.2 16-1 5.41 10.4 15.8 taecthrncttsr2tauLpahn1ohihehaulnlei3ombnro9aaiiicerstaedirbntmds8teolrunlteedefiaheteoa4usbelceidotpswry;trpneglohhodtw,,fbpioarahrafaaffeaaaceattioerrtsnnsen2tiybahedre2.u1hcosdatdd,elsas6s,e4oginc4(nineotpaatnf-hhndGouSh-htviDrlet2raDrtultp.raiherteaaashtcf..laheotuhn4taihfitctte(ilensreeuoeWitel,ol1tlrsro5vfyisdgirc9tnfthinswr-sheo.hielhnc8Tdktaafiuogloebthfu4ioddiymehetnrftjn)trhrweurd.hreafc,hareoofcrcenhefe2lhericiellIuotftrridaad,niinhorstrs4cgrnntsasee1tnre,hhiektga2aaau25Btxtoiosihtleat.f-ropwit4ne.efhTitrsdmehiwnetet-dnrith.seDarst1h,epraieiohoecmsin29nenrIgrmwrutn7of.watdakhoc4albott7kht1cisuhaaee-adelo)y9ieitDhaemcen.rsdntceru7ssshrlatsoehletsa8iu,rpLeeplaaeom-tts;faoixidrbnawqsiwuscnstuanlicvteLsduuessii2ntuairydrfotyvedemtiiis,eeeadhpiwnb4rserarttypoetm-(eileisebofafii1Dc,ootdpr,1itocndnsfimheo9hnpeo8tolatdan8mlthcr1e-nlriooil.cae0ta8lea2nespd,waoxt)ontta4ptrhdraiaupidsivatoroanaanrbnhblbooceethendylndldygoaeeytf.r References D rill V a , H ir a tz k a T 11953) T o x icity o f 2 .4 -D an d 2 .4 ,5 -T . A report on their acu te and ch ro n ic to xicity in d o gs. A rch [mi Hygiene O ccu p M ed 7:61-67 Franklin C A , G ro ver R . M arkham JW . Sm ith A E . Yoshtda K (1982) E ffe ct o f various factors on exp osure o f w orkers in volved in aerial ap plication o f h erb icid es. A m C o n i G o v ern Ind H ygienists Transactions 43:97-117 G e h rin g P J . B e ts o J E (1978) P h e n o x y a c id s , e ffe cts and fate in m am m als. E co l Bull (Stockholm ) 27:122-133 H a n s e n W H . Q u a ife M L . H a b e rm a n n R T . F itzh u g h O G (1971) C h r o n ic to x ic ity o f 2 .4 -d ich lo r o p h e n o x y a ce tic acid in rats and dogs. Toxicol A pp l Pharm acol 20:122-129 K ohli J D . Khanna R N , G upta B N . Shar M M . Tandon J S . Sircar K P (1974) A b so rp tio n and excre tio n o f 2.4-dich loroph eno xyacetic acid in m an. X e n o b io tica 4:97-100 K olm odin-H edm an 8 . Erne K (lysO) Estim ation o f occupational exposure o f phenoxy acids (2 .4 .-D and 2.4.5-T). A rch Tox icol Suppl 4:318-321 L a * y T L (1980) P ro je ct co m p letio n rep o rt. M easu rem en t o f 2 ,4 ,5 -T ex p o su re o f fore st w o rk e r s . 30 A u g - 3 O c t 1978. A ltheim er L ab o rato ry. U n iv o f A rk an sas. F ay etteville. A R 72701 L a v y T L '. Sh e p a rd J S . M a ttic e J D (1983) E x p o su re m e asu re m ents o f ap p lic a to rs sp ray in g 2 .4 .5 -T in the fo re st. J A g ric Food Chem 28:626-630 L a v y T L . W alstad J D . F ly n n R R . M a ttice JD (1982) 2.4-dichlorophenoxy acetic acid exposure received by aerial ap plication crew s during forest spray operations. J A gric Food C h em 30:375-381 L ib ich S . To J C . Fran k R . S iro n s G J (1984) O ccu p atio n al e x posure o f herbicide applicators to herbicides used along electric pow er transm ission line right-of-w ay. A m Ind H y giene A ssoc J 45:56-62 N a s h R G . K e a rn e y P C . M a itle n J C . S e ll C R . F e n ig S N (1982) A gricultural applicators exp osure to 2.4-dichlorophenoxy acetic acid. In: Plim m er J R (ed) Pesticide residue and e x posure W ashington. D C . A m Chem S o c (A C S Sym posium S e rie s 1982) P oland A P . Sm ith A . M e l t e r G . P o s s e ck P ( 1971) A health su rvey o f w orkers in a 2 .4 -D and 2 .4 .5 -T plant with special attention to ch lo ra cn e . A rch E nviron H ealth 22:316-327. S a u e r h o lT M W . B rau n W H . B lau G E . G e h n n g P J (1977) T h e fate o f 2.4-dich lorop h en oxyacetic acid (2.4-D) follow ing oral ad m inistration to m an. T oxicology 8:3-11 Manuscript receivedJuly 16. 193d and in revisedform October 26. 1984. t DOM2 I 5 t27 ^ ic - i s n ? . - 6 w ~*3: -1. :*-1S/3 PAHESEPSAETLCITCTHISDEOSF 521 'l u siruct b u lletin v*i y.1 't 'r i jj| J u n e - l)? :i - V o i . r. .N o. fi ;J Vj \ i >:-i I ; tf { 7 li - 11li 1:i ! 1' : i \ ' ! 1 \ ! .. I . 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I a M- !i . ^ v I . 11 ;' --! h: : *iit'.;:*:>1' 1If if : . :: :i . *. - . ; I l . . f I fl I . . I \ ;*!'! . i | i t I ' ' li fS ' I III* ltd i < li**.-. \| * I ` I ' ! * , \< N ^ I I K *. * ' - ! ( I i p i :. > I l i c r i u . i i I" ii.iiiM# >*l ;l|*flinn .it I sf| ( id .jtinis|>Ji*ru fin ir*Miiii* ti i . . , . i i *M t : . -I* \ . Mi d ' ' U p i ! 11* * ' .if"- ispf; h \ !i. ti .'i f i ' *:..! .* \ ip - 1 1 ;-i .ns i . , j . ... 1* rr IItt..*' ,,.* ** ii.* **rr' : .r:jt;:(p-..-. . I, ... i11,. iiii* *** *--1> / .i \ *. I *i- : : ! ; * : I. r r " ' **! p* ' . | i, I - ? -r ;:i .J *v ,. i u i 11 -n . ; *i it i* ' I.. 1 ip. .Ir- -U : d o - *!' . r ifu.* :*i i i . f i 1, i a : -.1 h f i * 1 ...i.i r r . p . iP . .1 i*. * . i a : III ' ll ;i : f - i !:j -it .1 >f i :* f r I**:- ! ::i di* ' V( f l : |. * d |- \ *.. l: ii- .| |s S 1 i i l l . -i;: 11:1 - 1 -i : / i> i -U ,i i | i ...I . i n i i l t f '* l i l S . Il II. : 1 1; ' 1 i* i | . r . ; . ! 1 . . *i a : I ,-.l - iii :1Jr ;*1 liifi--.1r f- -uh*i. ii. -1! h.ii1: H i .i' : 'i .ili` .*.j.*J11.iii n . .............. ii v* :-ito- * : ivi I. ; i j \ !I i*. i .i1<*1! \ ::ni io - }(i*r.; * 11 - \ ' K * ! d 4 m * r * s u |n 's Mil ( l . l V f l l M i l U i p p l f s 4 iu l i ;. : ! :i i(ui.ii : .i|* |ii i . i i i o i i . n u t i i *i i i m v u l 7 " 1' t :in->i ip;* * ?. - * :r f*t : > .1 i. : K . . Mi I* ' " i i <n.I ' f > pf i : *. ' . p i i . i ! tp*N i ' -i. (*( . . i . i . . .... i. -i Ti.1 f l u * u - : . i I l O p r o : I ' : i i [ i . 1 ... i h . . i '* H * . w *h i ' . I I ' - '' f k i Ml i. 1 > 1- *1. . j *f . 1 M- .1 : . i .. .: , ` ;-i" . :; i -a 1 A . : . ' h i ' - i f . U l . i ; .'l i i i n n : . 1 . 1 . i 1.1 III T . . : 1 1 : . III. i - . 1 .' ' l!ti I- . .1 IH1 ' l ; h i .i.H I.- .i. 1 .. H u- . : i- I i: i \ i 'll ii i h i . tii : > , i i - . \ . 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JT.h(eitDmoewra.<.hc(n.u(cu.J K( mnvinmpiamii.yI.I.MA.nllSu<nmd.uMii/c.liiie. .ui)i. Kost. \. K. Koi. .nnl J S. aed6trraaavdhae.sitpooe5slnpasptlpFit"otueyenehea.icafmcttverrhemtlntieeaeIhmerdefnrvbdyaeihotpe>tmealheu2u!dlfslfyaesimi.iaicde4.rsil1asd2imdlai.t2sydln?o.ntl4aii-oiesrVencd1.ierrmc5ah>dIwoic-l>i.u.naeIns,enIsayltr,,efyleutcisVslroeireneeaks\asovcnisbu2yltdilfities2lwesdroiuio.d2.asesi5apnritt(d.s..rrbi4.tv1ooiIuee0.ibn,.Icn5ne,nd.unIlest-rciWcrtste1dsuehyesvii7nJdeeeuinlmeUusteitlructpyriilurhdetior.lcued*uiairinsiiretnIisiuiecclKncmIuikbnsealduy.lsyosnlalessec.dhutsuunnurynl'uluatllIlusi-larttuia2Ultyiluetirlnoe.tv2lmril4eddynddiee./.i4s.seme5serds'.s-euI5iuuiddc1neau-lrruac1eodmltpssdh2thime.ele5huepcvaiooslklIduppifniudnisu.lnlveuain5iaasenesesn.tdtme.ermiiNiiutcap.ems.ca2umul:cau'nckfatulnvs7eoeciyliaudvtiuiulaelsuh2lulsptrraru.evac4eptsuinvirisaa.rollee5tcdu'ltsnsrdtu-ivrsupees1ieiItieu,renrhmtiwluucmlu5niiyttvamrirnidnyllivnwllcnalyuelduipyeauyl.niey.ssluenupar..Il1iecrtsnsIlIeo7pcutema'.titsurtry1ehduseeerle.eieircsvr.neutms*eeeiuh.svitndiyidliusuiuainnIormmsvlieiemlllshiliyyidudeeeel.l 7. /.//i*r/v n ! 2.4.5- / tllhl iit/h t nrv H N ur/itun il'i ini'/Ih * tih lt lln lm ll nt 11 ,2- I f |/c 'i/iii/i'n "S 1 In mtilf mviiin .</ n-pritiliHIhm. 1. \V. I . i m l i . J . \ . I i h >s i \s . M . ( I . M v v v iiin n iv . an d ( Y D i i k i s j u k . D ep artm ent o f Ptiarm acnlnyy and I rnlnyy. W es! \ irym ia I inversus M ed ical t einer. M uryanin w n . W est Viryim a. M a le m ic e tre a te d u h v a r y in g d o s e s ir.25. 12 5 n r 25 m y k y d a ily . 111. p o i u l 2 .4 .* - ir ic h ln r n p lic u n v y a c e tic a c id 12 .4 .5 - 1 l led In a s iy iiU ic a iii r c d u c iio n h i l l ie a b ilil s u l d ie pr stale y la in l lu a s s im ila te r a d io a c tiv e te s to s te ro n e I I - I I ' l . K c y u r d lc s s u l d ie d u s a y e . (Ik a s e r a y e re d u ctio n m d ie u p ta k e ul' I - I I * by d ie p r o s ta te y la in l a s a b o u t u tie -d iir d . I h is ir e a im e u t p eru sl d id nut cau se any siym lica n l ch a iiye s in d ie r e la lis c am o u n ts u l I -I I ' m etab o lites in d ie p r u s ta le . but d ie a b s o lu t e a m o u n t s o f u least d ir e v ru vlio ste ru u ls e r e lo w e r e d Ivy Ih is lie r h ic n le . I lie In y licsl d o s e re y tm en o f 2 .4 .5 - 1 iv t/ . 25 m y k y d a ily lit) c a u se d a 5 5 " .. r e d u c tio n m d ie levels o f d ih y d r n tc s to s ic r o n c -ll'. a 5 7 re d u ctio n ill .iin lr o sia n e d io l-l I ' a n d a 14'*.. red u ctio n m prostattc undrosieoednm e-l I `. A cu te dose reym ietis lulled lo alter d ie assim ilation ni la b e le d te s to s te ro n e by d ie m o u s e |roslate y la in l. I lie Ill-slay d o s e r e y im e n o f 2 .4 .5 - 1. h a d n o siyiutican l ellevl u p o n lint hm cnnverw oii ul I -II ` lo us rad io stero n l m etab o lites in lin n in - yeiiutes id lite r. I'nsilm ciM w ith 2 .4 .5 -1 d id m il alter cu ller die y ru su n etn e responses o f die m a le w s a i^ y v a ir y o r y a n s m ir d id it all'ecl p r o s ta te y la in l fr u c to s e le v e ls . A ll ln m y h ses a c c a ncessory ix y h jfc ( 1 `c A .M P a n d A I P le ve ls e r e u n a lfe c te u by d ie lo -d a y .id m im s lr a lio u o l 2 .4 ,5 -1. y^ttpM Kary d a ta in d icate d ia l eillie r d ield rm or 1 )0 1 alter diese b io clien m al l wiifiA&gj- / . :p ap a r a m e t e ^ M liip p o r t e u in p art by a y ra iil fro m ih e I iiv ir n iiin c m a i P ro te cim ti A y e iK s It. Ilh' Hi iml li'aHifnn l a/ 2. V- / )ii /ilm~ti{iJh*ii*\ I(/I i ll! I. Ill 1 2 .U- /11 um! 2.4 ..*.- /i nh/m'1'/ifh-iknimi-tH- tiul 1 2 .4 .5 - / i < . i/rn. W . (). lit Ks 111 ,u n l I . k i> s < iiiiH . I X `|varlm enl o f l*tiarm acoloyy an d lo sico h iy y und Ifcp u rtu icn i o f P lisM o io y y. Ila rim o u th M ed ical Sch o o l. H anover. New Iluni|K liire. iK . P. Sn iid ii. I Ik * lic r b tc id c s . 2 .4 -1 ) a n d 2 .4 .5 - 1 . a r e N u l l w eak o r y u n ic a c id s a n d im y h l he c*V(XXleil t o Ik * l<-tra n sp o rte d a c .n c l y by re n a l tissu e . I h is p ro(vosH n i lia s lY v n e v u n tm e d u s u iy tin.* tissu e slic e Cw] f-- r n .-V 0 528 527 : ' U tifl t ' * r f f best kS S44: XMSIH/U is; IUM I III M Mil IIM, e Iv. p C technic*. heertttXOp; uptake in expiated In renal tubular secretion. liolli r.il .mil cortical prepared by llie Irc-c-haiid procedure. All mcuhaiionx ere performed .i 25 ( ill UK",. oxygen uilleNN mhc-raise stated. I ie iitiK-cniirsc ot accumulation hy rabbit tissue un characterized hy a rapid mili.il phase and a lower seviMid.iry phase n! uptake, although mi steady slate as reached alter -1-5 hr of incubation. I miuIN 2.4.5-I uus ucciiiiiu- ISl.ilevl In it greater eMenl Ibun 2.4-11 I nr example. ut 5 hr the* iinmm.*slice:i)Kdium distribution rutin M l for 2.4.5-1 ux4Aund for 2.4-1). 2'l. I lie uptake of both compounds w.i siimulaivd h> ueeluie. p>ru\ale. and luclutc. and inhibited h\ MK.cin.ne. I Ik metabolic inhibitors. 2.4- diinlrophviMti ami Huionccfaiiiidc. decreased uptake hy `JO"... as did nitrogen. I Ik cihiipcii' ixv S MmhiNtnr ni' renal organic acid traiiNpnrt. probenecid. reduced (Ik h> Ml",,. Similar ir iiin- aI'nr! churaclcrixiicx wen; iMHeil I'nr rut renal cortical slices. Iii addilMMi significant pnia'Miiin requirement un noted for 11k uptake id hnlli ucutv I liese ilala are inlerpreteil In iik .iii lltat hnlli iKrhKidex are secreted actively hy iIk maiiunalian kidney. Such a process may account Inr (Ik relatively rapid piaMiia clearance reported m witue i n i mi nIiuIkn. (Supported hv 1*1IN rant AM l 't)2i. ` I :* \ . i-n ru h n ;f> iH ii\ i*/ 2 .4 .5 - Triihhtrnpln-nn i .i m i-tie . U n i in Wi m I c i i ! M in im i ttui/nilm. (.illIt . II. I> M mI \ . I . C m ami( n iiis, I.. ( km Mint.. Albany Medical ( nllette. Albany, Ne 'Inrk. Keports dial 2.4.5-tnehlomphenoxyaevtic acid 12.4.5-11 ullcvlN etnhiyniiic development in various npccm.*n. iiiaifiiy rodents. Ilave led unreMilved the ipicxtion of potential Iwurd in man resulting fromexposure to 2.4.5-1 containing a minimal anumnl of 2..V7.X-tc*tmchlorodihc*n/o- p-tlmcin t I ( D ill. An answer In ihis problem un Miutthl hy studying ihe acun of 2.4.5-1 iIk W. m nhinu. in pregnant rumhuman primate Mature female rheNiiN monkey ere mated nh inalcNof proven fertility. I orty pregnant femalcN were assigned in either the control itmup. nr in k of the doMT-levd itmup: 0.05.1.11. and 141.0myt k|t. leehmeal <irade 2.4.5-1 containing less than 11115 ppm I t 'DO a adnnniMered in a No. 5 icelatin capMile hy Ntnniach lube daily I'rumday 22 through day .1Hnt' pregnancy. ( M'Ihe lilcnntrn! iiKMikey'. 1 delivered hveiMfsptmg. 1 1heNfM>ianct>UNahnrtmn rate among untreated females in nurcnlnny inapproximately 12"...t Of ihe It) monkeyn in the tl.l>5 mg kg group, all gave hirth in normal babies. Seven f ihe IiunmonkcyN receiving 1.11mg kg dvises delivered live olfspniig: there aN I stillborn felu*. and I abortion, and I female yet In deliver. Six of the monkeyn rcceiving'IIHI nig kg do-ex hud live olfxpnng; there ere 2 abortions. mid 1 femaieN have not delivered. I lemamlogv. clinical chemixlry. and urinalyxix data obtained on all femalex prior to and immediately foliomg - ihe adnunixiniiHin of the 2.4.5-1' and at 2-itHmih intcrvalx until parturition indicated no toxicity to the female. IViailed examination ol' the live infants and the stillborn letux. inclu ding skeletal X-ray siudx-. revealed no gross developmental ahnonnaliiy in any of the groups, l.'ndcr (he conditumsof this experiment there is noesideiKv that 2.4.5-1 is teratogenic in tht rhesus iiMHikey. nor that n interferes in any way scnh nomtal ilex .`lopment of tlw ; . iSupported hy Kexearch<irant 2 H M-i SI4l22h-tM>front the Naimnal Inanuteot' l .nviror Health Scivncvs. N lll. and hy the National Institutes of Health I raining G iw v! I SUIIIH-tM.iI. III.DrTuhge /\Wiv mniliiactxxmlrar Ue uowf ^umWiitkhtnuiigltm-mil. P1U).e('t.m tn e m m in T n x it it y S ltitlic s . I . Ib t t a , Ffl u^m^H|||fe^||UcianiinaK mk thew ygariyil.iMig (I tvatnietU j^B B H fe^ nctfcatedk i uuy overt. lu i liappens in adtiutustraiion of varuius chcinieah, ocr healinglive tissue flicker early ; hul under continued dosage OCCUISt McNidcr l92S)ado(happarent ni^HHBinii|i^tarihc-nixieeifvct develops. \V .d c II I described it far thedescritKd trtjMWKB6>tt4ik*< renal and hepatic tissues; others the twwienne he*and aiveokir eptd iflSwt'awd for myiKardiuni. This type of tissue w eratcT 12) It is not spedile to ttaftc.HiintaHt featunts: t i l l ! develops icily alter an induced lesion. lasts during tile period 0i 1inducing agent, hul extends to agents causing similar lesions, l .'i It I interruption of die dosingi kdosingasell asf.*r varying nines thereafter. t4i Its duration alter to a I morphological or Iappears i khe fuiKltoti of the turnover rale of alfeeted i-r-i AUll J V-' X.J 537 * [H7S-] 1 AU - Enikeeva NA / AU - Elina UA AU - Dumkina GZ AU - Murtazina LF rm AA - USSR ~ Industrial husiene and health status of workers producing the herbicide amine salt of 2r4-D < SI - CA/086/160445C SO - v sb.r Aktual'n* V o p t . Gidiena Trudar Prof. Fatal, i Tiksikol , v Neft. Neftekhim. i Khim. Prom-stif 1975*45-50 <L LA - Russ AB -- CBAC COPYRIGHT? CHEM ABS Title only translated Dichlorophenoxaacetic acid amine health hazard Herbicide manuf /r 1/ health hazard ISt o S IZMOO _ _ . . T . - 7J-V- r'-.r'-: -f .-r "- A-- - t; . - -.'.I ; \ ...i -T- __" ; - --- ^ - *. - /< - 2 3 7 2, - ( t o c ..rol '00N2 I5S25fl68934 Chemical Abstract! Vol e 98 Puge 99 JcobnpeM.onfyeo6agsm8nPptdye3iip.lnrcn;3-ailidh5sddadmebei,uenGrxsaeteaitMsdmrxcSaipbhwacnpeoylladnaeosseirutneruzphrro)e-reoe.cMcd_,ipoyr_auarccinerrl-Celexatd'olnilytplnahiitcoost,oceaesnbhxnoudG.iorafo.enlnwli.mooneitgTe(tuhOisish!entiteemeilpr"oopa.'wncwls1yiC!ee9ooar7inbrrt4koee,[selrn9.aoar,z0ssoys0c9'mtnr1(Ii2sk-ntbe)0iusae,p8tbdsl.e-cj2c5vets3Beoe]c3llit-lsoi-ttrsvh9lhe..aeeadnnCHuadh(enceEdlexrtuwinviaidleogailattt)nsrhyha.,, mwiBBEyrno-naariiHoot6rstgoirtw8leaes.9xtr)ttini.tees9ap,,,l6csJatc.hihPotVnelheeoddeTnsurmrTthoniWctcoueocoe..xlydntfcSii(trcplhTtceohKioeiquth.ely.unaeseIrxft-Hn1ooaaee9crl.fnxfl7m;yfep4Leda,oocait(sbtfieRIou.5)lb,tnord(hye5bSri)osih[ia,nn5ftecaisl85tmmlbio6-n(Rnn8e7Hugoe,9-lsE8tr-oo.im9J6OpnfLo]oaD,htdtlldh(ani)wEv,ear;innhdStamgaioincip)ntihTa.tthgidopnhaothbgDsoicmlacebreoospolcseemslepuksses.,esimtgnisircnedtceEi/lIecgKeroflan.lonefmtueoiwinlooswaattlnny,r;.l t0bmleSapwgecS_tkbh(tNM1ehhR_2Jx.xrolrlrna9oi_0at.ooei6tronoo_5epgm7pmyocrhv5_oeoo69uscbta44_lroawerrN_iucao0dd9eppoi,a0e_zocsstnoi0giL.,n0obs.ilaa.e-unpl.wsei1hD08osrnel.dsmlttoa(yxg.meitsv0e2,.rts9t.inudhpsaroooa,i.k-)(iduraMscn1.ofe,VtgeLofismri]fUit.nEf.seoneacsb1rlnoe.meedoacnoepaS0faHc.Nast.uttftr7iweS6sbt.hihfrOeetle.v.y-asaRIhiide;emec9ddnlntirtgNrryi)titsasevtseotbye.caiaiiPeDlcyabtsoemorpctic./ao(ouyfaadovnlocdtofRoarvmisciiibfgoeitseAlddrmvnemu1ochBawousiptlmsidgsirnea.tnlwiin,owas1tyricutcouiodiet)o.P5nsanoentonti.i-sovdmemaaaunvkraofIudiesedovsdysahtcmfefludeaetldsrulaDacliolre,coctilmucyo-e,nahabieedtecrviiDhbnlsatfghvnunodiesLceeaieoyt<deieocrahr,.imcalbesp.ahraonroyitdiaeeVctntheuIdgndiRniheswafhnxieoame.erroeogc;rsyassenoesissoefro1tntaacdrobegee.dpp9mmenGzgnu-gavifer7aolafneoacnlrtrap4Unetaunmdhtuahttss,atnrn/dnu,eeistdneuzeehaosnh.trdcrdoyob,elsreieteta_aebeUjsp.a_iod(twe._ovca[ar9nvex_ewSl[c9._aan,)nhnaiedsc9ci_t,Ste0nfcfvtDidsohia0LLrfAiRt0cdi,e.mceore0te1.mam.il1ayg)aicxa[12.rsd.dpplGf-r1tci,itgieloi0-u0oeootnredcn.60.tirff-ond8n;pfst.vraecGi707f,rogf%e,-ioseesreteeu--ni5ifvehtnctuigD92.ascleh,hi]sahueol.s]t7.vtnyfeat,mv(si.riah-iuSVTo.Rieunnlaeioc7nO_anynmenmiao_kdh.vus]t_ttd.nain_fhetoeshptaottn_relthsFhsdh_iaVeruoilyassia_rt)eeyoek.e.anert.,.f...tl;,. 3aaiic'lStmivhiinetiiselsrIr,,, cepGoqhonues6t.in9rlomyiMblli6reeisp\dii, D2In8ys3kt-.h:4aniI(vvR;. pmhoenntyhls pihn. ctcIGVFf[tuh9hrhr.d6bail0.eoap)9iuc3d.rr0etl3(iiae0crLdo-nsCaco73eanoatt.3botaeg-.r/; awregrienisneep, E[paCoaW2crsflMo4pthi4ctiveehso-0nisceat-teiy7geniu9ltrthoLho. -Q-wgsaSawbhctiSwampr[t(FWdGAe(MnyheP6PphnrmppeueteLeea66tscopeuia0iornoadapppnhtrcrescp688rabueoctr-lreelhlecle'eko.98)y9s5)rimpithertoan.eataichay.c999mehg7asanrfsfsl;sawieoo87m.dt9aelebl-ieee,rtspfenm1dad9to,tiw,sdecoaoheOhoTi.]ofocDtoeucspdre.bihenocnGKnshtdrcEttDPalaDoeuna.heliblleteealreoaytiEtfr2nlcut3reEet,eVvttiLh.ifarl,0hn)tmdgodt-rm.dAeelvedrv.ePfy).yegin.1yonrfc.eeineeopPb2sesoe1ndelo,trlasncsfb5pis.oa.et-Jtacfn.feakotoe,y2Bmrodlaim.tnttalBon.ni-[Pbrh7eIvsnli)frN,loo6ftpsdei.4rire.eeEoh-ct6tel2twaotgDm0saOchm(iidoansSk%s7tw-rr,soHthuaeeoPaoDpfao7erta-1nsoalasmreiaardiEmum3ogtta5mcfvkVrsnpofuempanlrB-sokaopoeodeaalIepdlero7eiPtmf.ndinw.lfineieixalt,uest]enairdc.edhpdJvisehdsn1pCLtetodenkosyhye.3do>'seQ--xlendweht,doihylseilwrw.mcsreem(ocfumueeN54h)ZTZtcmeaaooham.ermeab0:hwlioearsdehannlsnalaptl.%hene.aenkuoaot(eTibdrpcarghotrIsantlaoTknde,hoosenhc..tilnntcdlo-digewk1eiainsseeaocoaOntR1dkhf9i.art13sdlntfwm(nim.foe0s7relo0iefIn-redczsudyo4onrem0olnStrcctnet,todEknw,hrlshdhemrtioste8Ateoari.ttomecenhel.ehom.mootlraoatncth3o2.aliwShrnosfteledcob(0gncy.aof1mwoerafiot4e,reliny9lahddtclzlorc1rrf)i<ei.Ia7esunoeceois,ete9,ftunihf4ceajowtlllei7asgn[;itaqeltU3,tcstgtn4e8t/suteh.abitut0mgt1ge,3rn6hchKdrifeiASa5%sb(cefni27eei-sldFu-kovaepinsoka.17bd-1digiipc.Lrrtda2Hm((noeei1a[ssaoepota3p3rdy76mldoietiycddAfEaG)n)dtmlhnc.-d0ezl,si,imsnie6rdttencBhboeex.e-tiie(l.i3M2rh]a5lwoo.sawEli,nndra/asl4st5vr1vevTtilans)liraifwtugebr1e-aoiein-cawkbgtn(nhed3nneid5rtu-eeaiaIlnasa)yodye5dosen.0esg),,s]t,r.,f,,,,/|1--|I1I, dsceasAathipoxnacgpenycrcdnpaeee.ilyedlpfiecx,ictLorcapasfancittotptine.eeto,rrdtnldmane,tbydiopuldisiffpetttipfotfdlereofAnearertoesfyrsotnerdaocnewuekpxevcphclseeo(oorItatmsa)wowsnel.[pliad72tnsnh93p.oo8daMsdtb5ot.ratAesig-eycda8awrnsrp.t5no,tmops-aib5oneecru]dwatonhmrtueteri,rlhlnoaddeeapacadrotctrfbooeodedamrrleirndifptdotctefhutoevoecerrtpebrroenreedupcenalotgdasitefnrdetrdiitobtoimyopmmntnbohseteapahbssitutethhsaldhieamt3ouotb3irwrbiaoaig4nnaengithiddgnhsstt ts2fcKW1hrto,69eaa4emh97egn-4e0eDtpln,0se,ane2amM.srvnaopieia(mnngr5snCaoe)iupy,nanaerenonelao8ddvcctD3e,iesdi-isnra4ns(toIe.lI0)tgmhn..ey0ssn(t[N2d.R2i%raAoc3ouPn0rlspdikycs0str)hhzao-.ocaian6lpnhtpn6.eos,age-s.vn25er.,got,]sM4iened-GdwoDsep.secteochrrNaofaeeewam.IKp;nso,rlieeaban-dtsneKiUhdot7tse.oShs.srze3SaabilbnRotlilet7cve)ttvi.ahwtdh(e,eIeleeeIV5o.naaayfo-mmm6pNpprim*r.aln.odereotaotPeinfc(aisLiatunpuaacalalmnaibitidn)r.r. OCHj COjH [wpiacImhE1n2nnure2Th3oo6sdtrSeda19tbn0d-.nen0itu73irlchen0F'c0-abniso53editao,autp5denotnsa-h(tnpl3,omRfhyoat]EwtNaeutahodrgsfe.maetsfLiruMtrve3)emc,m.1ec.ooa1n;atocnp/rmTraWetyUpo1soraol0fcssihagnitme1hdfenlh2tda6thenkoa.en54vsnegrtLd.-eonoserDDlp3amvtoft,1srtaWihpsocab,oeeymrnhRidUeoetnseo..fodaSanfttndFmehShteC.caeaRehenHttBdss()odoaRS.mA1miwarwr0eNeinea0neitaAXddtavihaisgnsMoentteprerfeC3,ogra1lrso-,/kaze5kSm1idrhdic7nipaa0unite/etmtiB.ctotcvthheNarihiLiyamdyfetalttaylslheeucyhemnrecheohio2om1cLfomn7ri9eDnaao7tinmnacis-4sfoIpetgc,oshospoisrduornltlteoitmteeh<eohn3s9dsidean3sse).., OCMj COjH TR6depodtPfeto(Ii(ahnrAvnPuf9olinrieNreaseaaahz9suonrzz&r66nanalpveni-bbeculyb997sostNhmteyorl.tspmme.ib900vxoipAteto.10(.0ecraBoae1e1e.a4rn5dt9tdGlaiseG/nsq,[ro72ctoeb93tot2oiktt(hs7ou0his)iRUhf.ve.Ln.nd0[ewiHu9iSmDAtMdm1tMahs0bySioi--isc1c.gitnxeie09sfR)nhel,t'td/g1)t9we.Didik,)otv.,cl'o--.s.eaigy64ichT2nivI2strk/8n]hsoinIP5e,dMnFeht-nh4lnse0aroa7seaaaiot-i.sor-bnlT.syb]Dr1naltyfto,itm:iDleiiictfGaimytcaterhza(hopno.aacNodlIi.lk(edIuor)nccllRovAgrkNKorgltsalaoyulDhamh.Acu[lenatpspc[oin9seahcrosnpgT5iriviv4sc)dnvaiom.aa7oa.fei,il-eionenponn-ok.7saon,vM8igeroist5rpevcLeea8riEoefaU-dhakat7,n.-7dnsipdoo,t5esS(Ged]eaTbiiIdlris]Stnh.r)tyao..aBe.yi.Ryensayfd(wradMgeanpcs.VaM(korii,eTreotvtsobofudexh.eexe;ys[g,aTeW.sr9bnciosecdM.ndtoi0enrnUhhUuloewKde7aTateITerposaSs9t)sniohDoositmnsteS-nvheheblle6grR'.aafieetec1a7.ls:[dii),re-9tiMin-9e[.ensmaro.781v20btecmcv4e]i3tani0ridtSo,d,,hinil,7end2uAan.uveiiaN--gs0ul3,iV2lcs0Itttsle7rl.ea6nytei12a.oeaei(np9-rsrv,D-6vnm8eg7tAi2oBlie)d.nceedP11eIf,].,l.. TCStsivikaspI2KNiooospmt.itln.cihra6o1frv6oxsadooaeocp9p4eGloo9oipinVpcucvaua0ht(clx0r.heeht)6iak.s0bcyiae0e:.ysen)sydsd9cbalrd8ss;iisn(ooSaovie-hste.uEuLs:i;r.tI(< Ri[oAo[wwLG86awaasbpbiniws73Nss7rffnntots0ntriTiouoe4d/6oi4i0iiaosirnooa1tdtmtqtub9tmt4uuioPs4ttehrh0srdphih-ehhhu0nu0oucccp0ne1uuhu-bev1id7non-3atler-ofl(9Inlrsuoe7;brti0;75ci3n.t.rfcri f- D0 M2156182 606 46 AU - Konstantinova TK > Shevelo F5 TI - Mutagenic activity of the combined effect of the herbicides 2,4-0 end 2,4,5-T - CA/099/017746Q - Gig. Senit.i ISS 4, 1983,21-2 - CBAC COPYRIGHT! CHEM ABS The combination of 2,4-0 (I) (94-75-7) and 2,4,5-T (II) C93-76-5) (given via the stomach as the Bu esters) uas mutagenic in rats in the dominant lethal assay. II uas considerably more mutagenic than I. The more mutagenic effect of I and II together, at a smaller dose, exerted a general toxic effects, suggesting selective action of these herb ie ides. nL II DOW2 I 56 I 8 I 607 2C AU - Konstantinova TK i Shevelo FS AO - Saret. Med. Inst., Saratov TI - Cytogenetie activity of the combined affect of the herbicides 2,4-0 and 2,4,5-T SI - CA/101/22451BS SO - Gig. Sanit.i ISS 9, 1984,28-9 ALBA -- HUS CBAC COPYRIGHT'- CHEM ABS A combined exposure of 2,4-0 C94-75-7] and 2,4,5-T (93-76-51 at dosas d o s a to threshold or at levels detected in the environment, showed cytogenetic effects. A combination of doses (0.05 mg/kgJ caused a greater cytogenetic effect in the rat bone marrow cells than that exerted by individual herbicides. This reflects a potentiating effect of the herbicides. The cytogenetic effect of the combined herbicides at small doses was selective and specific. The highest mutagenic effect in the bone marrow cells was .from the r L. I-- I [ r irL [ .< t ' . : ' DOH215 615 5 633 IS AU - BISHUN NP ; WILLIAMS DC ; MILLS J i LLOYO N ! RAVEN RN ; PARKE DV TI - Cromosome damage induced by chemicals. SI - HEEP/74/0A127 SO - CHEM-BIOL INTERACTIONS; 6 (6). 1973 375-392 AB - HEEP COPYRIGHT: BIOL ABS. During the past half century there was a substantial increase in the number and extent of usage of drugs food additives pesticides and other environmental chemicals. As a result mutation-induced susceptibility to disease once largely self-eradieating is now conserved and even propagated. In addition, over the same time period, there uere added to human internal and external environments, numerous synthetic chemicals, the cytogenetic properties of some of which uere reviewed, and to which man's metabolism has not necessarily been conditioned and adapted, and which may have the potential to augment the number of mutations of each succeeding generation. Far more must be learned about what humans are doing to themselves and their planet, and the fetuses of unborn children, and to the genetic heritage of these children, by the permissive use of the chemical wonders. It would be impracticable that one should wait for time to reveal harmful mutations before the chemical mutagens are researched and eliminated. Chromosomal studies and evaluation of mutagenic potential of all new and and established drugs, food additives and environmental chemicals should be integral aspects of the current practices of safety evaluation of these materials, and the same stringent principles should be applied to the numerous chemicals net with as solvents and intermediates in industrial processes. Persons exposed to high risk., such as those working in.chedical industries, or patients on continous chemotherapy, should be offered routine chromosomal moni toring, and the appearance of adverse effects of abnormalities notified and correlated. 17518 0SI9SI2HOQ: 63 8 AU - BALO-BANGA MJ ; ANTONI F 5 ALTMANN H i VINCZE I i KOCSIS F TI - EFFECT OF 2.A-D ON SEMICONSERVATIVE- AND DNA-REPAIR STNTHESIS (CASE REPORT: BULLOUS DERMATITIS AFTER EXPOSURE TO 2,*-0J SI - EHIC/73/01Vi6I SO - BER OESTERR STUDIENGES ATOMENERG> NO.2218:1-7,1973 LA - ENG AB - EMIC/ORNL SEE: CA 81-10307 I L ru . L [ [L iL rL D0H256146 L [ C L r L L r 642 76 AU - Anon AO - JRB Aisocinttii Inc. i McLean VA. TI - Review of Literature on Herbicides Including Phenoxy Herbicides end Associated Dioxins'- Volume I. Analysis of Literature SI - NTIS/PB82-147414 / SA - Veterans Administration Hashington. DC. Dept, of Medicine and Surgery. SO - Govt Reports Announcements ( Index (GRAtl) Issue 06 1982 OD - NTIS/P882-147414> 338p Pk - HTIS Prices: PC A15/MF A01 AB - TD3: Public Law 96-151 enacted Oecember 20 1979 mandated the Veterans Administration to conduv..' a comprehensive revieu and scientific analysis' of the worldwide literature on Agent Orange and other phenoxy herbicides. The need to conduct such a review was in response to an increasing awareness among veterans the Congress and the public of the potential long-term health consequences of exposure to these herbicides and the contaminant dioxin as used during the Vietnam Conflict. Volume I presents a detailed scientific assessment of the literature concerning U.S. military personnel exposures to herbicides such as 2>4-dichlorophcnoxyacatic acid (2>4-D) and 24.5-triehlorophenoxyacet1c acid (2,4,5-T). The following Topics are covered: environmental fate and monitoring metabolism enzyme induction and mechanism of action human exposure to TCOD from industrial and military uses toxicity and mortality; mutagenicity and carcinogenicity. Each chapter concludes with references. Final rept. rL CRI NUMBER \ i -/: yO s ; o u c r - / _ / 5 / r n p vc ~ }\ rn ^ ntlTT^r w -, DO/W CONFI NFo rm atio n R &D REPORT D O W C H E M IC A L U .S .A . R&O REPORTS SHOULD REMAIN ON THE PREM ISES OF THE DOW CHEMICAL COMPANY C 3 A S TMN T TOXICOLOGY RESEARCH LABORATORY I NUMC3 HZPQRTL A 9 0 R A T 0 R Y CO O i HET K-QQ2372-(27) d a t e .s s u e o .14 October L a U, NO. 1N9O.80 1 i 7 i 9 0 i0 i0 i0 i7 iQ i8 Dose Levels of 2,4-D in Forest Workers 19 *u, Thor >si pages in FULL REPORT J.C. Ramsey, F.A. Smith, T.L. Lavy, C,N. Park, and W.H. Braun fro Uj ' H- Pfriuvr* J *rk ip 'f/'s 0 P. V l i N E A * 3 S I G N A T U R E D ESCRIPTIVE SUMMARY WITH CONCLUSIONS: T h is report is: j ] INTERIM F IN A L a n d .Ttainly: X new r e v ie w The dose level of 2,4-D absorbed by forest workers during the helicopter application of 2,4-D sprays has been determined. Three crews, each comprised of 6 workers, were engaged in 2 applications of ESTERON* 99*C herbicide. During the first application the workers used normal clothinc and work practices. During the second application they were instructed to use more stringent protective measures to minimize exposure. Measure ments of airborne 2,4-D during the spray applications revealed that the respiratory route contributes an insignificant proportion of the total potential for exposure. Total daily urine samples were collected from each worker on the spray application days and for 5 days thereafter. Analysis of total urinary 2,4-D provided reliable estimates of the total amount of 2,4-D absorbed. Fourteen of the 36 exposures did not reveal detectable quantities of urinary 2,4-D. Of the 22 exposures with detectable quantities of urinary 2,4-D, the maximum dose level was only 0.0557 mg/kg and the lowest was 0.00038 mg/kg. Those workers remote from the operations (supervisors and observers) received even lower dose levels than did those in closer contact with the sprays (pilots, mechanics, and batchmen). The low dose levels observed following spray operations using customary precautions (first applica tion) were reduced slightly following spray operations using more stringent precautions (second application). Computer simulation of predicted body burden of 2,4-D upon repeated daily exposures demonstrated a maximum accumulation of only seven-tenths of the daily dose. In conclusion, the very low exposure potential demonstrated by this study, coupled, with the low toxicity of 2,4-D, supports the continued registration and use of 2,4-D herbicides. *Trademark of The Dow Chemical Company. ^Department of Agronomy, University of Arkansas, Fayetteville.__________ DISTRIBUTION: DEPARTMENT files R & 0 ADMINISTRATION C E N T R A L REPORT INOEX ( 5 S l d g , -- Mi d l a n d ) L copie.s D i * fri bu t ion I i i t s cont inuad an attached paga. FORM C-4300 PRINTED R-3 0 1D0H2155721 DOSE LEVELS OF 2,4-D IN FOREST WORKERS J. C. Ramsey, F. A. Smith, T. L. Lavy^ C. N. Park, and W. H. Braun TOXICOLOGY RESEARCH LABORATORY Health and Environmental Sciences 1803 Building Dow Chemical U.S.A. Midland, MI 4864014 14 October 1980 1 Department of Agronomy, University of Arkansas, Fayetteville - 17522 2 Z i S S I ZMOQi DOSE LEVELS OP 2,4-D IN FOREST WORKERS J. C. Ramsey, F. A. Smith, T. L. Lavy^ C. N. Park, and W. H. Braun ABSTRACT The dose level of 2,4-D absorbed by forest workers during the helicopter application of 2,4-D sprays has been deter mined. Three crews, each comprised of 6 workers, were engaged in 2 applications of ESTERON* 99*C herbicide. During the first application the workers used normal clothing and work practices. During the second applica tion they were instructed to use more stringent protective measures to minimize exposure. Measurements of airborne 2.4- D during the spray applications revealed that the respiratory route contributes an insignificant proportion of the total potential for exposure. Total daily urine samples were collected from each worker on the spray application days and for 5 days thereafter. Analysis of total urinary 2.4- D provided reliable estimates of the total amount of 2.4- D absorbed. Fourteen of the 36 exposures did not reveal detectable quantities of urinary 2,4-D. Of the 22 exposures with detectable quantities of urinary 2,4-D, the maximum dose level was only 0.0557 mg/kg and the lowest was 0.00038 *Trademark of The Dow Chemical Company. ri.r'5/ ?""rIT']T1h1 17523 liZZSS I ZHOQi -1 - mg/kg. Those workers remote from the operations (super visors and observers) received even lower dose levels than did those in closer contact with the sprays (pilots, mechanii and batchmen). The low dose levels observed following spray operations using customary precautions (first application) were reduced following spray operations using more stringent precautions (second application). Computer simulation of predicted body burden of 2,4-D upon repeated daily exposures demonstrated a maximum accumulation of only seven- tenths of the daily dose. In conclusion, the very low exposure potential demonstrated by this study, coupled with the low toxicity of 2,4-D, supports the continued registration and use of 2,4-D herbicides. 1752 msizMoai INTRODUCTION A reliable assessment of the potential risk to workers during pesticide applications in the field is dependent on accurate knowledge of the quantity of the pesticide absorbed into the body. This report concerns measurements of the amount of 2,4-D absorbed by applicators of 2,4-D formulations in the forest. EXPERIMENTAL In an experiment conducted by T. L. Lavy (1) eighteen different workers were each engaged in 2 separate forest applications of 2,4-D formulations (ESTERON 99C applied by helicopter at a rate of approximately 2 lb. acid equivalents per acre). In the first application (Tl) all personnel followed normal work practices, followed label directions, and operated in compliance with regulatory requirements. During the second application (T2), in addition to the foregoing procedures, the workers all wore protective clothing (disposable coveralls, chemically impervious gloves and boots, and clean hats), were instructed to wash before rest stops and meals, and were instructed in further good hygiene practices by research personnel in the field?- "^Deviations from prescribed operating conditions are noted in the report by Levy (1) . 1D0H21 55726 -3- near the batch trucks at the heliports revealed detectable levels of 2,4-D esters. Only 2 of the 5 air monitors placed directly in the spray areas revealed detectable concentrations of 2,4-D esters (equivalent to 0.033 and 0.167 pg 2,4-D per liter of air). Further corroboration of the negligible exposure hazard to phenoxy herbicides via the airborne route is.given by similar results following both aerial and ground application of 2,4,5-T sprays in the forest (8). Patch Sample 2,4-D. Widely varying quantities of 2,4-D were detected on the various patch samples. But the poor correla tion between the estimated quantity of 2,4-D absorbed based on these data, and the amount excreted in the urine (see following section) shows that this indirect method of estimating the absorbed dose has little validity. In a similar study with 2,4,5-rT spray applications in the forest, patch samples were shown to be inadequate indicators of the amount of 2,4,5-T actually absorbed (8). Urinary 2,4-D. The analysis of total urinary 2,4-D (on a daily basis) on the application day and for 5 days thereafter showed detectable quantities of 2,4-D for 22 of the 36 exposures comprising the study. The total quantity of urinary 2,4-D excreted on the application day and for 5 days thereafter DOH 215 5 7 28 -5- in the urine as 2,4-d and 2,4-D conjugates by a first order process with an average half-life of approximately 11 hours^ The foregoing data demonstrate that urine is indeed the major excretory route for 2,4-D in both rats and humans, and that urinary excretion is an efficient process that can be described by first order kinetics at non-saturating dose levels (i.e., below approximately 50 mg 2,4-D per kg (2)). Therefore, the measurement of total urinary 2,4-D and its conjugates during the spray application day and for 5 days thereafter (as reported in Table 1 and Reference 1) is considered'to be a realistic approximation of the total quantity of 2,4-D absorbed. Further support for the reliability of urinary 2,4-D measure ments in estimating the absorbed dose is derived from compari son with another closely related phenoxyacetic acid herbicide, 2,4,5-T. This compound is also excreted almost exclusively in the urine of rats, dogs and humans (5,6,7) by a first order process that is apparently independent of the route of exposure. And the PGBE esters of 2,4,5-T (10), like the PGBE ^Sauerhoff et al. (4) calculated the half-life for urinary excre tion of unconjugated 2,4-D as 17.7 hours. However, the inclusion of urinary conjugates of 2,4-D with these data (subjects no. 1, 2 and 3, reference 4) indicate an average half-life of approxi mately 11 hours for the excretion of both conjugated and uncon jugated 2,4-D. DO M2 1 5 5 7 3 0 -7- that the half-life values for the dermal absorption of the PGBE esters of 2,4-D and 2,4,5-T in rats are similar, approxi mately 20 hours and 24 hours, respectively (3,10). In order to calculate the pharmacokinetic fate of dermally absorbed 2,4-D in humans, numerical values for the rate constants of absorption and elimination are required. Based on the considerations above, the dermal absorption rate constant of 2,4-D esters in humans was assigned the same value as that for 2,4,5-T esters (half-life = 18 hours) (9). The urinary excretion rate constant of 2,4-D and conjugates was assigned the value previously determined in a human study (half-life = 11 hours) (4). These values then allowed the calculation of the amount of dermally absorbed 2,4-D that is excreted in the urine at any time following exposure (9). This calculation reveals that approximately 99% of a dermally absorbed dose of 2,4-D esters would be excreted in the urine as 2,4-D and conjugates during the exposure day and for 5 days thereafter. These values for the rate constants were also used to obtain a computer simulation of the body concentration of 2,4-D that would result from repeated daily dermal exposures to 2,4-D esters. The results of this prediction are shown in Figure 1 in which the body burden of 2,4-D is given in units iGc&'imLn,vi! hr-*xiiji*U, - 1D0W2155732 -9- usual (Tl) versus more stringent (T2) application procedures, possible differences between application crews, and different job descriptions within all 3 crews. Even though the dose levels' received by the workers operating under usual conditions (Tl) were very low, there was never theless a slight but statistically significant reduction (p<0.05, two-tailed Wilcoxon matched-pairs signed-rank test) in the dose levels received by these same workers when utilizing protective clothing (T2). Of the fifteen expo sures in which urinary 2,4-D was detected in one or the other treatment (i.e., either Tl or T2 ) , 11 exhibited a decrease in dose level during the second exposure (T2) whereas 4 showed an increase in urinary 2,4-D. Among the 3 different crews, there was no statistically significant difference in dose levels when compared by a nonparametric analysis of variance. However a nonparametric t-test revealed that the workers of crew 1 received a significantly lower dose than did the workers of crew 3 (p<0.05). As would be expected, those workers in closer contact with the sprays (pilots, mechanics, and batchmen) received a significantly greater dose level than did the workers more -V.-- '` *1 1 752? -11- DOSE LEVELS OF 2,4-D IN FOREST WORKERS J. C. Ramsey, F. A. Smith, T. L. Lavy, C. N. Park, and W. H. Braun HET K-002372-(27) Problem #: 179-0000708 Date: 14 October 1980 Oo ro <_n c--CnO4 WRITTEN BY: J /O^ Cr . R a m s e y j ^ J ^ l u D . 1 Toxicology-Research Laboratory 1803 Building 14 October 1980 `i iS 7 n -h '\c / g/ 3" / s-r>________ F. A. Smith, M.S. Toxicology Research Laboratory 1803 Building 14 October 1980 T. L. Lavy-, Ph.D. Altheimer Laboratory Department of Agronomy University of Arkansas i j / r 7U<_JL fc /iS / IC j C. N. Park, Ph.D. Health & Environmental Sciences 1803 Building 14 October 1980 ji-1 h) l o i >i f f *1 ________________ W. H. Braun ' Group Leader Toxicology Research Laboratory Health & Environmental Sciences 1803 Building Dow Chemical U.S.A. Midland, MI 48640 14 October 1980 now mm - i - 1 TD O W 2 I55 736 - 13- TABLE 1 ABSORBED DOSE OF 2,4-D IN FOREST WORKERS ESTIMATED FROM URINARY EXCRETION OF 2,4-D* CREW 1 - Filot Mechanic Bat chinan Supervisor Observer Observer mq 2,4-D/kg Body Weight** Ordinary Special Precautions Precautions 0.00179 0.00044 0.00215 nd nd 0.00055 nd nd 0.00053 0.00038 0.00056 nd CREW 2 Pilot Mechanic Batchman Supervisor Observer Observer 0.0557 0.00232 0.0189 nd nd nd 0.0237 0.00516 0.0196 nd nd nd CREW 3 Pilot Mechanic Batchman Supervisor Observer Observer 0.00206 0.0136 0.0377 0.00692 0.0011 0.0013 0.00192 0.00388 0.0219 nd nd nd *From T. L. Lavy (1) , Table 21, p. 48. **nd 3 not detectable at a detection limit of 0.04 ppm 2,4-D in urine. L i u I BIOCHEMICAL RESEARCH LABORATORY THE DOW CHEMICAL COMPANY Subject TOXICOLOGY AND HYGIENE: 2,4-DICHLOROPHENOXY ACETIC ACID \\ \ File T23.14-11-1? RChe ge .' d 1219 Fin'd 6-9-48 Work By E.M.Adams To: Britton's Div. Att: B. N. Schrauf R. C. Dosser J. B. Arnold Safety Dept. Att: John Knight Dr. H. H. Gay T2.2-10-1 chick /-.'c-yi' UNIT INDEX A summary of available information. INDEX HEADINGS Acetic acid, 2,4-dichlorophenoxy - Rept. By CD O fV3 <-n cc_-n CO SUMMARY 0? HAZARD The toxicity is such as to present but minor hazards of systemic effects. Skin irritation Is possible from heavy prolonged contact with strong solutions or the solid acid. There is no hazard of absorption through the skin. SUMMARY 0? TOXICITY The systemic toxicity was moderately high as indicated by single and repeated oral feedings to rats. For single doses: Largest dose survived by all rats = 0 . 3 g./kg. Smallest do3e to which all rats succumbed = 1 . 0 g./kg. For repeated (20) doses; 0.3 g./kg. rapidly produced serious injury and death, 0.1 g./kg. had but very slight deleterious effect and 0. 03 g . A s * had none. " --------------- ----------- THJS REPORT IS THE PF.C,r i*TY TM*T r-f.j 1; 1** v ;y 3 io c h e m ic a i R e se a rch 123*14-11-1 Page 2 L a b o r a n * . ?-r Examination of the affected animals revealed minor effects in liver and kidneys, the major action being local irritation In the stomach and gut. When lncorporatcd^lnto the diet of rats, there wa3 no adverse effect at concentrations which the rats would eat, 0.03$ and less. At concentrations of 0.1$ and more, the rats refused to eat. The dichlorophenoxyacetic acid had but very slight effect-- - the skin of C3 when tested in solution upon/animals. O There was no evidence of absorption throug.i the skin. ^ In making and processing 2,4-dichlorophenoxyacetic acid ^ there appears to be no serious hazard of systemic effects. Atmos- co~~on pheric contamination by dust offers the only concern and this would have to be quite severe to be excessive. Any such excessive exposure would probably be first indicated by symptoms referable to irritation in the upper respiratory passages or by gastrointe tinal disturbances. By comparison with other common substances, it offers very little hazard of serious organic injury, even from repeated exposures. Animal results Indicate little irritating action upon the skin. There is the possibility that prolonged heavy exposures to solid or to strong solutions could cause a dermatitis. This applies to both the f r e e acid and the sodium salt. c - c In the use of 2,4-dIchlorophenoxyacetic acid, the solution concentrations are sufficiently low and the total amounts involved sufficiently small*that there appears to be no hazard to the appli cator or to farm animals. ec*8 -r * l ________ ----- -----5.44 Safety Services iqS! Department D0H2 I 551(50 A STUDY TO ASSESS THE O C C U P A TIO N A L EXPO S U R E TO 2 ,4 -0 H E R B IC ID E S Date: January<3> Report: SSD-81-1 i *y Er ^ jt Health & Safety Division D0H2155451 Prepared by: yf &U S^T Libich Safety Specialist Industrial Hygiene Central Safety Services Reviewed by: J.C ^T o Supervising Safety Specialist Industrial Hygiene Central Safety Services Reviewed by: K .Y . Wong Supervisor Central Safety Services Approved by : D.A. Watson Manager Safety Services Department 1 JS 1 Distribution List for Safetv Services Department R* 1 i i w m G. Armitage(4) M. Haynes R.W. Steeves C.G. Bieber K.Y. Wong (12) R. Wilson 1. R. Hamilton D.A. Watson D.A. Lee J.W. Lawson J.A. Grieve L.W. Woodheed G. R. Childerhose J. R. Carrigan B .K. Smith V.D. Shute P.R. Greenway G.E. Estey G A Mackie L.B. Crossing N. J. McMurtie G.M. McHenry W.G. Morison All Safety Officers Librarian (H.O.) Librarian (Research) G.E. Fraser (2Q). S. Libich (.10). Sr. Health Physicist Health Physicist Sr. Health Physicist Supervisor-CSSAC Supervisor-CSS Director Manager-Health Services Manager-Safety Services Manager-Safety Policy & Program Assessment Director Technical Superintendent Director Manager-RMEP Technical Superintendent, RMZP Director Director Sr. Safety Officer Director Director Acting Manager-Safety Director General Manager Director BNPDS NPD GS Rolp Pickering G HSD HSD HSD HSD HSD HSD H5 G27 H5 G26 H 4 G27 H6 G4 H6 G3 H5 A27 . U5 A6 US B6 HI6 Al H9 Al D&D Branch H10 Al H3 A27 H16 Cl Z S H 5 IZMO O ! HI Manager-Distribution Operations U5 E6 Safety Specialist-Industrial Hygiene CSS ~i 7 1DOM2I551(53 TABLE OF CONTENTS 1.0 OBJECTIVES 2.0 SCOPE 3.0 INTRODUCTION 4.0 METHODS OF STUDY 4.1 Study Development 4.1.1 Breathing Air Sampling 4.1.2 Biological Monitoring (Urine) 4.1.3 The Urinary Model 4.2 Sampling Strategy 4.2.1 Air Sampling 4.2.2 Urine Sampling 5.0 RESULTS 6.0 DISCUSSION 6.1 Exposure vs Spray Operation 6.2 Major Exposure Pathways 6.3 Significance of Air Exposure 6.4 Significance of Urine Concentrations 6.5 Tordon vs 2,4-D/2,4-DP Exposures 6.6 Weekly Urinary 2,4-D Variations 6.7 Comparison with 1979 Urinary Levels 7.0 OBSERVATIONS AND CONCLUSIONS 8.0 RECOMMENDATIONS 1 *'*Tl o7 DON2155454 -1- 1.0 OBJECTIVES The objectives of the 2,4-D study were 1.1 To evaluate the exposure hazard to 2,4-D at selected work sites. 1.2 To evaluate improvement due to changes of work practices and personal hygiene. 1.3 To assess the need for further monitoring in the future. 2.0 SCOPE This study consisted of taking breathing air and urine samples during work with Tordon 101 and 2,4-D/ 2,4-DP at five selected work locations. Results of the tests are compared with existing guidelines for assessing the significance of exposures and with the type of work operations being performed. 3.0 INTRODUCTION The term "2,4-D" refers to the chlorinated phenoxy herbicide 2,4-dichlorophenoxy acetic acid and its 35 derivative salt and ester forms. 2,4-D is used to control a variety of broadleaf plants in home lawns, agriculture and in rights-of-way for power lines. To reduce drift and evaporation of 2,4-D most commercial products are produced as high molecular weight esters or as amine salts. These are diluted with water and applied as an aerosol spray. 2,4-DP refers to 2 (2,4 dichlorophenoxy)propionic acid and its derivative salt and ester forms. Its herbicide properties are similar to 2,4-D and is often mixed with 2,4-D in a 1:1 ratio. Tordon 101 is a trade name for a product made by Dow Chemical Co. containing 2,4-D and picloram in a 4:1 ratio. Herbicides such as 2,4-D are toxic to plants because they interfere with chemically similar plant hormones known as auxins, which control plant growth. Human and animal metabolic process is different from plants and adsorbed 2,4-D is quickly eliminated from the body via the kidney with no metabolic transformation. This difference in metabolic processes makes 2-,4-D highly toxic to plants but of low toxicity to man. 1 SS4SSIZMOQ -2 - Public concern about the potential adverse health effects of 2,4-D has intensified since the emer gency suspension of 2,4,5-T (2,4,5-Trichlorophenoxy acetic acid) in 1979. This concern stems primarily from the chemical similarity of 2,4-D and 2,4,5-T as chlorinated phenoxy herbicides and the question of 2,4-D being con taminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a manufacturing contaminant in 2,4,5-T. Evidence now seems to indicate that the harmful.effects of 2,4,5-T were caused by the TCDD contaminant. TCDD is not theoretically expected to be found in 2,4-D because the manufacturing processes and starting chemicals from which 2,4-D and 2,4,5-T are made are not the same. Other much less toxic dioxins are theoretically possible in 2,4-D and they have just recently been detected in trace amounts. 2,4-D has been in continuous use for more than. 30 years and now is the most widely used pesticide. More than 70 million pounds of the active ingredient are dis tributed annually. The scientific evidence available at this time does not indicate the potential human expoure at current guidelines is sufficient to result in human health effects. The objective of this* study was to systematically evaluate the exposure hazard of herbicide applicators working for Ontario Hydro. Due to weather conditions, height of brush and terrain in which spray operations are conducted these herbicide applicators are exposed to 2,4-D in varying degrees by breathing the aerosols or through skin absorption by touching wetted brush, hose or spray equipment. This report evaluates such exposures and assesses their significance from the occupational health viewpoint. 4.0 METHODS OF STUDY To determine the exposure level of workers using 2,4-D herbicide two methods of measurement were used; namely (a) personal breathing air sampling to determine average daily exposure level (b) biological monitoring (urine) to detect absorption during the work day. 4.1 Study Development cn 4.1.1 Breathing Air Sampling cc_nn It was decided to use personal sampling pumps to sample the breathing air of each worker as he performed the herbicide spray operation. However, a suitable adsorbing medium had to be found for the 2,4-D. The use of midget impingers (with ethylene glycol) was not suitable for 2,4-D in a field study because of the rapid evaporation of the adsorbing medium over the sampling period and the possibilities of.spillage and breakage of the impingers. Solid sorbents would be ideal for such field applications. It was decided to use the standard NIOSH fluorisil sorbent tubes. Methods for desorbing or extracting the 2,4-D from the fluorisil were then developed by Chemical Research. A series of spiking tests of 2,4-D on Fluorisil tubes gave recoveries of 86 to 99% with an average recovery of 92 5%. After extraction the -2,4-D is transformed to the propyl ester and analyzed.by gas chromatography. The loading on the sorbent tubes could not be estimated with any accuracy so during the first week of the study half and full day samples were taken in parallel. Each sample had back up tubes to determine breakthrough or transport of 2,4-D on the solid sorbent. Aft analysis of this first week of sampling it was found a single sorbent tube was sufficient to measure the full day exposure of the workers. 4.1.2 Biological Monitoring (Urine) Several studies have shown that the phenoxy herbicides such as 2,4-D and 2,4,5-T are absorbed by the body and almost 100% of the absorbed dose is eliminated unchanged via the urine. Thus the urinary concentration is a valuable indicator of the total body burden of 2,4-D i.e. that which adsorbed by inhalation, through ingestion and also absorbed through the skin. U lu lili 1 df} ZSiiSSUKOO 1 -4- In a previous study of forestry workers using 2,4,5-T (1) it was shown that inhaiati accounted for a very small fraction of the 2,4,5-T entering the body. The major fraction of the 2,4,5-T was absorbed through the skin. The quantity of 2,4-D absorbed may be quite different from the quantity to which workers are exposed under field conditions. During the handling and mixing of the concentrated chemical a very small skin exposure may be the equivalent of a full day of field exposure. Therefore, a proper assessment of the poten tial hazard to workers during herbicide appli cations is dependent on reliable estimates of the total quantity of herbicide absorbed under all conditions. Since 2,4-D is essentially unchanged by the body the urinary concentrations can be used as a guide to the minimum estimate of' the 2,4-D absorbed by the body. 4.1.3 The Urinary Model Previous studies with 2,4-D ingested by human volunteers at a dose of 5 mg/kg of body weight showed that the 2,4-D was absorbed into blood plasma by a first order rate process with a half life of 11.7 hours and then eliminated essentially unchanged by an apparent first order rate process with a half life of 17.7 hours in the urine (2,3) . No data exists for absorption rates of 2,4-D through the skin. The herbicide 2,4,5-T which is similar to 2,4-D absorbs through the skin in an apparent first order rate process with a half life of 18 hours and is eliminated in the urine in a consecutive first order rate with a half life of 23 hours (4). For the purposes of this model the absorption rate through skin for 2,4-D is assumed to proceed with a half life of 12 hours which is similar to that of absorption through gastrointestinal tract and in the same ratio as the absorption and elimination rates for 2,4,5-T. These considerations provide the basis for the model below. P P P PP FFFFP FF F FF FFF -5- Dit) B(t) E(t) where D(t) = amount of 2,4-D remaining on the skin to be absorbed at time t B(t) = amount of 2,4-D in the body at time t E(t) = amount of 2,4-D excreted at time t ka and ke are first order rate constants for absorption and excretion respectively. The differential equations and initial con ditions describing this model can be expressed as follows: Initial Conditions -lea D (t) dt D(o) = Do d B(t) = ka D (t) - ke B (t) dt B (o) = 0 d E-- ] = ke B (t) dt E (o) = 0 Calculating ka and ke from the previous studies, ka . 0^693 = _ 0 ^ 9 3 _ = 1>4 day-i t^ 0.5 day ke 0.693 1.0 day" 1 0.7 day Using the integrated form of the equations for the cumulative quantity of 2,4-D excreted as a function of time following exposure the following equation is obtained. E(t) = Do (1 -k-e-- e-kat ke-ka -k--a------- 0 -ket ka-ke 1 'DOW2155458 Figure 1 Fraction of Applied Dose of 2,4-D Eliminated in the Urine in Each Day 6*IZMOO m mm v i i i i i i i n i i n H i ' DON2 I551(60 6- - Substituting the rate constants above E(t) = Do (1 + 2.5 e"1,4t - 3.5 e_t) Using this equation the plots in Figure 1 were obtained. From this figure the following observations can be made. The maximum amount of 2,4-D is eliminated during day 2 following an absorption or ingestion of a dose Do of 2,4-D. This equals 38% of the absorbed or ingested dose. This figure indicates that after an absorption or ingestion of an amount Do of 2,4-D then 30% of this amount will be eliminated in the first day 38% in the second day, 18% in the third day, and 9% in the fourth day. In 4 days 95% of the 2,4-D will have passed through the body. If successive equal doses are applied daily then the body concentration or body burden will build up until the elimination rate equals the dose rate. According to this model and results plotted in Figure 1, this occurs in 4 or 5 days after the first dose. The total body burden becomes approximately 1.5 times Do which is the daily dose exposure. From the amount of 2,4-D eliminated in the urine an estimate of the dose ingested or absorbed can be made. If it is a single dose then the size of the dose will be approximately 3 times the amount eliminated in the first day after the exposure or 2.6 times the amount eliminated in the second day after exposure. If the exposure is in successive daily exposures then the amount eliminated in the urine will approximately equal the daily exposure after the fourth day. Therefore, if we measure the urinary concentration on Thursdays or Fridays then the amount eliminated will roughly equal the exposure rate during that week assuming the daily exposures are almost equal. JBr~V; 1/ ^ DOM2I55461. -7- There are many limitations to this model First and foremost, the dose rates are never equal on a daily basis. The amount of urine output, the biological half lives and the time of urine sample are several other potential factors contributing to uncertainties in relating 2,4-D in urine concentrations to exposures. With this in mind the elimination levels can only be viewed as a guide to exposure estimation. 4.1.4 Urinary Concentration as Exposure Guides Urinary 2,4-D concentrations can be transformed to equivalent daily exposure to airborne 2,4-D and an exposure guide developed using the current TLV of 10 mg/m3. The transformation is based on the standard man who inhales 10 cubic meters of air in an eight hour work day and eliminates 1.4 liters of urine in a day. The equivalent air exposure calculated assumes the person is subjected to approximately equal time weighted average daily exposures for at least 4 days. Thus the urinary concen trations as exposure guides are as follows: Urinary Concentration (mg/kg) _____________________ Equivalent Daily Exposure to Airborne 2,4-D (mq/m3)____ Exposure Guide _________ 0 0.7 0.7 - 7 7 70 >70 0 0.1 0.1 - 1.0 1.0 - 10 >10 Normal Low Moderate High 4.2 Sampling Strategy The study was originally designed to cover four spray areas. Two areas would be where 2,4-D/ 2,4-DP mixture is used and two areas where Tordon 101 is used. Also two types of spray areas were to be considered, i.e. roadside and right of way spray operations. During the study an additional operation was added. This is the mist-blower technique which was used in Kenor-a area. The table below summarizes the study. '1 5 4 62 TABLE 1 Selected Areas and Herbicides Used Area Herbicide Operation No. of ' Walkerton 2,4-D/2,4-DP Roadside 4 Tweed 2,4-D/2,4-DP Right of Way/ Roadside 7 North Bay Tordon Roadside/ Right of Way 6 Kapuskasing Tordon Roadside 4 Kenora Tordon Mist-Blower 3 The study period covered the months of June, July and August. 4.2.1 Air Sampling Air sampling was done daily for each area for five consecutive days or for as long as the weather conditions permitted during that week. Sampling was done only during the actual spray operations. 4.2.2 Urine Sampling Urine samples were taken generally on Thursdays. The strategy in urine sampling was to obtain (a) a pre-operation sample (baseline) (b) 4 weekly samples during spray periods (c) daily samples during air monitoring weeks. Each urine sample consisted of an AM and PM sample which were later combined in the lab to form a daily sample. These were then sent to the provincial pesticide lab at Guelph for 2,4-D analysis. i o CD <_n cn 5 .0 RESULTS 0-Cp3O- The analytical data for the breathing air samples for each of the areas monitored are given in Tables 2-6. The concentrations are all very low so the results have been expressed in micrograms per cubic meter (pg/m3). The 2,4-D:2,4-DP ratios are on average equal in the air samples reflecting 1:1 ratio of these components in the mix. The 2,4-D:picloram ratios also roughly reflect the mix being used; the picloram is generally much less than the 2,4-D concentration. The Tordon 101 spray has these components in a 4:1 ratio. The highest breathing air concentrations were encountered in the mist-blower operations. The urinary concentrations of 2,4-D, 2,4-DP and Picloram are given in Tables 7-11 for each of the areas monitored. In all cases the 2,4-D and 2,4-DP values are reported as the free acid. The preseason values were all generally very low except for a few workers. These may have had some pre-exposure to 2,4-D-perhaps in spraying it on their lawns for weed control. The individual urine concentrations show a marked day to day variation in many cases indicating a variable exposure to the herbicides on a day to day basis. In light of this daily variation it is beet to consider averages for groups of workers to determine trends. klllllflll 6.0 DISCUSSION The air samples provide a measure of the extent of worker exposure through inhalation of aerosols. The urine samples provide a further measure of worker uptake of the herbicides through dermal, inhalation and possible ingestions routes. Since daily variations cover a very wide range it is best to consider averages to detect trends and average exposures. Table 12 shows average air exposures and average urine concentrations grouped as to type of operation. Also the ranges are included for each data set. The broad spread of the data precluded application of normal or log normal statistics.  M am Worker Nl N2 N32 N42 N51 N6 ^ TABLE 2 2 , 4 - D a nd P i c l o r a m in B r e a t h i n g Air S a m p l e s ( p g / m J) Taken in North Bay Area Monday 2 4D Pic' T im et (min) Tuesday 24D Pic * Time t (min) Wednesday 2 4 D Pic' T(immien t) 25.4 5.0 240 15.8 2.4 285 15.4 2 . 8 390 20.0 2.0 2 40 1 8 . 2 1 . 0 205 8.0 1 . 8 300 15.6 <0.4 135 8. 6 0.3 255 3.7 0.9 268 4 .4 0.4 135 2 .9 <0.2 255 6 .2 0 .9 210 7.8 1.5 270 8. 8 0.9 285 9.0 2 .2 390 7 . 0 < 0.2 2 70 Thursday Friday 24D Pic* T i m e 1 24 D (min) Pic * T(immien|) 11.1 10.2 2.5 2.5 12.0 3.3 1.7 0.4 0.2 2.4 334 334 325 325 334 3.7 < 0. 2 325 * Pic = piclora I Time = Samplihg timp 1 - Right of W a " Spra < Operation 2 - Roadside Sp^ay Operation GO ]9*?SI ZMCjG Wl1 W21 W31 W4 i W5 2 W62 TAULE 3 2,4-D and 2,4-DP in Breathiny Air (py/m1) for Walkerton Area Monday, Jun e 23 T u e s d a y , J u n e 24 24D 24-DP Time : 24D (min) 24-UP Time (min) W e d n e s d a y , J u n e 25 T h u r s d a y , J u n e 26 24D 24-DP Time (min) 240 24-DP Time (min) Frid ay, J u n e 27 24D 24-DP Time (min) 5.1 11.5 5.0 11.8 3.2 6.3 3.1 6.7 2.8 4.9 2.4 3.0 3.0 5.4 2.6 4.1 340 173 346 138 339 156 334 140 9.8 8.6 15.5 17.0 10.8 15.6 10.3 9.7 3.9 3.3 9.7 10.1 1.9 1.8 < .3 < .3 325 60 255 155 360 155 360 105 , 6.7 8.0 15.6 17.8 11.5 10.5 14.6 11.2 2.6 4 .1 2.6 5.5 3.6 5.7 4.2 .6.9 348 90 348 143 355 150 360 175 8.1 10.5 30.9 37.3 8.9 10.0 3.8 4.8 2.6 3.2 2.6 6.5 3.0 3.7 3.3 5.5 370 110 370 110 365 150 365 170 13.7 12.3 300 23 24 135 4.0 6.3 4 .3 300 5.6 120 5.2 4.7 2.0 2.2 2.6 0.6 6.3 285 6.1 155 2.3 315 3.3 120 2.1 465 0.9 270 - R o a d s i d e S iray 0 rrerati >ns - Ricjht o f W y S p r ly O p e r a t i o n s SMS ; izh 00 r Worker Til T2 1 T3 1 T4 1 T51 T6 2 T72 TABLE 4 2,4-D and 2,4-DP in Breathing Air (|ig/mJ) for Tweed Area Monday, July 7 T u e s d a y , J u l y 8 W e d n e s d a y , J u l y 9 T h u r s d a y , J u l y 10 24D 24-D1 Time 24D (min) ! 24-DP Time (inin) 24D 24-DP Time (min) 24D 24-DP Time (wg) (min) F r i d a y , J u l y 11 24D 24-DP Time (min) 11.6 12.7 361 0.37 0.48 310 8.1 9.9 322 8.8 12.3 317 10.7 14.8 337 13.3 19.2 4.4 6.1 16.7 22.2 9.4 12.6 14.9 19.8 12.1 16.4 6.1 7.9 120 140 126 127 121 165 165 13.6 19.1 5.3 7.0 13.6 18.8 23.2 28.4 10.1 12.6 345 342 345 245 325 30.5 40.4 6.6 7.'8 18.6 23.9 17.1 19.5 16.5 19.1 12.1 15.5 7.9 10.6 384 243 376 380 382 330 330 35.3 44 .1 218 11.7 12.7 213 24.9 32.4 213 15.7 17.1 216 17. r 23.1 216 13.5 19.5 200 7.0 9.5 200 1 -- R i g h t o f W ly S p r jy O p e r a t i o n 2 - R o a d s i d e S iray O jerati m ' 9 i t s s 1 ZMOC 3 Worker Kll K2l K3l K4l TABL1S 5 2,4-D and Picloram in Breathing Air (pg/m3) for Kapuskasing Area Monday, July 28 Tuesday, July 29 Wednesday, July 30 Thursday, July 31 24D Pic * Time t 24D Pic * Time | 24 D Pic * Time | 24D Pic * Time j 24 D (min) ; (min) (min) (min) Pic* Time l (min) 2.4 0.3 203 1.0 <0.2 219 1.7 <0.2 222 2.5 <0.15 333 8.2 10.5 171 7.2 0.6 223 2.7 0.22 369 12.7 1.4 306 13.3 3.6 390 8.7 3.8 368 15.6 3.8 390 8.7 2.4 391 3.1 0.6 356 5.6 0.6 396 5.7 1.5 383 1 - Roadside S jray 0 perati an * Pic = piclori m t Time = Sampl. ng til te i 9</SS 1 ZMC Q i i a l i m n TAULE 6 2,4-D and Piclorani in Breathing Air (pg/in1) for Kenora Area TABLE 7 2,4-D and Picloram in Urine (mg/kg) for North Bay Area I' ' W H W ' M ' M ' H H * W Uri, M, TABLE 0 2,4-D and 2,4-DP in Urine (my/kg) for Walkerton Area TAULE 9 2,4-D and 2,4-DP in Urine (nij/kcj) for Tweed Area Worker Kl1 K2l K31 K41 TABLE 10 2,4-D and Picloram in Urine (mg/kg) for Kapuskasing Area June 12 24D Pic July 1 24D Pic July 17 24D Pic July 24 24D Pic July 28 24D Pic July 29 24D Pic July 30 24D Pic July 31 24D Pic August 1 24 D Pic ND ND 0.35 ND 0.04 ND 0.27 ND 0.63 0.33 2.54 0.44 0. 12 ND 30.55 0.18 6.81 0.84 6.18 1.30 6.11 0. 22 3.09 0.14 2.69 0.01 1.92 0.01 8.15 0. 14 0.01 2.69 0.12 0.44 0.28 1.53 0.19 0.96 0.03 2.21 0.12 3.17 0.22 4.71 0.16 7.28 0. 03 ND 1.41 0.0 3 0.44 0.03 0.16 0.01 0.24 0.08 0.98 0.15 2.24 0.14 3.08 0.03 0.21 0.08 AVERAGE 1 - Roadside ipray Operc cion 2.07 1.45 1.87 2.85 6.17 . Z, : t S i 1ZM OG TABLE 11 2,4-D and Picloram in Urine (mg/kg) for Kenora Area ! fllfl C TABLE 12 Average Air and Urine 2,4-D Concentrations for Different Spray Operations Operation Air Samples No. (|jg/m3) Men Samples Mean Range Pre-Spray Mean Range Urine Samples (mg/kg) During Monitor Week Season Mean Range Mean Range Roadside 13 53 6.4 1.0-15.6 0.28 0-1.87 1.2 0.04-8.15 1.6 0.04-30.5 Right of Way 7 38 13.0 0.37-35.3 0.15 0-0.38 1.7 0.15-5.74 1.9 0.04-6.62 Mist-Blower 3 9 55.2 16.2-91.3 2.6 Lai cC."?? 3 iitseIZMOQ- m m m m -10- 6.1 Exposure vs Spray Operation The data in Table 12 shows that roadside spray operators received the lowest exposure to 2,4-D herbicides and also has the lowest urine concentrations The mist-blower operators on the other hand had the highest air exposure levels. The mist-blower operators encountered 4 to 8 times higher air concentrations but showed only 2 times higher urine concentrations. 6.2 Major Exposure Pathway To determine the fraction of body 2,4-D intake via inhalation and dermal exposure the roadside and right of way data are considered together. The mist-blower data set is very limited and is considered separately. The average spray operation is just under 5 hours per day. During this period an average worker will inhale approximately 6 m 3 of air. Using a mean air 2,4-D concentration of 10 yg/m the average worker inhales 60 yg or 0.06 mg of 2,4-D. The average man excretes 1.4 litres of urine per day. Using an average urine concentration of 1.5 mg/ the average excreted was 2.1 mg/day of 2,4-D. This indicates that the majority of the 2,4-D must enter the body through dermal absorption; air inhalation accounting for a very small fraction. In fact, 35 times as much 2,4-D was excreted via the urine on average as was inhaled. This finding is supported by a study of 2,4,5-T exposures where dermal absorption was estimated at 1000 times the amount of 2,4,5-T inhaled with air. (1) 6.3 Significance of Air Exposure The current TLV guideline for 2,4-D in air is set at 10 mg/m3. The average exposure of this study is 0.1% of the TLV and the maximum exposure measured is less than 1% of the current time weighted average exposure for an eight hour day. f i ^ s s i zmoqi 92<iSS I ZHOQ -11- 6.4 Significance of Urine Concentrations The TWA-TLV of 10 mg/m3 would result in a maximum daily intake of 100 mg for an average man breathing 10 m 3 of air in an eight hour day. This guide does not consider other absorption routes. . Using the urinary model developed earlier the equilibrium dose rate is approximately equal to the excretion rate to maintain a constant body burden. Thus an average excretion rate calculated earlier of 2.1 mg/day allowable dose. represents only 2% of the mnaximum ' 'l ` The maximum excreted by any man was 30.5 mg/kg, or approximately 43 mg/day. This falls in the range of "moderate uptake" as defined in the exposure guide in Section 4.1.4. 6.5 Tordon vs 2,4-D/2,4-DP Exposures Table 13 shows the average worker exposure levels using Tordon and 2,4-D/2,4-DP herbicide formulations. TABLE 13 Tordon and 2,4-D/2,4-DP Worker Exposures Herbicide Tordon 2,4-D/2,4-DP Component Air (yg/m3) 2 ,4-D Picloram 8.6 1.6 2 ,4-D 2,4-DP 10.0 12.5 Urine (mg/kg) 2.37 0.34 1.37 3.28 m I v. 01 If 0 H 2 15 5^77 - 12- The significant items here are that air exposures to 2,4-D are about equal for both herbicide formulations. The urine concentrations appear signi ficantly different. On average the urine concen trations were higher in 2,4-D when using Tordon, however, the urine concentration of 2,4-DP was more than double that of 2>4-D. In Tordon the 2,4-D is formulated as an amine whereas 2,4-D/2,4-DP are formulated as esters. This may account for differences in absorption rates through skin and elimination rates in urine. 6.6 Weekly Urinary 2,4-D Variations The daily air and urine concentrations showed wide variations. The duties of driver/ sprayer etc. were often rotated among the workers so individual job classifications could not readily be brought out. In a few instances, e.g. Kapuskasing area where two workers were mainly involved in spraying these two had significantly higher exposures to 2,4-D than the other two workers who were drivers. If the average of all the workers for each area is taken on a daily basis we-begin to see the result of cumulative daily doses. The urinary concentrations are generally low on Mondays and increase through the week to reach a maximum on Thursday or Friday. This is illustrated for each of the regions in Figure 2. Variations in type m of spraying operation work methods, equipment, herbicide formulation, etc., can account for the different levels observed in each of the areas. Most of the mixes used were 100 parts of water to 1 part herbicide liquid as received from the manufacturer. The only exception was in the Kenora area where the mix used with the mist-blowers was 16 parts water to 1 part herbicide. This may account for che much higher air concentrations observed for the Kenora area. Table 14 gives the average air and urine concentrations of 2,4-D for each of the areas. fT -13- TABLE 14 Air and Urinary 2,4-D Exposures by Areas Area Air ug/m3 North Bay Walkerton Tweed Kapuskasing Kenora 10.0 5.2 13.4 6.6 55.2 Urine (mg/kg) Monitor Week Season 1.40 1.10 0.6-7 0.60 1.5 1.8 2.7 3.6 2.55 6.7 Comparison with 1979 Urinary Levels Two weeks of urinary data were taken in 1979 to measure worker exposure to 2,4-D herbicides. That data consisted of a Monday sample and an end of week sample, i.e. Thursday or Friday. \ Figure 3 compares the average of the 1980 weekly urinary concentrations for all the areas studied with the two sets of data obtained in 1979. This shows that the improved awareness and improved personnel protection in 1980 has reduced the average urinary concentrations by 3 fold during the course of a week's exposure. It has been shown that the majority of urinary 2,4-D comes from dermal exposures rather than inhalation. The wearing of gloves and removable coveralls probably accounted for the major reduction of worker exposure to 2,4-D. Now that we know dermal exposure is the major exposure pathway then the protective equipment and operating procedures can be reviewed with this in mind. 00*12 ( 5 5 * 7 8 m g/kg I ZM0Q FIGURE 2 - Weekly Urinary 2,4-D Variation -K - North Bay - Walkerton A - Tweed 0 - Kapuskasing x - Kenora 17563 00M2I55'(80 I- 1 1 1 m m m m 9.0" 8 .0 _ 7.0 - 6.0 ` 5.0 Co o> E 4 .0 - FIGURE 3 - Weekly Urinary 2,4-D Variation for 1980 and 1979 0 m 3.0 - i m 2 .o r* 1 .0 ________L . MON ____ L_ TUE _ i ________________________I-----------------------------------L_ TOD THURS FRI f7iJ <Ku ` I9 HS S I 2M0 -14- 7.0 OBSERVATIONS AND CONCLUSIONS As a result of this study the following conclusions can be made. 7.1 The major route of worker exposure to 2,4-D herbicides is through dermal absorption. Comparison of the breathing air and urinary data indicates at least 35 times more 2,4-D is absorbed through the skin than is inhaled with the breathing air. 7.2 The average breathing air concentrations were 0.01 mg/m3 which is 0.1% of the current TLV of 10 mg/m3 for 2,4-D exposures. The maximum air concentration for a single day was 0.1 mg/m3 which is 1% of the current TLV. 7.3 The average worker excreted 2.1 mg/day of 2,4-D in urine. This is 2% of the maximum daily allowed exposure via inhalation. The maximum urinary elimination encountered was 43 mg/day. This maximum falls within the range of moderate exposure to 2,4-D. 7.4 Mist-blower operation provided the greatest air exposure to workers at 55.2 ug/m3. The right of way spray operations average 13 ug/m3 2,4-D and the roadside operations provided the lowest worker air exposures to 2,4-D at 6.4 ug/m3. 7.5 Improved work procedures, protective equipment and training provided to the workers reduced the maximum average weekly urine 2,4-D concentrations by a factor of 3 times over those measured in 1979. This reduction may also reflect increased worker awareness to possible hazards of these herbicides. I n i ;r* gr s u) J Z 8 H S l ZHOQ -15- 8.0 RECOMMENDATIONS 8.1 Work procedures and protective equipment used by herbicide applicators should be reviewed keeping in mind that the major worker exposure pathway is through skin absorption. Inhalation exposure to 2,4-D has been shown to be minimal. 8 .2 Further reductions in 2,4-D intake can be achieved by washing of exposed skin areas and changing of . clothing which has been exposed to 2,4-D residues as soon as practically possible after exposures. 8.3 There is a great variability in urine elimination rates throughout the day. Better exposure values can be obtained if 24 hour urine samples are collected rather than spot samples through the day. The 24 hour samples can be better related to the urinary model for total exposure calculations. The 1981 herbicide monitoring program can be restricted to urine monitoring as air exposures have been shown to be negligible. Urine monitoring should be continued to check work control methods and to continue our data base. ERtiSS I ZBOQ -16REFERENCES (1) T.L. Lavy, J.S. Shepard, J.D. Mattice Exposure Measurements of Application Spraying 2,4,5-T in the Forest J. Agric. Food Chem. 1980 , 2j8 626-630 (2) M.W. Sauerhoff, W.H. Braun, G.E. Blau and P.J. Gehring The Fate of 24-D following oral administration to man. Toxicology 1977, 3-11 (3) P.J. Gehring and J.E. Betso Fhenoxy Acids: Effects and Fate in Mammals. Ecol. Bull. (Stockholm) 1978, 27_ 122-133 (4) T.L. Lavy Project Completion Report: Measurement or 2,4,5-T Exposure of Forest Workers University of Arkansas 1O U.S. DEPARTMENT O F HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Healtn rrm s Soft Tissue Sarcoma Risk in Swedish Agricultural and Forestry Workers u Keratin Wlkiund, B.Sc., 3 and Lan-Erik Holm, M.D. 3 C? O r-o cc_nn ABSTRACT--Th# risk of soft tissue ssreoms foiiow ing possibls xposurs to pbsnoxy acid hartotdda* wss studied in 354,620 Swed ish m en, who wers sm pioyed in agriculture o r forestry according to a national census in 1960. This cohort was further divided Into sis subcohorts, on sssumed exposure to phenoxy acid herbicides. The m ost commonly used phenoxy a d d in Sweden was (4-chlo ro 2-m ethylphanoxy)acat(c a d d (CAS: 94-74-6). The reference cohort encompassed 1,725.846 Swedish men em ployed in other indus tries. A ll persons were follow ed up in the cancer-environm ent reg ister during the period 1981-79: A total of 331 cases of soft tissue sar*om as was observed in the study cohort and there w ere 1,508 cases In the reference group [relative risk (R R ). 0.9; 95% confi dence interval, 0.8 -1 .0 ]. No subcohort of agricultural o r forestry workers showed any significantly Increased RR, nor was there any significant difference in RR betw een the subcohorts. Despite the greatly increased use of phenoxy a d d herbicides from 1947 to 1970, no tim e-related increase in th e RR o f soft tissue sarcoma was found in the total cohort or in any of the subcohorta.--JN C I 1986; 76:229-234. srwseoossaaostomfpwwe(tbfmfpttooi7otriteiooulfrfdnnrhihsaouooliiienn-daIpSuuIpysgpttdtfeneasnd1mnnsnththhmiuhonomnpasonhnsrecto1icseeylfemdegdoedorfoeocd)doshtrltasnistes.Shofelnoirxxieiasli"lasa.aaodtntoopawewtitfroyatllyOaillensighgiilmtdwssxelmnrxsscsdecHaansteiancitaiesib.taeehydno.scuhcndfgiotoouaxidxegdnsseetuiabceaTssrmsnanheetcpusHrnrsrddytottnolwtouehdidheseghmotes(,iarstsuasos6ewcsaedededesidhsskashrep)aebrtsuetatmsidSt.ersthcadarusduespsnoornhhr(ccaaercTvowropeiem1iodgrffobacrelosttifemororohp2lsiiucnempfotkesitvtm,doesfttdid-fheolodocmahrsoacso2rihaa(sudamdieShsfuncasletsu3s2spproetooiceiluwadelofnehl)ceow)(anhetwosrwtsttrStb,1o-uoroainiisreooogoerartseoej)ohlwtsrx-nrdowsehanamfeesra.ssaovgaibnaysessprgsclueoels.rotoenrtSsdtpeto.snptoihderrieax"hirenrrssooonlTbooni.tar,idekiayr.bcoulufsufstsogAngnmdvhnieAtfmthueaheuotmknesmTaiiaepdeoeerrlennoetcgcsoedccidostvchinhflssblrptcasluohasfitsroerceiuey(adeuetunsotrxrpmt2dedlcmed(netgaheurodacpmift)hhx4hoxaydnntolferewol.imeaoatioaa-poenieupiotixdnerl6tnfcotteocrsoslddonoihxyiwtbo)udatotbrfaocsowstnap(.hopotsirglioeelrnaboi3uthnstcaectneeoginoDhdnihfsaruar-reiesorvcdcgsbeckceedca6eelnsihrseomutlnrtserdoveeecpeoe)hoydirecrvureetrrmsainspfaoniiaeaowaesessroiihodnsslhtot.sssfvsmsniabkahearuheo(eaeefpeenrctrpm1a-evbpertswannoiHrefhyecede3rsrlxoeesbiaonrypsaieroeooneogn,tatopaftnibrodctuorwnlginrdrmr2ebnfhoruiaoasehukldprodorrt1esstdeegsoiuststngtrilieetoiroteuxnleeeheeesoee)euhoebsretairslrf.pyddnnkddgyseeessss-sllt coaciodcbpwt1nroonoef9areeocT6tmvndtrnwrrma1iessdkehopoitreaseuadeodaroef.srin,sgetnnsseatddreewediiemits1sncinih1tr9tsgasci9(i4sisni2cac77fusokt3chs3oehtfepe)a,mhoe.scrnotoefhrspTsdbngreceasmaeeahrarir1tettbpcsehiawie9aessolrlse7etseoeiCmla0gseoybntnEednnaoap(yn2iRisawpans4ti1notisgtci)9sinuhtt.rnrm6tohdaetu1toufasueydasntsS-maeyghberlinwdaeratdeowidirlteeecragnedisusutien1reisnles9ifdsectnho7uuo1ot9rtoopr9chCtr.afhape7ooaElBnnel4npnreaRrdt-enhams7lacel,yeo9niayocensnscudztvenhocisaesevottuxenherewtfpyoddihooaasfeuerftawdelsttirodrihotsismhiisntnudunstrkidhgkeyssses,P* MATERIALS AND METHODS sacmnsaiascwPstisrusnutphnlcoyHhueahoSbTcdlooCdm)rdstrucownemumhesoy6i8oabiridrnechn0d8flehheaceisasi.%oinnoognoccotnntrTaeahmargrh,ogbtdwntiactot.rahhscioo--odtfedrothteiuoiisgmoivtgnnoolnartpsTferithut.nofePteunwh--PwiaerocarfwHebreeeenetHrelaicsyosiTydsarrdtvlsotueehzs6efhreotdn6soe0ouiyroilbedcn0c.iynrtdretncsoehew.oxyesutaftgme9fhhtippcgipouronc0teoeoaorahr%doebberfehstcsdyhatteeisuoeaalohototdatirecmriwrbdatcntrentytloyntoi.iyleencanntehcoeoAweogotonooci3oac9mmopmnccrop7og-r1trhcsud%pfirnrek8icuneepiirwso9eogcnipvoata1aramscaueinoaistcettcsodilaatxditdotiuucsiaanluyoodvnespscwdr1nfivaiuaaca1evt,ssceomly-37to1ditltdi52rdu.9rigowdekouiv54ded4rgndTsir,i,dii0oyh86ntienthytuhe4we2dagg(ifxe5pri0nl2neo(nbepiis5rditrtnnSSvcineoooe)dawoewwswsdet9ghdlrtuhctuseier7rhraehtrioyodade%sihxdeosef,t dA(ipn4ehbg-nebdcnrteckaeex*vnryinoas)tu-ate2sciro-veinainiinlsce(tsahU)i;dy9SldE62p;R0tb4;Te-nCDCRaED*xR<RyD=)2^ar.c4cc2ae-iJadnt,iti7ccicve,h8arel--doed*nreio:tvsrpkPiarh(dHosei)nnl;oi6on0x2eo"y.m4d)pai,5bocre-cpeTniuigac=lioa(s-a2ttiped.o4-rdnd.5:iC-oa3xnMr3idincChc.h1*PolooAnurfo=si- S(O0P8B13trnoS1e18/S8ccvR4Du4okte-oep2)lehnoc.c7ppotegkiXaolivyhmvr-ert,oe6mtdleH8RmCde8Aaen5a.dabnp-tSi0lycrutowIhieAmglferAr8)dCha,S,esneanos1amtno.cs9nci8crdefea5irtraeo;ytttmaEi,ho(cpe8KncKi3e,da:Spit9ernhtwo1mege)ldei.iGSndoStswiluhsokehseepgatdtayeSiPHfsmwahrVoonbesMddJdepuuriiesDcbt2hdati5eillce,pFCaaea1alnor9rFdRtnm8mu5terIne.seonrednslsa'tt(ri8c3otSu2hofa3tafCeGe3r,td3oeyS)un.-ne(a11trnch04aid4ell- 2 2 9 JNCI, V O L 7. NO. 2. FEBRUARY 1966 1769 Cf*frCC 1 230 Wlklund and Holm tfosertswccd2ssbbsstP7ehtwkospwutht1rohoioehoiiitmuhoi,o4esnaaeoioh9ipHvxsa4radoTiSieOniHTdTmsmLOCtorO-svee5hatnntteemsn,onpeirs6es5hihdssiwtpe0mkhnhdaohofscetoenlnl)tbnmmh6dtauleo-ehi'veoi.heseneoeseeeneitnrne0nsaTiarebsric.sflnhyirestetxemsnidxbteos,neatlelcgaT.whiiocnhhnrerseerispisufaycrgenfsifun,(ioennmeeoeeghoutdrane1ootnuctamCroaaflrtrhsiomuhrrggr9motoeaamlpgisugdldnpnreboAbctueoycsre7btaeteefur(dalrsrrsueouuaghfdbieartee1nssnxrfedSoiiebutr2onddiytnsetcutuercns..tie./etteotoi:shslti,sfi--nowedo:srtsoedaeuurt1n4rendis.meutTnreiw.ol:n9snnsenrur,ewlly,beSdaebs1fSgTo,5otht5h1OtgseussdntISrohhasnouius0uce.aw-r-fapaetpownstoehs:fgtona07uudifTrrroniaebrvenphceshmremeteSaeve6dshnbihndcuhedpcMtecdiaaahmd,nlre-htemenauricdmodaos,imaeh5depusnfedinnatnsoisofbooebterCs)hiehrlrenhpeaneodglaetdetirbcifshefonhcMtiisioatsriaenPdntarriawrlord,ncfebnea/ndoosai,nSepotsnnsitgmgAonucnanaekafpiCcenluarshvteumpwhoSfooydungnrpssaiteadtesosdeec4oPsonumexrwinrutrlandentd.dp2tealresyaenmtofAnasmiyssesysatd1ewdauTfeuoncdp,nbdoiinn:eoperw8fssoi,eydon5uatrariraidoaaemdhdtsaa0fd(liSnfmnetiiicntrat2iflra2msn.drt.ensaednnihnhytotk,aeuhmespd,sc42mohduhnstad4oTagdelllrbEs:eub)eeai,iilniyrewmrctyo-lhei4v.f,tionaoefsrswghycnxSeDhrfho,tio-fesectheriwc1oocneroriaernc:Dpseuenmo,oorrone9toieeuiricretirohdsoeihrcb(bscnlk7r.ohfnemlmecnrschSh.Cpyfsosteaeu51i-sc.vonfecalbctuLviMftodauuuyer2iyAtn9oopilcratsitowuaeleetpostcttedbreyrh,7nenirvuhioheSurCn4npxseelt6angamme7eciedstryvioleueo:s1r,csdapttr.iaPpcoits5r,ahi,psdierwsae9utnnaeubttrolnSu9oAh-olttEilode7synrhsdcegmeraTso4afcilwoMnork,s30eeoxrdtognurwenso-een,tsatursse'si(e7wephulmorrhsosonttsCf,Ciuoh.l(tlr.itse5dotin,etosrcg2rfainmehleebhronruAPdpo-tenegsyuces.4sk1rviw.vhet7wec)hpgedgonmaAceugalloS)p..oe)ooulaT,eefthatureecr:attrlaiasahadudpprrehmoaehvavwano,oifntturavbn9naomeeghehrrretennaeidmnnearablaee4etisidwndndrerrehdnddyeossssl-t, Table 1.--Numbceorhoofrmte<madntda ptberssnofntrftnacr*t oc/ofhooilrotto-up in Uu thtdy Cohorts sod subeoborts Mc(1ee9nn6su0in)s oP(f1fe9on6llo1oo-w7--y9ur)p ARgeTOLHOSfriaeittoilmhhrcnvreueeditbcnrrilcuetacufuarlenotrglcurdtcaruueor/ioecrathettruenorinldryattgu/norirmefaolrehsutsrbyandry 1,32766521176144514,,......342018612118522407533566 38401,..,310201113374690219038946.,,,.,..677720367868512141941076 eeeohcovbNafialaccth(ONssaehoimnnaddoratttittfibaPttttifouihiCnooinheihrohxxntxournirnsobvsxireioflacaaaasibooHoucoitesigey:gumdeSFgeeesArpepapmfAbyPCdssihmstctbttdxhtrecsndtrsscruooeedeaoiisiue.etn,doioooucootoheu.ye.eyoSscEsohaynadcnndmtmharsgrre6lsvssoasdepegtlflraoaehtrComstn:,mevieuacreRt1naeoilaueuaoo0treot4dihaarnoaanpesteasoffcdresspapcfr-rtoEl1drgpdgrrerrthersume-tireonacfdoi,d3hfarieeoc.wtsieeweeh7iyawa6urtbdroitoipdc,eReeixbotfnr.raodxrddeotmooeseeecr4ogesaitotr-ponitc.dorand2sbepm,ittticninyefiosmcmxshtm6renu,ninoonoorscqtwiw,enasitooicaaoisprsdCotoAsn-T4nttehvidolonnapxovaamdrhiinpsbauuosz0hesmeasyraxreia-ervscineihi;iExwhCrereig.lsnu,eo1nnudye;Dssredntedanrtoc--ylcadenicaeahitdaoyyieettees-Recmr-tmnrgdDeeetshcoiccfoo;ehacdvn6dtlpgeupeserouacinStrnh)sdiohCuiienwaexbsff)emebtaaytsDreoram-aeninilsnthtcofd,PowiecahhnswddrlpneidenhhmadsixrrettcflfiiakgacfoicrroefcaiswudebiaHuseainotsnoodtsieeseedcoiddocenasltaaeraghuwio,Rouneeosbendbdoddhmmrtrhsdtdsosnosofshuescnhsghsnlrna;oexecmrsnruleeorieueReainam.:nrteuioh62cmhiyoneaoaaonlofsesduaittuaacderdresrtdonnclrTao0te,ponfhuahidgoraeesrhfneercneailt4nhdarTwdfablthertnnbrts.hasxebebbrmCnrdoa.erriai-wptidesitneeiave.owanerxholedtbDpnytteadimolhfdrmancnawDroryoofocispfgotordcdenageptsienosoeoOsseteoaiieerooocwoccufapariruraaugbamalieocDsitsmwsd5cmribnnano2cetCrusmsyoimssenhbsnn;osluluenebrioehstoanetdtctsst,is;is.txmaoiaghiceytetEycelnecertei4cdmaegsatmniannuadbiudoteyhtcltreepuserrcidlorncdooeoms,)asRtyryn,mlhpsmedtypnTevseot.5oerahosauyrcshseahtin2'pa2uatdialalangi.fu,i-ninadtaahsiosvrnotenmhqspmsayaoic,ordfhaensnoTb,tntfatoee4upprturntecdte4dmivsueeuetTugaiusretasbeiaeatccdtoregiio,araosorttbgasrhu,aetmdmuerlf5nvmunt2aoltoamosehy5dal:iiilclotntmsniwtiegieebtsts-oz;ooddiinnf,aummne-u,cbPgceaoaoabof,s4scTdyotRgtrotictewrTupgnnaeddedroueinermeaonx)oHaer,oacrnJaaodo;eatscesi5ha,tirewedrsttncslieRiiarsuhhlynnu,,scia.ahonhonntoanoct2hren-e,feretasunctloupaehstnifdigTtnaohgloedmrssmn6mine,rtimretoonewtbiydotvy4fnrrsyoo.hgsnuahr0teehdrc1ytoatbrtrymdtras.g-eireoiahrokfhmtaei.aeh9dnbbahMtuntiptoaDtnmeniluos;hrhdurfet6teilwaeennnisnpieacniesileTxteDgfhgyioiepsofsc1b.sdossmegminuoaoaiigg,goadrbirCtiioaio.ethsuuwtuftoheehedretsgnporurstoTltttniihynrmi;orahraosxhaedbhtbhiyptomEClasitfeofeotpdegrctoioiaaybsehlnwnohrinueinseoco,cfebminyicrsRufloeliEcntrsTnrraencosnstdreecdormeoootidner)foucexc,ntsuamdohtostuee.htrsReo.acgC)sfhwmhewloelsolteetrmtaopdwlmsilsaluooTutttcsi1phkhtosaouaTawmneDssvosohwoshuuauboismeohhyhmdo9gpteeeetcentrahidnroeaouorinhuhcbelearoronrbo7aoenaDaaettnsrickairrsriydfdyrgeyieesensnnsshsdencrey9sef.estr,sst- JNCX V O L 78. NO. t FEBRUARY 1966 17570 D O N 2 1 5 5 4 4 6 Sarcoma In Fannara and Foraatry Worker* Tabu 2 Observed muter of oft tim * sarcomas in 1991-79. RR, and 35% Clfor th* total period and RR for th* thrt* tim periods ObosefrcvaesdesNo. OB 1961-66 RR* for y r 1967-73 1974-79 TOOSHLiiattolmhhhvnrueeditbcsirrcebuafaruanlogtlncTrdutruuedor/isocrtrettteyaurirnlylatgsuntuirmedyalcohort 253 33411191350 0.9 0.8-1.1 000001......988608 (00001.....481473------11LL1U...07459 0.9 --_ 0.9 0--.9 1.0 -- 1--.0 1_ ._0 0.9 __ 0.9 0.9 *-- =*ths number o n i a in the subeohort was too small to permit division into different time priode. ddwsafSaSgssa((toefpptw(lscco1OoaihrMlatutndliecta9feeectrtcaauoaeesti,STTcoegTroaIuc7dbjrrcreattsnemdrdnaauntrisfctnturh9osuduehtchwohoedhatyonodidcskeiietrippocbfedeoec.nttotrnifaa-Phdohcoaeiltmuoaeohi.oncyg-lrresohioeamaHclntrntrclyndfnoont-reusxrieelnelta-uiuHueodeaoicmguahitrmcda1ntzdecrmla6cnacaunir/rtora9maee(acito,rirho0cecneor2blst6earllottrasbwaolinoguepheer6tdGro0nutolwfloe,btahsrapd)cleesrteraafbidore.edncddvrdaeduazrntwdnndsef,aeoiftsiedrhiaodeuetelonhatrtficefaeinahertaelfhfamro1ffuocgrgaahegidlrtifdoieethe9neaymposciunncoennheicarsiro6basesdtiensco,rnbaeagttuColdei0tdnlmleesssraoisssnJsnecufebnitsfhusl.iri(arrwhvoitstdrieocdtc--sddvcudbnoahnognrpeiffa;ioneshpoyeedsicefweeoa,frurencuAnr-harbpn)1iruogseeifrayraascoeipgooltM9aedcdplpnhrnbuealrernhniRopirr6oenreoeeoteygascslnrrtsdiafytfl1arydrrwseRrrniiooeottdns-ittpbnyd,strhol1timnooChteMh6ustsaiyhneelo,leoeonfwdBn6-iarmseetnEe)antseolyia1f,gn-h.,stv-crdrvttiesnRo9laryhehhHne.cdidefasimr1reTi6lftfsaeoeotseeeernndttrule9oy1aFrlaaheeinhffehlsigdto6drreerletrntevrrmohe)suaeeidouh7hwansdbir.rundvtivrefsste,ptw-urnwehasdpilesheagak7elenrazredtrewurilwt.r(r-ir3taeeticremohriwet2ioehudhalbgnf,idnaehaliAntyef8meo)olpedeehiesebgeDaec,m)sm(tedreetscegrl.nisirea5ttfephkmeensltennriornrotewjed-ye.mecesonThgooffyftcanfarsatreaaoadocorTehorururatbchradst1msstsaloeiirrreloolpcythbh9eedoesacmlmncyefuabdon.c,7occeCnenleguuc,seodnpaeu4rooawaordwtCaarlfewlts(dcrwder-sttahhootl2rswR7s-iaioonsithicttt3foeiootu7ouhnhdhC9--hetetcnnuoaaoeR1sir)rnhnppoged.eedeesl)f.rr,tlt aesdDRocriaoRscfTTyttgorrheritei(niebdn2nsui9esdnht)iuthst.giyeyoepisntsnooaeamttrhBsRacueoborRsbelnmeiscgs.flaooosohwrwufotbaarhhscaneoodtmwehthsDoeotrerregaeadeyencaa(sae2cntlui9cdctd)oyu.yraldaminiptneoedgrnRigotwRodsistuBahbgwregaaesirrlnoPeosuowttpiessshastneoeotdndf RESULTS ctiassBseuesetwinseaetrhnceom1r9ea6f1eirneanntchdeeg1sr9tou7u9d,py awcoetohretoaorltbsoaefnrdv3e3ad1.toTcathaseelsoRfoRf1,ws5o0af8st Metric Relative TabLX i3n.--thN*utmotbaelrcohoofrttoifnttit*h**ut*hrtoa*ratinmta** wptritiohdRt sRtuadniedd95%Cl Time period No. of cases RR 96* Cl 111999667714---767369 11633470 001...990 000..887---111...112 TiXe(ir-atT-tx-i--mnn-GkaBtUedRcklussc1er.--omfR_p{R2h4ea)n.toVxtomyiladt-idsss*u!1e9u4ssa7er-.co7o6fm. pDahea1nta9o-6xo1yn-7oa9dndimns arteedlacuisenRartRoe JNC3. V O L 75. NO. 2. FEBRUARY 1966 17571 232 Wlklund and Holm D0K215544? Ta b u _____ 4.--Numbers o/ casts, R R and 95% CIhibstttowloeegnic1t9y9p1e aonf sdof1t9t7is9sfuosrsOaructowmoalsargest subcohorts and total cohort according to Histologic diagnosis Landhaunsbda/onrdraynimal NCSoM. oOf RR 96% Cl Timber cutting Ncaaicoo RR 96% Cl Total cohort Ncuo.eosf RR 96% Cl LVAFLiieanohbpirugioroisoosimtuoisutorsyauscacromoTrocyscomttaoooohrmtmrcmeaaolraoaasm,ft,uomnaomrerarhovmleirogsmyunxsaaonnssgytaisfrotciembomrmao!ua-s 43 5766 2625382 0.9 0.6-1.2 O1.R0 00..68--11..14 011...900 000...878---11U..15 7 208 4977 0.7 0.3-1.6 01..92 00..74--11A.7 011...180 000...734---112..36 54 10716 3336173 0.8 0.7-1.1 01..90 00A.8--11..13 001...909 000...787---111...302 cTapcsssbteowcpttltubthoiiaaaouunosehufoenssheerbtrTtmTIybbshtstetiagcriecsnwlrhuttumceconelhaeeeyeoiaoeeeooenssrohsjce;mt,pafscteeetehhtg2sxoyesetosscnbxtataoeon.pyshrd,ashtimu,(tfrdrfroemuoro-titocoetotRNtadhacsfprsbmstrofrrabihbtdo,eRstocogtmmrsawewtuleahmdliouanu,iwesarbslbiema0secrahnsureisnaaiecudhcr.oegssod9bcndeei2ouitfmnsonrsiioc-cid,otih1thnn(ttot.afhnhatousom9fro3oi1ntnCenedhlno5th)rtw9dattmrohni.tiodhgl*hese4snensdonre,fT/cene7imgaoRicfCpnoata-otibRhi.oohr7nrnRatnmnRlwtreeotet6Ru:elyothaRalsbaRt.marlu0lfaneenRdecestifoMsRs.lhnuonclhio8Rdirarmbnmotangvr-eCsihetotses1othfanijthawdisbuvoPefou.Rtrosicueln0ecebefifnAadtrlostcrR,itoiirrcastthyenceotshuhtotiatdtapuadi1ocmtshraithso.ancni.rstyeinbe2smaoeetsfnobdtestushlbtddorh(tiaeseuiceetdphg0ali.omcnuo-aebniner.n2aaremssdbfr7egarea)rleasfitt4r-g.ielref,lelihtsry1oy.aoyinircraTecmt.odtoesuiao8niIesaanhsirnmuptntm)addsinneewcegpc.tmfesdttdeaenosotholteTtsdnhyrpyiuhenroaeifolthueexlnietamifiufnfdnomeemcrfoirsdsibrdagtostessoRnuohhbbtwrnoeoanhdibomoyoieeeRstrffnngoes.frrtrttt DISCUSSION scewtfa2esetiiheehinoax0fxxgasrtaeTTrhpppeesncttyooaenhrohh(oif4eovcrcsfeseeeom,taitufeeuxecuresrlorrapo5sdpaaanseef,,ri)nttgotdneehii,aatestmrntnsgeooeub.eeettcrrsaiehrtxxn1yimphtetpteocc5phteweihefue-cesodtcos3smoee-sclststpr0treineuuuuuveeprnrcosyrpdleerdsiheehaxesaalyustieytekahyaletobten.irmonneodffsosooaattrniIstfpa(xiicdflhsu3alnfnhaysatedo0eblcauctoeld)erslcraendngf.heyenotsdyorsetIaccohtiodtn,arxsyanraibuosseysycnndtisoprsowcfduoitwwubasonsinbccode.sd,aorsteieeeRhsNddariesdrsdsketaeasvaRf.ooieersrotseofcarrulrpsudntswiiionmuiesan,intmdkfmrtonegeadoifyuSsxelaerptottslrihtswhdhfrdsuoeiseoetnoienetssshbabtdeucosoataelaissetgbfiosnvetabstehhie1neyietrlmtni5txcepgwscitbcossat,haadRreeueusmtleoinieeeuebdlsRfinydndndaeer dSsdacsadqd2olnppeeetasetiiset(tawtitl11ahetnthu3uonseoieshanc5imimrwdxauhurbi9u5torsssseto)eTmceTrcroono-deOsHpmedoe6nr*df.sateanceer6ppserrannsyspwainoh1vnhscesdsikdoeposanOa4slliitbgceono-isst,oeooeotesafevhiPsmhprorio7noysermemsitttrneesdxysrytwnyoatalifri.3Hcfefhhrdphtpshaeadxnceeyoenmsinn(pesiidaa1eoeAtrdchgeactopugleiduwtxnahhhs9tpeeariolnksareutevotaniltmntgoai5a6xsoeesfboeresiohtgfhnrmr(Scesdtc0neivuv0onfiritnrrac3eboeeaneoestpacpn-bntweisnd1eferoosocs)fakirp(tcdiffsoctoetle1s9tvisies3dufosixiteei0eouhsbgonrtaine5atan9so;exis,1sirdadpf.n-iysitfl.teelh0ngx5osnnaelln6dogt)cnotwoittsiaeonyent'u,.eeoeepswuusdreo0iftsasao1fhsnt(nsauvooohnchdso.owroos)iarOutt,ndu3asesm.S1ot1hitlaroixytrafffrrmss2itcsendiotCdsikcofoomnwel3Nolnrctuavsnyacto)hixtindasuwoedrshe.flE*uabgouweernhtfeepo.lneasratailhtedaltsedhnrssaRhfldesdsiarcoThtwnlitoenO.omeafsiotetsdimsihtrbreidos(ste-eerdrioszhnhstedureeg3to4rotesibyevnanraesdeuhotestpnassar1pecis-s*adrhc0aessesepsdisdpaccb96nluhhowstdst.eeetdfioeys6osch7uib)hoibeensaaotneroprxqevlactys,o0ahitnotlapruaeaevdfdeirornxnrlupsutoiit-enrteovsnlusirnomaicevetanwbtceypcwmlo1nerdvoyiiss(aeecdnnyoraldohsar9ontiis4tgeswvphinr(ntobendrnen1iulisie5ploeu6hsut-yinistsnynmoareedel9tdfd2b0rs6ud,ccfheriorkuorawtosdregro6eaiyh)hah*xerhiae3uwesgteeaonvhrdio.s1e,wsnao(hledaepgn,4nsrdgekpg3leei-swcsnemOmbssisocowyrod)dto8osf7r1atdshocmehilotroumrosiporfla9fu*bv)niiceetaiwebfuiceseksoffc.ndorfhlteeuspeariouiyn.arutpalmd(ealwueaekincnrtteaulluuosln3lylioe.TphhlarliodonnoAtn,elntdmnstoet3saesolueo.terctIhyuirednd.tcrso)yiadctsehbslnteoifrRane.otxeei,Oro,uibhtnenmestseiholoehAstezilddspshsnmaRre.aeeohrch,fmyefruaeneoirustpooetaosmrnoreoAun-atvfaiiteiaafeptioeelyahscnrovntmw1ocnhstrgeinowpfflRcoue9tcpopenrgefmlioedeetytanealsotsaepscrgo0enneolsmRCtoixrtlvtcees6asmbryfusmasuapt*roulteutyflpiftEtaerhstetrihirjrpibroartidxdfghheoeloriroeuoooeeeehveyebtRoooaolatnlry.'yynoedeendndflefrsrssree,eftffr JNCJ. V O L 7.NO. 2.FEBRUARY 19SS j1L *i* Kv_>' s 9 ' D 0 M 2 I 5 5 4 4 0 Sarcoma in Farmers and Forestry Workan ; soAacao(sgivwgcwtswcbttiruuhtsptttwmTta1iob(oaftwrsewstu4losioiwiauaiiaaonn2uihrnaruiosynieeepo9oovetrodtehltxohos-soortseerrnATI3efSesodsuetteshdzroolrd5e6enpdnrtOecnecrspptnrecenhaiureset,)rc.ecbaerodsrewu0ksun)kousonuuka..o,orostodhksoe,san.n;okaifrwl-ieAeyelemetantidtaferlmdlfwsgdtSiernieeot7ngdrFmciehhmneenfSrdaryberunfonmresosersadntpadu9fsowdwcsaredaaetstdahoaswutssddctbieosiptpiioie,ooeeeucin-rascvecuwrsoreuiws1lnc(oteifyxeccesrutsfeoreosucrrmiomxtdtssbso1nevsfm5mehunaedttffnvootaoeoecptsdmwieoernhneuywapey2i0einaufhncnpdeoidkirxeort.uielhecirnnfeooccobt)lecsaelaeogdilsasesoroedaeeteehmstednilrtuhoeshrlaotwornnoathnewrdmnhdahunrtt,tausyrr,,eeesiospaSsontkndnieri"tftienudatocoenseaicssattdirfohnicotwuaatgiefcwosaezidncdsttetptsaUniierntfessdpqoenanytussbcrrhlotefcocgoaioitcooSthlhshlmeaiysuceur1hnttomdsbecttauntfaoinyooortnrctbhuioes,edwhi-eednn!,heUeyaeueinnlaoitdfia5dlmmfpoisreemandinubtecniiftoibsralntt.oiipeefssiunihsgo.lfRaezoRnowhsumdanelofncSedtneaoadthodhtAfaaocredgdnJuatrioi7irsirruetrlisstxdtye.RyRioehoixrtmf1eogfhsthoaeoeaatrtnshcortaasndieccuyeiue.oeuSn9eyaahconugsatsonbshhlpeeoegctncartyornsptdnhrb5uaiwddoolttsnehstif.hpeniayaardhhdssnrieagoadtumun0lositeenenwfuyhnaoselchtfcidsaesceiyegelet1owtnttrnimydutsqateIdodaesacnritoheint,osadnewrna9odinsn(tsaoshcidelrgwsuso.tfefoottrspnw5ran3haeiooaanoesdsthta,tidniiiseeinnpdsiirfpmo0oes5nptirdeoeonocdeodlrwcobwnretaek,aoaiitnoofetaassenr)hrlsdecskyrrtnrctuhncrnauoCdglege.oufedstnshkwtaaaatstatspsoeituidhswendofeusrwutisooreogsuhsSWtwprerEidta(gsionaesrscfipwioismofeoikdnd1.nnfcnrsiueteoopoctecr.(insRetcieaisacnsuitol5h(tdcar7deiervltaaairsabbpmttrlnoohxeorlrag1tl1TtcyAieodet)-ohpetenieisd-nscinsthiysegiuhrdnrr.spbahg3cs9uetr1aefetereroscbhdonotdecscygehracchntti6vaco)awyttetsis1itlcmenceaoohiiioedhahvbcnrtrehoatabC9sioetiarsfaen)cepuaarutuogeeiacdwnomeioueaieeaelr,naimiyoutwmacxgxanlagahrdtpcdesmselmnroidndrtlpmrstcdaortluhrnicapoanwncat,gsysdtebteieplohofpecetaesgycHnnehtotdltiom,wocoblmocnshnegesuoavhaeesseeaetntgocrsd(odeeneltyroseiunuaeesaeaeoicrrnltdxo(ee1rrseeiiaodthcotoscieslrthrsten1ifsmctlersrlolensslo2gpaucaunaniaentrhrhedadyrdaiod4aicdtsswtcrseea(iel-nxolidpniSdddnhrlaioplsoee)mnttpoto3ec1snrany"cpptsi.hhshehiruwitgadrglftrkw6txahmcfno9psgvnahlcanwuef.tlhathstogaeafoaiontllic)ieahepo)sttfeerirtoeeectrfgitsvoeI.eraotehr.wtsortdoeseMdomoiertebtohrstFefnfarprattihasinneennfnihhomeaerxuiveftasreutsapsTsonlTatnpitrdskrcieioodesrotrgscesuttssrlpinnhusspgoceonctlailftrebtrheuitithaaurtoxhiirareurddehshooodrranaogocyateaasreglaetttrareeirlliilynfedeykdyyeeeeoooysyself.e-.ttsl.lf.rrtt caosgaowtRtHwtishp(wbmilEUt11hulihin1aaonnaf9aneh9sannRaeaon6irredorTAS7rnvdtsd4ersetscargcrwd)iruur0lhte9ctnesh.dtgolokyhtlues,rwesielieeaoaoeemrenmttueendt(nWwdwwesnleananrxnl1scncdeiionlyaatpnsaaod9oeteeyeoowreoipytd,Srr)assrsgrncs(rahdrr1.ce(ek.oatya3htktadtaiatkeo1ri9ioisanercdmon-oenteTcmiseots8r4etfkim6irshrehvfwaddrctetvno)8nsnhfsdeos)suena,sliea,esaacu.a.terele-onpdncarWtyresraerlndwgcos(segrNyanmceexsnR2adcotmtcosrnaeiladauphgo0rbibaniafidRnswlfdnnndoodgeoeanf-eaattaec1ye2igoessysgatnsrssacrdane9whdaeut2sne1sem,etneigar6dsibhdh(ef)ddbeudheryonooli3r9i.iaiersearricgsacnininrro7ofertstescenaov(ieanpoycsga,)nBnnn1uisG4ggen,hriefl.lonc7asfeerl2asistodae1eiftois)snspfaphtin,cputdm.5raesatiru4lcshdioprcetoaeomeartsrebe,iAorewiohrtdn5emsahftoadetfhcdnhaten-tdhiioiefngioecaianuTnonnatncgeCyrodsoraihnicamncxeiooennssdNo5ordsgtRaydicxDgwnaeiegi%autnelrngurooeebyn-iaRuatncnieaoscwndsrrfnngelscmarlmdtisaoiroaieetefrurtRngc,wkfpwmrodiyvodndZabaooliaeegreeRpcesctuasutidemfceasnrunracaltelsacetosnryasc,aocaimrurdanan,tcolndeynalfnfhotartinfdiafoTroshoirnlRidnanrcescctyfesraauoenrhntocddxoieo1Rnseucsnnmsgutdreip.rrhrrigRcoro7hd.cwsdnepaoiee,riaffaye1ardefscDsaaatstm1rgiot9uiiuoptrwewsustie9bnnebtetwrre5iltlnkfuaii4reoiirssrhtahah0ssetrcd,7tbsoosssapinssssho-ikotmuotdlnoaceiu7ehuaiaioratrelittflnndhdoydde8yeoeecseseltftt REFERENCES (/) (2) (3) (4) (3) (6) (7) (8) {9) (10) (11) JWOHoCMHHEHoroitaoaaocccoaIacSSmlDANthB111ioitnknrroosrhhnnr9w9as9nreikaledddmsRcds8d7dlldn5acdwseJooMlsuse714hgeeleiiodaReMcrr..oi;Pegg-lnlaCuniMHoiGssnx5hnaRsnn1laloesSrei.7paplho,aec:,aarasdo.t.i6FhnLLLo)iMnlaairtnxSPer.o1osceeEcsll..1,HdiDtts,Ai8t,.edounnh9L,.hSOoEJ-rSmrio,a81lteH6KNAoipboeyrLap19tlxK11UReOafeshxuamD5n;o.it9pte9.aeddooei-4nr7c3.Erdx.otSnrvtpnerL.g9m&idivRlcps5spr,lrhosmo;aAauhtaU5ejosth2eolUIn3cntB.xreulisccs7neJlimI9oeihcmu.telooT.rBU-nsnta:leMS,krinaa7uL,ooSttsinetmL3oeHUt.mc!algaoAa.i.m,saaA11reoOnWinLnfJ.pc,Ucln9c-atn..dBca7oa8hna.LsdBuEIi.ettu11mkAulcCnnieiSrat.up;7sonbaWtttgsnawcoasr.an12hosnn1taCouksscwut9e.exa:iHeneeaeg1U2ad8dNdaiRiyn-ntrdn,r6r1iOeninc5mnsatscODeo8;ne1aodi-Sicer/s-snsvra:T92r.,HneeM2s.Ciocn6:eeg,o.lstt6U4eof1SairVrxo.e.A9n0Atcttso;matmp/nnro..iSiClnSit1aooattlsacecoyiLrd:codAsnasmss11ahaf1u,ftssm9td3l0NutoeduLSr7Uo7tp-st-Cdee-oer7et0oir1oOhrntidsyl:o.oaef3sautesii:tp'ofsnsplr.v7cu2Rin-eiauhsctha4eetSG1orcpier.eyerlr:eescox.hhgu2senss1nndoMfsyil7naearuotto:toiamaarn5iyesexOsrrnlhcntv3so,Hcaotyio'eaec:us-asasx.op12mlrario:sdnymys9htbaM7rcunLayUdta8csdei5aoegaatds1.ioaonn4iIdslcrs.ondBCmsocaaoesiobnc(deeagnsnrlCfoaioyesssssrrtyddnJsr-...f.,,t,. JNCI. VOL 75. NO. 2. FE3RUARY 1986 j. 234 Wlklund and Holm (72) 113) {14) (13) {16) (77) {IS) (19) (20) (21) (22) (23) (24) (23) SSMGWHNBABBBWRmulaalxaiOJiscaaZaadiao(levsi1mnAn1L1a1lsCrohcaizuaaklntmnnne:ne9Ct9o9maeuiiO1Lantrrluuirnoorcdlot78d8tahgdxwcmS4keeUnahsepdsrg90r3ltacnhSoy/6neoTaaedbmleNA.dea;:;socHtrtAoawaa4cnsnscuixnoUiaGluOc76Clu1rokcs,yd-pdoihrpmHHRSe:1e1p1!dTeee7obicGhhCmu.E.Oid-o0t4duKFttJs.ne3.hefV.eeyoJni-sJ.isM6eCkc1-s.eJosi.nMtmlNrurHt7,JnPC55hnaoahdcR-SLMiair.o9ea&r.ee3sr.twsgCoomriSmeeaO.ixedrAPo1etdknsrWokTa7ruansae.nwJasyunC.bcidoocpnpttt.l1icnhioOtatiohlgnTnarMuaenhr.i9eh1aslcuaBefmngt-erUdmnrc79genJHS1eapdttmooatgdeupaiie96rrt9chnlX.sohdiOeicdaihimstNOnrr;4b8eehncsteolUrmexsehdy;Lo20srecsklPJ1aELcaodiin,slU.;c1n7a.edMnn9nfvcuoam.n,w,htioA73:noA8reuLtngonr7hgAsL.7s:ox3tuFxdBioopOt1t1)4ciu.rnen:h;pXfnytmCayirti1r1.9c1ealsbaaCckMe1ttne1hd8iSu81uhadal-hBtacaui9esMuc2th127eenWpi1lntpemheder7zdb.leSia:;8erd4esdc-dt7tai8njdtltsodJuym-.ir5tx1JEiaKeii7at;1sadspHd.sr1ie1r11pnrdte9,S2ot8Dotpoeta1faohe:Cd99eaoudii-75f3.n-1sc7rlndcon88he7sOeeleesf7o:ap19.usi,e40.1ndxac8oistxtn9.8pb,.hetw;ti;y0Ktco11imipd3s-caepaleTno22a6peta59exo;.eosunnriL:sn2-tiet4o5mhedet4Jryr5o.e1rud.di:sk05tf8eeec14aaea2fdtLfE1-eWai.mic:i7Mdonio11d(cic59rco.pnculhe-idd.e9sri6o.e6aao5inefodn.Solxo63Sn6nsgfi0Hcoaraeg92r;pleotaG-kcw.trrvocApitB5..rneoofeaipc14uccgocpte6erAorlusi2pEp.audsbiirul.d8dl5u:clxttmheimnlgnopi7l.yelie-icsrcisteccr6LivnedatsiauaNairsounn9Jead.yitsiamtnuaarri.cudrvtooFoeonanIopnt)Eoehypoenrlao.nRlcnpnpdesrsplsn:naesowsarxlmtiii(eldC.atgiidHw2lrpnctgcNnorpoeae.eoahacJoa4rie1rdrpamaxtNNtknosFltu,at9hoerhi5otuhpemcllo8aeriuiCro-ternrroeoeaiw2tshnTrsiena-t.arIlrl;-.. '(((((((2232233(((((33336J70891237463))))))))))))WKHCBMBTCFBRueDuaiecrrtESicEaaVXu111hExienein[SJftBEhnatp3sso9l99enplrSnhSpiastpLuotiintga8tvao867nnnLaruorelsriDveiorWiuol.njct0d5ad3iiaenmOutaana-gbihmmncSrnpr1s;.w.glrerwrrzmtjoelWatkouo.og1ddacpias3meeEfnchnsBoojhrW3lhmnofmHmei1n2akhtsoxrBA]umfiK-ooNiN.iru9okee31no)ogaepIH,Clt6lf..rE.1Bfln1---mEErelmisDnyIiled4e39k.Ee8nSeetRWnOneW.aM..in.r1J8GC3:.ptpaania6tvlyu.hs9vn1.wmcI8meDollAo4dAi.EuoK8eLt;iechArP.irrhs:wrouwiar4sronoll,2euoitto;jvroKcke&ea;fslshvuwnng2ooeHnpomnTe1rmhtnrt1:Skrinrsfugaray9m.1aoeaNsahnHySo3ktloevt8tystrtn-rClfJhncliao:.nehetn1eE:y1br1ioeJ.doohbtenrAmiurnaW:e2tsde1.Fia,Sndsacencslai6trt7:2.lTiauasrtk.WmeaathgrtSoD.1oc:-yihml(LLsAnshE6vJh1cieo9oxSctien..e4oa1.asiac6SDLefkmCriifrInCm-.15liia0obElnl9ealhc.6ilm.iWt9anHo.leefamhfsc8thCpao7e6igeutSssubca4ewMemrs:ite.El4te,etuedhennmmetoxlty.aNneo,talooognnoee-tcifp.sm1snycrli,tcsmiHSrediaaoocuksWcL1cu.ohfrnstgtmoCatsseom9aoo-iiisneedluosoneir6ShtSmrernotonasisGceon4lrgnrwao9oncuereotaoHsfevialr-nh,nfht(pCnesretle3,rilSftoice.eairaadahcsta0nodispoOtiCtsda.nleeosnrreSnbhtgmaenomlasaNnujdUhet.tnoermuBLmreph.dpcPnmPogcoekriU.ouuioisthAurrnH.ee1nAeSovrusmortlp.bnn9as1n9aae..lci.nf.oS98Lltuer.claitaateaSitd8i4gAsawISutslnBe.Eotnmy4Aca:irtnyd4doseina1aeaputicso1iRiilgs9nlL(dna.iiHrSnosngey)sftCdneJinid.Cuurtfuasnrssea2aSeAadSdatdei:shm.musrasgrSttStrJtyyneiNe.aiculacrnmoaotsdoisatidtahoe9.iarcenciWofnIsnai1svclS0iaIunPetfocSitrc99aoira-o1cisltyoeMucgec66tcttln9manararuu1arhhio1s0s8kndcei9-Jialar.,l-fe..4n1ddaeit;. DON 2 15 5 4 49 JNCJ. VOL. 76. NO. 2.FEBRUARY I9M 00H2I55385 ~?.i Zii C_'P sn^n Trichlorophenoxy Acetic Acid Trichlcrphenol Sodium Chloride Freeze Point Color 74& 98.93/^ 0 .76% o <6$ 150.6C. W h ite 2 ,^ -D Diohlorcphenol Sodium Chloride Freeze Point Color LCT/i/rJ V U / 50 l t 7fi 99.35% 0.18% 0.035% 136.5c . White y . e . j& L. C. White Britton's Division 2-.2o7 Building q.Sr.S 0.2.17 0 .. <5^ /3-T. . % 3 y z - - C (c k No. Z3..2A. - I f t V-a&U. ) <S^ W ' / I 6 . 0 - 6 * ' * / 8H BIOCHEM. FILE-.T 3 . J . Y - / / - ^ TO BIOCHREEQMUIECSATLFORRESBEIOALROCGHICALLABTOESRTATORY 7* 'A n* C. R . I . , F i l e Name : ^ y- Cl m X - i*h ^ -J 7" Structural formula: Molecular formula.s....(^....TM...ir?... O*' it o - M Constituents in copolymers or mixtures: ; / _1--> o ^ v i - v . Suggested solvents: -LX -jrriA-*~ ^ j X J ^ h -a- 1 (1 f D iscussed W ITH.... . Requested b y ....... fV3 cc nn CO Date as 7 - & -sro Made ......... .3 .7 .1 : .? . - r s Sent L /< j/ 4 MP.................................... C BP........................................C at.....m m . H g Dens..... at.. ..... c / ......... ........ c Handling Precautions.................... ...................... 'Product state: Research...... Development_______ /.Spe c. Chem...... ...Plant...... USE CONTEMPLATED...................................................................... Tests requested: / , . - r~ r-- - r.5> ='**&_- Charge No . sJ- i(^ 'iA s z X s L i t . Re f . o J - XT ______________ Discl. No ........ ,,Patent. (Please do not write below this line) Tests By Date General screen ing............................. Jts Noted By. C---' '--/ Sample to___ ....... Date.tL..---i../..i/...By__________________ Date___ Initial and date all entries - no erasures permitted. wi <v W,-' BIOCHEMICAL RESEARCH DEPARTMENT THE DOW CHEMICAL COMPANY Subject : RESULTS OP SKIN IRRITATION AND SKIN SENSITIZATION TESTS CONDUCTED ON HUMAN SUBJECTS WITH OLD AND NEW PREPARATIONS OP 2,4-DICHLOROPHENOXYACETIC ACID Pile: Charge : Rec'd.: Pin'd.: Work by: 'T23.14-11-6 12 2 9 -0 2 3I /O3 /IIO/5 O /5 0 Industrial- Toxicology Laboratories To : Check Rept. by: Britton's Division (1) Att: J. W. Britton R. C. Dosser C. A. Highhill /y-"5 S7<*-_ y 0 - y e - s ~ % ,\ Agricultural Projects Committee W. W. Allen (1) W. C. Dutton/1) 7 H ib I J i I 1 =. P i ' 1- : L ; ( C7 THE DOW CHEMICAL CCi.iPA.'T D. D. Irish (1) J. P. Kagy (Seal Beach, Calif.)(l) O G. E. Lynn (1) ro Executive Research Committee (1) c_n UNIT INDEX cn 2,4-D acid produced by the new method of manufacture Ca oO produced no significant irritation when applied to the skin of 0 humans, nor did it produce any sensitization. A sample of 2,4-D acid prepared by the old method was significantly irrit ating to the skin of humans but did not produce any sensitization. INDEX HEADINGS 2.4- Dichlorophenoxyacetic acid Phenoxyacetic acid: 2 ,4-dichloro-, Acetic acid: 2,4-dichlorophenoxy-, Acetic acid: phenoxy-, 2 ,4-dichloro-, PROBLEM 2.4- Dichlorophenoxyacetic acid is a major product of The Dow Chemical Company. A new method for preparing the material which gives a whiter and essentially odorless product is now being /manufacture . Are there any toxicological advantages between the old and the new material? r H( fcf ^C> 7/ Eiochemical Research Department T 2 3 .14-11-6 Page 2 MATERIAL Name : 2,4-Dlchlorophenoxyacetic acid Formula: Structural: C l /, ,,Cl \ K " /) -O-C-C-O-H (/ H 1 DOH2155381 Empirical: C8H6C123 Source: L. White, Britton's Division, 267 Bldg, Reference: 23W-122, 3/20/50 Description of samples: K2372-19 is a sample of a new product which is essentially white and odorless. K2372-20 is a sample of the production by the old method. It is slightly off-white in color and has an appreciable odor. Assays of these two materials revealed the following: 2,4-D K2372-1Q 99*35$ K2372-20 9 8 .8$ Dichlorophenol Sodium chloride 0.18$ 0 .035$ 0.277$ 0.08$ Freezing point 136 .5C. 135.6C. Color White Off-white Reference no. 23W-122 23W-122 EXPERIMENTAL PROCEDURE A sensitizer is a material which has the ability to produce an increase in the susceptibility of an individual to that material; thus, initial contacts with such a material may not produce any appreciable skin Irritation, but contacts Biochemical Research Deoartment T 2 p .14-11-6 Page p at a later date will produce a prompt reaction of the skin. To determine whether or not a material possesses this potent iality, it is customary to apply the material to the skin of the inner surface of the forearm or to the backs of human subjects. The first application is allowed to remain in contact with the subject for four or five days, at which time it is removed, the area washed, and any reaction noted. (This is primary irritation). About three weeks later the same individual is again tested w i t h . the material in the same way except that the exposure time is 2reduced to \ or ^8 hours. Observations are usually made immed iately and after 24, 48 and 72 hours, and also after a week or ten days. The occurrence of a more intense reaction after the second application than after the first or a significant rise in the frequency of reactions among the group as a whole is indicative that sensitization has occurred and that the test material is a sensitizer. EXPERIMENTAL RESULTS In these human tests the two samples of 2,4-dichlorophenoxyacetic acid were tested by the technique described in the preceding paragraph. In both instances, the dry solid material was used. With K2372-I9 (new method material) there was no significant amount of primary irritation and no sensitization noted. With K2372-20 (old method material) an appreciable amount of primary irritation was observed but no sensitization developed. These results indicate clearly that the material prepared by the new process is distinctly superior from a skin irritation stand point to that material prepai'ed by the old process. DOH2 I 55382 Biochemical Research Department T23.U-11-6 Page 4 CONCLUSIONS Although neither the material prepared by the old or the new method is a skin sensitizer, the difference in ability to produce primary skin irritation is substantial and the liklihood of skin- irritation developing in handling and use is much greater with the old product. 'DOH2155383 bc-10 17580 O T. r o 75UNITED STATES ENVIRCNMEN AL PROTECTION AGENCY en 2 ,-D F A C T S H E IT eCOn N o v e m b e r 19 S 2' O A . Background 2 , 4 - D i c h l o r o p h e n o x y a - c e t i c a c i d ( 2 ,4 - D ) is a s y s r t c i c h e r b i c i d e w i d e l y u s e d to c o n t r o l b r o a d l e a i w e e d s . T h e cert: 2 , 4 - 3 i n c l u d e s the p a r e n t a c i d as w e l l as the 35 d e r i v a t i v e s ( e s t e r s a n d s a l t s ) . It has been used in the U n i t e d S t a t e s for over 30 y e a r s . There are approximately 1500 products containing 2,4-D registered w i t h t h e E n v i r o n m e n t a l P r o t e c t i o n A g e n c y . O v e r 60' m i l l i o n p o u n d s of 2 , 4 - 3 a c t i v e i n g r e d i e n t w e r e a p p l i e d d o m e s t i c a l l y d u r i n g I 9 6 0 w i t h the m a j o r i t y u s e d for the c o n t r o l of b r o a d l e a i w e e d s in snail grains, field corn and on range and pastureland. I n t e r e s t c o n c e r n i n g the p o t e n t i a l a d v e r s e h e a l t h e f f e c t s of 2 , 4 - 0 i n t e n s i f i e d f o l l o w i n g E P A ' s e m e r g e n c y s u s p e n s i o n of 2 , 4 , 5 - T a n d S i l v e x in M a r c h 1979. T h i s i n t e r e s t was due to the c h e m i c a l s i m i l a r i t i e s of 2 , 4 - D a n d 2 , 4 , 5 - T . T h e r e was in p a r t i c u l a r c o n c e r n that 2,4 - 3 w o u l d be c o n t a m i n a t e d w i t h 2 , 3 , 7 , 3 t e t r a ch 1 or odi ber.m o - p - c i o x i n ( T C 3 D ) as w a s - 2 , 4 , 5 - T . This dioxin has been linked with potential fetotoxic and carcinogen? e f f e c t s . H o w e v e r , the 2 , 3 , 7 , 8 T C D D has n e v e r been f o u n d in any s i m p l e of 2 , 4 - D . T h e A g e n c y i n i t i a t e d a t h o r o u g h r e v i e w of c r i t i c a l t o x i c o l o g i c a l I n f o r m a t i o n a v a i l a b l e on 2,4-3 in an a t t e m p t to a n s w e r q u e s t i o n s r a i s e d c o n c e r n i n g p o t e n t i a l h e a l t h e f f e c t s a s s o c i a t e d w i t h t'*e u s e of 2 , 4 - 3 in 1979. T h i s r e v i e w w a s c o n d u c t e d to d e t e r m i n e w h e t h e r regulatory action was appropriate. A z e nc v R e v i e w A f t e r a r e v i e w of the e x i s t i n g t o x i c o l o g y data base s u p p o r t i n g 2,4-0 r t j l s t r a t i o n s , E?A concluded that the s c i e n t ifically valid C on t : when The A 2.4-3 Scion it r . e r n u S toxi u .d sed *"cy t 0 7.i t ti m h e^ 1 c u i c t ology s e of n acc did c o 1og i :eA d v i s h ex? sted1, u4ladu-npi3dcreeeos,ppwoehsorienott dhiwe2es,alva4e-bwsr ,0eiagls r y t s Pa , na eglr ,e e c d o n w s i i t s h t nd t hiidndfaieitrcceneaconsnotts-itaroerinynhs.deI ia n cfal 3notAhdtrnem hpai anttr ichedoaacentra?due the tonincoennst , i n g of t o x i c o l o g i s t s and the Agency's conclusion. 17581 1) 1J UeSSIZMOQi c. A e nc v A e t 1 ons T h e E n v i r o n r e n t a l P r o t e c t i o n A g e n c y , u n d e r a u t h o r i t y of S e c t i o n 3 ( c ) ( 2 ) ( B ) of the F e d e r a l I n s e c t i c i d e , F u n g i c i d e and R o d e n c l c i d e A c t (717?. A) ray r e q u e s t any a d d i t i o n a l d a t a f roc p e s t i c i d e r e g i s t r a n t s c o n s i d e r e d n e c e s s a r y to rai n tain t h e r e g i s t r a t i o n of e x i s t i n g p r o d u c t s . On A u g u s t 29, 1 5 2 0, after c o n s u l t i n g with the S c i e n t i f i c Advisory Panel, the ; Agency issued an O rder and Notice, w h ich required all 2,1-D r e g i s t r a n t s to s u p p l y d a t a i n the f o l l o w i n g a r e a s of p o t e n t i a l health concern: acute toxicity, turor fcrzation, reproduction, birth defects, neurotoxicity, and cetabolisr. D . S t a t u s of 2 , A - D D a t a C a l l - I n M a j o r r e g i s t r a n t s of t e c h n i c a l 2 , A - D p r o d u c t s s u b j e c t to this d a t a c a l l - i n h a v e f o r c e d the " I n d u s t r y T a s k F o r c e on 2 , 1 - 0 R e s e a r c h D a t a " to j o i n t l y p r o d u c e the r e q u i r e d data. T he Task F o r c e has s u b m i t t e d to the A g e n c y acute oral and dermal toxicity testing results for manufacturing-use 2,1-D p r o d u c t s . T h e c h r o n i c e f f e c t s s t u d i e s wi l l be c o n i n g into E ? A as they a r e d o n e , w i t h i n the n e x t 1 to A y e a r s . E . Dlcxin Question In 19S0, the C a n a d i a n government announced that some 2,1-D produ c t s m a n u f a c t u r e d in Canada w ere c o n t a m i n a t e d with coo- A g e n c yp o u n d s of the dioxir. f a m i l y , a l t h o u g h n o t n e c e s s a r i l y the very toxic 2,3,7,3 TCDD. The co o p e r a t e d with the C a n a d i a n s to i d e n t i f y the p r o b l e m , and also b e g a n to s a m p l e ,1-D products made in this country. The concamination r obl e m a p p e a r s to result from the m a n u f a c t u r i n g p r o c e s s e s Chep r i n c i p a l l y u s e d in C a n a d a r a t h e r t h a n the U n i t e d S t a t e s , and Canadian Government has taken appropriate regulatory a c t i o n co r e s o l v e the p r o b l e m . The U.S. G o v e r n m e n t c o n c l u d e d that no change in r e g u l a t o r y p o s i t i o n s c o n c erning 2 , 1-D uses or p r o d u c t i o n m e t h o d s was c a l l e d for in this c o u n t r y . Conclusion AE ? ' * r e c e n t e v a l u a t i o n s of 2 , A - D d c n o t i n d i c a t e ics c u r r e n t l y r e g i s t e r e d u s e s p o s e u n r e a s o n a b l e r i s k s to p u b l i c h e a l t h or the e n v i r o n m e n t . As w i t h any p e s t i c i d e c h e m i c a l , if e v i d e n c e o: s u c h r i s k s d o e s a r i s e , the A g e n c y w i l l -take a p p r o p r i a t e a c t i o n to r e d u c e or e l i m i n a t e t h o s e r isks. -1t. uu V. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY \ 2,4-P FACT SHEET October 1982 \ I. 2,4-D DATA CALL-IN A. Background 2,4-DichIorophenoxyacetic acid (2,4-D) is a systemic herbicide widely used to control broadleaf weeds. The term 2,4-D includes the parent acid as well as the 35 derivatives (esters and salts). The structure of 2,4-D acid is given below: ct r There are approximately 1500 products containing 2,4-D registered with the Environmental Protection Agency. Over 60 million pounds of 2,4-D active ingredient were applied domestically during 1980 with the majority used for the control of broadleaf weeds in small grains, field corn and on range and pastureland. Interest concerning tne potential adverse health effects of 2,4-D intensified following EPA's emergency suspension of 2.4.5- T and Silvex in March 1979. This interest was due to the chemical similarities of 2,4-D and 2,4,5-T. The public was concerned that the same toxic effects attributed to 2.4.5- T would also be applicable to 2,4-D. There was also concern that 2,4-D would be contaminated with 2,3,7,8 tetrachlorodibenzo-p-aioxin (T C D D ) as was 2,4,5-T. This dioxin has been linked with potential fetotoxic and car cinogenic effects. The 2,3,7,8 TCDD has never been found in any sample of 2,4-D. A report of EPA's analysis for dioxins in 2,4-D is presented in part II of this fact sheet. There was also concern because the n-Butyl ester of 2,4-D was used in a 50:50 mixture with n-Butyl 2,4,5-T to produce Agent Orange, the military defoliant widely used during the Vietnam War. Agent Orange has never been registered by E?A.: for civilian use in the U.S., but its use by the U.S. military in Vietnam has resulted in claims of adverse health effects to .American military personnel which are currently under review by tne Veterans Administration. 17333 The 'ic:ency initiated a review of information available on '* ,4-D in an attempt to answer questions raised concerning potential health effects associated wivih the use of 2,4-D. This review was conducted to determine if 2,4-D should be reviewed under the Rebuttable Presumption Against Registration (RPAR) process or if another regulatory action was appropriate. B. Agency Review After a review of the existing toxicology data base supporting 2.4- D registrations, EPA concluded'- that the scientifically valid toxicology studies on 2,4-D did not indicate that the continued use of 2,4-D posed a significant health hazard when used in accordance with label directions and precautions. The Agency did conclude, however, that more information on 2.4- D toxicological properties was necessary to better assess the potential health hazards associated with the use of 2,4-D. C. Agency Actions The E.\-vironmenta 1 Protection Agency, under authority of Section 3(c)(2)(B) of the Federal Insecticide, Fungicide and Rodent.icide Act (FIFRA) may request any additional data from pesticide registrants considered necessary to maintain the registration of existing products. On August 29, 1980, after consulting with the Scientific Advisory Panel, the Agency issued a n O RDER and NOTICE which required all 2,4-D registrants to supply- data in the following areas of 2,4-D toxicology: Acute Toxicity, Oncogenicity, Reproduction, Teratogenicity, Neurotoxicity, and Metabolism. On January 27, 1981 a letter modifying some aspects of the original ORDER and NOTICE was sent to all 2,4-D registrants. This letter stated that the requirement for the studies on acute oral toxicity and acute dermal toxicity of end-use products containing 2,4-D is deferred until the Agency groups the 2,4-D end-use products. Testing will then be required on a representative sample for each group. Registrants of manufacturing-use products are still required to submit acute oral and dermal toxicity studies for these products. D. . Status of 2,4-D data Call-In Major registrants or technical 2,4-D products subject to this data call-in have formed the "Industry Task Force on 2.4- D Research Data" to jointly produce tne required data. The Task Force has submitted tc the Agency acute oral anu dermal toxicity testing results for manufacturing-use 2,4-D products. 17584 I I . ANALYSIS FOR DIOXINS IN 2 ,4 -D A. B ackground ' TAbc hhe endezimoegnixeceinanelrlryiainslgasssa nt rydiunicbmt eteeurnmcrzobeoenr-npf oeo-crdf tieodadxi oifnaxbmsyi nisaalyndpi soacfi rgoicnvoosemfinspotoixbunyenglgdoeswno :kf naottowwmno s . TedohdFafotiEhentatfoirieaobbestrcccmoeehatohohtnann2.ltnroe.hezzor,ix3dvceeoof hieT,are(c--c71rplpettth'9,halhra--e8y8ebdbdiIarnln0eeliiiedoooc)eTftndoongCixxaudreDwicimrmnennedrdDahbere.iaiesccf72ata(trcheeii5nTte,onou4cddCTr mnot,sDpih5essgD2p,toid-oisS2e)ooTta.naeesnnodviiirninscavntaiotinoTfoliiiomdyfceaalfhrnaenegelfebrysdho,fraeenlaintieosenesSUcciiosrcxattp.nmnsSboitrhn.er.ftiierhsasednbroonedsesitgumohaTrifgmeexcohholeihifeeifacirnpnegs2clllkd2rh,p2uet ehso,lpoi,dye3sotfiiloseVoy,ro7dANofttctmooh,aEfh8aext2b2elsteypoh2i,irpn4cosT1yrtoo-Ceni6adDtsnDotuca1reirDaoosl.ftcnaoegtnthtecdeeTtiildshanaCsoomtDllrmeoiDindrne, oe.ra n t rCCrwCpwrc2spaafi1aanreanse,hra9aaoehn4nmpdernnrnl3m-iggseoowatlaDa0peeehedbRrrdd)leddnetaieh.3iiileen,aca8sa2llildnnleagcaaaffirrtmaoSiehtttoooedeosxos2fteimminddoxaun,fts4mhet32stpt-eeead0Cbc52(piDenmn7p0ebsihoilnb9ne'wmaiutplpdoeedo2tttlblopoesynsep,tirt)or4ohsacspo4cl.zku-meb.x2haosodn1D0heaiv7ndn-ipn0oM5onsapsitial-2npascettaox-icedeoispdoallinoaycrndopopnliensobhznobpilc.dote,xlban,fttaehnxyda3i.timnhdnecd2.iLlt,n6dresa,iiiei4bnsn,LelEfcv8-oeAaa4s"nneDenrawtItt1vlvllemmesocz9tloeieder8rifaeorlrpudot0eso2os-arlnpd7bfa,ftadc4moedyowst-ecti-eaddrr2febtheDedmmeoi,iatnrel4oceecaafotpnu-hxcn"gtpilrDlzlidstlCliareoraoeonoooosn(dthndru-Cidacaadioloppmmrlccbiuooydone-citlcecriidznipeysxnnnifhtnbenrives-erilroozedtneasaeatamonxhnssntwlefme-dzeeoeisfsepndnoinodorAtrno-mee-retfetladwgipoerrDttnnuaiewrc-eflotginilddchaisocaexgtir,pnxstuleoeisitt.aiinldodhx,ncttrneuisatnsrl e -3 - B. Agency A ctions 2,4-D S an p lin g \P ro g r^n rmwaftmpeSdCapcsA(pa(eornp1tuxnacairhraaeidusorpom9ontlsiisctnnpcdbdxsraod3dtahph2a)3em,iiutIu0dulnlehc2sn,cpnea)coc3prpsa2st.sctlve.ttorlsei,lo.esesariel7voudvnmscvownsg,eio-wgteRwTpwa8uaeterh;TlnlirlremnoaelyehgoeinhrpystfmddT.aiedoaaeiersrCnnaousafsotlietiDdeeitdgsncnycsaftoeDmTrueelsa.ae-ildaendhnrtltbledittemayohieeads,,jinnannz3noecrtF(itsduhteeLnscsstdx,Lvooeidi6apeeRtieafotraedmnnc,/imttlrbGnd8ovhoioaiusUtpovoCenun/eariscfl1r.ercedumt/eloifttoSaMeanyohhros,slUnts.p3telgenw.roS-iipotl.dpo,sawi)Sraelaow7qoorymnmmssti.enowuoh,sAailtr9eiiddnaeneoennfawrntleuogthesreoltaaeidecoupmattfttolroeeedhsneyaslABrsensddotaeed2ttastroogmehsa.lu,cial4usoermlptE2sotcpt-isdenPte2ir,lcDslahlni4Axoceltus,ovul-geiasphs7ocasonDlnimcnrieCfnta-lrgnedutvwdadliorihegpengcrCppatuieeddeer,csa2alrprmroeiud5eoespsehlcbrsieoCvMd.beohlceesyogefrsc2ueraapnnatahpxr,lrrcnwr4rantzoaFoEbrttyeiae-doersoPafaali-liDdcdaAaenmnrlt;-aicneeldp2eaeifi'adntswl5E2t1ti-osetecBdr2c,ot,nend4ece2aa,ofigrfi-coohre,lloonrD4o.ls:2raanxrltynv8-.pcorii3doceenhgrla/siyl, c-crl~cc R esults r TdTTHpppcbssfl oawoie,--eohreomuddo3innrnsaanxeii,pziflsood7neiottilonihirxxe,gftv-9miislitpenneovaaeEt-ahnmvtditfdeeetPsbiii(fpyosntaosTeearlomenxa.ecraamksp.lwitbcpsns,teolhhloheTwereslNrnRHswhoieedeEatlareoreiRe)wasteosrv.Ln2ttehdehedpseaal,iecan3crleobycmtvCoLf,tese7hzeonaeepiandec,rnftlvrl3dziistLeaoreveodsmtllaldery-iTswoibanopeCsafoicdaDex-rtlifrehdansDsoi1annoi1rtftohgooHwwaaxeemnrrwc2tRaedyoyiso,r/oen7GehpnrueCnisrf(1tngHreaap3dei/toMhnmsiseEvitmnecrrpReSpaefnhrprt.(Doldwnec<lb2eroses5od..mlomrateolehpootuttiddoeepMSffttiictbRaoobe)tma7tttenedehhr8ttsp/dineeeoGeclzetphfathCroodrpitialgcnhe-/boi1cMhchr.xtr,nehhe3aotSeelnrrld,ooya6ircrb,oo8tesd-/niz- o - . C onclusions OOdf oifnorlmyx33iuntlhssaartemdi oeepntleswecsetereeoxdaf mc wo2inn,e4etr-adeDm:, in3t e02act,7ehwdnedircewi caihltfhrl oegerraoanddyoeifbfoedarnicmozi dxo,oi-nfpe-dcsdotiioeonrxtxaiimnann.,idn 1Tst,2hai oe,l4tn . tter inczhcl -opr o- ddiiobxe innz.o - pT-hde i o2x, 3i n, 7 ,a8n d t e1t,r3a ,c6h,l8o/r1o,d3i,b7e, 9n z ot -ept r-adci oh xlionr o d i isom er was n ever d e te c te d in any sam ple. -4- i t-v t4-r Q '.-J 7'?, IDOH2I55367 Ja n u a ry 23, 1981 P act Sheet on 2,4-D wtcptACdpttaiceenhifoc-ileaottgeoadrmtrnrneirctxaciaaohiopecoifcdcnenuxof.honihursasitlfcllennouisctoeteau,rTrioisrnonmooefrhontmneide.o1rptdn2aeifa,lidb3ediC,otb4niesid,2Tifaoen7-on,ihnDn4nogxet2mea-ezxtsi,dsD4rnsoof,ppaitir-tnse--crroDeppoorsahphmdswn.-d-darldcnospcuuhoii5ocdrrccioocuooWotfuttahxxsnspdndchkpcii2utetinneebasnwbts,cd4hnia.etnhm-eswttiniDeohynclaphdzeah.sSclioyecofsaoCtodhimw-tptlaohdupwTepnnnei-fifrahelrddsoaoildroineisthxfamloobpal,iigmx,etptrarhhehbaeticrahenenaosealttyednie,2ffseofnCes,ln7eyattCatttnaohhccmnntadetzr8,diinapeeGnsicidaldceCcpte1odihOahbs2rin,enao3abtl2,tyoyn4sydpt,r,e6pero3mu,p5dcse,mbtcrl.5ada7-ths.erTani,otikdb3rhgsn.oekeeeNftedntothcnienoe - CU?.?.SKT I?A ACTIO!! a22TtATptdperhhe7nhh,rsihg7veeooeateaeiexdossnleeerdEycAiAfuwnyiscnggcptpoiteevhsihhacnnfrrioeoaocrcclcnooyysnsdtdthnrsetiuuaoambvwtsinccemms-eiaitsetdsgtstsspiinetiaitsn.eleotinsaweaiaedvnsxmns.lnefediartopnase3oPrl0nrptsTimroneaathioranegmoser2tkdaefed,1p4merpcpcule-npopotirrcDpenieopfrntlogslebedccinsw;sctemieherscfpineesnio3ArotntohactfnrggnaCoitaetryslrtAaifntaayyenicimnogcnydntahnhriUofiednioeistniafic.nogsaSxfriudnbic.silnnieaacdtatnhglumm,poaleogertnrowipeesuon2cralresos,eddml4ihsCa1myuinrn0eisatc.gnp0eDclaaintveclostaleieapaat.adnntscswsplaitgomab.ihdfnaoTi.feenio.thiftnt+hWelahldonst2teohhhddifTr,ewn4eeinhrg-esc1s:sf , t TUUa h..SSes ..i gZPaanAnniddf iscaCi nmaannpCtdl iianadngniafdfcpaear. ronegunrTfacamheci sd btuoeor taiwnvdgeaebt enep r hod2 ua,c4ese-sDctsooe np s .dfrioirfmdfueecrdtesnt chseaoslt d btheinetwr eethe eni s UTtttlhhhah.eeeteSon.rU,UAyag..SftSeoa.n.r,cecymxt itotoharfrenreekmeteofltetosol-ylpplltcorahhlowocaahwenitingbgeltaiehrt evercerepueaelrrssorioetdihsnnu(eltscern.tsoiuosfsnrejTeusthheeosaotfnipoff2frio2,1c4dd0,a4-0iuD-tocDixpotsppinnprbostr)eod.fsoodutrrucetcdscrtesog^finrnuiotnam^ithn e i1 7 c` ButdTluesiahrsoisenisexrngdeignt-ooasiusxn,vsiaecbltihiul aetptthtbrlaoelpiendxr euilddtscihtaatmiesttnaaignd,2oaa,3rtdvhyn,aa7eotia,alt8ancboaai ntpllneeydpctseierecoaansnar-ttdretttaoihhstoeaixotpthniTcne-trohyexeffioocaauuArnnehegddfeesfnaeiicilgnnytchnt shlU2fah,.LsSo4ac.fz, ac5aomtnr-hdTntael.d.nys"uuecftaecd Ofl-GQI NG SPA REVIEW ACTIVITIES 89ESGIZHOQ UEptchPar.AenoS d . hscuapaocsfrtneosstdaiytusontceuotsmndf etblw2teye,rh4rim-cpoDhrifno. derheuavcvwTieehehewe2atA,hl4raege-rceDantdUciyyvp.Sriowb.t iedeiemulsnlcatnstuceuonsfindantetecirntdtuuh.wreeianygrtoat o np sgr aoaemcs. osepefsl ess s et hs2e,4 - D wTdIanhpahetipacarhAdoodgpnmeirntaiiytcaohytneeb e,lwyt hiwnlrbeeleeeedwceocdidoml lnipoadlnxmueditacnektsewe dah.aiedndreeeant astthsii lefeeissedsemd sreetni unvt ide2iowe,f4s -oaDsfdhdotpihurteiol oddnaumavclatosis.lst at b u le di e s T3TrnaSehhd(eoceegpdty)itiiec(sAt2meihtgo)rabe(anvaneBnearcre)ytl s2atana,coocletsu1figova9toe8tliht0hltieiaaaensSrtsidPetnAeaggcucihlhssnoefntdrnrooneiagcnrtrn-aitcwatljesoar2tdjmion,oa4xttft-oaeiDc2pf cpf,ir4toporay-edrrDloptlu-ddaciupruatneinrtcoaodtnsnfedoorounrostcwuiftc2tsabhey.t,j4hee-eutcDonMtt e.ddasrteajoetrotiqaOrn.nuPtghIiPer.re.A wTbAdsri neeihegavcestereelucnruroEcalmdPymtrnAseeitpnvewliedoiaeeis,ftwlewcl dbodohomuereeebrvfftpvoyhelirtaeleehoetrntwheepaeiatlnht2ryhgeect,t4iehgim-caaeDienascngllhttorectriahnroot eteegmniins-ioptctlreoniaeonruvstmungoitsrdextwsawiars. ncestooudgirlsadktTuohrilhgdeeapciyyssotl oamrnerwsaayvptrroueielfreeodkpwt rsiseoeuup.ssboabliamftmnicaoinoi2ttndwmt,te4epdi-dtilDrhs.lee,thoe n tTohe y ; avjii ? 1 4 0' IS I nIu k .iw j . 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V*I*'V IU |t l | J i* **:\v **. f 1tu i n M i r . i t i ..i iti.- ' **"*P* `il:.* ..e , : `t ,i^ : . 1ievo vetie^ ni* j i u l M IM' ..re "..1 1 1K'nJH* I n v i . a III* I teNp* ' 'lini* Nl.s'*.t.t: 1 1.,(! ; am i ' ' M " li \ ..il : *: IIN4' 'iiii" . M I v . - . u I I I I li. - I I I >r IV ti K- . In i-., i l i.p i : II ii: i.. I .! i. -, r I \ \ . :.! l i . . l >> I*- m i.. I I >1 ' 1 ' i i i v i Ii i h I I mc il v li- i inni; tu il ut Ih m Iv u -U **l v ip iiiu iri* li : . 4 I J alili : . 4 . < I / I l ' ' ' - i In -, ri : i.-, i i ........ I - ; I >I III. -, : pi:.,--IH ! 1 II.vili- .! ! -I aliai t u - i . ' iv. . 11.l.i. * 1' : -Il :\ : p ii ", ,i 1.';, . ; |M II -p . .||l*.1-;.1Id--:Im.it.i111d1.1: 1--': 1- -.1 In la i. 1 Il i 1 1' .1 : a. I !i la - V OFFICE COPY 4 . . ; DOW CONFIDENTIAL INFORMATION ` R&D REPORTr dM n u m o c a D O W CHEM ICAL U.S.A. R&0 REPORTSSHOULDREMAINONTHEPREMISES OFTHEDOWCHEMICALCOMPANY U S O A * T O R r P O * T S C S E SET K-002372-F241 9 D ec e m b e r3 A TE IS L .3 198' 0 L C ? ARTMCNT TOXICOLOGY RESEARCH LABORATORY LAU. N. j L i ' x n O. 1 |5 ,5 3 , 1,3 |7 ,2 ,2 ,4 P hrt ru ea rm a c o k in e tic s o f 2 , 4 - D ic h lo r o p h e n o x y a c e tic A cid in 31 F isc h er 344 Rat3 PAGES IN F U L L REPORT * l. T r t O f t tSi .i CRI NUMBER DESCRIPTIVE SUMMARY WITH CONCLUSIONS! mwwTgEp1wbshaitsisn5yialihraaiegmavv0d.egtssr/sueeekaahmenmdgprladit-ynaaddSyheepgbwdsefe-qia/rsiknitacctliruoenenhepsgmobiorafrenpegenrsnmitadoeoocrdllecceeokrpls,irleoenbytpiaionodnaekeogoicorntdrdnidrfrtrrrnaot-eima9ieatrnoe2ufyiralfata%oticnaipni/viclonpneAcdddseaeenlesoaotianndedoFroftfssoareaoedfmaiolupssadbtfeycmhscayi6iecfstndeho2tciri ecsvdrelprffer,ya4aderiaolrriaretoaots-t^ssyssi0aecesC36sfmoteses4s,l--ese4oaChitonhawobairrTrnerre.oiiafaLdensalptsflo-hdeldt5tl2wy3heaApaera^, 4e.anplfl4ttair-anCpakpttmoDshddaldrimmamFogncioiimsnnsar39xosemoio0dieaborinutnwmatlKs^idincoeiccmml4titsteadoeuh,aCsatgtndvnenv.ote/etdkrvrgecfalreeysgsriolilandoasugea^ntuaitex74ulcohnptC9aa1,tclehdnbsa0arneobrp,.eeutt atovotlxitgrahnpieu22rfa/cosemgh5rtr,mniiaTi4,e35aolnnn-c0a-th.sDnge4edoe5ii ncd0mcnwWrhiafKlcgresammcotieo/ehihnacktrrtemanosrehgebnfnatmoxu1iirnnnc5wu1trttarpehhce00iirtreandeneiie2.rnnoe4eetrioeene, d O rv> c~n ______________________________________________________________________ c n [Contain* relata* fa trad secret*, confidential or proprietary information. aonj of the industry task torca oq 2 .4?D ; arch data,**" d i s t r i b u t i o n -. department files R A O ADMINISTRATION 566C E N T R A L R E P O R T I N DE X i 3ldq. - Midland) FORM c 0300 PAINTED R-3-ao COPI ES atrochad paga.on0 i rr i b u t i o n l i s t is c o n tin u a d 1759(1 D0HZI55Z88 f PHARMACOKINETICS OF 2 , 4-DICHLOROPHENOXYACETIC ACID (2 ,4-D ) IN FISCHER 344 RATS F. A. Sm ith, R. J . N olan, E. A. Hermann, and J . C. Ramsey Reviewed by: W. H. B raun TOXICOLOGY RESEARCH LABORATORY H e a l t h DM&owiE1dC3nl0ahv3neidrmoB, incuMmaillIedni4nt8a.g6Sl4.A0S c . i e n c e s 9 December 1980 "coreCofsnotefhnaiedtraecIinhnntdsidauaolstrtoarryr.'e1pltaarotsepksri(teootractrrayaodinnefos2rem,c4ra-eDttiso,n DOW CONFIDENTIAL INFORMATION CS0I7O -i y jl i iDOHZ155289 - i- SUMMARY The pharm acokinetics of 2,4-D , a p la n t growth re g u la to r and h e rb ic id e , w ere d efin e d in m ale F isc h e r 344 r a ts . F ir s t, groups o f 3-4 ra t3 w ere g iv en s in g le o ra l doses o f ^4C-UL2 .4 - D sodium s a l t ran g in g from 10 to 150 mg/kg o r i n t r a venous doses o f 5 and 90 mg/kg and th e c o n c e n tra tio n -tim e p ro file of ra d io a c tiv ity in th e plasm a and e x cretio n in the u rine were determ ined. A nalysis of the data in d icates th a t 2 .4 - D is ex ten siv ely absorbed and ra p id ly c le a re d from blood i n a b ip h a s i c m a n n e r. E ig h ty - n in e to 92% o f th e d o se was e lim in a te d v ia th e u rin e w ith in 24 h r. Second, groups of 6 r a t s o r a lly a d m in is te re d 10, 25, 50 o r 150 m g/kg w ere s a c r if ic e d a f t e r 6 h r . A t d o se le v e ls above 50 m g/kg th e re was a d is p r o p o r tio n a te in c re a s e in plasm a 14 C c o n c e n tra tio n accom panied by a d isp ro p o rtio n a te decrease in the amount of excreted in u rin e and in the kidney /plasm a ra tio s of 14 G c o n c e n t r a t io n . The Km f o r s a t u r a b l e c le a r a n c e rrora plasm a i s a p p ro x im a te ly 79 y g /m l. When th e plasm a concen t r a t i o n d e c r e a s e s b elo w t h i s Km v a lu e , p la sm a c le a r a n c e i s adequately defined by firs t-o rd e r k in e tic s. "cor'eofCsntoefhniaedtraecilnhnntdsidauolastrtoarrr.y"eplt'aarotsepksri{teoptarctrrayadoinenfo2sermcraeAttiso,n CONFIDENTIAL INFORMATION C-50170 1D0H2 I55290 r- INTRODUCTION Phenoxyacetic acids as a group are g enerally absorbed re a d ily from the g a s tro in te s tin a l tr a c t, are re v e rsib ly bound to plasm a p ro te in , and in th e case o f 2,4-D and 2 ,4 ,5 -tric h lo ro phenoxyacetic acid (2,4,5-T ) are excreted e sse n tia lly unchanged v ia the u rin e (G ehring, 1977). U rinary ex cretio n occurs by an a c tiv e p ro cess w hich can be overwhelmed when la rg e doses are given (Hook, 1974) , re s u ltin g in M ichaelis-M enten ra th e r than apparent firs t-o rd e r k in e tic s . Evidence fo r th is dosedependent fa te of th e phenoxy acid s is u su ally com prised of an increase in fecal excretion, an increasing apparent h a lflif e of elim in atio n and an in creasin g fra c tio n (though 3 till m inim al) of the dose being m etabolized. Khanna and Fang (1966) in d ic a te e lim in a tio n o f 2,4-D may be d o se -d e p en d en t and t h e i r d a ta im ply u rin a ry e x c re tio n may become n o n -lin e a r when doses a t o r above 100 mg/kg are given to W istar r a ts . They a lso show u rin e is th e m ajor ro u te o f ex cretio n and th e p aren t compound is excreted unchanged (99%) i n th e u r in e o f r a t s . S in c e 2 ,4 -D i s n o t m e ta b o liz e d t o a s i g n i f i c a n t e x t e n t , th e tim e - c o u r s e o f 14 C a c t iv it y fo llo w in g th e a d m in is tr a tio n o f 14C -la b e le d 2,4-D w ill re fle c t the tim e-co u rse of unchanged 2,4-D . "ocreCoisnotefnhaidetraeciinhnntdsidaualostrtaor.ryr*e'pltaarotsepksri{teootractrrayaodinnefos2re,mc4ra-eQttiso,n C-50170 DOW C O N F I D E N T I A L I NF OR MA1T7I5O83N 00112 155291 -2- S tro o , McCormack and Hook (1979) have shown a s in g le dose o f 20 mg/kg 2 ,4 ,5 -T to Sprague-D aw ley r a ts d ec re a se d re n a l anion and cation tra n sp o rt in vivo 4 hr a fte r treatm ent but th e e f f e c t was no lo n g e r a p p a re n t a f te r 24 h r. In c re a s in g th e dose to 100 mg/kg produced e ffe c tiv e in h ib itio n of an io n tr a n s p o r t 24 h r a f t e r tre a tm e n t. R epeated d a ily ad m in istratio n of the above doses of 2,4,5-T produced e ffe c ts on ren al ion tra n sp o rt sim ilar to those observed a fte r a sin g le exposure. This suggests th a t ren al tissu e does not p ro gressiv ely accum ulate 2,4,5-T in vivo on chronic exposure. These data also support the conclusions of K ashier and B em dt (1976) th a t th e d ecrease in anion tra n s p o rt is V not a m anifestation of to x icity but rath er re fle c ts the com petition of 2,4,5-T w ith endogenous m aterials fo r the anion tra n sp o rt system . As s ta te d , th is same dose dependence of u rin a ry e x c re tio n also e x is ts fo r 2,4-D . I t is th e re fo re im portant to d efin e a t what approxim ate dose le v e ls sa tu ra tio n of the elim in atio n process occurs, since the increased body burden of 2,4-0 re s u ltin g from re p eated s a tu ra tin g dose le v e ls would n egate the lin e a r e x tra p o la tio n o f to x ic ity a risin g from high dose le v e ls to th a t expected a t low er dose le v e ls. "ocrCeofsnotefhnaiedtraceiinhnntdsidauolastrtoarryr"epltaarotsekpsri(teootractraryaodinnefo2sre,mc4ra-eDttiso,n C-50170 DOW C O N F I D E N T I A L I NF OR MA T1I7OENa4 OOMZI 55292 The purpose o f th is stu d y was to d efin e th e dose-dependent fa te of 2,4-D in r a ts . The m ajor o b je c tiv e was to id e n tify the approxim ate dose le v e l a t which th e k in e tic s o f elim in a tio n o f 2,4-D began to 3how evidence o f s a tu ra tio n e f f e c ts . METHODS A nim als. M ale F isc h e r 344 r a ts o b tain ed from C harles R iver B reeding L ab o ra to rie s, P ortage, M ichigan and w eighing between 200 and 260 gram s w ere u sed. Upon a r r iv a l a t th e la b o ra to ry , th e ra ts w ere exam ined fo r h ea lth s ta tu s by a q u a lifie d pro fe ssio n a l and subsequently acclim ated to the te s t environm ent according to stan d ard o p eratin g procedures. The ra ts were id e n tifie d by a m etal ear tag in serted w ithin 2 days a fte r t h e i r a r r i v a l . When re q u ire d , c a n n u la s w ere im p la n te d in the le f t ju g u lar vein using standard su rg ical techniques (Harms and O jeda, 1974) a t le a s t 2 days p rio r to in i t ia t io n of the study. P rio r to the in itia tio n of the study, the ra ts were housed 2/cage in w ire-bottom ed holding cages. They w ere in d iv id u a lly housed and acclim ated fo r 2 days p rio r to dosing in a ll-g la s s R oth-type m etabolism chambers designed fo r the sep arate c o lle c tio n of urine and fe c e s. The study was conducted in a room w ith a 1 2-hr lig h t cy c le , a co n tro lled tem perature of 20-22C and a re la tiv e hum idity o f 40-60%. R a lsto n P u rin a Lab' Chow and ta p w a te r w ere provided ad lib itu m . __ _ "corCeofsnotefhraitedtraeciinhtnttdsidauoalstrtoarrry."epltaarotsepksri(teootractrrayaodinnefos2er,mc4ra-eDttiso,n DOW CONFIDENTIAL INFORMATION -4- S62SSIZ=M0a T est M a te ria l. U nlabeled 2,4-D , re fe re n c e OC-559-141, was f u r n is h e d by The Dow C h em ical Company, M id la n d , MI. The compound was p u rifie d by re c ry s ta lliz in g once from eth y l benzene and tw ice from p erch lo reth y len e. This re c ry s ta lliz a tio p ro cess r e s u lte d in a compound o f 99.9% p u r ity . U niform ly 14C -rin g la b e le d 2,4-D (14C-2,4-D) lo t number 71106, w ith a s p e c ific a c tiv ity o f 4.71 mCi/mmole, and a re p o rte d p u rity o f >98% was o b ta in e d from P a th f in d e r L a b s, S t . L o u is , MO. Upon a n a ly s is in our la b o ra to ry th e rad io ch em ical p u rity was fo u n d to b e o n ly 84%. The fo llo w in g te c h n iq u e s w ere U3ed to p u r if y th e 14 C -2 ,4 -D p r i o r to th e i n i t i a t i o n o f th e stu d y (L. H. M cKendry, A g r ic u ltu r a l P ro d u c ts , RSD, 1 9 7 9 ). The m ajor im p u rities were e ste rs o f.2 ,4 -D . The e ste rs were hydrolyzed by tre a tin g the resid u e (d ried under n itro g en ) w ith a 10% sodium h y d ro x id e s o l u t i o n a t 50C f o r 1 h r . T h is s o lu tio n was a d ju s te d to n e u t r a l pH w ith a d d itio n o f c o n cen t r a t e d h y d r o c h lo r ic a c id and th e n to a b a s ic pH w ith th e a d d itio n o f sodium b ic a rb o n a te . The b asic so lu tio n was then ex tracted th ree tim es w ith petroleum e th e r and the organic phase d iscard ed . The aqueous phase was then a c id ifie d w ith concentrated hydrochloric acid and ex tracted four tim es w ith petroleum e th e r. The petroleum e th e r phase was then d ried w ith magnesium s u lfa te ; th e so lv e n t removed under vacuum and the residue redissolved in acetone. Contains or relates to trade secrets, confldentlaJ or proprietary information of the industry task force on 2 4-0 research data." * DOW CONFIDENTIAL INFORMATION C-M170 -5- The s o lu tio n was sp o tte d on s i l i c a g e l p la te s in two s e p a ra te so lv en t system s. The re s u ltin g chrom atogram s showed a product o f a p p a r e n tly >99% ra d io c h e m ic a l p u r i t y c o n ta in in g o n ly 0.1% o f the m ethyl e th e r o f 2 ,4 -d ich lo ro p h en o l. However, 2,4-D and 2 -, 3 -, and 4-m onochlorophenoxyacetic acids c o -elu te on th e s e two TLC sy ste m s u s e d , and a n a l y s i s by HPLC show ed a p p ro x im a te ly 4% c o n ta m in a tio n w ith one o r m ore o f th e s e m onochlorophenoxyacetic acid s. D0H2I55294 P re p a ra tiv e re v e rse phase liq u id chrom atography was then used to s e p a r a te th e re m a in in g im p u r itie s . A 50-100 u l (maximum) a liq u o t was in je c te d onto a p re p a ra tiv e rev erse phase m icro Bondapak C^g colum n (W aters A s s o c ia te s I n c ., M ilfo rd , MA). E lu e n t was a 30% a c r y l o n i t r i le / 7 0 % H20 s o lu t io n b u f f e r e d to pH 3 .0 w ith HgPO^ an d NaOH. By m o n ito rin g th e u l t r a v i o l e t re s p o n s e an d r e t e n t i o n tim e f o r 2 ,4 -D , th e a p p r o p r ia te LC fra c tio n co n tain in g th e 2,4-D was c o lle c te d and th e im p u ritie s discarded w ith the rem aining e lu e n t. The to ta l c o llec te d fra c tio n o f e lu e n t co n tain in g 2,4-D was e x tra c te d th re e tim es w ith benzene, th e e x tra c ts w ere combined and evap orated to dryness under a stream o f dry n itro g e n . The compound was then red isao lv ed in acetone. A liquots o f th is so lu tio n were in ja c te d in to th e Bondapak C^g colum n, f r a c tio n s c o lle c te d and counted fo r 14C a c tiv ity . The re s u ltin g chrom atogram s show ed a 93% r a d io c h e m ic a l p u r i t y . Two m in o r u n c h a r a c te r iz e d im p u rities com prised the rem aining 1 %. to" Contains or relates trade secrete confidential or proprietary informatic of the industry task force on 2, 4-Q DOW CONFIDENTIAL INFORMATION CJ0I7Q r ? 5 & 7 fDON2 155Z95 -6- D osinq S o lu tio n . U nlabeled 2,4-D was d isso lv ed in a m ixture o f acetone and w ater (25:75, v/v) and converted to th e sodium s a l t by th e a d d i ti o n o f 0.2N NaOH w ith g e n tle h e a t in g . The s o lu tio n was n e u tr a liz e d (pH 6 .8 -7 .2 ) by th e a d d itio n o f 0.1N HC1. The d osin g s o lu tio n s w ere p re p a re d by m ixing a p p ro p ria te volum es o f a 30 m g/kg sto c k s o lu tio n c o n ta in in g th e sodium s a l t o f 2,4-D , th e ^ C -la b e le d 2,4-D and d is tille d w ater. The c o n c e n tra tio n o f 2,4-D in th e d osing so lu tio n s was a d ju ste d such th a t the ta rg e te d dose was ad m in istered when 1 and 5 m l/kg of the i.v . and p .o . dosing so lu tio n s, re sp e c tiv e ly , were adm inistered. Study D esign. T his stu d y was conducted in two se p a ra te segm ents. The stu d y d esig n o f th e two segm ents fo llo w s. 1. To d e te rm in e th e tim e c o u rse o f 14 C c o n c e n tra tio n m plasm a and th e r a te o f e x c re tio n o f u rin a ry 14C, 3 groups o f 3 ju g u lar cannulated ra ts were adm inistered o ra l doses of ^ 4C -2 ,4 -D a t l e v e l s o f 10, 50 o r 150 m g /kg . The p lasm a c o n c e n tra tio n o f 14C a c ti v i t y was d eterm in ed a t s e le c te d tim e i n t e r v a l s f o llo w in g a d m i n i s t r a t i o n , and u r i n a r y 14C a c t i.v it y was m easured fo r 72 h r a f te r d o sin g . T o ta l re co v ery o f C a c tiv ity was determ ined fo r th o se groups o f r a ts re c e iv in g e ith e r 10 o r 150 m g/kg. In a d d itio n , s im ila r m easurem ents orcefosntefha'iedrceihnntdsidaual^sttaor.yrr"ept,aarostekpsrfiteootractreryaodinnefo2sreme4na- DOW CONFIDENTIAL INFORMATION 50170 1 7 5 3 8 362SSJZHOOi -7 were made follow ing intravenous ad m in istratio n to 2 groups of 3 jug u lar cannulated ra ts receiving dose lev els of e ith e r 5 mg/kg o r 90 m g/kg. Blood sam ples o f ap p ro x im ately 75 y l w ere c o lle c te d a t a p p ro x i m ately 1, 2, 3, 6, 9, 12, 15, 18 and 24 h ours a f t e r d o sin g and a t 12-hour in terv als th e re a fte r u n til rad io activ ity in the plasm a was le s s than th re e tim es background. A dd ition al e a rly sam pling tim es were tak en a f te r th e 5 mg/kg i .v . dose to more p re c ise ly d efin e th e d is trib u tio n phase. The blood sam ples were c o lle c te d in h ep arin ized c a p illa ry tubes and cen trifu g ed to o btain the plasm a. At term ination of the experim ent the ra ts were k ille d by exsanguination, re su ltin g i n b lo o d sa m p le s o f a p p ro x im a te ly 5- m l o r g r e a t e r . W eighed a l i q u o t s o f th e p lasm a w ere ad d ed d i r e c t l y to ACS ( l i q u i d s c i n t i ll a ti o n f lu id ; Amersham C o rp o ratio n ) and th e ra d io a c tiv ity q u an tified in a liq u id sc in tilla tio n spectrom eter. U rine sam ples were c o llec te d a t 6-hour in te rv a ls fo r the f i r s t 24 hours a f te r dosing and a t 12-hour in te rv a ls fo r th e n ex t 48 h o u rs. The u rin e was c o lle c te d in dry ic e cooled c o n ta in e rs. W eighed a liq u o ts o f th e u rin e were added d i r e c t l y to ACS and th e r a d i o a c t i v i t y q u a n t i f i e d in a l i q u i d s c i n t i l l a t i o n s p e c tro m e te r. The pH o f th e u rin e was d e te rm in e d u s in g MDLTISTIX r e a g e n t s t r i p s . F e c a l sam ples C 9017Q -8- s~ w ere c o lle c te d a t 2 4 -h r in te r v a ls . Skin and aqueous homo genates of feces and carcass were oxidized in a Harvey In stru m ents B io lo g ical m a te ria ls o x id iz e r. The ^C -C 02 produced was trapped and q u a n tifie d using standard lab o rato ry p ro ced u res. 2629SIZNO0i 2. To determ ine th e e ffe c t o f dose le v e l on kidney/plasm a r a t io s o f 14 C c o n c e n tra tio n , 5 g ro up s o f 6 r a t s each w ere given s in g le o ra l doses o f 10, 25, 50, 100 and 150 mg/kg 14 C -2,4-D and a l l r a t3 w ere a n e s th e tiz e d and k il l e d by axsanguination 6 hr a f te r dosing. Plasm a, u rin e , and kidneys w ere c o lle c te d and a n a ly z e d f o r 14 C - le v e ls . W hole b lo o d was co llected in heparinized containers and centrifuged to o b tain plasm a. Plasm a, u rin e and kidney sam ples were analyzed f o r 14C a c ti v i t y as d e s c rib e d above.. P harm acokinetic M odeling. Blood plasm a c o n c e n tra tio n d ata were f i t to th e pharm acokinetic model shown in F ig ure 1. The model was d efin ed by the ap p ro p riate s e t o f sim ultaneous d iffe re n tia l equations and the values of the tim e-dependent v ariab les were determ ined by num erical in te g ra tio n using the C o n tin u o u s S ystem M o d elin g P rogram (CSMP, IBM, 1 9 7 2 ). B e st estim ates of the pharm acokinetic param eters of the model were obtained w ith an ite ra tiv e fle x ib le polygon search ro u tin e using th e le a s t sq uares c rite rio n . The ap p aren t volume of d istribution __ (Vd.) v a rie d w ith adm inistered dose lev e l, and coreof"snCtefhoaiednrectainhinntdisdauolastrtoarrry."epltaraotsepksrifteootractrreyadoinenfos2er,mc4ra-et0tiso,n DOW CONFIDENTIAL INFORMATION 17800C-5OI70 iD0H2I 55298 -9- the b est estim ates fo r the volumes of d is trib u tio n were obtained a t each dose lev el using prelim inary values for a ll other pharm acokinetic param eters. Then, the values fo r th e volum es of d is trib u tio n were fix ed and the e n tire 3 et of blood plasm a c o n c e n tra tio n d a ta a t a l l dose le v e ls (by e ith e r ro u te o f a d m in istra tio n ) was used to fu rth e r re fin e the pharm acokinetic param eter estim ates. Thus, the b est param eter estim ates were obtained by sim ultaneously f ittin g a ll blood concentration data a t a ll dose lev els for e ith er the i.v . or o ral route of adm inistration. A reas under the blood plasm a co n cen tratio n versus tim e c u rv e s (AUC) from 0 -7 2 h o u rs w ere d e te rm in e d by n u m e ric a l in te g ratio n using the values of th e' pharm acokinetic param eters o b ta in e d a b o v e . The AUC w ere e x t r a p o l a te d from 72 h o u rs to in fin ity as described by G ibaldi and P errier (1975). RESULTS O b s e r v a tio n s No c h a n g e s in a p p e a ra n c e o r d em eanor w ere seen a f te r o ra l o r i.v .- a d m in istra tio n o f 2,4-D in th is stu d y . ^C -M aterial Recovery. The to ta l recovery of a c tiv ity fo llo w in g th e 10 and 150 mg/kg s in g le o ra l dose is p re se n te d in T ab le 1 . A lth o u g h n o t d e s ig n e d as a 14 C re c o v e ry s tu d y , "coCof notfhniedtaeiinnntdsiauolsrtorryrepltaarotsekpsrifteootractreryaodinnefo2sre,mc4ra-et0tiso,n DOW CONFIDENTIAL C-SOI70 -1 0 - fDOM2155299 th a re c o v e ry o f 14C fo llo w in g th e 50 mg/kg o r a l d ose is a ls o p re se n te d in T able 1 fo r com parison. O v e ra ll, 97 and 95% o f th e a d m in is te r e d r a d i o a c t i v i t y was re c o v e re d i n 72 h r from th e 10 and 150 m g/kg s tu d ie s , re s p e c tiv e ly . P lasm a 14 C - C o n c e n tr a tio n s . The tim e --c o u rs e o f r a d i o a c t i v i t y in the plasm a follow ing intrav en o us and o ra l ad m in istratio n o f 14 C -2,4-D is p re se n te d in F ig u re s 2 and 3, re s p e c tiv e ly , in which co n cen tratio n of ra d io a c tiv ity has been expressed as ug e q u iv a le n ts 14 C -2 ,4 -D /g p lasm a. The d a ta p o in ts a re mean S.D . fo r th re e r a ts , and th e s o lid lin e s re p re se n t the concentration p redicted by the b est pharm acokinetic param eter estim ates fo r each s e t of data f i t sim ultaneously to th e m odel shown in F ig ure 1. The estim ates fo r th e pharm acokinetic param eters follow ing both intravenous and o ra l a d m in istra tio n a re shown in T able 2. The m u ltip le c o r re la tio n c o e f f ic ie n t fo r th e b e s t f i t s o f th e se two d ata s e ts was 0.90 and 0 .8 6 , re s p e c tiv e ly . Intravenous A dm inistration. The con cen tratio n of rad io a c tiv ity in th e plasm a fo llo w in g th e 5 mg/kg in trav en o u s dose was lin e a r and d id n ot re v e a l any in d ic a tio n o f sa tu ra te d c le a ra n c e . The te rm in a l (o r 0) c le a ra n c e phase a t th is dose was n ot c le a rly e v id en t because th e c o n c e n tra tio n of 14C - a c tiv ity f e l l below a n a ly tic a l lim its . "coCofnotfhnidetaeiinnntsdiauolsrtorrryepltaratosepksri(teootraetrr*yadoinenfos2er,mc4rae-t0tiso,n DOW CONFIDENTIAL INFOFTfflXTlON ctro 176 0 2 lDOM2155300 -1 1 - The plasm a d a ta fo r th e 90 mg/kg i .v . dose was c le a r ly b ip h asic and showed evidence fo r the sa tu ra b le (M ichaelisM enten) c le a ra n c e o f 2 ,4-D from plasm a in th e downward curvin g tre n d d u rin g th e f i r s t few hours a f te r a d m in istra tio n . The h a lf - lif e fo r th e i n i t i a l (a) phase was 0.92 h r a t both dose le v e ls . The h a l f - li f e fo r th e term in a l (8) phase a t both dose le v e ls was 14.4 h r. O ra l A d m in is tr a tio n . Two h o u rs a f t e r th e 10, 50 and 150 mg/kg sin g le o ra l d oses, th e plasm a co n c e n tra tio n s were p ro p o rtio n a l to th e a d m in iste re d dose le v e ls o f 14 C -2,4-D . However, th e i n i t i a l downward curving tre n d a t th e high dose le v e ls was in d ic a tiv e o f sa tu ra b le clearan ce from plasm a. The c le a ra n c e from th e plasm a was c le a rly b ip h asic a t a ll th re e dose le v e ls w ith a te rm in a l (S) p hase h a l f - l i f e o f 18.0 h r. The i n i t i a l (a) phase h a lf - lif e was 1.01 h r. The a r e a u n d e r th e c u rv e s (AUC) show ed a d is p r o p o r ti o n a t e in c r e a s e from th e lo w e s t to th e h i g h e s t d o se l e v e l . The r e l a t i v e ALJC (ex trap o lated to in fin ity and norm alized to the low est dose le v e l) w ere 1 .0 , 0 .6 and 1 .5 a t th e 10, 50 and 150 m g/kg dose lev els, resp ectively. ''Contains Or relates to trade secrets, confidential or proprietary information of the industry task fores on 2, 4-D research data." DOW CONFIDENTIAL INFORMATION 17603C-50170 -1 2 - iD0W2I 5530 I U rinary E x cretio n of R a d io a c tiv ity . R a d io a c tiv ity was ra p id ly excreted v ia the u rine follow ing intravenous or o ral adm inis t r a t io n o f 14 C -2,4-D and th e p h a rm a c o k in e tic p r o f i le was very sim ilar follow ing both ro u tes of ad m in istratio n . T y pically, o v e r 85% o f th e a d m in is te r e d ^ C - r a d i o a c t i v i t y was e x c r e te d in th e u rin e d u rin g th e f i r s t 12 h r fo llo w in g th e dose. The p e rc e n t o f dose reco v ered in th e u rin e 72 h r a f te r o ra l a d m in istra tio n is shown in T able 1. The p ercen t of dose reco v ered in th e u rin e 72 h r a f t e r in tra v en o u s a d m in is tra tio n was 100.26 and 90.56% from th e 5 and 90 mg/kg dose le v e ls , re sp e c tiv e ly . The p a tte r n o f u rin a ry 14 C - r a d io a c tiv ity e x c re te d p e r 6 h r in terv al exhibited a rapid lo g -lin ear decline fo r the f ir s t 24 h r fo llo w in g th e d o se , fo llo w ed by an a p p a re n tly slow er and poorly defined ex cretio n of ra d io a c tiv ity . Since th is slow er e x c re tio n o f ra d io a c tiv ity was com prised o f w idely s c a tte re d d a ta p o in ts , and re p re se n te d a to ta l o f no more th a n 1% (mean o f a l l d o se l e v e l s by e i t h e r r o u t e , ra n g e was 0 .23 to 2.04% f o r th e 5 m g/kg and 150 m g/kg dose le v e ls , r e s p e c tiv e ly ) o f th e u r in a r y 14C - r a d io a c tiv ity , i t s c o n t r i b u tio n to th e u rin a ry e x c re tio n p ro cess was co n sid ered to be n e g lig ib le . *cor*eofCsntoefhnaiedrtaceiihnnntdsidaualostrtoarry.r"eptlaarotsepksri(teootractraryaodinnefos2er,mc4rae-t0tiso,n DOW CONFIDENTIAL INFORMATION C-50170 l r-O'i p ^ IDN2I55302 -13- The predom inant p o rtio n o f th e u rin a ry ra d io a c tiv ity was excreted in an apparent f ir s t order manner during the f ir s t 24 h r, and th e re s u ltin g slo p e o f th e se m i-lo g a rith m ic p lo t of percent adm inistered ra d io a ctiv ity excreted per 6 hr in te rv a l v ersus tim e was determ ined by lo g -lin e a r re g re ssio n . The re s u lts fo r both i .v . and o ra l ro u te s are shown in F ig ures 4 and 5, re sp e c tiv e ly . The mean h a lf - lif e v alu es fo r u rin a ry e x c re tio n o f ra d io a c tiv ity was 1.75 and 2.10 hr fo r th e i .v . and o ra l ro u te s, re sp e c tiv e ly . The mean f i r s t o rd er ra te co n stan t fo r both ro u te s was 0.3670.076 hr~^ which corresponds to a h a lf - lif e value o f 1.89 h r. An in d ic a tio n o f n o n - lin e a r ity o f th e u rin a ry e x c re tio n o f 2 ,4-D r e s u ltin g from h ig h e r dose le v e ls was seen by th e delayed in itia tio n of the lo g -lin e a r excretion phase a t su ccessiv ely in creasin g dose lev e ls in F igures 4 and 5. The f ir s t 6 hr urinary c o llectio n in te rv al represented an average o f 41, 2 6 , 'a n d 6% o f th e a d m in is te r e d o r a l d o se a t th e 10, 50 and 150 m g/kg d o se l e v e ls , r e s p e c tiv e ly . S im ila r ly , th e f i r s t 6 h r i n t e r v a l r e p r e s e n te d 90 and 8% o f th e a d m in is te r e d i .v . dose a t th e 5 and 90 mg/kg dose le v e ls , re s p e c tiv e ly . mioenoci or proprietary informs rOefstehaercihndduasttar.y"task orca <o*n1 <2. 4d-. DOW CONFIDENTIAL INFORMATION C-50170 >00X2155303 -14- T issue and U rine C oncentration o f 14C a t 6 H ours. The co n cen tratio n o f ra d io a c tiv ity in the plasm a and amount of 14C e x c re te d in th e u rin e as a fu n c tio n o f dose a re p lo tte d in F ig u re 6 as th e mean S.D. fo r 6 r a ts a t each dose le v e l. The so lid lin e s were drawn by in sp e c tio n . The plasm a 14C c o n c e n tra tio n 6 h r a f te r d osin g in c re a se d d is p ro p o r tio n a te ly a t dose le v e ls above 50 m g/kg. A lso , th e amount o f 2,4-D ex creted in the u rin e during th e f i r s t 6 hours d ec re a se d r e la tiv e to th e dose le v e l a t doses above 50 mg/kg and appeared to approach a lim itin g v alu e. The average amount o f 2,4-D ex creted a t 100 and 150 mg/kg was 8.73.3 mg, e q u iv a le n t to approxim ately 1.5 m g/hr. When plasm a c o n c e n tr a tio n i s p lo t te d v s . k id n ey c o n c e n tra tio n o f 14 C a t 6 h r a f t e r d o sin g (F ig u re 7) th e plasm a co n cen tratio n in creases re la tiv e to the kidney co n cen tratio n a t the higher dose lev els. D IS C U S S IO N The absorptio n of 2,4-D by the o ra l ro u te of ad m in istratio n i s c o m p le te a s e v id e n c e d by e x c r e t i o n o f o v e r 85% o f th e d o se in 12 h r and r e c o v e r ie s o f 97 and 95% o f th e 10 and 150 m<?/kg o r a l d o s e s , r e s p e c t i v e l y , a f t e r 72 h r . In c o m p a riso n the amount of dose excreted a fte r ^ t r a v g ^ ^ d m i g y ^ r ^ o n ^ ^ confidential or proprietary information of the industry task force on 2. 4-0 research data." DOW CONFIDENTIAL INFORMATION C-SOI 70 176G6 ID0H2 155304 -15- shows 99 and 86% o f th e d o se e x c r e te d in 12 h r and r e c o v e r ie s o f 100 and 91% o f th e 5 and 90 m g/kg d o s e , r e s p e c t i v e l y . The ab so rp tio n of 2,4-D is a lso ra p id as shown by th e ab so rp tio n ra te co n stan t of 1.41 hr ^ d eriv ed from the plasm a d ata. Plasma p ro file s a re c le a rly s im ila r by both routes, o f adm ini s tra tio n as shown by th e b ip h asic curves a t a ll doses (F igures 2 and 3 ). By b o th ro u te s o f a d m in is tra tio n th e re was an i n i t i a l downward cu rv in g tre n d a t th e high dose le v e ls in d i ca tiv e of sa tu rab le clearan ce from the plasm a. The area u n d e r th e c u rv e s (AUC) s u p p o rte d t h i s s a t u r a t i o n show ing a d is p r o p o r ti o n a t e i n c r e a s e o f AUC w ith in c r e a s i n g d o se lev el. The above sim ila ritie s support th a t the pharm acokinetic model i3 th e same by both ro u te s o f-a d m in istra tio n and a t a ll doses. The pharm acokinetic model chosen fo r plasm a in co rp o rates sa tu ra b le c le a ra n c e . I t is known 2,4-D is n o t e x te n siv e ly m etab o lized (Khanna and Fang, 1966) and is e x c re te d alm ost e n tirely in the urine. T herefore, th is satu ratio n effect probably re fle c ts satu rab le u rin ary ex cretio n . Support o f th is is shown by th e plasm a/kidney ra tio s d ep icted in F ig u re 7. T his c le a rly 3hows in c re a sin g plasm a co n cen tra tio n s re la tiv e to kidney co n cen tratio n s w ith in creasin g dose. "ocrCeofsnotefhnaiedtraceiinhnntdsidauolasrttoraryr"epltaarotsepksritteootraetrrsyadoinnefo2sermc4ra-eDttiso,n DOW CONFIDENTIAL INFORMATION 0-50170 i"i C: *7 X i^ J D0H2I55305 -16- F urther support of th is saturab le excretion is seen in the p a t t e r n o f u r in a r y 14 C - a c tiv ity e x c re te d d u rin g th e f i r s t 6 hr in te rv a l a fte r dosing. A delayed in itia tio n of the lo g -lin ear excretion phase a t successively increasing doses by e ith e r ro u te is seen (Figures 4 and 5). The f i r s t 6-hr u rin ary c o lle c tio n in te rv a l by e ith e r route represented an a v e ra g e o f 4 1 , 2 6, and 6% o f th e a d m in is te r e d o r a l d o se a t th e 10, 50 and 150 rag/kg dose le v e ls , r e s p e c tiv e ly , and 90 and 8% o f th e a d m in is te r e d i . v . d o se a t th e 5 and 90 m g/kg dose lev els, respectively. The average h a lf - lif e fo r the a phases by the i.v . and o ra l ro u te s a re 0.915 and 1.01 h r, re sp e c tiv e ly . The average h a lf-life fo r the S phases by the i.v . and o ral routes are 14.4 and 18.0 h r, re sp e c tiv e ly . F u rth er s im ila ritie s are s e e n in th e Vm v a lu e s (4 6 .1 and 5 3 .7 u g /m l h r f o r i . v . and o r a l , r e s p e c t i v e l y ) and in th e Km v a lu e s (6 1 .7 and 7 8 .9 pg/m l fo r i.v . and o ra l, re s p e c tiv e ly ). These s im ila ritie s fu rth e r su p p o rt th a t th e p harm aco kin etic model is th e same by both routes and a t the dose lev els stud ied. T herefore, to x ic ity stu d ies a t sim ilar doses but by d iffe re n t routes would be expected to be e q u iv a le n t. uruustry 1 reSrcfi data." DOW CONFIDENTIAL INFORMATION C-30170 1 7 8 0 8 ' -17- `DON2155306 The model d e p ic te d in F ig u re 1 (G ib aldi and P e r r ie r , 1975) was u tiliz e d to calcu late a and 8 and th e ir associated h a lf-liv e s shown in T able 2. These v alu es are based on th e assum ption th a t the f ir s t order ra te constant for clearance is approxi m ated by the ra tio of The re su ltin g a and 8 values are th erefo re dependent on th is constant ra tio . C alculation of these a and 8 values and th e ir associated h a lf-liv e s is a v a lid approxim ation only when th e blood co n c e n tra tio n is s u b s t a n t i a l l y l e s s th a n Km. The l i m i t i n g c a s e f o r th e r a t i o o f is approached when th e blood co n cen tratio n approaches approxim ately one-tenth the value. B ased on th is stu d y d o se s g r e a te r th a n 50 m g/kg a re needed to b r in g th e p la sm a c o n c e n t r a t io n above th e Km> A t o r above th is dose sa tu ra tio n o f clearan ce becomes ev id en t. I t should be em phasized th a t even a t dose le v e ls above 50 m g/kg plasm a is s t i l l cleared e ffic ie n tly and 18-24 hr a fte r dosing, the b lo o d c o n c e n tr a tio n i s w e ll belo w th e Km_ v a lu e . A m u ltip le dose sim u latio n was perform ed based, on the pharma c o k in e tic model of F ig u re 1 and th e param eter v alu es shown in Table 2. This model p re d ic ts (Figure 8), th a t upon r e p e a te d d a i l y o r a l d o s in g , 99% o f th e s te a d y s t a t e w i l l be "coreofCsntoefhnaiedtraecIinhnntsdidauolastrtoarrry."epltaarotsepksri(teootraetrrsyaodinnefo2sre,mc4ra-et0tiso,n DOW CONFIDENTIAL INFORMATION 17609 tD0M2I 55307 -18- reached in 2 days fo r e ith e r th e 10, 50 o r 150 mg/kg d o se s. The ra p id e lim in a tio n o f 2,4-D in the u rin e , the sm all co n trib u tio n of the 0 phase and th is m u ltip le dose sim ula tio n , a l l in d ic a te a low p o te n tia l fo r accum ulation o f 2,4-D in the body. WRITTEN BY: FTS198.ro0D.x3AeiRc.cBoeeSmlsuomebigaleyidrrtcihnhR1, g9eMT8s0eo.aSxr.ic,choSlLtouagdbiysotrDa tiorreyc to r TRP198.or0Dox3Jjjei..cecTBoecNmlutuoobAigLleldyaerwinanR,1dg9ee8Prs0he ./D3.- 7 arch - P o _________ L ab o rato ry TER/198.oe0Dxs3A7eie,ca.cBorecHmluohebiglreydmCrihanR1neg9nme8,s0iesBat r.cS/ 2h. - * 7 _______ L a b o ra to ry REVIEWED BY: T198o0Dx3ieccBoemluobigleydrinR1g9e8s0e a rc h L a b o ra to ry WGTMD193o.orwi0oDxd3uHielpCca.cBonehBLmldeuo,rembigalaeyuMdidrcnieIanR1lrg4,9eU88s6B0e.4Sai0.roActhr. a nLsafboor mra atotiroyn, UH&nEiSt "cor'eofCsntoefhnaidetraeciinhnntdsidauolastrtoarryr."epltaarotsepksrifteootractrrayadoinnefo2sre,mc4ra-eQttiso;n DOW CONFIDENTIAL INFORMATION C-50170 X. pi ^ c A ... -19- DON2I55308 Th1s rep o rt represents data generated p rio r to the enactment of the FDA Good Laboratory P ractice R egulations. The study was conducted according to standards used in th is laboratory a t th a t tim e. The rep ort accurately re fle c ts all of the data generated. All data and reports are located at the submitting laboratory. Study S ta rte d : September 1978 Protocol A udited: September 1978 DataS.OA.Pud. ited: 28 August 1978 Final ReportA udited: 20 November 1980 Report Issued: 09 December 1980 Reported: September 1978 Reported: 28 September 1978 Reported: 21 November 1980 nWQTHMD18oo.euwi0uxdaa3EillltCcta.ihoBtnhy.Hldeuo&m,oigA#loiydMEcvsi*aIsnenRlurvg4rieaU8rson6e.nc4Same0.rAceh.ntLalabSocriaetnocryes (Date) 17611"coroeCfnsotefhniadetraeciinhnntsdidauolasrttoarrry.e"pltaartosepksrifteootractrreyadoinenfos2re,mc4a-rt0eiotn "20" DOW2I55309 1) GRSPeSwhfwiefseeheeknddrsoceiinxntsshyag. n, dAAanPccdEa.iddneJsfvm.aiyart eonandnodmifnTeBShnmceetaiatiesrmlnomEcD, eafilJsofs..exCciEntoPs.sn",rf,eeMsr(e1eFon9ned7ctebe7erd)ou af"arCyAPthhcl6etothn-iroe1oinxn0yaR,, toeSaHydctaeoiladclksthh o lm , 2) sHj uiamgrmup llsea, r pPvr. oecGine. d. aunrJed . Of oAjrepdpcalh., r oPEn.hiycRs.icoal.n(1n93u76l.4a, )ti3o7nA1. or afp tihd e anr da t 3) oGH1 f2oeo(h22kr,,)i4n, J,g5.2, -0TPB9 .-.2b, y1J .8Br. aa it(l1i e9an7, d4 )Md. o gIDn.k, vidJiont rheony s . oa nnF,adlJy. .sCisTo s. o,mfeatnt. rdaTnosxpioc or tl . 4) CRI noetfneetrirnne unaoct iueosnMSaaylnsutBaelmu sIiBMnMeosdNs eolM.inagScHhPi1nr9oe-gs7r0aC0m1o-rI2pI.oIr.a tioPnrog(r1a9m72) 5) FKl aohboadenlneCadh, emS2 .., 4a1-nddi(c5hF)la,onr5go0,p0hS-e5. n0C3o .x. y a(c1e9t6ic6) a cMid etianb orlaistms . o f J C. 1A4 -g r. 6) MKDooawrcciChb ah4,e.mRi.c aJl., T o(1x9i8c0o)lo g yP eRr seosne aarlc hc o mL ambuonriactaotriyo n, . M iHd&laEnSd-O, SMA,I, 7) TKpthrooeexstcrimcehoeaicelt.mhr,aEenFnins.vtmirJwoo.niftmhanr. ed2nH,4Bal,lte5hr-t.ntrrda2itnc.,,hs Wp2l o3o. r2ro0-t 2p. d3h4ee.p(n1ro9ex7s6sy)iancgeStcatuatueds.iee ds J .obny. 8) hdL eaarnt bag)ihc. oidr seDts,owMinA. nLhau. ml yatn(i1c9ua7rl8in)Ree paDonredtteMbrmlLo ioAndLa t7si8oa-mn50po2lef5s2p, h(eMvnaaoylxi dy8a. t i o n 9) Ldi naa ntgago)h.aotr sDtti,oswsMuA.enLa-. l yfta(i1ct 9,a7l8l i)RveepDro, erttkeMirdmLnieAnyLa t7ia8on-nd50mo0f8u0sp,chlJeeunno(xevya7lh.i dear bt iiocnid e s 10) wRcanooidwtlhoeag, ntihVc eae. vliKrai.lnuufasaonetrdi.mo nHaAytiommof.ansJt, ho. enTV. h2eA,at4.z.-aDRrd(es1asn9. d5to41)25l,(i45vS,75eu)-sm,Ttmoa6crt2kyy2p-e6oa f 2s 9sho.teocr xbiaiicteidd e s r5ostehZaercihndidua^sttar.y''Ptar0skPrt,oetraeryon*2*Za DOW CONFIDENTIAL INFORMATION C-50170 !D0H2155310 -2 1 - 11) HSa8n4tedr5no-ao8pl5r, of4ulW.on.ncgEtei.od, n Mea xlcpCeoofsrfmueracec.tks, JoK.f. MT2 ,o.4,x,5iac-noTdl. aHn&odoEkS,nivJliv.reoxnB.. a Hf t(le1th9r 7. 9a)c5u, te 12) MG iabrcaeldl iD, eMk.k earn, d NPewe rYr ioerkr ,, pD.. 15(119. 75) " P h a rm a c o k in e tic s " , "Contains or re/ates to trade secrete, confidential or proprietary information of the industry task force on 2 , 4-o research data." DOW CONFIDENTIAL INFORMATION C-50170 -22- i D0H2 15531 I FIGRE 1 . Two-com partm ent pharm acokinetic model d e sc rib in g th e d is trib u tio n and sa tu ra b le clearan ce o f 14 C-2,4-D in the blood plasm a of r a ts . The inp u t fu n ctio n is an instantaneous input for intravenous adm in istratio n, o r a f i r s t o rd er ra te c o n sta n t (k0 i) fo r o ra l adm ini s tra tio n . The tra n s fe r c o e ffic ie n t k ^ and ^21 between th e c e n tra l (blood) and p e rip h e ra l com partm ents are f i r s t o rd er ra te c o n sta n ts. The cle a ra n ce o f 2,4-D from the c e n tra l com partm ent is d escrib ed as a sa tu rab le process maximum w ith ra te a a t maximum a blood r a c te on of cen tVrma t and io n M ichaelis co n sta n t). See Table 2 fo r one-half the of th e Kmd i ( m the ens i o n s of the pharm acokinetic param eters. DOM C O N F I D E N T I A L ''Contains or relates to trade secrets, confidential or proprietary informatio of the industry task torca on 2, 4 - 0 research data." -23- z i ees i zwoa D/OST Drt 'V H S Y H FIGUT3E 2 . S o e f m14i lCo sin g le garithm ic activ ity , in tra v e n o p u l a s o s t d o ug os e e th q/ of e g p , S lasm a re su l o r 90 t c o n c e n tr in m g g/k gfro1m4 a tio n a C -2 ,4 - D . DOW CONFIDENTIAL "Contains or relates to trade secret confidential or proprietary informatk Of the industry task lores on 2 , 4 -0 research data." -24- IDOW21553/3 PLASMA, \iG EQ/G PIGURE 3. S14eCm ilog -act ar iv ithm ity , ic a s p lo ug t e o q f / g th , e r e p s lasm a u ltin g c on fro ce m nt a ra tio n sin g l e o f o ra l dose o f 10, 50 o r 150 m g/kg ^^C -2 ,4 -0 . D O W C O N F I D E N T I A "cOCofnotfhnidteaeiinnntsdiauolsrotrrryepltaratosepksritfeootarterrysadoinenfos2er,mcr4ea-tt0sio*n research data." 1-j. -25- cn FIGURE 4. Semilogarithmic plot of percent of intravenously administered 14C excreted in the urine per 6-hour interval versus time. Data points are mean S.D. for 3 rats. Solid lines were determined by loglinear regression for the time intervals shown (6, 12, 18 and 24 hours at 5 mg/kg; 12, 18 and 24 hours at 90 mg/kg). The percent of administered dose recovered from urine during the 24-72 hr interval was 0.24 and 1.33% for the 5 and 90 mg/kg doses, respectively. DOW C O N F I D E N T I A L ! :- rotates to trade secre "Contains o r re ** etary informal cOofntfhideenintdiaul s^try^/* r,torcaon 2.4research data. 17617 -26- i UUH2155315 PERCENT OF ADM INISTERED fcihr"1) t^/2(hr) 10 mg/kg 0.323 2.14 50 mg/kg 0.444 1.56 150 mg/kg 0.266 2.61 FIGUHB 5. Semilogarithmic plot of percent of orally administered 14C excreted in the urine per 6-hour interval versus time. Data points are mean S.D. for 3 rats. Solid lines were determined by log-linear regression for the intervals shown (12, 18 and 24 hours at all dose levels). The percent of administered dose recovered from urine during the 24-72 hr interval was 1.2, 0.44 and 2.04% for the 10, 50 and 150 mg/kg doses, respectively. DOW C O N F I D E N T I A L . or .elates to trade seer I75TS DOSE (MG/KG) FIGURE 6. Plasma concentration and amount excreted in the urine 6 hr after a single oral dose of 14 C-2,4-D. Solid lines are drawn by inspection. DOW CONFIDENTIAL "Contains or relates to trade secrets; confidential or proprietary information of the innustry task force on 2, 4-0 research data." 17619 -28- ED0H215531? PLASMA CONCENTRATION ( mG /G ) 1 .f i g u r e Kidney concentrations versus plasma concentrations o 14C 6 hours after an oral dose of 10 to 150 mg ^C-2,4-U/kg. Solid line drawn by inspection. D0W ^ ) E N T ' r ' 1/ iA L or"coCofontfnhitdeaeiinnntsdiaulsotrrryepiatratoespksrtiteoctratcrrayadoinenfso2emc, r4ae-ttiec research data.'* XYo \ -29- /'N V .. SDOM21553 18 (DAYS) FIGURE 8. Multiple dose simulation, 10 mg/kg, based on the model shown in Figure 1. Seven daily oral doses with a recovery period aura shown. This simulation and that of the 50 and 150 mg/kg oral doses (not shown) all predict that upon repeated daily oral dosing, 99% of the steady-state will be reached within 2 days. "Contains or relates to trade sec. J*< confidential or proprietary inform DOW C O N F I D E N T I A L of tha industry task fores on 2, - research data." X y Oi* ) C3 o o o =T2 fc----* C3 m =2 --t "T=s7O3l <--- A ? ; C' TABLE 1 72-HOUR flECQVERY OF RADIOACTIVITY FROM RATS GIVEN A SINGLE ORAL DOSE OF 14C-2,4 Urine Feces Plasma Cage Wash Skin Carcass * Percentage of a Single Dose (Dose Level, mg/kg) 10 50* 150 92,53 92.59 91.00 3.22 ND 2.15 0.46 0.93 0.68 0.47 0.52 0.15 0.55 - ND 0.53 ND 0.37 * TOTAL; 97.2412.94 94.8811.12 ND = not determined; - = below 3s: background. *50 rog/kg was not designated as a balance study (feces, skin and carcass were not analyzed) and is presented for comparison. 0L 1 61CSS IZNOQi DOH21553Z0 - 31- TABLE 2 PHARMACOKINETIC PARAMETERS DESCRIBING THE DISTRIBUTION AND SATURABLE CLEARANCE OF 14C-2,4-0 IN THE BLOOD PLASMA OF RATS FOLLOWING INTRAVENOUS OR ORAL ADMINISTRATION1 *01 k12 (hr'1) k21 (hr'1) Vm (yg/ml/hr) Km (ug/ml) a (hr"1) t l / 2 (hr) 0 (hr"1) tl/2 Intravenous Administration (5 and 30 mq/kq)^ - 0 .0 1 0 0 0.0487 46.1 " Oral Administration _ (10, 50 and 150 mq/kq)j 1.41 0.0081 0.0391 53.7 51.7 78.9 0.758 0.915 0.690 1.01 0.048 14.4 o CHO 0.039 1Based on the pharmacokinetic model shovm in Figure 1. Volumes of distribution were 182 and 252 ml/kg at the 5 and 90 mg/kg dose levels, respectively. ^Volumes of distribution were 119, 263 and 265 ml/kg at the 10, 50 and 150 mg/kg dose levels, respectively. D0 W CONFI DENTI AL Subject TBHiEochDeOmWicalCHReEsMeaIrCcAh LDCepOaMrtmPAenNtY > INTERIM REPORT ON THE ACUTE AND SUBACUTE %ORAL TOXICITY OP 2 ,4-DICHLOROPHENOXYACETIC ACID FOR DOGS. Cbg. 5 8 6 2 1-5 Rec'd 12-16-49 Fin'd 8 - 3 I - 5 O Work By Dt .V.A.Dt I Wayne Unlv. To J. W. Britton Check Executive Research Committee Rept. By ?-3/- 5* iOONZ155249 UNIT INDEX A copy of a report of the acute oral Judies and a progress report of the 3 month studies being carried out by Dr. V. A. Drill of Wayne University on 2,^-D is given. INDEX HEADINGS 2,^-Dichlorophenoxyacetic acid Acetic acid: 2,4-dichlorophenoxy- Phenoxyacetic acid: 2,4-dichloro- MATERIAL The material used in this study was designated as K2372-f`' It was supplied by L. White of the Organic Semi Plant Laboratory; it bore the reference number 23W - 7 9 J and it had a freezing point of 1 3 2 .8 . PROBLEM In order to have some toxicological information relative to the effects of 2,^-D when fed repeatedly in single doses to a larger laboratory animal, the dog, a project was set up with Dr. Dill at Wayne University. A progress report of this work which was filed as an exhibit in evidence at the P.D.A. Hearing for the establishment of residue tolerances on fresh fruits and vegetables comprises a part of this report. CONCLUSIONS Dogs appear to be somewhat more susceptible to 2,^-D than rats ia (5) 17624 1D0KZIS5250 KNo.2.3.7..-./? C.R.I.. File Name : *&// Y/ - J P Structural formula: TOBIOCHREEQMUIECSATLFORRESBEIOALROCGHICALLABTOEbSRTiAocThOeRmY. fiLE.2!ir^_3.:.^y"^ - Molecular formula i"L--'o'. ~j~i-7J C- ' ' ' V '4jL 3 3 P, " ^ 1 6 1 2 4 3 Bi.M:iiern. "=s. UeotJ Constituents in copolymers or mixtures: 99 i"-J>........................:..................... ......^ ...........................................................................................AJ Date Suggested solvents: ................. y& eDiscussed with. Requested by... .... .. ................. Made by__ .................... ................. Reference______________Amt . Sent... .... a e ..............1 2 2 , 1 -C BP....................... C at.... Hgmm. Dens..... at.... C/.......... C Handling Precautions...... Product state: Research... ___Development.... ..ISpec . Chem......... Plant...... Use contemplated_________ Tests requested: - ff - 7 Chargeu n A r u i c iN o . . . . . ' ? . . . . ? ". . ^ . . 3 T r . ........... Lit. Re f _______ __________________Discl. N o ........,,Patent................ (Please do not write below this line) Tests By Date ...............................................................................................................* ... _ 4 \.. General screen ing............... s)!r....\..... 7 ^.1 i i i Sample to..................... t S k tT k b d .______date..L?/,^7A i ...Noted B y By.................................... D a t e .................................................................. 1" In i t i a l and date all e n t r ie s no erasures p e r m i t t e d . OOMZI5525I 7 " x i . / 4 -// ACUTE AM ) SU B -A CU TE CRAL T O X IC IT Y OF 2 ,4-D IC H LC R Q P H E N O X Y A C E T IC A C ID FCR DOGS V ic to r A . D r i l l , Ph#D, M.D. ' Professor of Pharmacology Wayne U n iraraity College of Medicine 2,4-dich larop h en o xy acetic ac id (2,4-D ) is known to a c t a s a p la n t hormone and aa a h erb icid e (1 , 2, 3) In one i n i t ia l re p o rt 2,4-D was men tioned to be non-toxic to animala and humana when adm inistered o ra lly ( 1 ) However, larg e doees produced symptoms in m icet r a ta , ra b b ita and doga, which sim ulated those seen in c lin ic a l myotonia^iM ore d etailed observations were re p o rte d by H ill and C a rlisle (3) who stu d ied the to x ic ity of 2 ,4-D acutely and sub-acutely in various species of animals* There are no rep o rts in the lite ra tu re on the acute oral to x ic ity or chronic o ra l to x ic ity of 2,4-D in dogs. The p resen t stud y was d esig n ed , therefo re, to observe the acute effe c ts of single doses of 2,4-D and the chronic e ffe c ts of 2,4-D when adm inistered o ra lly fo r 90 days* O bservations were made on the m o rta lity , symptomatology, body w eight, blood count and gross pathology of the animals* A microscopic study of the tissues is under way but a t the p re se n t tim e is not completed* Methods Adult mongrel dogs of both sexes were used* Most of the animals were housed in the lab o rato ry fo r a period of 2 to 3 months before the study was started * During th is con tro l period they were Immunized against d is temper with the Green vaccine* The dogs were fed a standard stock d iet (F risk ie s) ad'lib itu m . The 2,4-D used was commercial m aterial with a p u rity of 98*52 In the acute stu d ies the calcu lated dose of 2.4-D was adm inistered as a single oral d o se 'in capsules* The dogs were observed l'cr a period of 14 days a t which time survivors were autopsied* In the chronic study the 2,4-D was adm inistered o ra lly in capsu les, 3 days a week over a 13 weok -2 - [DOM2155253 period. Each capsula vas imbedded in a 4 to $ gram piece of ccnm ercial canned deg food. The animals consumed th is re a d ily , thus avoiding the con tinued trauma of the stomach tube. During the study the animals vers sighed twice a week. Control blood counts were taken before the adm inistration of the drug, on th e 30th day and rFth 90th day a t the com pletion of the stud y . Hemoglobin was determ ined w ith a p h o to e le c tric colorim eter (6 ). Upon the death or at the were taken from com the pletio lung, n of hea th rt, e l stud iv e r y , , k th id e animals were ney, adrenal, autops spleen, ied, thy riont iitdses^suat inendse ovary or te s te s and fixed in 10%fcrm alin. RESULTS I . ACUTE ORAL TOXICITY A. Symptoms produced. The e ffe c t of various doses of 2,4-D on su rv iv a l fa r 14 days is shown in Table 1 . The o ra l LD^q is approxim ately 100 mg/Kgm. In dogs th a t died the symptoms produced by 2,4-D varied from a mild ataxia and stiffn ess in the hind legs to a definite myotonia. In itia l e ffects were often noted 6 hours a fte r the oral adm inistration of 2,4-D. The anim als were mare q u iet than normal and a slig h t a ta x ia was occasionally present a t th is tim e. The hind leg s were always affected f i r s t , the forelegs la te r or not a t a ll. There was usually a progressive increase in spasm in the hind leg s a sso c ia te d w ith in creasin g a ta x ia and seme dogs spontaneously extended the hind limbs in a sp a stic movement la s tin g a few seconds. The knee jerk was e ith e r normal or h yp eractive. In the early stages of acute poisoning the anim als were usually q u ie t. I f the anim al is l i f t e d and made to walk the spasm and a ta x ia are n o ticed , but when walked fa r a w hile the spasm and a ta x ia tend to d ecrease. In the la te r stages of in to x ic atio n the anim al, when placed on h is f e e t, is -3- 100M2155254 unable to stand and a its or lie s in an awkward p ositio n with sp astic limbs* p a rtic u la rly spasm of th e hind limbs* Other dags w ill stumble and r o l l on the flo o r in attem pts to rig h t themselves* An occasional dog has shown evidence of i r r ita tio n or pain when the skin over the back of the neck is grasped* Some dogs* when held up by the shoulders would show extension and crossing of the hind limbs* As the toxic e ffe c ts of the drug progressed the dogs eventually refused the various types of food offered. Although occasional d iarrh ea was obtained, vom iting was not produced* Such symptoms may a lso be seen in dogs th a t survive the lower acute doses of 2,4-D fa r 14 days (Table 1 ). The symptoms in such cases are re la tiv e ly mild and were lim ited to spasm in the hindlegs and a s lig h t atax ia. B . Body w eight. The animals dying g en erally showed a lo ss of weight, the loss being least in animals that died during the firs t 4 days of in to x ic atio n (Table 1)* There was no lo ss of weight in the animals th a t receiv ed 25 mg* of 2,4-D per k ilo . Although food intake was not m easured, the dogs ate less food than normal and those th at died refused even canned dog food towards the end of th e ir survival* G. G ross Pathology* The ch ief g ro ss changes noted were in th sm all in te stin e * The in te s tin a l mucosa in some cases showed a m ild to d iffu se redness (Dogs 58 73 75 8 1). Deg 86 had a sin g le indurated u lc e r in the duodenum* Dog 82 showed what appeared to be o ccasion al sm all circum scribed hem orrhagic areas in the lungs* In deg 76, 902 of the middlo l e f t lobe was a m ottled purple-black* Sim ilar changes, but le ss extensive, were present in the other lobes* Dog No. 73 showed sim ila r g ro ss changes in the middle zight lobe and le f t lobes* 17629. -4- I I . CHRONIC ORAL TOXICITY ' 1 . M o rtality . A ll dogs re c e iv in g 2, 5 or 10 mgms. of 2,4-D per k ilo survived the 90 day te s t p erio d . Both dcgs rec e iv in g the 20 mgra. per k ilo died during the study. The same to ta l d a ily dose divided and adm inis tered twice a day to two doga__caused.death, a fte r a longer time in te rv a l, in only one animal (Table 2 ). 2 . G eneral symptoms. ' Dogs th a t survived the oral ad m in istratio n of 2,4-D fo r 90 days were fre e of any symptoms. The three dogs th at died w hile receiving the highest dose of 2,4-D showed symptoms and signs d iffe rin g somewhat from those observed in the acute stu d ies. The dogs were q u ie t, weaker and le ss responsive than normal. Muscle tonus was higher in the hind le g s, p a rtic u la rly on passive extension. The hind leg s were held more s t i f f l y than usual when walking and a s lig h t atax ia was p resen t. During the la s t 2 to 3 days of th e ir su rv iv al 2 of the dogs showed d if fic u lty in chewing or swallowing and even tu ally even refu sed a ss& ll bolus of canned dog food (u su ally re a d ily consumed). There was also seme oozing of blood from the gums and buccal mucosa. 3. Body w eight. Changes in body weight are lis te d in Table 2. The only sig n ific a n t change was observed in the dogs th a t fa ile d to survive the study. The weight lo ss in these anim als began 7 to 12 days before the death of the dog. 4 Blood count. The ad m in istra tio n of 2,4-D did not have any e ffe c t on the hemoglobin or red c e ll count of anim als th a t survived or died during th e stud y (Table 3 ) . Cf the anim als th a t d ie d , one deg (No. 104) showed a moderate decrease in to ta l w hite c e ll oount. However, as a sim ilar change was observed in a control dog (No. 62) i t was concluded th a t th is was n ot a s ig n ific a n t e f f s e t of the dru g. (Bie d if f e r e n tia l count was not [DOMZI 55255 tD0H2155256 s ig n ific a n tly a ffe c te d by 2,4-D with the p o ssib le exception of dog 64 This dog shewed a marked drop in the p er cent of lymphocytes before death* How ever* a sim ila r change was not p resen t in dog No. 104 ju s t b efere d ea th . 5- Gross pathology. Gross changes in the in tern al organa were minor. In dog 6l the renal capsule stripped with d iffic u lty , and a few iso la te d red a re a s (1-2 mm.) were p re se n t in th e duodenum. Dog 91 showed a slig h t diffuse redness of the duodenal mucosa. 6. Organ w eights. There was no sig n ific a n t change in the weight cf the thyroid, adrenal, h eart, liv er or kidney in animals that survived the 90 day t e s t p erio d . An in crease in some of the organ w eights can be noted in dogs 64, 91 sad 104 th a t re c eiv ed the h ig h est dose of 2,4-D and who died during the experiment. D iscussion. The symptoms produced by the high sin g le acute doses of 2,4-D are co n sisten t with those observed by Bucher (4) The general symptoms seem to be q u ite sim ila r in e ith e r the mouse, r a t , ra b b it or deg, and are ch aracteristic of a c lin ic a l myotonia. Other effects occasionally observed in the dog are sneezing, and rubbing the eyes, or occasionally d ia rrh e a . Vomiting was not observed in the p re se n t study. Soma of the dogs dying of the acute doses showed a m ild to d iffu se redness of the duodenum mucosa and occasionally areas in the lung th a t appeared to be hem orrhagic. The higher doses of the m aterial produced anorexia and consequent weight lo ss. Death from large single oral doses of 2,4-D is delayed and occurs days a fte r the in itia l ad m in istratio n . The ir r ita tio n and pain observed in sans dogs when the sk in of the back of the neck is grasped may in d ic a te men in g eal i r r i t a t i o n , and the extensio n and c ro ssin g of th e hind le g s in seme dogs, when lif te d by the shoulders, may p oint to a sp in al cr c e n tra l le sio n . In the chronic study the dogs survived doses of 2, 5 of 2,4-D per k ilo of body w eight. Doses of 20 mg. per k ilo , however, did tDOH2 I55 25 ? -6 - produca death when adm inistered over a p erio d of 18 to 49 days This is in conformity with sub-acute studies in dogs performed by H ill and C arlisle (5 ). They adm inistered 2,4-D in tra v en o u sly in doses of 25 or 50 nig. Per k ilo fa r 6 in je c tio n s. Such anim als died or were sacrificed between the 3rd and l6 th day of the study. I t is evident^jthen th a t th ere is some cum ulative a c tio n of 2,4-D in the studies of H ill and C arlisle and in the present study with the 20 mg. p er k ilo dose. The dogs su rv iv in g the chronic doses of 2,4-D do not show any s ig n ific a n t change in hemoglobin or blood count. The doses of 2,4-0 did not sig n ific an tly a ffe c t the white blood count. In one animal th at died there was a marked f a ll in the per cent of lymphocytes in the d iffe re n tia l count before death. H ill and C a rlisle (5). adm inistering 25 or 5 2,4-D per k ilo intravenously fo r six days, have observed a f a ll in the polymorphonuclear leu cocy te count and in the p er cent o f lym phocytes, although noitnj^all dogs. The symptoms produced in anim als dying from the 20 mg. per k ilo dose of 2,4-D d iffered somewhat from those seen in the acute stu d ies. With the chronic adm inistration the animals exhibited chiefly a stiffn ess of the hind legs and a ta x ia , weakness, and bleeding from the gums. Sans af the animals also showed d iffic u lty in chewing or swallowing. Summary. 1 . The acute o ra l IDjjo of 2,4-D is approxim ately 100 mg. per k ilo . Doses in th is range or higher produce a d e fin ite myotonia which was accompanied by anorexia and a lo sa of w ei^it. 2. In chronic oral feeding the animals survived dosea of 2, 5 and 10 mg. per k ilo fo r 90 days. Such doses ware w ithout a ffe c t on body w eight, blood count or organ w eight. O ccasionally upon autopsy some redness of the duodenum mucosa was noted. Three of the 4 dogs receiv in g 20 mg. par k ilo of 2,4-D died d u rin g 'th is experim ent. Evidence of c lin ic a l myotonia 17632 1D0W2I55Z58 -7waa le a s in these dogs although such anim als a ls o showed some bleeding fra n the gums and n ec ro tic changes in the buccal mocosa accompanied by d if f ic u lty In chewing and swallowing. In the anim als th a t died there was no sig n ific a n t change in the blood p ictu re except fa r a decrease of lymphocytes in one dog. 1*7633 THE HEALTH EFFECTS OF HERBICIDE 2 ,4 ,5-T A Report by the American Council on Science and Health 'I VEdlJ The American Council on Science and Health is an? Richard Main, M,..Sr independent educational scientifically balanced association evaluations promoting ' D A M of chemicals,' W TM L9 IC C IJ J i l *JConsultant |f / ' \ ; (] the environment and human health. Sidney Shindell, M.D. LL.B. Medical College of Wisconsin The Council is a nonprofit association exempt from federal income tax under Section 501 (c) (3) Terrence Smith, M.P.A. of the Internal Revenue Code. A U contributions American Council on Science and Health are tax deductible as provided by law. Henry F. Smith, Jr., Ph.D. Individual copies of this report are available at University of Pittsburgh a cost of $10.00. Prices for ten or more copies are available on request. Kenneth V. Thimann, Ph.D. University of California, Santa Cruz This report on 2,4,5 - T was researched and written by Mary Katherine Hayes, M,S,f Research Associate for the American Council on Science and Health (ACSH), ACSH gratefully acknowledges the comments and contri butions of the following individuals who reviewed this report and its contents: Elizabeth M. Whelan, M.P.H., Sc.D. American Council on Science and Health William L. Williams, Ph.D. University of Georgia Ernest E. Campaigne, Ph.D. Indiana University > Robert M. Devlin, Ph.D. University of Massachusetts E.M. Foster, Ph.D. University of Wisconsin Virgil Freed, Ph.D. Oregon State University William R. Havender, Ph.D. University of California at Berkeley William E. Hazeltine, Ph.D. butte County, California, Mosquito Abatement District Thomas H. Jukes, Ph.D. University of California at Berkeley Robert H. Kupelian, Ph.D. Rutgers University Robert MacVicar, Ph.D. Oregon State University March 1981: first printing July 1981: second printing (updated) v* I ! I 17635 Introduction 1 Position Statement 2 Chronology of Events Involving 2,4,5-T 3 Herbicide Production Statistics 5 Uses 6 2,4,5-T Chemistry Chemical Synthesis of 2f4,5-T Chemical Stability of 2,4,5-T Summary 10 11 13 13 Hazards Spray Drift Residues Toxicity Summary 14 14 14 15 21 Polychlorinated Dioxins 22 2,3,7,8-TCDD Chemistry Summary 23 23 28 Toxicity Kociba et al. 1979 McConnelT and Moore 1979 Allen and Van Miller 1977 Kociba et al^ 1978 Summary 29 33 38 40 41 45 Teratogenicity Mutagenicity Carcinogenicity 46 59 59 Human Experiences with 2,4,5-T and TCDD Dow Chemical Plant Workers Monsanto Plant Accident, Nitro, West Virginia Arkansas Cleft Palate Study Humboldt County Denny, California St. Louis, Missouri, Horae Arena Seveso, Italy . Alsea I Alsea II Hanify, Metcalf, Nobbs, and Worsley (1981). Swedish Occupational Epidemiologic Studies Summary 65 65 67 68 68 70 '71 72 75 75 78 80 87 Agent Orange History Present Complaints about Its Alleged Effects Agent Orange-- Future Plans Scientific Studies Summary 88 88 89 89 90 91 EPA Regulatory History Conclusion 92 94 17636 * I JO I INTRODUCTION This paper by the American Council on Science and Health was prepared as a result of the controversy con cerning the suspension and possible cancellation of reg istration of the herbicide, 2 ,4,5-trichlorophenoxyacetic acid. Use of the herbicide is currently being questioned and indeed may cease permanently after scheduled hearings by the Environmental Protection Agency (EPA), which began March 14, 1980. Registered in 1948, the herbicide, 2,4,5-T, is not a newcomer to weed control. But studies within the last ten years involving both human and animal exposure to the herbicide have raised questions regarding potential health hazards accompanying its use. In 1978, the EPA issued a Rebuttable Presumption Against Registration (RPAR) (EPA 1978) and Continued Registration of herbi cides containing 2,4,5-T, initiating the process to question the need for continued registration. However, on February 28, 1979, the EPA exercised its option by citing an "imminent health hazard" and called for an immediate Emergency Suspension of 2,4,5-T (EPA 1979c) on rights of way, forests, and pastures. Exempt from this suspension order were rangeland and rice paddy applications. Proponents of the ban argue that the herbicide is very toxic to humans. They illustrate their point with a variety of studies that attribute an increase in mis carriages, birth defects, and certain forms of cancer to exposure to 2,4,5-T. Opponents of the ban defend the use of the herbicide. Interested parties in this camp feel that the scientific evidence does not substantiate the claims made by critics of the chemical. They therefore feel that the EPA's proposed cancellation is unfounded. At the heart of the matter lies the chemical 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD). Regarded as one of the most potent toxins known to man, TCDD is a consistent contaminant of 2,4,5-tL.. The American Council on Science and Health seeks to present a balanced and unbiased assessment of this cur rent public health issue. In preparation of this paper, the Council has diligently studied the history and past and present uses of this herbicide both in the U.S. and 1abroad. Furthermore, it has scrutinized available data on the effects on human and animal health. In addition, !j it has reviewed information about 2,4,5-T in the'popular press and from interested parties on both sides of the issue. The American Council on Science and Health appreciates the problems encountered in making a definitive decision regarding the use of 2,4,5-T. A thorough analysis of the 2,4,5-T dilemna is complicated by a paucity of human evidence, the need to extrapolate from animal data and a lack of sophisticated detection equipment. The Council recognizes valid arguments submitted by both parties involved in this dispute. The Council presents its paper as its own opinion and interpretation of the infor mation studied and hopes that it addresses all pertinent arguments in this important public health matter. I 2 D0*t'2 I 5 5 I 4 * POSITION STATEMENT Based on its review of the scientific evidence, the American Council on Science and Health (ACSH) concludes that there is insufficient evidence to support a ban on 2,4,5-T. No scientific reports presented to date have shown any convincing relationship between the traditional use of 2,4,5-T and adverse health effects in humans. The toxicity of 2,4,5-T and its contaminant, 2,3,7,8TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), has been dem onstrated under laboratory conditions at doses far high er that those to which humans are exposed. Estimates of hr eulmiaanb l he e. althFurrtihsekrmdoerrei,vedthofsreomriasnkismalwhiecxhperhaivmeentbseenarecalun culated for 2,4,5-T and 2,3,7,8-TCDD are extremely small. ACSH recommends that the current uses of 2,4,5-T in rice fields and rangeland be continued and the suspended uses in forests, railways and highways, and landscaping be reinstated. ACSH recognizes the problems posed by 2,4,5-T's unavoid able contaminant, 2,3,7,8-TCDD, and urges that every ef fort be made to further reduce contamination during the manufacturing process. ACSH recommends that applications of 2,4,5-T, particularly aerial spraying, be strictly mon itored to minimize unnecessary environmental and human exposure. ACSH believes that stringent safeguards for the manufacture and application of 2,4,5-T will effective ly reduce any potential adverse effect of 2,3,7,8-TCDD wniie allowing for the continued use of the herbicide. Ct vO c*p" V "i 1945 - d e v e lo p e d a s an h e r b i c id e > I Sb U5 1948 - registered with USDA as a pesticide 1949 - accident at Nitro, West Virginia, 2,4,5-T plant 1957 - 2,3,7,8 - TCDD impurity in 2,4,5-T made known 1962 - Vietnam defoliant spraying commenced 1966 - USDA and FDA order residue tolerances be estab lished for most pesticide chemicals in or on food crops 1967 - deadline for obtaining tolerances for residues of most pesticide chemicals including 2,4,5-T on food and feed products and by-products 1969 - 2,4,5-T and 2,4-D were reported to produce birth defects in animals 1970 - USDA requested further teratogenic studies 1970 - Department of Defense cancels use of 2,4,5-T in defoliation procedures in Vietnam 1970 - USDA cancelled all use of granular 2,4,5-T formu lations for use around the home, recreational areas and similar sites and all food crops. intended for human consumption 1970 - USDA suspends use of 2,4,5-T in lakes, ponds, ditch banks, and all liquid formulations for use around the home, recreational areas, and similar sites 1970 - Congress directed DOD to contract with National Academy of Sciences for study of ecological and physiological effects of use of herbicides in Vietnam 1970 - use of 2,4,5-T banned in Italy; it is also banned in Sweden and the Netherlands 1971 - accident at racecourse in St. Louis, Missouri, involving exposure to TCDD resulting in animal death and human illness; 2,4,5-T not involved 1971 - FIFRA Advisory Committee recommends continued use of 2,4,5-T on forest, range, rice, rights of way; stipulates TCDD (dioxin) content be reduced to 1971 1972 1972 1973 1973 1973 1974 1974 1974 1974 1976 1977 1978 year, and applied; in ;a,manner that will not contaminate humans 1 EPA prohibits use of 2,4,5-T on most food crops Amendments to Federal Insecticide, Ftngicide and Rcdenticide Act (FIFRA) enacted requiring registration of all pesticides and their use plus certification of applicators-- Administering Agency for FIFRA is EPA Dow Chemical obtains an injunction against EPA enjoining further action against 2,4,5-T The study "Primary Carcinoma.of the Liver in Vietnam" released in medical journal Chirurgie by Dr. Ton That Tung U.S. Court of Appeals overturns injunction; can cellation proceedings continue Notice of Intent to hold Hearings on all uses of 2,4,5-T. Public hearing scheduled for April, 1974, following completion of intensive monitor ing for TCDD in part per trillion (ppt) range National Academy of Science Report - "Effects of Herbicides in South Vietnam - Part A Summary and Conclusions" issued information hearings expanded to include all insecticides and herbicides using 2,4,5Trichlorophenol in their manufacture EPA withdraws from cancellation and information gathering proceedings because of its inability to accurately monitor food for TCDD residues EPA establishes Dioxin Implementation Plan to identify good analytical methods for detecting TCDD in ppt range explosion at ICMESA Italy, releasing an eChs teimmicaat eld Plant in 1.7 kg. Seveso, (3.74 lb.) TCDD in an area with population of 100,000 decision to continue use of 2,4,5-T in New Zealand issued by government Ministries of Agriculture, Fisheries and Food (MAFF) of United Kingdom - Advisory committee announce that herbicides containing 2,4,5-T were safe, "if used in the recommended way for the 3 recommended fYWPOsee* continued! im UlIU approval given for tneir 1978 - Agent Orange Victims, International formed by U.S. Vietnam veteran 1978 - EPA publishes Rebuttal Presumption Against Registration (RPAR) and Continued Registration of 2.4.5- T, citing research that" indicates 2,4,5-T and TCDD cause tumors, birth defects, and fetal deaths. RPAR allows continued use pending final decision 1978 - airing of ABC-TV's 20/20 News Magazine two-part program detailing 2,4,5-T and Agent Orange 1979 - suspension hearings commenced on April 19, 1979 1979 - hearings stopped on May 15, 1979, after all registrants withdrew from the hearings 1979 - "Politics of Poison," a documentary on 2,4,5-T shown on NBC San Francisco affiliate KRON-TV 1979 - Dispute Resolution Conference on 2,4,5-T held sponsored by the American Farm Bureau Federation 1979 - availability of EPA Position Document on 2,4,5-T 1979 - hearings before-House Sub-committee on Oversight and Investigations on Involuntary Exposure to Toxic Herbicides and Pesticide Products 1979 - Pendulum and the Toxic Cloud by Thomas Whiteside published, dealing with the Seveso, Italy, dioxin accident 1979 - Notice of Intent to Cancel Suspended Uses of 2.4.5- T by the EPA 1979 - Alsea II report submitted to the EPA which pro vided grounds for initial suspension action by the EPA 1979 - EPA issues Emergency Suspension Order for 2,4,5-T on rights of way, pastures, forests, home gardens, aquatic weeds, ditch banks, and ornamental turf; exempt from this suspension were rangeland and rice paddy applications 1979 - FIFRA Scientific Advisory Panel reviews nonsuspended uses of 2,4,5-T and issues opinion 4 1979 - PBS airs "A Plague on Our Children" as part of t its paries dealing in part with 2,4,5-T 1979 - EPA issues Final Determination Concerning the RPAR for certain uses of Pesticide Products and Notice of Intent to hold a hearing or; mt o 1980 - Dow Chemical filing against U.S. Government claims r negligence in misuse of Agent Orange and failure to inform servicemen of potential dangers of exposure to Agent Orange 1980 - Cancellation hearings of 2,4,5-T began March 14, 1980 1980 - Operation Ranch Hand - in depth study of Vietnam veterans scheduled begins Forty years ago, while researching the properties of naturally occurring plant growth hormones, scientists discovered the phenoxy herbicides (Peterson 1967). Considered as synthetic plant growth regulators, the ptienoxy compounds were developed to mimic the properties of a naturally occurring plant growth regulator, indoleacetic acid. Concurrent research in the United States and Great Britain revealed the capabilities of certain phenoxyacetic acids, including 2,4-dichlorophenoxyacetic acid (2,4-D), as active herbicides, selectively killing many broadleaf weeds in cereal grain, grasslands, and coniferous forests (Bovey and Young 1978), (Nutman, Thornton and Quastel 1945), (Blackman 1945). The mili tary furthered their investigation by studying phenoxy herbicide use as a vegetation control weapon in 19441945. By 1946, 2,4-D was used extensively to control weeds in turf, small grains, and corn. However, its efficacy did not extend to brush control. Research for an effec tive substitute began. Use of 2,4,5-trichlorophenoxyacetic acid began after its registration by the Amchem Products Company, Ambler, Pennsylvania, on March 2, 1948. In the years that followed, 2,4,5-T made its mark as the material of choice for effective brush control on rights of way, rangeland, forestry, and certain weeds in rice, wheat, corn, and sugarcane (CAST 1978). Although many phenoxy compounds have herbicidal capa bilities, most are not commercially available because of i prohibitive cost or narrow effectiveness range. Phenoxy herbicides presently in use today in the U.S. include 2.4- D, 2,4,5-T, MCPA, Silvex, 24-DB, MCPB, dichlorprop, mecoprop, 2,4-DEP (Weed Society of America 1974), and i dichlorprop-methyl (Federal Register April 7, 1980).- 2,4-D predominates in the U.S. today, due to its low I cost and high effectiveness. Other phenoxy herbicides | are employed only in instances where they exceed the ; capability of 2,4-D. In 1975, the United States used 59 million pounds of 2.4- d , 6.7 million pounds of 2,4,5-T, and two million pounds of Silvex (Stanford Research Institute 1976). MCPA, 2,4-DB, dichlorprop and mecoprop find important but limited use for specialized applications (Klingman and Ashton 1975). 2,4-DEP, a chemical related to 2,4-D, acts principally through soil transport (Crafts 1975), but it is not used with the same frequency as 2,4-D. w.ie iiuiiured companies hold federal registrations and formulate 424 products containing 2,4,5-T. Eleven companies have applied for federal registration of 21 products containing 2,4,5-T previously registered only in certain states (EPA 1974). In 1969, 11,626,000 pounds of 2,4,5-T acid, esters, and salts were produced in the United States alone. In 1970, the quantity rose to 12,335,000 pounds. Between 1971 and 1974, 738,907 pounds of 2,4,5-T were imported into the U.S. averaging a total of 148,000 pounds per year (EPA 1974). The phenoxy herbicides gain entrance to the target site by penetrating the plant foliage, roots and soft stem tissue. When applied as a drench in diesel oil, they can soak through the dry bark of trees and enter living tissues (Crafts 1964). Accumulating in the actively growing parts of roots and stems (Crafts 1964), they cause the leaves and buds to twist and curl and new growth of stems and leaves are malformed. Sensitive young plants may die in a few days. Hardy shrubs and tre'es may succumb only after weeks or months or may survive without injury (Bovey 1977). A phenoxy herbicide enters a plant in an imperfect and uncontrolled way. Once inside the plant, it interferes with the regulation of growth processes normally gov erned by the plant's own naturally occurring growth hormones (Ashton and Crafts 1973). The phenoxy herbi cides interfere with cell division (mitosis) and cell enlargement, food utilization and various other processes necessary to stabilize life. Scientists do not.know the precise mode of action of either synthetic or natural plant growth regulators. They do know that phenoxy herbicides are far more toxic to green plants than to animals. Plant growth regulating compounds act on plant cell compounds such as cellulose and lignocellulose which are not present in animals. O vGt HsP* ) 5 USES D O H 2 I 5 5 I 4 8 Land management personnel utilize phenoxy herbicides in various situations. The following discussion lists kinds of uses and the preferred herbicides for the job. Timber Management - Foresters have included the phenoxy herbicidesamong their timber management tools since the early sixties (Bentley 1967). Forests cover a third of the U.S. (approximately 750 million acres), and two thirds of this land is usable for commercial timber purposes. The remaining, approx imately 250 million acres, either produces too little timber for commercial classification or has been utilized for other functions, namely wildlife, water yield, grazing, or recreation (CAST 1978). According to Walker (1973), competing undesirable vegetation causes about 300 million acres of commercial timber land to operate at less than two thirds of its timber production capacity. Over one hundred million acres of historically high yield areas, now support no significant timber growth because competing vegetation robs trees of vital space, sunlight, and nutrients. Phenoxy herbicides applied here literally shift the advantage to the desired trees, increasing productive land for forest purposes and allowing re-establishment of mature forests. Traditional forestry methods emphasize hand cutting for thinning and culling of forest stands (Newton 1973), a procedure proven satisfactory as well as economically sound. But nationwide manual attendance of such large forest areas is economically and physically unfeasible. Kimmins and Fraker (1973) have cited 280 references to herbicide uses in forestry, and Johnson and Lawrence (1977) have listed more than 0 references in a more recent review. In California, herbicides are extensive ly used to control weeds in Douglas Fir forests, Ponderosa Pine mixed conifer forests, and Red Fir forests. Personnel used herbicides in two ways in forests: site preparation for stand establishment and conifer release. The site preparation method involves treatment of land before planting desired conifer seedlings. Fires, logging, and other natural or inten.-.ional situations often leave a forest area overgrown with herbaceous and 6" woody "undesird" growth which must be controlled for successful seedling establishment. This area is first prepared by clearing the site and crushing or burning th waste. A broad spectrum herbicide is applied during the next spring to prevent new growth. After the coni fer seedlings are planted, foresters then employ a selective herbicide for continued suppression of rapidLy growing plants. This application takes place within one to two years after the desired plantings during the late spring season, a peak time for rapid growth and resprout ing of broadleaf competitors. Some areas may be treated with herbicides prior to the initial burning and planting. With either of these treatments, conifer seedlings establish themselves with in six to twelve months. Occasionally land management personnel may find it necessary to re-treat areas because undesired growth has returned (Bentley 1967), (Schubert and Adams 1971), (Gratkowski 1975). In California, low volatility ester formations of 2,4-D and 2,4,5-T, alone or together, are used for brushfield control, while amitrole, atrazine, dalapon, dicamba, and simazine regulate herbaceous plant or grass growth in site preparation (California Department of Foods and Agriculture 1978). The conifer release method of herbicide control protects conifer seedlings from competing vegetation which robs young conifers of sunlight, nutrients and moisture. To accomplish this, aerial application of phenoxy herbicides takes place in early spring or late summer when conifer buds have not broken or hardened, avoiding any damage or injury to new growth (California Department of Foods and Agriculture 1978). Repeated treatment may be necessary depending on the species of brush or hardwood involved. Because conifers are relatively tolerant of 2,4,5-T, it is the herbicide of choice for broadleaf control. When the control of certain grasses and herbaceous growth is necessary for conifer release, the herbicides atrazine and simazine are used. Conifers are tolerant of these compounds unless their root systems come in contact with them. In addition to suppressing new growth, conifer release management may also involve control of mature hardwoods, such as oak. On an overstocked plantation or forest, conifers may be thinned out through direct injection of the herbicide into the base of a tree or direct applica- tion into a basal cut or frill (Fannls 1967). Cacodylic acid, MSMA, and 2,4-D amine are registered specifically for this purpose; picloram is also used. Type Conversion - Type conversion replaces one type of growth with another. Land management personnel primarily use type conversion to replace brushland with more suit able ground cover. Phenoxy herbicides aid in this trans formation . \ The object of type conversion is to rehabilitate per manent pasture, range or brushland, create fuelbreaks, maintain wildlife habitats, and manage watersheds. In all cases, workers modify brushland or chaparral, thereby permitting another vegetation to dominate. Type conversion increases forage for livestock, reduces fire potential and increases water run-off and yield, and provides favorable habitat for wildlife preservation (California Department of Foods and Agriculture 1978). Range or Brushland Rehabilitation - The United States Forest Service treats approximately 3500 acres per year with herbicides for the purpose of range rehabilitation p(oUsSsDiAbl1e9741)2.0 , 0 0T0hatacraecscooufntslanfdoraopnplryoprtiwaoteperfcoerntsucohf' the procedures. ......... Routinely, areas of sagebrush, chaparral, oak, and other hardwoods are changed via type conversion, to open grassland and meadows for grazing purposes. Herbicides of choice here include the 2,4-D esters, 2,4,5-T, picloram, and Silvex. MSMA and AMS substitute when phenoxy acids cannot be used. Herbicidal applications are made aerially, often after mechanical clearing of the area. If the terrain permits, ground spraying takes place. Herbicide application can be repeated every five to ten years should the situation warrant it. If the area really lacks a substantial amount of desired plant growth, personnel may elect to re-seed the area with a proper foliage plant (California Department of Foods and Agriculture 1978). Fuelbreak Maintenance - Fuelbreak maintenance involves the control of specified areas, usually strips, to pre vent fire hazards and to avert water run-off problems. This is accomplished by applying herbicides to strategic areas on grassland, particularly shrub border areas. Successful treatment here allows no brush growth whatso ever beyond these borders. In the event of brush fire, firefighters can rely on well marked control areas free from the threat of brush intervention so they can then plan appropriate strategy. After mechanical removal of brush or burning, land management personnel aerially spray or treat individual plants with 2,4-D, 2,4-pP, and 2,4,5-T two to three years later. Management goals are accomplished when all brush species are replaced with grassland cover. Maintaining this altered state in fuelbreak and other high hazard areas may necessitate repeated applications of herbicides (California Department of Foods arid Agriculture 1978). Maintenance of Wildlife Habitat - Type conversions for this purpose are not uniformly used. The premise remains the same as for other categories of type conversion. Less productive browse speqies or brushland give way to pre ferred grassland. The resulting preferred foliage may provide more palatable browse for various species of wildlife. This effect appears largely as a secondary gain, however, and not as a principal effect of herbicide application. Rights of Way - Rights of way represent a hallmark of our industrialized society. Whether for a highway, rail road, or utility apparatus, a properly maintained right of way is essential for a problem free operation. About 3.8 million pounds (41 percent of total use) of 2,4,5-t are used for this purpose in the United States annually (EPA 1979=). 2,4-D, 2,4,5-T, and Silvex provide selective vegetation control here, although 2,4-D alone accounts for about half that use. acres involved, railroads occupy 2 0O0f, 0 0t0hemi5l0esm,illainodn plus high ways account for nearly four million miles. Overhead electric wires require two million miles of air space, with 300,000 wires devoted to high capacity circuits occupying over four million acres (CAST 1978). Phenoxy herbicides used in rights-of-way control vege tation that represents potential fire hazards, and inter feres with access to power, telephone and transmission lines, or obscures roads or makes them inaccessible. Most utility, highway, and railroad rights of way are initially cleared mechanically. Costs vary with labor prices and terrain. Roads and Highways - Roadway maintenance crews use the phenoxy herbicides to aid in preventing fires and elimi nating obstruction of signs and safety signals, thereby providing optimum visual fields for the driver. They also remove tall weeds which promote snow drifts, elimi nate weeds declared noxious by appropriate authorities, 7 CM .CO I JDON2155150 CO allow drainage and aid in aesthetic development, while leaving preferred grassland and low vegetation intact. After mechanical clearing, booms on large tank trucks distribute the herbicides, although in some areas, spot treatment by hand equipment may be necessary. 2,4,5-T and 2,4-D and other herbicides have eliminated the need for plowing, hand cutting, and burning and also permit fewer mowings per year, thereby reducing fuel costs and conserving gasoline and diesel fuel. Chemicals are particularly useful on steep slopes, wet areas, and areas obstructed by guard rails or other structures hindering conventional machine mowing. Phenoxy herbicides find limited use in those areas where desirable vegetation is so close to the weeds to be sprayed that it is suscep tible to damage by drift of 2,4-D or 2,4,5-T. Utility Rights of Way - Herbicide application on utility rights of way frees various wires and lines from inter fering brush and foliage growth. Such maintenance is necessary to control fires and allow access to transmission lines and structural facilities. Workers apply herbicides via ground spray methods primarily, although they may use aerial application in some cases. Ground maintenance includes all applications made with tank spray rigs in accessible areas or made by manually operated backpack spray units. . On power and communication rights of way, control entails use of 2,4-D and 2,4,5-T (Bramble and Byrnes 1972). Newly constructed lines cleared with mechanical equipment may require two herbicide applications initially to control regrowth. Maintenance operations involve the following: e(s1)tersseleatctirvaetesbaosafl12s-p1r6ayspouonfds2,p4e-rD/21,0 04,5g-aTlloorns 2,4,5-T of oil; (2) foliage or stem foliage sprays of 2,4,5-T or 2,4-D/ 2,4,5-T mixtures in water at rates of three to four applied with ground pounds of chemical peerqui1 p0 0men-t gallons of spray mixture; and (3) aircraft applications of 2,4,5-T or 2,4-D/2,4,5-T mixtures at rates of up to 12 pounds per acre, often as invert emulsions or combined with a thickening agent and applied by special equipment to reduce spray drift (Barnhart et al. 1976). Silvex and dichlorprop may be injected into tree species resistant to, 2,4-D and 2,4,5-T, but they are not generally used because of their limited effectiveness. Railroads - Vegetation management along railroad rights of way involves applicaton of herbicides directly to the track beds and ballast or to the offtrack right of way parallel to the trackbed (California Department of Fo' L and Agriculture 1978). Undesired growth limits sight lines, hinders train inspection and yard, work, prevents proper drainage of the ballast, presents fire hazard, causes potential train fouling and is aesthetically displeasing (Parker 1965) , (Yazell 1965). Administration of the herbicide proceeds by use of spray and tank cars riding directly over the tracks for on-track application. For the surrounding areas, a fire hose nozzle attachment distributes the chemical from the tank car. In areas which are difficult to reach, four-wheel drive vehicles equipped with spray apparatus are used. Aquatic Management - Herbicides function not only on land, but in water as well where they are used for aquatic vegetation management. Plant life covers most surface water areas. Providing a primary source of nutrients for aquatic life, these plants can also cause problems. Uncontrolled growth and overpopulation of these weeds can clog streams, lakes, reservoirs, and canals; start floods; interfere with recreation and the flow of irrigation and drainage water; restrict navigation and impair fish and wildlife habitats (Pennsylvania Water Resources Coordinating Committee 1971), (Florida Bureau of Aquatic Plant Control), (Timmons 1960), (Timmons and Klingman 1959). About two million pounds of 2,4-D and one half million pounds of Silvex are used annually in the United States for the control of aquatic vegetation (Stanford Research Institute 1976). Unlike its close cousin Silvex, 2,4,5-T is not employed for any aquatic management purposes. Turfqrass - Turfgrass includes lawn, shrubbery, shade trees, andother forms of greenery which can be categor ized as ornamental turf. There are 15 million acres of ornamental turf in the United States. About one tenth of this land is devoted to golf courses. Home lawns consti tute about one third of all ornamental turf, and homeowners currently hse 2,4-D, mecoprop, and dicamba to control weeds.. To manage growth on other ornamental turf, landscapers employ 2,4-D, 2,4,5-T, Silvex, MCPA, and dichlorprop to limit dandelions, plantains, garlic chickweed, and other broadleaf and non-grass weeds. For control of crabgrass and other annual grasses, greenskeepers apply DCPA, benefin, bensulide, arsonates, and siduron among others. Simazine and atrazine control many annual weeds. DCPA and dicamba work on some phenoxy-tolerant broadleaf weeds as well'.as some of the annual grasses. Dicamba poses some problems. Since roots this chemical from the soil, nearby shrubs -1?asdhialdye adtsroeresb can be injured. Phenoxy herbicides are also used, in a variety of -state', county, and regional public health programs to suppress growth of nuisance weeds. These chemicals can eradicate poison oak, ragweed, poison ivy, and other allergenic plants by direct spot treatments of the toxic foliage. Agricultural Uses - Four fifths of the 72 million [xaunds of phenoxy herbicides used annually in the United .States are devoted to agricultural management of crop and range land (CAST 1978). In 1975, 55 million pounds of these chemicals were used to treat crop lands in the United States (Stanford Research Institute 1976). Phenoxy herbicides are used primarily on the grain crops, wheat, corn, barley, oats, and rice. 2,4-D application at a rate of less than one pound per acre is standard for many of these crops (USDA 1973). MCPA is used on rice in Cali fornia. Non-grain crop production also depends on phenoxy her bicides. They are useful against weeds in apples, asparagus, blueberries, cranberries, flax, pears, potatoes, strawberries, and sugarcane. Bach crop has specific requirements and formulations of the phenoxy herbicides. Variables such as crop rotation, method of application, and selectivity all influence the choice of herbicide used. Farmers prefer a variety of herbicides to combat their agricultural weed problem. Alone, or together with other weed control practices, a change in herbicides can be as effective as a change in crops. By rotating crops, and therefore rotating the herbicides that handle their weed problems, the farmers select different cultural methods and activities for their farmland. This not only helps protect the crop currently being cultivated, but also helps to support growth of the rotation crop not presently grown. Small Grains - Small grains are almost constantly infested withannual and perennial weeds that respond favorably to the phenoxy herbicides. If left unattended, these weeds substantially reduce crop yields, interfere with harvesting, and reduce grain quality, i.e., wild garlic bulblets harvested with wheat grain give the resulting milled flour a garlicy taste rendering the wheat essentially worthless. 2,4-D is the principal herbicide used for grain crops in the United States today. About 60 million acres of feed and food grains are protected annually by 34 million pounds of 2,4-D (Stanford Research Institute 1976), at a rate of one quarter to one pound per acre (Crafts 1975), (OSDA 19^3). When 2,4-D is not effective on certain weed complexes, farmers often choose to use MCPA. Although the cost for MCPA far exceeds that for 2,4-D, approximately four million pounds of MCPA are spread on eight million acres of U.S. land yearly (Stanford Research Institute 1976) , (Klingman and Ashton 1975). Currently, application of the herbicide 2,4,5-T on rice lands survives as one of the uses of the herbicide not suspended by the Environmental Protection Agency. Together with 2,4-D and MCPA, farmers can kill broadleaf weeds that interfere with a successful rice crop. 7n some instances, a plant such as the curly indigo may be tolerant to 2,4-D or MCPA. In southern states, where these weeds prevail, farmers may choose to use 2,4,5-T exclusively'for rice land management. Farmers have few alternatives to phenoxy herbicides. Mechanical and hand tillage of the land are impractical substitutes. Special herbicides for selective weed grain problems do not act as thoroughly as the phenoxy herbi cides. For example, dicamba controls some annual and perennial broadleaf weeds in oats and wheat, but not in barley. Furthermore, it does not regulate woody mustards and other important weeds (Anonymous 1977a). Dicamba has a toxic effect on small seeded legumous plants. It must therefore be ruled out as method of choice in the central and eastern United States where small seeded legumes are often interspersed with small grain crops (USDA 1973) . Bromoxynil curbs many annual broadleaf weeds in small grains but is ineffective on many perennials. Again, it cannot be used where small-seeded legumes are sown (USDA 1973) . Dinoseb, another herbicide, acts primarily on annual broadleaf weeds in small grains. However, denoseb does not move internally in plants and therefore remains ineffective against perennials. As an added deterrent, dinoseb is far more toxic than the phenoxy herbicides on warm blooded animals (Weed Society of America 1974). There are essentially no alternative replacements for the phenoxy herbicides, particularly 2,4,5-T, in effec tive management of rice land weeds. Corn and Other Grains - Alternatives to phenoxy herbi cides in agriculture include cultivation supplemented by hoeing. While cultivation holds a significant place in crop management with or without herbicides, it cannot remove weeds directly occurring in the crop row (CAST 1978). For this, farmers must resort to basic handwork. 9 iDOM2I55I52 Proposed as an intermediate step (Aly and Faust 1964) in the manufacturing of commercial 2,4,5-T, the compound uarlnesadocetriaoptnph.eearcso2 n,di4in,t5it-ohtnersipcnrhoeldcouercsotsaanrdiyuseolfeotrocaisnttsepalisn(oc1 o)mbepalndehtyeydireolldyzed methoxydichlorophenoxyacetic acid as a side product (Aly and Faust 1964). Cl ., i:j' W CO rH -ci OCH2COOII CH3O 5-methoxy,2,4-dichlorophenoxyacetic acid Cl Cl \ / OCH2COOH OCH3 2 -methoxy,4,5-dichlorophenoxyacetic acid 2,4,5-trichlorophenol arises of the sodium phenoxide with from incomplete chloracetic acid coinndesntseapti(o2n). OH Bis-2,4,5-trichlorophnoxyacetic acid From the 1,2,5-trichlorobenzene in benzene raw material, the by-product 2th,e5-dtiecthrlacohrlooprhoe-no- xyacetic acid results. Additionally, some sodium 2,4,5-T and sulfate ions appear in the final product due to the acidification process outlined in step (3) . Dioxin, however, is considered the most notorious and noxious by-product formed in the manufacture of 2,4,5-T. It arises as a trace impurity produced under the condi tions listed in step (1). Because of its chemical nature and its obvious importance in a thorough review of 2,4,5-T, it will be discussed as a separate entity later in the paper. 2,4,5 -trichlorophenol Bis-2,4,5-trichlorophenoxyacetic acid represents a signi sftiecpant(2 impurity since the chloroacetic acid involved ) routinely contains some dichloroacetic acid. in K 2,3,7,8-tetrachlorodibenzo-p-dioxin Assay methods for 2,4,5-T usually require a simple titration for acid equivalents. A procedure for a n a l y z i n g the herbicide by gas chromatography exists, ? standards for this assay are given although analysts ra .y employ iliis method. The marketed 2,4,5-T product generally contains 97 to 98 percent acid equivalent. According to t.he Department of Agriculture, herbicide titre can -run as low as 85 percent in commercial materials and still main tain a 97 percent acid equivalent specification. Chemical Stability of 2,4,5-T Photochemical degradation - Many of the phenoxy herbicides such as 2,4-6, readily undergo oxidation, reduction, and substitution (mainly hydrolysis) in aqueous solutions when activated by sunlight in air. Although 2,4,5-T absorbs some ultraviolet light in sunlight, the amount is small and this herbicide is relatively unreactive (seven percent hydrolysis -in 48 hours). -However*,-the presence of ferric salts and zinc oxides in the soil water will result in an increase in photolysis rate (Crosby 1976). Hydrolysis - Esters of 2,4,5-T are readily hydrolyzed to free acid under either acid or basic conditions. Crops rarely exhibit ester residues. The rate of hydrol ysis depends basically on the particular ester substitu ent's stereochemistry, decreasing as the bulk of the ester group is increased closest to the oxygen linkage. Thermal stability - 2,4,5-T is stable at least to its melting point (156^-158 C). Biochemical degradation - 2,4,5-T degrades slowly in soil containing organic matter under warm, moist condi tions. Half life for the herbicide under these optimal conditions approaches several weeks. Metabolic degrada tion is caused by two concurrent processes: binding of the herbicide molecule to other compounds, mainly glucose, to form a non-toxic complex, and actual degradation of the molecule. The latter proceeds by the removal of the side chain and replacement of the chlorine atoms with hydroxy (OH) groups, followed by an opening of the benzene ring. Formation of the corresponding phenols is a minor route of breakdown in plants and a major route in soil and rumen. Decay, however, does not follow first order reactions because metabolites of 2,4,5-T greatly increase in number in the presence of the herbicide. If the area is pretreated with 2,4,5-T, degradation lifetime is signifi cantly reduced. Three months is generally accepted as the time span for the herbicide to disappear completely from the soil. Disappearance rate is independent of the amount of herbicide present. The degradation of the herbicide varies with plant species as well as environmental condi tions (President's Science Advisory Committee 1971). Summary 2 .4.5- trichlorophenoxyacetic acid is a white crystalline solid with a molecular weight of 255.49 daltons. It melts at temperatures of 156-158 C and has a solubility of 278 ppm in water. Technical grade 2,4,5-T contains 90 to 92 percent herbicide and eight to ten percent impurities. Preferred formulations of 2,4,5-T are its ester and amine salt derivatives. 2.4.5- T esters are readily hydrolyzed under acidic or basic conditions. Chemically stable at its melting point, the herbicide degrades slowly in warm, organic soil. Its half life approaches several weeks, with a total degrada tion time nearing three months. ........... Metabolic degradation occurs by two concurrent processes: the binding of 2,4,5-T to other molecules, i.e., glucose forming a nontoxic complex, and actual degradation of the molecule. This proceeds by the removal of a side chain and replacement of chlorine atoms with hydroxy groups and opening of the benzene ring. Even in the presence of sunlight, 2,4,5-T remains relatively unreactive. 13 TDOH2I55I54 HAZARDS Hazard is the probability that injury will result when a particular substance is used in a particular quantity and manner. A hazard implies warning. It signals caution before proceeding. It implies potential harm. A hazardous roadway may increase the likelihood of auto mobile accidents. A hazardous area may mean danger for those not familiar with it. A hazard to one's health may result in bodily injury or even death. Two kinds of hazards may be considered. The first are hazards that are inherently dangerous. By their very nature, members in this category forebode danger. Cir cumstances fail to alter underlying jeopardy. No matter how or when you consider them, their presence threatens to disrupt states of synchrony and well-being. Natural disasters such as earthquake, fire, tornado exemplify hazards in this category. The second are hazards that are situationally dangerous. In these instances, the situation dictates the chance, risk, or danger. Here, the hazard can vary in degrees, and in fact may not even exist at all should the situation change. Automobiles and prescription drugs readily come to mind in describing this category. Hazard implies some quantified risk, and understanding the amount of risk is necessary in evaluating what is a real hazard. From a public health standpoint, the hazards that con cern us are those that affect bodily health and well being. Increasingly, we are reminded to consider hazards in the environment we live in and in the foods we eat. Sometimes, these hazards take the form of chemicals. When a chemical is labelled a hazard, it is immediately categorized by pre-conceived notions and handled accord ingly. However, specific considerations are needed in evaluation of the hazard. They are toxicity and exposure. Toxicity is the capacity of a substance to injure. It is a universal property of matter varying only in degree. Exposure is the quantification of the degree-- in this case, the degree of toxicity. These two elements must be ascertained and related in a thorough analysis of a chemical. A difference exists between an element that is highly toxic but has a low exposure level, and one that has little toxicity but high exposure. In both of these categories amounts are all important factors. Hazards of the phenoxy herbicides stem from their selective herbicidal ability. These chemicals have the power to kill certain plant life. The beauty in their 14 action, though, is their lack of effect on certain other plant life, causing them no harm. The phenoxys, as mentioned earlier, direct their killing action towards the broadleaf plants such as weeds encroaching on various agricultural and non-agricultural lands. A problem arises, however, when these herbicides come into contact with vulnerable but desirable species. This failure of selectivity can cause injury and even death of plants. Selective mortality is the result of several circum stances. Among them are overdosing a plant. A certain amount of phenoxy herbicide is applied to control popula tions of plants, but should the plants receive an excessive amount, they will be wiped out all together. This could happen if poorly calibrated spray apparatus is used in spray distribution. Overdosing can also result if the herbicides involved are mismeasured. Exposing a susceptible plant during its sensitive stages of growth can also result in unwanted injury (Linn et al. 1959). Emergence and budding are usually the vulnerable states. There are three major potential hazards to be considered when assaying phenoxy herbicides: spray drift, persistence of residues, and toxicity. Spray Drift Spray drift to non-target vegetation remains one of the most critical problems of phenoxy herbicide application (Mullison 1970), (Stewart and Gratkowski 1976), (Akesson and Yates 1975). Advanced technology allows up to 97 to 99 percent of phenoxy herbicides to land in the target area either by ground or aerial application (Akesson et al. 1971). However, great care must be taken to assure minimal exposure to non-target areas. Production of small drops and the discharge point to ground distance with aircraft or ground application affect spray drift (Gratkowski 1976) as do wind velocity and direction. Together with pesticide formulation,, these variables can either greatly enhance or reduce exposure of susceptible crops to phenoxy herbicide activ ity. Air temperature and humidity also alter crop response and influence spray evaporation (Stewart and Gratkowski 1976), (Akesson and Yates 1975), (Butler et al. 1969). Preferable conditions for application in a hazardous situation require the phenoxy application be made only when a light and continuous wind is blowing away from susceptible crops (Stewart and Gratkowski 1976), (Akesson and Yates 1975). Phenoxy herbicide application, in fact all pesticide .application, may cause problems in instances of atmospheric inversion, when a warm layer of air is overhead under 1500 feet elevation (USDA Forest Service 1977). Stagnant air resulting from atmospheric inversion or lack of wind reduces turbulent mixing or ventilation. During an inver sion or when the air is still, build-up of small drops and vapor in the air can drift as a concentrated mass to sensitive crops. Non-target susceptible vegetation exposed to phenoxy herbicides may exhibit tell-tale symptoms such as bizarre growth. Often,-the appearance of injury to the plant is greater than reality (Goodman 1953). There are several ways to avoid the problems of spray drift. Spraying herbicides in large and heavy droplets (500 to 1500 microns) causes them to fall and settle rapidly in the target area (Akesson and Yates 1975). Droplet size can be increased by using higher spray volumes and lower spray pressures. Droplets may be increased in size through use of nozzles with special design or nozzles with large openings. In addition, air craft may also be equipped with special systems that closely control droplet size (Stewart and Gratkowski 1976), (Gratkowski 1976). Thickening agents can be added to the spray which act to increase drop size and decrease the risk of fine particles (Stewart and Gratkowski 1976), (Akesson and Yates 1975), (Gratkowski 1976), (Gratkowski and Stewart 1973) , (Butler et_ al_. 1969) . There are areas where spraying should be eliminated altogether. Certain crops cannot be protected from spray drift even when conventional methods to eliminate drift have been instituted. When highly susceptible crops such as of cotton and large scale grsappreasyianrgeopgerorwantiownisthi(novetrhre1e0 0 to five miles acres per day), there may be crop injury despite routine precautions. Beans, tomatoes, melons, and certain ornamental plants also succumb easily to damage (Linn e. al_. 1959). Federal regulations address these situtations (Akesson 5 and Yates 1975). They forbid the spraying of herbicides ' at certain times of the year and require special permits for particularly hazardous applications of phenoxy herbicides. R esid u es 1D0H2155155 Residues can be found as an after-effect of almost any product application. A residue is an accumulation of a product for a period following initial application. Dirty wax build-up on wood furniture results from accu mulated polish residues. The film inside the coffee pot is the residue formed from the percolation of the coffee beans and water forming that brew. Residues occur when the initial product is not totally degraded. The persistence of a residue can cause problems. If use of a known toxin leaves sufficient residues in active form, the extent and duration of that toxicity must be recognized and appropriate cautions followed. It is imperative that we realize the amounts and effects of residues when analyzing an environmental chemical. A chemical's persistence on land, in water, and in the air may profoundly affect the plant or animal that encounters it. Some residues may prove injurious or even fatal to the untargeted species. Residues do not last forever. Their reduction or dis appearance from the environment depends greatly on the half life of the particular chemical, and the conditions where it is deposited. It can range anywhere from hours and days to months and years. The ill effects of chemical residues can be diminished by avoiding use of potentially hazardous sprays in areas where drift and/or accumulation may be expected or already occur. Common sense dictates that the same care and caution given to areas during spraying should be given to crop areas subject to herbicide residues. Residue accu mulation in soil, water, air, and animals should each be considered separately. Soil Residues - Scientific studies demonstrate that phenoxy herbicides break down in soils (Audus 1960). 2,4,5-T and 2,4-D form carbon dioxide, inorganic chloride, and water as final degradation products (Reigner et. al. 1968). Classified as slightly persistent, 2,4,5-T takes anywhere from two to six weeks for a fifty percent disappearance rate. The tendency to volatilize from the soil complex reduces this soil persistence. Volatilization will occur with or without water evaporation (Plimmer 1976). A decrease in soil moisture will lower the soil pH. This favors the undissociated form of both 2,4,5-T and 2,4-D and can possibly enhance vapor loss. 15 i D0H2 I 55156 vH Soil leachingjexprimente involving 2,4,5-T suggest that amine salts are leached more rapidly than free acid (House et al. 1967). with massive greater than a1p0p, 0l0i0catpiaorntsrapteersmialnldiosnoil(pcpomn)c,enatnrdatiinonan alkaline desert environment, the half life of 2,4-D and In 1974, the National Academy of Sciences Report corre lated the effect of herbicides on soils of Vietnam with other soil residues (Blackman et al. 1974). Listed are some of the general conclusions: 1) The behavior of herbicides in the soils of South Vietnam was similar to that reported for soils elsewhere. 2) Residues remained only where excessive doses of 2,4-D and 2,4,5-T were applied (Pran Bari). These residues remained ten years after application at levels above the levels likely to induce phytotoxic symptoms in some plant species. 3) When applied to mangrove soils at total doses approaching 10 lb/acre for both 2,4,5-T and 2,4-D, the levels of herbicide residue at the end of 30 weeks had no effect on the establishment of two major mangrove species. 4) In geographical areas subjected to one or two military herbicide missions 1.5 years before sampling, no soil phytotoxic residues could be detected. 5) Soils that received a directed application of Herbicide Orange at a rate of 27 lb/acre safely supported the growth of crops sensitive to 2,4-D or 6) 2,4,5-T four to Claims that the six months herbicides following application. rendered the soil sterile were without any foundation. The United States Air Force conducted feasibility studies for the disposal of surplus Agent Orange-- a 1:1 combination of herbicides 2,4-D and 2,4,5-T. The field study, con ducted in 1972 on the Air Force Logistics Command Test Range at Hill Air Force Base in Utah, determined the effects and.remaining amounts of.herbicides 2,4-D and 2,4,5-T. In administered croenpcleinctartaetdiosnusb-osfurfeaictehertes1t,s0,0 0r,es2e,a0r0c0h,erosr 4,000 pounds of*herbicide per acre. Stark t al. (1975) took soil samples at three different time periods during 1973 and analyzed soil content for microbial species (bacteria, actinomyctes and fungi). Bacterial countB were higher for soils with greater concentrations of the herbicides and with greater moisture content i.e., those samples collected in mid-winter from the 4,000 pound per acre subplot. Mycoflora experienced no significant effect from the herbicides. Arnold et 1^. (1976) monitored the herbicide level in these plots. Sampling the plots on eight occasions from 1973 to 1975, they determined the concentrations of the n-butyl esters and the free acids bot' ,4-D and 2,4,5-T. Their research suggested that 16 2,4,5-T occurred in the range of 150 to 210 days. The cooperative studies by Stark et_ al_. , and Arnold et al demonstrated the applications of 2,4-D and 2,4,5-T at massive rates not only did not sterilize the soil, but indeed stimulated the growth of certain microflora, and that this stimulation may have contributed to the degra dation of the herbicide (Young et. aj^. 1978). 1 Norris soil for e2~t~4a,l5-.T (1977) examined foliage, forest floor residue. The conclusions, summarized and in the journal Weed Science, were that within six months of application, herbicide residues declined 90 percent; within one year,less than six percent of the herbicide remained. The authors also found little leaching of 2,4,5-T from the forest floor to the soil, and no residues were found deeper than 15 cm. (Maximum residue found was a level of 0.08 ppm despite rainfall of 24 cm the first month and 70 cm the first three months after application.) ! j ' Wiese and Davis (1964) found that 2,4,5-T remained in the! upper six inches of agricultural soil even after applica- | tion of 4.5 inches of water over a short period of time. 1 Helling et al. (1973) found that 2,4,5-T is relatively mobile in soils. However, that movement decreases as organic content increases. 2,4,5-T therefore becomes moderately mobile in clay soils and only slightly mobile in mulch. Morton et al. (1967) found that both amount and fre- ! quency of rainfall affected leaching and microbial decom- position of 2,4,5-T. | Water Residues - 2,4,5-T acids and esters re soluble in water. In addition, 2,4,5-T rapidly dissipates in streams by dilution (USDA/EPA 1979) and photodegradation in water (Crosby and Wong 1970). Concern for chemical residues found in any water supply stems from fears of contamination of various life forms. If the body of water involved is a reservoir, and were to contain high residues, countless people could conceivably suffer ill effects simply by drinking a glass of water. If a stream, lake, or pond is involved, the resident aquatic-life could be jeopardized. The residual effects of chemicals in water therefore can be far ' "hing if concentrations are sufficiently high. Current information indicates that, although some 2,4,5-T may enter streams flowing through or located adjacent to herbicide spray areas, residues in the streams remain very low (EPA 1974). The National Academy of Sciences Safe Drinking Water Coothmemrittseuerfafcoeundwattehratbycon2t,a4m,i5n-aTtiio3n of drinking water extremely unlikely or (limit of detection/ppt). The report projected the tox icity of 2,4,5-T and TCDD, their acceptable daily intake, and suggested no adverse affect levels (National Academy of Sciences 1977), (Merck Index 1976). Research reports involving stream contamination from land spraying in tions of phenoxy Ohreergbionciddeesmonssetlrdaotmedexcteheatdedpea0k. 1 concentra ppm. These residues rarely lasted for more than a few hours in almost all the streams (Norris et. al. 1977). However, herbicide application to marshy areas may result in high- level, long persistent chemical residues in nearby streams. The Report of the Advisory Committee on 2,4,5-T to the Administrator of the Environmental Protection Agency seated that all available data indicated that a small amount of 2,4,5-T is present, but does not persist long because clay or the biota absorb the herbicide within a matter of days (EPA 1974). There appears to be little likelihood of 2,4,5-T's presence in alarming quantities in ground wpter or drainage channels due to local appli cation. Brown and Nishoka (1967) reported that 2,4,5-T was not detectable in samples of water-suspended sediment , mixtures from 11 streams in the western United States. Using improved techniques, a subsequent report on the same streams listed positive residues of 2,4,5-T in 28 of the 235 samples taken from 17 rivers as well for the time period during 1966-1968. Twenty-one of these samples were from three rivers: the Arkansas, the Brazos and the Canadian. All seven samples taken from the Canadian River were positive. Actual residue amount remained very small, ranging from 0.01 ppb to 0.07 ppb. Samples col lected throughout the year, demonstrated little or no seasonal effect on 2,4,5-T residue levels (Marigold and Schulz 1969). Samples for this experiment were analyzed as they were received. Water and sediment were not separated. The possibility exists that a high percentage of the 2,4,5-T residue was contained in the sediment since there is evidence that phenoxyacetic acid residues persist longer in sediments than in water (President's Science Advisory Committee 1971). (Table 1). Trichell et al. (1968) studied the effects in runoff water of 2,4,5-T application at a rate of 2.24 kg/ha to *00H2I 55 I57 aod-covr^d plots of three percent slope. After the application, 1.3 cm of rainfall was simulated to produce the runoff. They recovered 2 ug/ml of the herbicide after 24 hours. Four months after the application, this measurement had diminished to 0.04 ug/ml. Table 1. Estimated Maximum Level in mg/1 (-ppm) of Residues of 2,4,5-T at Various Rates of Application to Bodies of Hater Ranging from Three Inches to Ten Feet in Depth Hater depth Rates of application, pounds per acre 1 2 4 6 20 26 80 100 3 inches l.S 3.0 6.0 9.0 30.0 39.0 120.0 150.0 6 inches 0.75 1.50 3.0 4.50 I5.OO 19.50 60.0 75.0 1 foot 0.38 0.75 1.50 2.25 7.50 9.75 30.0 37.50 2 feet 0.19 0.38 0.75 1.13 3.75 4.88 15.0 18.75 3 feet 0.13 0.25 0.50 0.75 2.50 3.25 10.0 12.50 4 feet 0.09 0.19 0.38 0.56 1.88 2.44 7.50 9.38 S feet 0.08 0.15 0.30 0.45 1.50 1.95 6. UO 7.50 S feet 0.06 0.13 0.25 0.38 1.25 1.63 5.00 6.25 7 feet 0.05 0.11 0.21 0.32 1.07 1.39 4.29 5.36 8 feet 0.05 0.09 0.19 0.28 0.94 1.22 3.75 4.69 9 feet 0.04 0.08 0.17 0.25 0.83 1.08 3.33 4.17 10 feet 0.04 0.08 0.15 0.23 0.75 0.98 3.00 3.75 Sourcet President's Science Advisory Committee 1971. Following application of 11.2 kg/ha of 2,4,5-T, Edwards and Glass (1971) monitored runoff and percolation of the herbicide for 14 months after application. They deter mined that 5.5/g/ha (over 0.05 percent) of the herbicide was lost from the treated area. The majority of 2,4,5-T was removed in runoff during the firah four months after application. More than half of the loss occurred the first month after treatment. 17 DOM2 I55l{ The method of contamination, i.e. drift or direct application, determines the amount of levels of residues deposited. If a very fine spray is used in an area where dense weeds extend above the water, much of the total herbicide will not reach the water directly. This also holds true for heavily forested spray areas. Much of the foliage intercepts the herbicide to reach the surrounding water. before As much itasha8sB a chance percent of the total herbicide may be intercepted by such plants as liveoak, which are considerably less dense than such water species as water hyacinth or alligator weed (Tschirley 1968). Little information exists on the possibility of release to water of herbicide residues in plants (President's Science Advisory Committee 1971). Phenoxy chemicals may enter the water but diminish due to the forces of volatilization, degradation, adsorption on sediment, adsorption by biota and dilution as addi tional Btream water passes through the site (EPA 1974). Almost all authorities agree that adsorption on the bottom sediment takes place. Esters of 2,4,5-T are hydrolyzed within a matter of days in all but highly acidic kinds of water (Kenaga 1974). Under laboratory conditions, the 2-ethylhexyl ester of 2,4,5-T was applied to water at a concentration of 1 ppm; 58 percent of the ester eight hours; arnedmai1n2 edperacfetnetr four hours; 33 percent after 16 hours. after Air Residues - Prior to 1970, the phenoxy herbicides were used forpre-emergence control of broadleaf weeds in wheat crops. Air samples were collected and analyzed from the State of Washington during the spring and summer seasons where the herbicide was employed for wheat weed c0o.n06troulg./m3Roefsul2t,s4-oDfantdhis2,a4n,a5l-yTsirsemdaienmeodnstirnattehed up to air ws3o0aummlpdl3/edsbaeyt,aiknehanta.litnhAgisut1hl. 6oervseulgexoptfhreanppohoxelynaotxheyedrbhietchriabtdieciadpemera.nedxaipynohsau(lroeir,ng 0.025 ug/kg of body weight/day for a 70 kg man) (Johnson 1971). The National Air Monitoring Program conducted ambient air monitoring for pesticides in the years 1970 through 1972. Table 2 records the arithmetic mean of residues of 2,4,5-T detected in this program. 18 Table 2. Air Monitoring Data for 2,4,5-T in 28 State Monitoring Programs (1970-1972) 1 State 2,4,5-T ester monitored for ng/m^ 1970 ng/m^ ng/m^ 1971 1972 Louisiana Montana New Mexico Idaho Illinois Oregon Tennessee Tennessee Oklahoma Isopropyl ester BOEE Isooctyl ester - ND - ND ND ND 1 .1 ND ND ND ND ND ND 3.6 0.5 ND 2.7 14.6 101 ... 809 1.7 ND ND ND ND ND ND = not detected; ng/m^ = nanograms per cubic !meter Source: EPA 197a T-'l to if*" vH i, ! i EPA Air Monitoring Data for 2,4,5-T over a three year period showed that no monitoring location had a detect able herbicide residue in more than one of the three years tested. The iso-octyl ester of 2,4,5-T sprayed in Tennessee and Oklahoma left the greatest amount of residue recorded in the second year of testing. From these data it would appear that 2,4,5-T residues are neither consistent nor cumulative. Animal Residues - PerhapB the most important residues are those ound in animals. Animal residues accumulate because of herbicide build-up elsewhere. If a residue covers pastureland, then grazing animals ingest these residues. Carrying this one step further, a slaughtered animal, having grazed on residue covered land, can pro duce residue carrying meat samples-- thus demonstrating a satellite effect of an initial chemical accumulation. However, animals rapidly eliminate about 95 percent of ingested 2,4,5-T unchanged in the urine (Sauerhoff et al. 1976), suggesting a low risk of residue accumulation in grazing animals from any but very heavy applications. Many researchers have studied 2,4,5-T residues in a variety of different animal species. The following summarizes the results of selected papers. (Tables 3,4). i I DONZ1551 59___ J_____________________ .Table J. Summary o Literature on 2,4,5 * T Hetaboliam and Lose Rates Speciee and Route Administered Dose Plasma H Llfa Urine Clearance Author Rat Oral 100 mg/kg 50 mg/kg 3 . 0 hra Erne (1966) 69 after 7 days Grunow (1971) Rat Oral 5 mg/kg SO mg/kg 100 mg/kg 200 mg/kg 4.7 hra 4.2 hra 19. hra 25.2 hra 13.6 hrs 13.1 hra 19.3 hrs 28.9 hrs Piper (1973) Rat Oral . 0.4 mg 1 mg 10 mg 3.5 hrs 75+7% after 24 hrs rang et 1 , Rat 5 mg/kg 10.7 hra Sauerhoff (1976) 100 mg/kg 1 1 . 0 (from 0-84 hrs) 69.3 (from 94-16* hra) Dog Oral 5 g/kg 77.0 hra B6 . 6 hra. Piper (1973) Han Oral 5 mg/kg 23.1 hrs 2 ng/kg J g/kg 5 ng/kg 1*.0+3. 1 hra 88.5+5.11 after 96 hrs over 50 in less than 48 hrs Gehring (1973) Kohl! (1974) Table 4. Summary of Selected Studies on 2#4i,5-T Residues in Animals after Ingesting Peed Containing a Known Concentration of the Chemical Sample and Species Dose Length of Exposure Residue Author Milk or cream: cow 10-30 ppm 100 ppm oral, total diet for 3 weeks <0.05 ppm Lang 1977 Hi lk: cow 300-1000 ppm untreated feed Calves t Calves: Calves: Calves: Calvesi Calves: Calves: Calves: Calves: Calves muscle fat liver liver muscle fat liver muscle fat 300 ppm 300 ppm 300 ppm 900 ppm 900 ppm 900 ppm 1800 ppm 1800 ppm 1900 ppm 1800-2000 ppm in diet for 28 day* after 1 wk untreated feed Sheep: fat Sheep: kidney Sheep: kidney. muscle# fat# liver 0.15 or 0.75 mg/kg 250 mg/kg 0.15 or 0.75 mg/kg 4 oral doses for 4 days 28 days, after 1 wk *Maximum dose of 1800 ppm caused anorexia and minor weight lose. 0.15-0.5 ppm 0 . 1 2 pp* 0.38 ppm 0 . 2 ppm 1.0 ppm 0.24 ppm 0.38 ppm *7.9 ppm 1 . 2 ppm 2 . 0 ppm 0 0.08 ppm 368 ppm 0.05 ppm Palmar,Clark 1971 Clark 1975 to vH '1 1 1 1 ! t 1 | f 1 19 weather conditions, poor equipment, temperature, humidity, and improper distribution practices increase the risk of spray drift. Effects of this hazard can be greatly reduced by following certain protocol and deciding if, when, and how herbicide application takes place. Residues result when immediate chemical degradation does not follow initial application. Residues can accumu late in soil, water, air, and indirectly in animals and humans. from the Residues do environment not can bree mapirnediicntdeedfintihtreoluyg.h Their loss the chemi cal's half life in various media in the environment and a knowledge of the chemical's physical characteristics. Consideration of toxicity and hazard in relation to 2,4,5-T stems primarily from a contaminant, T C U D , a potent toxin. Direct effects of toxicity will be discussed later in this paper. 2 i D0H21551 g f >-LY-Ci'!-fIil" EP ' The generic term "dioxin" pertains to a family oi cori- pounds which are structurally similar but vastly differ ent in toxicity. It designate one member is of often used the family, in2 c,o3r,r7 e,c8 t-ltyetrtaochloro - dibenzo-p-dioxin (TCDD). There are 75 possible poly chlorinated dibenzo-p-dioxins (PCDUs) with a million-folc: spread in the dosage level required to kill laboratory animals. all four Those with four or five lateral positions (2,3,7 canhdlor8i)neasre located at extremely toxic. one or The more toxicity chlorines istoprpoegrir-epsossiivteiloynsdec(r1e,a4s, 6ed by or 9m)o,ving and/or by having fewer or more positions substituted. Low levels of polychlorinated dibenzo-p-dioxins (PCDDs) can be formed as byproducts during the manufacture of chlorophenols under alkaline conditions at elevated tem peratures and high pressures. The reaction is a two-str-p process involving bimolecuiar condensation of chlorophenates followed by internal ring closure. The number and position of the chlorine substituents on the dioxins depend on the chlorophenates present in the reaction mixture. In all, 75 possible PCDDs could originate from conden sation of chlorophenols with two to five chlorine sub stituents. Of these, 22 are tetrachloro isomers. Ilowevet only symmetrically substituted isomers with an even number of chlorines are likely to be formed from reaction mixtures containing predominantly one chlorophenol such as in manufacturing processes. Other isomers could also result from progressive chlor ination or dechlorination of lower or higher analogs. However, photolysis in solution appears to preferentially remove chlorines from the lateral positions (Buser and Rappe 1978). Thus isomers substituted at the 2,3,7,8positions are not likely to be formed from higher PCDbs by the action of light. 2,4,5-Trichlorophenol is used as a slime control, as a defoaming agent in paper and cardboard manufacture, and ii the manufacture of dioxin arises as a 2,4,5-T. by-product Siinnce2 tetrachlorodibenzo-p,4,5-trichlorophenol manufacture, it is possible that TCDDs may get into the various products and thence into the environment. On the other hand, researchers have not observed formation of TCDD from trichlorophenol under the action of sunlight, simulated sunlight, or by microbial condensation in soil. Tho higher chlorodioxins (6 , 7, and 8 chlorine atoms) may be expected to arise in the production of pentachlor ophenol. Pentachlorophenol is produced in the U.S.' by chlorination of phenol at nearly atmospheric pressure, without alkalinity, and at temperatures of about 200 C (J50 F) . However, the production of sodium pentachlor- ophenate involves the same conditions (high temperature, pressure, alkalinity) as that of trichlorophenol. Hexa- rliLorodioxin has indeed been found in almost all samples of commercial pentachlorophenol und octadioxins, the latter two tested, along with at levels of up to h1 e0 p0 0ta- ppm (Firestone et aJL. 1972; Plimmer 1973) . Formation of hoxa- and heptachlorodioxins has been observed when chips of pentachlorophenol treated plywood were burned. Hexa- and octachlorodioxin have been formed from pentachloro phenol under the influence of ultraviolet light. Pentachlorophenol is extensively used for the same purposes as trichlorophenol but also as a wood preserva tive, for the preservation of hides, starches and glues, in paper designed for contact with aqueous and fatty foods, as antioxidant in rubber articles used in produc ing, processing or holding food, and in manufacture of curtain plastics used in the food industry. Production in the U.S. in 1967 was 44,000,000 pounds and in 1970, 4in7,c0o0m0p,a0r0i0sopno,undpsr,odmuocsttionofofit2 used as wood preservatives, ,4,5-trichlorophenol (including salts) in 1967 was 25,000,000 pounds (no data for 1970), and of 2,4,5-T including salts and esters in 1967, 42,000,000 pounds and in 1970, 12,300,000 pounds (U.S. Tariff Commission 1967 and 1970). Thus, it is likely that hexachlorodibenzo-para-dioxins enter the environment from pentachlorophenol unless production methods are used which reduce the contamination of these substances to acceptable levels. 2,3,7,8-TCDD is the most toxic among the chlorodioxins studied, together with hexachlorodioxin and probably some dtiroi-xinandathedpatialcyhldoorsoedsiooxfin0s..0 1 Hexachiorodibenzo-paramg/kg caused reduction in the rate of body weight increase in pregnant rats and their fetuses and induces ede'ma in chickens. A ten-fold increase in dose caused abnormalities in some fetuses (Schwetz et al. 1973). These doses are roughly 10 to 30 times higher In contrast, 2th,a7n-dTiCcDhDlodroos-e,s1 c,a3u,s6i,n8g-tseitmrialcahrloreof-fecatnsd. octachlorodioxin have very low toxicity, and no demonstra ble teratogenicity at the highest doses tested. The LD 50s and were over 100,000 no teratogenicity times higher was found at 1t0h0anmgt/hkogs/edafyo.r TCDD, ' D O H 2 I 5 5 I 6 I 2' 3' 7' e' TCD Recognized in 1957 as an impurity in the manufacture of herbicide 2,4r5-T, TCDD is one of the most potent small molecule toxins known to man. Small amounts of the chemical can cause enormous changes in animal cells. Currently, technical grade 2,4,5-T in the U.S. routinely contains TCDO levels at or below 0.1 ppm. Chemistry 2,3,7,8-tetrachlorodibenzo-p-dioxin exists as a white, crystalline solid, having a molecular weight of 322 grams per mole. It melts at temperatures between 303 and 305 C and decomposes at temperatures between 980 and 1000 C. About 99.5 percent of the dioxin decomposes at tempera tures of 800 C. 2,3,7,8 -tetrachlorodibenzo-p-dioxin Table 8 . Solubility of 2,3,7, 8 - Tetrachlorodibenzo- p-dioxin in Various Solvents at 25 C Solvent Solubility g/ 1 0 0 ml wt percent o-Dichlorobenzene Chlorobenzene Perchloroethylene Chloroform Benzene Acetone Dimethylsulfoxide(a) Methanol Water 0.18 0.080 0.068 0.055 :0.047 0.009 0.01 0.001 0.00000002 0.14 0.072 0.048 0.037 0.057 0.011 0.01 0.002 0(.00. 02 0 0000 ppb) 2 (a) DMSO caused detector fouling and a better value could n0o. 0t1 be obtained. percent. However, solubility does not exceed 23 DON?I 55 I62 in co rH TCDD is poorly soluble in most organic solvents and .. ; water. vents areTheshoswonlubinilTiatbylecha8 r.acteristics withJvarious so'l t 2,3,7,8-TCDD arises during the hydrolysis of tetrachlorobenzene to form 2,4,5-trichlorophenol, the industrial precursor of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). The hydrolysis occurs in an alkaline environment at high temperatures and under pressure. Each of these conditions favors the formation of the chlorodioxins unless they are very carefully controlled. the environmental monitoring of food chains would require a detection level of 1 ppt. For a one gram sample of biological tissue, of one picogram (1 ptghisorwo1u0l- d1 2 require grams) a limit of detection (Baughman 1976) . Such analyses can only take place using ultrasophisticated detection instrumentation and large samples of tissue. Because of difficulty in detection, model ecosystems are often employed to predict the mechanics of TCDD in the environment. Matsumura and Benezet (1973) developed an aquatic eco system to test TCDD residue on sand affecting brine shrimp, mosquito larvae, and fish. They found that TCDD uptake rates were very low in brine shrimp and fish. Mosquito larvae, which are bottom feeders, showed a faster'rate of TCDD pickup. The authors attributed TCDD's failure to accumulate in as many biological systems as DDT to its low solubility in water and its low partition coefficient in lipids. Since TCDD displays low water solubility compared to its higher fat solubility characteristics, researchers realize the potential for bioaccumulation, described as the uptake or the accumulation less metabolism, and excreting by an organism from its surrounding environment. Bioaccumulation processes may concentrate TCDD in lower animals and result in a possibly significant exposure to higher tropic levels. Prior to 1973, the detection limit for TCDD was 0.1 ppb for soils and 0.05 ppm for biological tissue (Woolson et al. 1973). Kearney et al. (1972) and Dost et al. (1975) ascertained that a one pound/acre application of 2,4,5-T contains 0.1 ppm. TCDD applied directly to the soil rcouli df result soil. in a maximum Baughman and of 0.1 ppt TCDD Meselson (1973) in the top )^ have calcul d it Isensee and Jones (1972) exposed several organisms to C14-labelled TCDD for up to 31 days to determine the distribution and bioaccumulation potential in an aquatic environment. The authors found that TCDD accumulation was directly proportional to the water concentration of 2th. 0e ctoont2a. m6 inxan1t0.* 0.05 to 1330 ppt. Values ranged from times the water concentration for snail, mosquito fiBh and daphnids, and averaged 4.9 x 10^ for duckweed algae and catfish. No metabolities of TCDD were found in submerged soil, water, snails, mosquito fish, and catfish. Isensee and Jones also reported that 85-99 percent of the labelled TCDD originally added to the model ecosystem at the start of the experiment remained in the soil at the experiment's conclusion. Total recovery for the ecosystem averaged 92.2 percent, illus trating the relative stability of TCDD in this test. Kearney et al. .(1972) analyzed the persistence of TCDD in Hagerstown and Lakeland soils treated with 1, 10, and 100 ppm TCDD. The researchers conducted analyses after 20, 40, 80, 160, and 350 days after chemical application. After one year, 56 percent and 63 percent of the origin ally applied TCDD were covered from Hagerstown and Lake land soils, respectively, indicating a TCDD half-life a1 p0 p0 0ropxpimmat2i,n4g,5-otnericyhealro.rophIennoslo,ilsno receiving 10, 100, detectable levels or of TCDD were found after 70 days. This suggests that TCDD was not biosynthesized by microbial condensation reactions. The long half-life of TCDD suggested to Kearney et al. that it-was not readily metabolized by soil micro organisms. TCDD's high toxicity also account for the chemical's to long sohiallfm- 1i bes may Nash and Beall (1978) studied the fate of TCDD in plants, soil, water, and air of a microagroecosystem. Tritium labelled TCDD was sprayed on b.luegrass turf in a growth isoctyl chamber at ester of 20co(n2c,e4n,t5r-attriiocnhsloroofph4e4noaxnyd) 500 ppb: The propionic acid (Silvex) contained the chemical as a contaminant. The authors determined that: 1) TCDD were concentrations in water leached below the analytical detection litmhirtoug(h1 0 soil -3 g/g water). 2) T(C1D0D"1 concentrations ^ g/g grass), on but grass after were four initially 20 ppt weeks were at or below 1 ppt. The half life of TCDD was approxi mately six days. 3) T0(C0. 2D- 2Dpccptomn)ca.enndtrmaotsiton(s80%i)n or on soil were less than was near the soil surface 4) TCDD concentrations in application) less than a1 i0 0r wfegr/em3 (immediately (femtogram -af1t0e- 1r5 g/m3) and after four weeks decreased to less than three fg/m3. 5) TCDD (or its degradation products) concentration in earthworms were less than 0.3 ppt. 6 ) The major repositories for TCDD were the soil and thatch. Authors Nash and Beall concluded that volatilization (approximately ten percent) of TCDD provided a major mechanism for the exit of TCDD from the microagroeco system. After volatilization, TCDD then was dechlorinated in the direct sun, filtered sun, and also even in shaded areas. They concluded that TCDD is sensitive to photo dechlorination in the vapor phase even without the presence of ultraviolet light. This supports the sugges tion of Crosby and Wong (1977) that TCDD, once on foliage, degrades in ultraviolet light fairly rapidly, never reaching the soil system. Indeed the most significant accomplishment in the study of the environmental degradation of TCDD belongs to Crosby and Wong. They found that herbicide formulations with TCDD as a contaminant lose most or all their TCDD within a single day when the leaves, soil, or grass of the treated foliage receive natural sunlight. Photo chemical dechlorination causes this degradation of TCDD. While the stability of pure TCDD as a persistent residue in the environment is accepted, it is not stable in the presence of its herbicide vehicle. Appearing on the foliage in a thin herbicide film, the contaminant diminishes as it is exposed to sunlight. cro3Dy,and Wong have established three requirements for as2ri)eg:nthiefi1 cp)ardneitssesndocielouxtioifnonbanreinaorkagdaonwlinicghitnh-ydttrrhoeagnesenmn-ivdtiotrnioonnrgm,enftis.lumc;h Thasey a solvent or pesticide; and 3) ultraviolet light. They propose that all three conditions are normally met in applications of 2,4,5-T. Therefore they feel that these data suggest that environmental residues of TCDD often will be considerably less than previously expected. Numerous studies have demonstrated amount and location of TCDD residue found in various animal species as well as in water and rice. Table 9 represents findings of' several investigations. 25 * 001( 2/55164 Cattle Sheep Table 9. EPA Dioxin Implementation Plan (1976) Sample TCDD Residue Level of Detection 43 beef liver sanples of 43 teBted 1 beef fat sample of 85 tested 2 beef fat of 85 tested 5 beef fat samples of 85 tested 77 beef fat samples of 85 tested No TCDD found 60 ppt 20 ppt may have between 5-10 ppt no detectable TCDD 4-8 ppt sensitivity 10 ppt 10 ppt 10 ppt 10 ppt Shadoff (1977) Sample . Arkansas ricelands water, mud, catfish bass from pond in riceland Reservoir west Texas water, mud, catfish, walleye pike TCDD Residue No detectable TCDD No detectable TCDD Level of Detection 10 ppt 10 ppt Jensen - Dow Chemical (Dow confidential 1978) Sample TCDD Residue Level of Detection Rice from high treatment fields and related stores 300 ppm 2,4,5-T and 24 ppt TCDD for 28 days Liver, kidney Muscle 300 ppm 2,4,5-T and 150 ppt TCDD for 28 days Fat and liver Muscle No detectableTCDD Initially 95 ppt fat 10 ppt 2 ppt 10 ppt 2 ppt ......... 2 ppt 2 ppt Two times the dietary concentration 1 / 8(20tipmpets) the dietary concentration 2 ppt 2 ppt 17858 00 HZ 155165 Dairy Cow Table 9. (continued) Sample TCDD Residue Level of Detection Fed 5 to 500 ppt TCDD in diet for 2 to 3 weeks at each level Residues increased proportionally to increased TCDD levels Milk 5 ppt 500 ppt Cream 5 ppt Not detectable 89 ppt 10 ppt ppt ppt After diet with TCDD stopped, TCDD content in milk declined rapidly for several weeks and then continued downward at a slower rate. Kocher (1978) Sample TCDD Residue Level of Detection Range Cattle Fat Grazing on sprayed pasture 3 of 7 samples 3-4 ppt 4 of samples no detectable level 3 ppt Baughman and Meselson (1973) Sample TCDD Residue Level of Detection VieatnalNyazmedwat2e*jryesaarmsplelsatetraken in 1970, Fish - interior rivers of Viet Nam Fish and shellfish coastlive of Viet Nam Cape Cod Butterfish(control) 70-810 ppt 18-79 ppt Not detectable ppt ppt ppt Dow Chemical Company Sample TCDD Residue Level of Detection Fish sample from water downstream to Dow's Midland, Ml plant Catfish 230 ppt ppt 27 Table 9. (continued) EPA 1980 (unpublished) 1QQH?ISS Ifieo -V-TT Sample TCDD Residue Mother's milk (human) No detectableresidues 103 samples from spray and control areas Meselson, O'Keefe, Baughman (1977) Sample TCDD Residue Mother's milk 18 samples from humans living on 2,4,5-T treated rangeland 6 controls (Boston) 4/18 with 1 ppt No detectable residues Level of Detection ]-4 ppt Level of Detection 1 ppt Before completing a discussion of residues, we must consider the most recent reviews of the action of TCDD in the environment. Recently, the Dow Chemical Company of Midland, Michigan, released a report demonstrating the production of TCDD as a by-product of normal combustion processes. Analyzing samples from a number of combustion products, such as refuse incinerator emissions, gasolinepowered automobile exhausts, fireplace soot, ch&rcoal grills, cigarette smoke, and particulate emissions from a chemical plant powerhouse, researchers quantitatively assessed the amounts of TCDD present. Finding measurable amounts of TCDD, they concluded that... "refuse incinera tors and fossilfueled powerhouses are sources for both airborne and waterborne particulates which contain chlorinated dioxin..." (Dow Chemical Company 1979). These conclusions have been supported through the research of Olie et al. (1977). However, Ximble and Gross (1980) have taken exception to all fossil fueled power plants labelled as major sources of environmental dioxin. Analyzing one sample of coal fly ash collected several years earlier, they were unable to detect any TCDD residues at a sensitivity limit of 1.2 ppt. They therefore consider it invalid to extrapolate results from chemical plant powerhouses for application to coal fired power plants. Should environmental presence of dioxins from combustion processes be further established and supported, the ramifications will be great. For it will become increas ingly difficult, if not impossible, to link environmental residues unequivocally and solely to herbicide spraying. Summary 2,3,7,8 -TCDD exists as a white crystalline solid, with a molecular weight of 322 grams per mole. Melting at temperatures between 303 and 305 C, 99.5 percent of TCDD decomposes at temperatures of 800 C. TCDD can form during the hydrolysis of tetracholorbenzene to form 2,4,5-trichlorophenol in the 2,4,5-T manufacturing process. Displaying low water solubility and high fat solubility properties, dioxin can accumulate in the environment under some conditions. TCDD is readily decomposed by ultraviolet light. This helps to diminish potential accumulation of the chemical. Residue experiments have monitored the TCDD levels in land, water, and various species of animals. For the most part, TCDD residue levels directly compare to the amount of initial TCDD application and are not detectable in many instances. Recently the Dow Chemical Company has suggested that dioxin contaminants result from various combustion processes in the environment. Should this be confirmed, allegations of 2,4,5-T as the primary produce! ` dioxin in the environment will become increasingly t e . j u s . T O X IC IT * Different animal species show toxic responses to vary ing amounts of 2,4,5-T. The usual way of expressing a chemical's acute toxicity is through its LD" defined as the amount percent of of chemical sufficient to cause the test animals. Likewise, an dLeDa9t0 h in 50 signifies a dose potent enough to kill 90 percent of animals tested. Tor most analytical purposes, an LD .is most commonly used. An LD50 value can differ due to such variables as age or sex of test animals, nutritional state, formulation of toxicant, time of day, route of administration, and temperature. Mode of entrance and chemical form of the substance can also alter an LD . On the other end of the LD spectrum from LD*- lies a "No observable effect level." Generally a NOEL signifies a toxicological endpoint. Chemicals administered in this concentration cause no observable adverse effects. Toxicologists generally assume that an animal no-effect level can provide the basis for estimation of human safe exposure levels. According to the EPA, a "safe" level for humans is set at some level lower than the animal no-effect level to provide a "margin of safety" that takes into account differences in sensitivities among species and within a single species. This "margin of Table 1 0 . Summary of Literature on the No Effect, LD5(> and L D * TM Levels of the Acute Toxicity of 2,4,5-T Animal Route of Administration and Chemical Form Mouse Mouse Mouse oral - acid oral - isopropyl ester oral - mixed butyl esters Rat oral - acid Rat oral - isopropyl ester Rat oral - mixed butyl ester Rat oral - mixed amyl ester Guinea Pig Guinea Pig Guinea Pig oral - acid oral - isopropyl ester oral - mixed butyl ester Chick oral - acid Rabbit oral - mixed butyl e3ter Dog oral - in capsule acid Dog oral - in capsule acid Dog oral - in capsule acid Pig oral - acid Tox. Dose Single Dose mg/kg LD50 LD50 LD50 369 551 940 LD50 LD50 I.50 LD50 500 495 4111 750 LD50 LD50 LD50 381 449 750 LD50 310 LD50 712 LD100 LD50 250 100 No effect 50 Anorexia, 100 vomiting, diarrhea, ataxia hemorrhagic enteritis liver and kidney congestion Author Rowe and Hymas 1954 Rowe and Hymas 1954 Rowe and Hymas 1954 Rowe and Hymas 1954 Rowe and Ilyinas 195 4 Rowe ami Ilym.iM 1'4 Rowe and Ilyinas 1954 Rowe and Hymas 1954 Rowe and Hymas 1954 Rowe and Hymas 1954 Rowe and Hymas 1954 Rowe and Hymas 1954 Drill andi Hiratzka 1953 Drill and1 Hiratzka 1953 Drill and Hiratzka 1953 Bjorklund and Erne 1966 29 1D0H2 15,,5,, 168 CO CD safety" does not represent an infallible indicator of potential hazard to humans. The EPA further asserts that error could be introduced because humans may be more sensitive than the test species by a greater degree than normally allowed, or by the incorrect choice of a no-effect level. Safety factors of 1/100 of a no-effect dose are commonly used in safety assessments. . Since 2,3,7,8 -TCDD consideration of the LiDne5v0 itofabltyhechoenrtbaimciindaetesalo2n,e4,5c-aTn, no be complete without considering the LD5 of the accompanying dioxin (Tables 10 and 11). Table 11. Summary of Literature Data on the no-effect, LD5 and LD100 Levels of the Acute Toxicity of TCDD for Animals Animal Route of Administration House (CD-I strain, C57Bl/6Sch strain) Mouse Mouse Mouse (C57B1/6 strain) Rat Rat Rat Rat (male) Rat (female, Sherman strain) Guinea Pig Guinea Pig (Hartley strain) Rabbit Rabbit Rabbit Rabbit Rabbit (New Zealand Albino) oral oral oral intraperitoneal ; oral oral oral oral oral oral oral oral topically to the sk-in intraperitoneal intraperitoneal intraperitoneal Tox. Dose T_100 LD Singulge/kDgo1se 50 ALDf1e0w0 sporadic deaths 1-130 150 LD50 120 No effect 8 NL.oD1e00ffect LD50 LD50 LD50 LD5 LD50 LD50 16 32 22 45 0.6 2.1 115 275 No effect 32 2 of 5 died 252 3 of 5 died 500 Author Vos, Gupta, et al. 1973 Schwetz, et al. 1973 Goldstein, et al. 1973 Vinopal, et al. 1973 Schwetz, et al. 1973 Schwetz, e-t a-l-. 1973 Schwetz, et al. 1973 Schwetz,-et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 Dog Dog Dog Dog (Beagles) Monkey (Rhesus) oral oral oral oral oral No 1e00ffect LD No effect No effect LD50 300 3ooo 30 100 50-70 Schwetz, et al. 1973 - Schwetz, et al. 1973 Schwetz, et al. 1973 Schwetz, et al. 1973 McConnell, et al. 1978 *1 mg/kg - 1,000 ug/kg 30 17562 With increasing amounts of ingested herbicides, animals approach a threshold of intoxication, and from this point on will suffer toxic effects. Initially producing '%w, if any outward signs, toxic responses from increased or prolonged doses increase in severity until they ultimately caus^t.death (Table 12) . Table 12. Summary of Literature Involving Toxic Effects of 2,4,5-T Animal Dog Dog Dose 20 mg/kg day,5 days/wk TCDD not slated 10 mg/kg/day, 5 days/wk Length of Study 65 days 65 days Dog Sheep Steer Steer Steer Rabbit Rabbit 2.5 mg/kg/day 100 mg/kg/day, repeated doses TCDD not known 100 mg/kg/day repeated doses 500 mg/kg/day 100 mg/kg/day acid moistened 2000 mg/kg acid cuff technique 91 days acute acute acute 3 days acute 3 days application 10X to abraded skin 1 day Rabbit Rabbit butyl ester 2000 mg/kg butyl ester 10X to abraded skin on belly 1 day House 978PF House CD-I House F dihybrid House NCTR strain 30-140 mg/kg gavage 140 mg/kg gavage 120 mg/kg gavage 60 mg/kg gavage 6-14 days 6-14 days 6-14 days 6-14 days Effects Author death within 11-75 days in Drill and Hiratzka 1953 all animals overt signs of toxicity Drill and Hiratzka 1953 weight loss, stiffness of hing legs, muscular weakness, occasional bleeding gums, no fatalities no adverse effects Drill and Hiratzka 1953 no adverse effects I Rowe and Hymas 1954 no adverse effects Rowe and Hymas acute toxicity Rowe and Hymas 1954 fatal Rowe and Hymas 1954 slight reddening and swel Dow Chemical ling at application site slight reddening and swel Dow Chemical ling at sight of application cuff slight reddening and swel Dow Chemical ling - moderate burn in one animal intact skin - no fatalities Dow Chemical abraded skin - 1/3 fatalities varied strain Highman, et al. 1976 (62) I t moribund Highman, et al. 1976 53-82% fatalities Highman, et al. 1976 ill or dead Highman, et al. 1976 House CRBL strain House 378 90-120 mg/kg gavage 6-14 days 60-120 mg/kg gavage 6-14 days 60 mg/kg 120 mg/kg 6-14 days 6-14 days TCDD level 0.05 and 0.005 mg TCDD/kg no effect varied Highman, e_t al. 1976 Highman, et al. 1976 (60) most animalB outwardly normal** many animals appeared outwardly normal** 31 001121551^0 CO CD XQ Table 12. Summary of Literature Involving Toxic Effects of 2,4,5-T (continued) Animal Dose Length of Study Effects Author Rat 30 mg/kg dose per animal 90 days no effect in feed IARC 1977 Rat 100 mg/kg dOBe per animal 90 days anorexia, depressed weight IARC 1977 in feed gain, threshold toxicity Rat 300 mg/kg dose per diet 90 days no effect IARC 1977 1 mg TCDD/kg Rat 1000 mg/kg dose per diet 90 days toxicity, no deaths due to IARC 1977 treatment, tissue changes noted Rat 3000 mg/kg dose per diet 90 days growth retardation in males, IARC 1977 no deaths due to treatment, tissue changes noted Rat 10 mg/kg/day Rat 30 mg/kg/day 11 days 2 years liver enlargement only decreased weight gain, Rip and Cherry 1976 Kociba, et a l 1979 increased kidney weight, i increased urinary volume, increased coproporphyrin, increased uroporphyrin, slight morphological changes in liver, lungs, kidney, Rat 10 mg/kg/day 2 years no blood dyscrasias minimal effects, mineralized Kociba, et al. 1979 deposits renal pelvis male-- increased coproporphyrins Rat 3 mg/kg** 2 years no changes Kociba et al. 1979 *3 mg/kg considered no effect dose level for chronic exposure to 2,4,5-T. **histopathological changes noted. 3 U\JHL I J J Animals suffer toxic effects from 2,4,5-T in doaageB ranging from 10 milligrams per kilogram of body weight per day (10 mg/kg/day) in a dog to 140 mg/kg/day in mouse. However, since several of the studies listed in Table 12 were performed in the .L950s and 1960s, the TCDD level in the 2,4,5-T feed was either not known or not mentioned. TCDO was a significant contaminant in all 2,4,5-T produced at that time, and it could have been a significant factor in the animal toxicity studies. Weight loss and muscle weakness with accompanying tissue changes represent the most common effects of 2,4,5-T toxicity. Variations are expected by differences wjthina species (e.g., mice), alternate modes of chemical entrance into the body, and variable lengths of time for the duration of the experiment. This last consideration expresses a fundamental aspect of any toxicological investigation. A large dose of chemical toxin will profoundly affect an animal in a short time. The results demonstrate acute response. However, thorough investigation also includes a long term chronic exposure response to determine effects of rela tively low doses of chemical. Toxicological responses generated from these amounts may not appear within a short period of time; but after longer duration, they indeed may elicit some sort of physical change attributed either primarily or secondarily to chemical exposure. | Both acute and chronic no-effect levels are important Iin understanding the toxicology of any material. Kociba et al. 1979 The Kociba et al. study reports the effect of chronic long-term toxicity resulting from exposure to 2,4,5-T (no TCDD found at detection level of 0.33 ppb). Studying the effects of the herbicide on Sprague-Dawley rats, the investigators monitored them for their general health, possible toxicological responses, and change in body weight. Body weight and food consumption provided the basis for determining the test levels of (control) 0 , 3 , 10, 30 mg/kg body weight distributed in rat feed. Rats /ere maintained on this diet for a total of two years. Selective killing of a few rats representing all test jroups took place on days 118 and 119 of the experiment. \utopsies were performed to determine the health effects liter this relatively short period of treatment. These interim findings were later compared to effects noted at :ho conclusion of the experiment. I/ I Analysis of feed samples indicated theT2,4,5-T concen tration level approximated fi5 ppm in the 3 mg/kg diet, 230 ppm in the 10 mg/kg diet, and 677 ppm in the 30 mg/kg diet. Body Heights - There were no statistically significant differences from controls in the mean body weights of any of the rats in the 118-119 day study. Mean body weights of females given 30 mg/kg showed a statistically signifi cant increase four times during the course of the twoyear study. Males at this dose showed a trend toward slightly lower values. At the 3 mg/kg or 10 mg/kg dose levels, there were no statistically significant differences from the control values. Food Consumption - No consistent deviations from the control rate appeared in either sex at any of the exper imental dose rates for either the sub-chronic or the chronic study, indicating that consumption remained the same, even in the presence of weight change. Histopathological Changes - See Table 13 Mortality - Incidence of male deaths at the 30 mg/kg dose level decreased during the latter part of the twoyear study. This occurred as a secondary effect of the less severe chronic renal disease seen in these rats. The female mortality rate at the high dose level did not differ from the control rate significantly. Analysis of mortality rates at the smaller dose levels demonstrated no toxicological significance. Hematological analysis - No statistical differences from the controls appeared in any tissue studied or any dose level during the sub-chronic or chronic parts of the study. Urinalysis - In males receiving 30 mg/kg dose per day, investigators noted increase in total urine volume, and in excretion of coproporphyrin and uroporphyrin excre tion but only in the early phase of the study. In females receiving the larger dose, increased coproporphyrin appeared at most of the sampling times. Uroporphyrin excretion decreased after 119 days but increased after two years. No significant differences in total urinary volume or excretion or urinary creatinine, coproporphyrin, uroporphyrin, or Y-ALA were recorded in males at 3 mg/kg doses or females at either 10 mg/kg or 3 mg/kg dose levels. 33 'ftCD IvH. ! 1D0N2I 55 I 72 ir Ce Oj Table 13. Summary of Major Gross and Histopathological Observations in Rats Maintained on Diets Containinq 2.4,5-T for 2 Years** Lesion Dose (mg/kg/day) Kidney Mineralized deposits in pelvis Localized reaction adjacent to mineralized deposit^ Moderate to severe chronic renal disease Increased pigment in renal tubular cytoplasm Mineralization secondary to renal disease seen in:; Pulmonary alveoli Myocardium Myocardial blood vessels Gastric mucosa and muscularis Liver Enlargement Focal biliary hyperplasia Periportal inflammation Focal aggregates of reticulo-endothelial cells adjacent to. degenerate or necrotic hepatocytes Multiple foci of hepatocellular alteration (swollen hepatocytes) Focal hepatocellular cytoplasmic vacuolization Lungs Focal interstitial inflammation Focal accumulations of alveolar macrophages in alveoli Focal cholesterol clefts Focal accumulations of secretory material in alveoli Cardiovascular syster Dilated flaccid ventricle Periarteritis Left atrial thrombosis 0 56/86 13/86 5/86 12/86 25/86 11/86 9/86 29/86 34/86 21/86 28/86 6/86 28/86 20/86 12/86 No. of Rats Affected/No. Examined Male Female 3 10 30 0 3 10 30 NE NE 28/50 NE 8/50 3/50 6/50 13/49 NE NE 30/50 NE 4/50 2/50 5/50 9/4 9 NE NE 22/50* NE 1/86 25/86 6/86 0/86 0/50* 0/50 0/50* 1/50* 1/50 19/50 6/50 0/50 NE NE NE NE 5/50* 8/50 22/50 37/50 2/50 1/50 0/50 11/50 NE NE NE NE NE NE NE NE 3/50 6/50 7/50* 7/50 8/50 9/50 NE NE NE NE 20/50 12/50* 1/50* 14/50* 28/50* NE 36/86 NE 15/86 8/50* NE NE NE 17/50 4/50 NE NE NE NE NE NE NE 21/50 34/50' 6/50 3/50' NE NE 5/50* 5/50* 16/50 13/50 4/50 5/50 NB NB 27/50* 29/50* 9/50* NE 0/86 NE NE NE 2/50 NE NE NE 2/50 NE NE NE 4/50' 15/50 12/50 6/50 7/50 8/50 4/50 9/50 8/50 3/50 0/86 1/50 NE NE 2/50 3/50' NE NE NE NE NE *= No treatment-related effect ``Selected from the results of examination of all organ syBtemB to depict the effects considered to be related to treatment The tumour incidence in all the organ systems was considered to be unaffected by any level of treatment. Values marked with an asterisk differ significantly (by Fisher's Exact Probability Test) from the corresponding control incidence: *P 0.05. Source: Kociba, et al. 1979 34 " Table 14. Summary of Literature Involving Toxic Effects of TCDD (dioxin) in Animals Animal Single Dose Length of Study Effects Author Mouse C57Bl/6JFh (J67) strain <n specific pathogen i*-- gastric tube in in <NI O Q 0.5 ug/kg/wk 1.5 ug/kg. 10.0 ug/kg 20 ug/kg 0.5, 1, 5, 10, 20 ug/kg .. 0 .5 ug/kg 1.0 ug/kg .1I ].1 .1 Mouse 1 CD 1 1 oral 1, 10, 50 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks single dose no effect on wt gain no effect on wt gain Thompson, Faith, McConnell, More 1975 no effect on wt gain significant decrease in wt gain no effect on mice challenged with Herpesvirus suis no effect on mice challenged with Salmonella bern significant increase in mortality of mice challenged with Salmonella bern hematological changes at one wk Zinkl, Vos, Moore 1974 after dose, normal at 3 weeks cc CO CO 2> v"4 Mouse 25 ug/kg/wk 4 weeks J\ C57B1/6 strain i Jj Rabbit -- 1-8 ug on inner surface of ear topical route single 2000 fold increase in carboxyporphyrins in the liver epithelial thickening, follicular prominance Goldstein, Vos, Hickman, Bergman 1973 Dow Chemical Rabbi t 0.4 to 400 ug/kg 4 weeks 5 days/wk applied to inside of ear i.33 .3 3 'Clinical Chemistry - Analyses of serum samples for BUN, SGPT, SAP, bilirubin, total protein, albumin, and glabulin showed no alterations related to 2,4,5-T treat ment after either 118 days or two years for any dose level in either sex. This 3 tudy concludes that 2,4,5-T given at a 3 mg/kg chronic dose per day signifies a no observable effect dose level for Sprague-Dawley rats. But mention must be given to the discrepancies of TCDD values in this study and commercially available 2,4,5-T. The herbicide used in this study was "purified." It contained no TCDD limit of detection 0.33 ppb (or acne with increasing severity Schultz, Norris, Sparsches as dosages increased 1973 0.00033 ppm + 0.33 g/kg). Commercial samples of that same herbicide routinely contain 0.1 ppm TCOO. Such alterations in chemical composition must be con sidered when analyzing true chronic effects of 2,4,5-T (usually from a commercial source). Toxic effects of TCDD vary from species to species with dosage but invoke a similar response within animal groups. Numerous reports have described TCDD induced lesions in animals at different dose regimens for different time spans. (Tables 14 and 15). 35 I McConnell and Moore 1979 i00M2 I5517 McConnell and Moore reviewed the toxicopathology char acteristics of TCDD-like compounds in a 1979 New York Academy of Sciences publication. Generally they observed a commonality of lesions in: 1 ) the thymus, and to a lesser extent, the lymphoid tissues; 2 ) bone marrow and hematological dyscrasias arising from it; and 3) monkeys which exhibited cutaneous and gastrointestinal lesions; rabbits displayed some cutaneous abnormalities but fewer than monkeys. In most cases, the degree of tissue destruction is insufficient to determine the cause of death. However, lesions of the immune system may result ' in secondary disease syndromes, particularly in long term, low level exposures. Animal manifestations ultimately resemble those of a starvation-like syndrome. ' The differences between acute high-level and low-level chronic exposures are mainly quantitative. McConnell and Moore detail the process of TCDD intoxication using the monkey as an example. The first indication of toxicity is apparent weight loss. In lethal doses the weight loss is progressive, totalling almost one third of the original weight in monkeys. A cutaneous syndrome, manifested by alopecia and edema, is another character istic feature of TCOD intoxication. The face and eyelids are the target areas here. As the toxic response progresses, chloracne develops in the hair follicles of the face and lips. Classically, TCDD poisoning causes chloracne which technically is designated as a comedone formation, with metaplasia of the sebaceous epithelium to the Bquamous type, often accompanied by thickening of the superficial layers of the skin. A waxy build-up fills the external auditory canal due to lesions in the ceruminous glands. The skin on the remainder of the body, especially on the extremities, becomes dry and scaly. The finger and toenails often fall off with no accompanying pain. In terminal states of the toxicity related illness, the monkey becomes progressively weaker, but t^is does not interfere with its response to external stimuli. Overt signs of TCDD intoxication cannot be found as easily in rodents. In the rodent family only rabbits exhibit the acne-like eruptions, which increase in severity in a dose related manner. Other than weight loss, very few clinical signs appear in rats and guinea pigs* These animals usually experience an immediate, dose related and progressive weight loss. Directly pre ceding death, mice and chicks may exhibit abdominal d Js- "nsion from ascites (fluid in the abdominal cavity) There seems to be a time threshold for death to be caused by TCDD. Death from an LD50 dose of TCDD usually occurs within weeks if it is to occur at all. Adminis tration of superlethal doses does not appreciably hasten the onset of death. Females and neonates tend to be more susceptible to the effects of TCDD than adult males. While lesions differ, investigators consistently find* thymic atrophy and weight loss in all species. At lethal doses thymic involution occurs and the thymus rs reduced to almost one fourth its normal size. This reduction occurs by necrosis of cortical lymphocytes, demonstrated by macrophages phagocytizing necrotic debris. After thymic involution, necrotic action is my$n less conspicuous. Sub-lethal doses of TCDD do not change the microscopic appearance of the organ, but the relative' weight may be significantly less than normal (McConnell and Moore 1979) . r- Reduction in the size of lymphoid tissues, such as in the spleen and gut, may also occur, but not to the extent as that seen in the thymus. The cutaneous syndrome seen in the monkeys results primarily from changes of the sebaceous glands within the affected tissues. Secretions change from a normally oily consistency to a keratinous form. This can cause plugging and rupture of glands with subsequent inflammatory acne like changes. Chicken, mice, and monkeys all exhibit ascites. Hypoproteinemia or direct vascular damage are related to its presence in these animals. Ascites and hydropericardium changes represent such characteristic manifestations in fowl that they can be diagnostic for TCDD-like compounds in that species (McClure et al. 1962). Monkeys feature proliferative gastrointestinal lesions as a result of exposure, especially chronic, to TCDD and its related compounds. Here, parietal cells give way to mucous secreting cells. Hyperplasia and subsequent hypoplasia of glandular epithelium accompany this alter ation. Gastrointestinal lesions in other species are of less diagnostic importance, appearing only in the terminal stages of the disease. In this instance, hemorrhage, usually in the stomach and proximal small intestine, results from loss of integrity of the small vessels of the lamina. Damage to the liver from TCDD exposure varies much among species.' In mice, rabbits, and chicks, hepatic pathology is marked and conspicuous. In monkeys and .nea pigs, damage to the liver remains minimal. In al_ instances. however, hepatomegaly (both percent body weight and absolute) consistently appears at exposures considerably below the lethal dose (McConnell and Moore 1979) . Researchers attribute the increase in size and weight to hepatocellular enlargement, specifically the endoplasmic reticulum. In rats and mice, hepatic lesions consist of focal necrosis of hepatocytes with inflammatory infiltrates, cytomegaly, and fatty change. In acutely toxic doses, rabbits characteristically exhibit hepatocellar necrosis with hemorrhage. Bile duct hyperplasia in varying degrees persists in chronic exposure to all animal species. Mon keys, in particular, demonstrate a striking enlargement of the common bile duct. * TCDD causes significant urinary tract lesions only in the guinea pig and monkey. Damage here involves hyper plasia of the transitional epithelium of the renal pelvis, ureter and urinary bladder, with the epithelial lining increasing as much as three times its normal thickness. Testicular degeneration has occurred in the mouse, rat, guinea pig, and monkey. Seen as restricted degenerative changes in the seminiferous components, the damage here may ultimately result in the remainder of a single layer of germinal tissue. In most cases,-though, this occurs near death and has not been demonstrated as a direct response to toxicity. Ilypocellularity of the bone marrow appears in all species although the degree of reduction differs among species. Particularly evident in moribund animals, this change can also take place in animals receiving a sublethal dose of TCDD. Lesions of the adrenal glands seem to be restricted to animals that die or have been killed while in the moribund condition. Such changes range from adrenal hemorrhage, experienced by many species, to abcess and atrophy of the zona glomerulosa of the adrenal gland in the guinea pig. Hematological changes resulting from TCDD toxicity not only vary among species, they also differ within species depending on whether the exposure is acute or chronic. Rats and monkeys show no blood alterations as a conse quence of acute exposure, but they both show signs of pronounced anemia (especially monkeys) when given chronic doses of the chemical. Mice and chickens also exhibit anemia. The bone marrow depression cited earlier is the most likely cause of this blood dyscrasia. Leukocytosis (increased white cell count) appears in ..'.onkeys after acute exposure to TCDD but is replaced by leukopenia (low whiH:e'cell count) in cases of chronic exposure. A decrease in the amount of circulating lymphocytes causes this lessening of the total white cell count in the monkey. Mice, rats, and guinea pigs also experience leukopenia. Rats, however, respond to the toxicity via leukocytosis, especially in long-term studies. By contrast, the leukocytosis in thi3 case results from an increase in neutrophils, not lymphocytes. Thrombocytopenia (a reduction in platelets) is reported in both monkey and rat studies. Specifically, thrombo cytopenia with accompanying hemorrhage has been incrimi nated as a cause of death in chronically exposed monkeys. (Other animal investigations have not released information on this parameter.) In general, females seem to exhibit more hematologic dyscrasias than males. Their overall susceptibility to intoxication by these chemicals may correspond to this phenomenon, however (McConnell and Moore 1979). Monkeys, mice, and chickens develop a reduction in total serum protein. Rats and guinea pigs do not. This decrease primarily occurs in the albumin fraction although other specific globulin fractions may also be altered. Alterations in serum enzymes reflect the histopathologic damage to the various organs involved. Increased SGPT and SGOT values indicate liver lesions. Serum choles terol levels are increased in rats but decreased in monkeys. Alternately, serum triglyceride levels increase in monkeys but remain normal in rats. Other species investigations have not studied these parameters. Lowered glucose levels are apparent at the terminal stages in all species. This represents generalized debilitation. Parameters of renal functioning such as BUN, creatinine, and serum electrolytes usually remain within normal limits. Porphyrin levels (particularly in the liver) rise dra matically in mice and chickens, and moderately in rats, rabbits and monkeys but not in guinea pigs. This increase, at dose levels well below the lethal range, substantiates claims calling TCDD the most porphyrinogenic compound ever produced by man (McConnell and Moore 1979). Two studies on the toxicity of TCDD are particularly noteworthy. They are a two-year study detailing the chronic exposure of TCDD in Sprague-Dawley rats by Kociba et al. and a nine-month study describing long-term toxic effects of TCDD in Rhesus monkeys by Allen and Van Miller. 39 ID0N2155176Allen and Van Miller 1977 Researchers Allen and Van Miller housed 16 adult Rhesus monkeys, each weighing 5.6 kg, in an environment simulat ing their natural habitat during mating season. For six months, investigators monitored general health and hema tologic values and established control parameters for the study. At the end of this time, they divided the monkeys into two groups of eight animals each. One group was placed on a diet containing 500. ppt TCOD. The remaining group ate an identical diet without TCDO. Food intake was quantitated for each group over a nine-month period of time. After six months on the experimental diet, the females were mated with males from the control group. After nine months, the experimental animals ceased eating the TCDO contaminated diet and ingested a control diet for an additional three months. Researchers estimated total TCDD levels for these animals at 5.8 0.9 ug after three months, 11.3 1.7 ug after six months and 17.9 t 2.0 ug following nine months on the diet. After three months on the diet, monkeys developed peri orbital edema, loss of facial hair and eyelashes, acne, accentuated hair follicles and dry and scaly skin. After six months, these changes became prominent in six of the eight animals concerned. At the six month analysis, monkeys also experienced a decreased hemaglobin and hematocrit. These lowered hematological parameters became especially exaggerated in six of the seven monkeys that survived nine months on the experimental treatment. Animals in the experimental group lost weight despite no change in feeding habits. After Beven months, one monkey became severely pancytopenic. Prior to death, the animal had virtually no platelets or immature red or white blood cells. In the following four months, four additional monkeys experienced similar clinical changes and died. Of the animals that survived the regimen, all displayed significant hair lo3 s and periorbital edema.. During the twelfth and final month of the study, one monkey developed a reduction in both platelets and white blood cells. Autopsy findings revealed several areas of damage from TCDD exposure. Focal areas of hemorrhage appeared in the skin, heart, lung, stomach, intestine, adrenals, skeletal musculature, brain and bone marrow. Fingernails and toenails grew irregularly, often accompanied by gangrenous necrosis. The animals also suffered from ascites and subcutaneous edema. Hypertrophy, dilatation, edema, and hydropic degeneration of the myocardium occurred in all the animalB. The biliary ducts showe" marked dilation, without associated jaundice or obstruc tion. Animals exhibited moderate hyperkeratosis of the skin and cystic keratosis of the hair follicles and sebaceous glands. Monkeys also demonstrated a marked decrease in the hematopoietic process in the bone marrow and hypocellular lymphoid tiBsue. Cellular hyperplasia appeared on many levels, especially in the mucoussecreting cells, epithelial lining of the biliary system and the transitional epithelium of the urinary tract and goblet cells of the palpebral conjunctivae. They exper ienced a concurrent hypoplasia of parietal cells in the gastric epithelium. Allen and Van Miller conclude from their study that the primary target area for TCDD in non -human primates (monkeys) is the hematopoietic (blood producing) system. As exposure lengthens, cellular degeneration involving the lymphoid system, responsible for the formation of white blood cells (leukocytes) and bone marrow responsible for red blood cell (erythrocyte) formation, increases in severity. In addition, atrophy of the thymus, spleen, and lymph nodes also occurs. The authors further assert that there is considerable difference in the level of TCDD necessary to produce intoxication. While an LD^ range of 50-70 ug/kg body weight signifies death in 50 percent of test animals in an acute space of time, a considerably lower.dose of 3 ug TCDD per kg body weight will also yield the same results when administered con tinuously over a nine-month period. Allen and Van Miller also demonstrate that the pathological changes caused by the two dose levels remained quite similar. Therefore, they believe their data indicate that exposure to extreme ly low concentrations of TCDD can produce widespread deleterious effects in primates. (Table 16). ?DOH2 1 5 5 1 7 / Table 16. Hemograms and Body Weights of Rhesus Macaques Fed 500 ppt Of TCDD for 9 Months Animal Number Initial Body Wt. (kg) 7d 239hh 31* 32 38 41* 49 , ___ 6.19 6.74 6.62 6.02 5.00 5.63 5.73 5.39 X pre-experiment (N = 8 ) White :Blood , Cells X10 /mm 2.3 2.4 3.8 10.4 . 4.1 3.8 8.0 8.7 9.3 + 1 .2 Terminal Experimental Values Platelets X103/mm3 Hemoglobin g% Hematocrit. % Terminal Body Wt. (kg) 23 4.0 12.0 5.86 44 6.9 21.5 5.74 28 12.6 40.0 5.03 480 10.7 35.5 5.35 50 6.0 19.5 4.22 34 6.6 22.0 5.22 340 11.5 44.5 5.44 54 8.5 29.5 4.46 327 + ,57 13.9 + 0.5 n 4/29 + 1.8 aValues at necropsy. ^Values at 12 months on trial. c+ 1 SD Source: Van Miller and Allen 1977. jJ Kociba et al. 1978 Kociba et^ al^. investigated the chronic effects of TCDD using Sprague-Dawley rats. Their study, a long term chronic toxicity and oncogenicity investigation, continued as an outgrowth of their earlier sub-chronic 13 week research describing the toxicological effects in the same species. The investigators randomly placed male and female Sprague-Dawley rats (Spartan substrain), aged six to seven weeks, into suspended wire-bottom cages. Food and water were available to the animals ad libitum. Groups of 100 rats (50 males, 50 females) ingested a diet that contained 0.1, 0.01, or 0.001 ug of TCDD/kg/day for up to two years. The diet of the control group of 172 rats (86 males, 86 females) contained only the carrier and no TCDD. The TCDD sample used in this study was provided by the Dow Chemical Company. After purification, the TCDD pro duct had a purity exceeding 99 percent as determined by electron capture gas chromatography. One mg TCDD, dis solved in 40 ml acetone and mixed with 100 g of contrcl feed formed the stock premix. A sufficient amount of stock premix was then mixed with control feed to form a working premix to be used in preparing the test diets. The test diets were prepared by diluting the working pre mix with control feed to provide dose levels of TCDD as required by body weight and food consumption determina tions in order to maintain the designated dosages on a microgram per kilogram per day basis. The concentration of TCDD in the test diet was determined by gas chromatography-masB spectrometry after extraction and suitable clean-up. All rats were palpated on a monthly basis. Investiga tors recorded any palpable masses. Body weights and food consumption of 20 male and 20 female rats at each treat ment level were routinely recorded for each week of the first three months of the study and at monthly intervals thereafter. All remaining rats were weighed monthly throughout the study. D0N2155178 Eight rats per sex per group provided blood samples { O f hematological investigation at three, twelve, and twentythree months of treatment. Studied parameters included: RBC, WBC, thrombocyte count, reticulocyte count, packed cell volume, and hemaglobin. Urine samples were collected from seven to eight rats per sex per group at these same time intervals to determine specific gravity, pH, sugar, protein, ketones, bilirubin, and occult blood. A consult ing laboratory analyzed urinary excretion of creatinine, coproporphyrin, uroproporphyrin, and Y" amino-levulinic acid in four to five rats per sex.per group at months 3-4, 12, and 23. Automated analysis determined serum levels of BUN, SGPT, bilirubin (both direct and indirect), cholesterol, and triglycerides in seven rats per sex per group at month 2 2 . Similarly, it determined alkaline phosphatase (AP) activity, total protein, albumin and globulin levels in seven rats per sex per group at month 23. At terminal necropsy, investigators collected serum samples from all survivors or a maximum of 10 rats per sex per group for determination of BUN, SGPT, AP, and total bilirubin. Additionally a consulting laboratory made determinations of gamma-glutamyl transferase activity (GGT). All rats dying or culled during the course of study underwent gross pathologic investigation and representa tive portions of major organs and any lesion suggestive of a significant pathologic process or tumor formation were preserved in 10 percent formalin. Terminal necropsy examination took place at the end of two years of treatment (105th week). The weights of the liver, kidney, brain, heart, thymus, spleen, testes, and ovaries/uterus were recorded for a maximum of 19 rats per sex per group. Researchers also prepared bone marrow smears from most rats. Furthermore they froze portions of fat, liver, and kidney from a maximum of five rats per sex per group for possible TCDD analysis. Subsequent analysis of liver and fat samples from three females/ dose level took place using gas chromatography-- low resolution mass spectrometry. Additionally, the Kociba group preserved in formalin fixative portions of the esophagus, salivary glands, stomach, small intestine, large intestine, pancreas, liver, kidneys, urinary bladder, prostate, accessory Bex glands, epididymis, testes, ovaries, uterus, brain (cerebrum, cerebellum, and brain.stem), pituitary gland, spinal cord, peripheral nerve (sciatic), trachea, lungs, spleen, thymus, lymph nodes, heart, aorta, skeletal muscle, mammary tissue (' 'ales), adrenal glands, thyroid, parathyroid, tongi 4.. !> o - . vH" lower,ja^, skull (Including nasal turbinates and ear canal) and any gross lesion. All rats from the control and the high dose level, regardless of whether they died during the course of the study or were killed upon its completion, underwent histologic investigation of an extensive list of tissues, intended to include a majority of those tissues listed above as those collected at the time of terminal necropsy. All rats from the two lower dose levels were subjected to histological examination of those selected tissues identified as possible target area organs in addition to gross lesions suggestive of tumor formation. Statistical evaluation of gross pathology data collated for the entire study compared the data of each of the treatment groups with the data of the control group of that sex. Lower dose levels included the same evaluations as higher dose counterparts at target organ areas (Table 17) . i D0 H2155179 f> t T a b l e 17. Major Histopathologic Findings in Rats Attributed to Ingestion of Diets Containing TCDD for Two Years Dose Level of TCDD (ug/kg/day) 0.1 0.01 0.001 Liver Hepatic degenerative inflamatory, necrotic and proliferative changes Cytomegaly, distortion of lobular pattern and atropy of cordB, cyto plasmic vacuolation, fatty change, altered tinctorial properties, he patic necrosis and inflammation, multinucleated hepatocytes, foci or areas of hepatocellular alteration (swollen hepatocytes), pigment ag gregates, bile duct hyperplasia, periportal inflammation fibrosis Hepatocellular carcinoma (Fe) Hepatocellular hyperplastic (neoplas tic) nodules (Fe) Livers had much lesser degree of change No changes. Livers of females had statistical increase in foci or area ohfephaetpoactyotceesl) l, ulaanrd alteration (swollen livers of males had statistical decrease in area of hepatocellular alteration (swollen hepatocytes) Hepatocellular nodules (Fe) Reproductive Decreased incidence of uterine hyper plasia, cyst formation and polyp formation (Fe) Questionable decreased incidence of uterine polyps (Fe) Mammary Tissue Decreased incidence of mammary tumors Endocrine Pituitary-decreased incidence of pi tuitary hemangiectasis and ade noma formation (Fe) Adrenal-decreased incidence of medullary hyperplasia (M,Fe) and pheochromocytoma (M) Increased incidence of cortical ne crosis and hemorrhage (Fe), corti cal adenoma and hematocyst (M) r ***** r*" vH 43 .aid c o n c lu s io n s found in this study are an extension of a shorter duration thirteen-week investigation performed by Kociba et al. This research also studied the carcino genicity of TCDD. The results pertaining to that aspect of TCDD response will be dealt with in the Carcinogenicity section of this report. In this chronic two-year study determining the effect of TCDD on Sprague Dawley rats, Kociba et a JL . found that: continuous ingestion of diets containing approximately 2200 ppt TCDD (0.1 ug/kg/day) for two years caused multiple toxic effects, including increased mortality, decreased body weight gain, slight depression of certain hematological parameters, increased urinary excretion of porphyrins and Y - amino levulinic acid ' I T ALA), increased serum activities of AP, GGT, and SGPT, and morphological changes primarily of the hepatic, lymphoid, respiratory and vascular tissues of the body. This high dose level seemed to reduce the incidence and severity of chronic renal disease in aged male rats. Female rats given this high dose for two years had 24,000 ppt TCDD present in the liver. This compares with 34,600 ppt TCDD present in the liver of female rats given this dose for thirteen weeks, thus indicating attainment of steady state concentration in the early phase of this two-year study. Ingestion of the intermediate dose level of 0.01 ug TCDD/kg/day (approximately 210 ppt in diet) caused a lesser degree of toxicity. Here, researchers found: 1 ) increased urinary excretion of porphyrins (females) ; 2 ) liver toxicity, including an increased incidence of hepatocellular nodules; and 3) increased incidence of focal alveolar hyperplasia in the lungs. Terminal liver and fat content of TCDD averaged 5100, and 1700 ppt, respectively. This compares with 3700 ppt present in the liver after thirteen weeks at this dose level. Lifetime ingestion at a dose of 0.C01 ug/kg/day (approximately 22 ppt in the diet) caused no effects considered to be of toxicological significance. The liver and fat each contained 540 ppt of TCDD at the end of lifetime ingestion at this low dose level. To summarize their results, Kociba et al. demonstrated a dose related toxic response to TCDD. At the lowest levels of TCDD tested, 0.001 ug/kg/day, the authors could find no toxic response attributable to the inclusion of TCDD in daily diet given to rats over a two year period of time. Toxicity Summary Since TCDD inevitably contaminates 2,4,5-T, no consid eration of toxicity of the herbicide can be complete without proper attention to the toxicity of the accom-. panying dioxin. Toxic response to both 2,4,5-T and TCDD vary among and, in some cases, within species. The values for 2.4.5- T range from a single 100 mg/kg dose in the dog (acid form) to 500 in the rat (acid form). In the mixed butyl ester form of 2,4,5-T, the mouse exhibits an LD^ of 940 mg/kg, single dosa. For TCDD, the LD^ for the quinea pig is 0.6 ug/kg. The mouse has a 120 ug/kg LD^O. Dogs, however, show no effect at doses as high as 100 ug/kg. LD^ for that species is 3000 ug/kg. Initial toxic response to 2,4,5-T appears at dosages of 10 mg/kg in the dog and escalates to 140 mg/kg in the mouse. Weight loss, muscle weakness, and accompanying tissue changes represent the most common effects of 2.4.5- T toxicity. In a chronic two-year study detailing the effects of 2.4.5- T on Sprague-Dawley rats, Kociba et al. (1979) ascertained a level (3 mg/kg) where the animals exhibited no toxic effects from chronic exposure to 2,4,5-T. However, the herbicide used in this project was "purified" 2.4.5- T, containing 0.3 ppb TCDD. Commercial samples of the chemical routinely contain 0.1 ppm TCDD. This must be considered when analyzing results from these data and extrapolating from them to populations exposed to the commercial form. The thymus and, to a lesser degree, the lymphoid tissue and bone marrow (including hematological dyscrasias derived from damage there) are the primary areas which exhibit a toxic response to TCDD. Mice are least sensi tive to TCDD's. toxic effects. Guinea pigs and chicks suffer the greatest adverse effects. Initial toxic response appears after single doses of 3 ug/kg in the guinea pig and up to a dose of 100 ug/kg in the rat. Studies of chronic TCDD toxicity include a nine-month exposure of Rhesus monkeys to 500 ppt TCDD in the diet reported by Allen and Van Miller (1977). The authors detailed toxic changes leading to death in five of the eight monkeys studied after what they determined to be 45 CO $> CO sT* ^=4 i ;D0H2 155 I 8O 1 1t! 1t'o- IT* vH Table 17. Major Histopathologic Findings In Rats Attributed to Ingestion of Diets Containing TCDD for Two Years (continued) Dose Level of TCDD (ug/kg/day) 0.1 0.01 0.001 Pancreas-decreased Incidence of acinar adenoma (M) Thyroid-occurrence of various iso lated follicular changes of ques tionable significance (M) Parathyroid-decreased incidence of parathyroid hyperplasia, secondary to chronic renal disease (M) Lymphoid Isolated cases of thymic/splenic atro phy (Fe) Respiratory Focal alveolar hyperplasia, pigment Focal alveolar hyperplasia (Fe) aggregates, accumulation of alveo lar macrophages and cholesterol clefts, pulmonary edema, focal in terstitial inflammation and fibrosis Keratinizing squamous metaplasia (Fe) -- Keratinizing squamous cell carcinoma (Fe) -- --- Cardiovascular Isolated cases of hemorrhage in CNA (Fe) -- Increased incidence of mesenteric and Increased incidence .of periarteritis (M) thoracic periarteritis, with cases of thrombosis or hematoma forma tion (M,Fe) Increased incidence of myocardial -- degenerative changes (Fe) --- -- *(-) indicates observation was not noted at that dose level, or incidence was comparable to control data Tabulation excludes voluminous data considered unrelated to treatment with TCDD Source: Kociba, et al. 1978. I Up to day 17 after conception in humans there occurs a "refractory period." From day 18 to day 30 the embryo becomes very susceptible to outside interference. At this time, the early stages of tissue and organ'differ entiation take place (from gastrulation to organ differentiation). Thereafter, the embryo shows an increasing resistance to teratogenic forces as organo t genesis advances to completion in days 55 to 60 in man. In all species, the period of organogenesis remains most fragile to outside teratogenic influences. Upon completion of organogenesis, outside influences can generate an adverse change, but these are usually in the form of growth or functional alterations. Figure 3. Curve Approximating the Susceptibility of the Human Embryo to Teratogenesis from Fertilization throughout -- Intrauterine Development in co a> vH The highest sensitivity, at least to structural deviation, :occurs during the period of organogenesis, from about days 18 to 20 until about days 55 to 60, although the absolute peak of sensitivity may be reached before day 30 postconception. As organogenesis is completed, susceptibility to anatomical defects diminishes greatly, but probably minor structural deviation is possible until histo genesis is completed late in the fetal period. Deviations during the fetal period are more likely to involve growth or functional aspects because these are the predominant developmental features at this time (Wilson 1973). i 47 \ r-' Vo 1 0 0 HZ I 5 5 1 84 30 Wilson (1973) lists six generalizations of teratologic susceptibility: 1) Susceptibility to teratogenesis depends on the geno type of the conceptuB and the manner in which this interacts with adverse environmental factors. 2) Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence. 3) Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate sequences of abnormal developmental events (pathogenesis). 4) The access of adverse influences to developing tissues depends on the nature of t.he influence (agent). 5) The four manifestations of abnormal development ai death, malformation, growth retardation, and functional deficit. 6) Manifestations of abnormal development increase in frequency and degree as dosage increases, from t h e no-effect level to the totally lethal level. Almost any chemical substance possesses a teratogenic potential when administered in excess amounts during a susceptible period of development. A variety of examp 1 describe a broad spectrum of compounds responsible for myriad of biological and chenfical effects. Table IB. Some Types of Drugs and Other Chemicals that Have Been Shown to be Teratogenic* in One or More Species of Laboratory Animal Drug Type Examples Salicylates Certain alkaloids Tranquilizers Antihistamines Antibiotics Hypoglycmies Steroid hormones Alkylating agents Antimalarials Anesthetics Antimetabolites Solvents Pesticides Industrial effluents Miscellaneous Aspirin, oil of wintergreen Caffeine, nicotine, colchicine Meprobamate, chlorpromazine, reserpine Buclizine, meclizine, cyclizine Chloramphenicol, streptonigrin, penicillin Carbutamide, tolbutamide, hypoglycins Triamcinolone, cortisone, testosterone Busulfan, chlorambucil, cyclophosphamide, TEM Chloroquine, quinacrine, pyrimethamine Halothane, urethane, nitrous oxide, pentobarbital Folic acid, purine, and pyrimidine analogs Benzene, dimethylsulfoxide, propylene glycol 2,4,5-T, carbaryl, captan, folpet Some compounds of Hg, Pb, As, Li, Cd Trypan blue, tryparanol, diamox, et. Teratogenic effects were usually seen only at doses well above therapeutic levels for the drugs, or above likely exposure levels for the environmental chemicals Source: Wilson, J.G. 1977 48 There are certain criteria used for recognizing a new teratogenic agent in man. Wilson (1973), in his book, environment and Birth Defects, lists the necessary criteria 1) An abrupt increase in the incidence of a particular defect or association of defects (syndrome). 2) Coincidence of this increase with a known environ mental change, i.e., widespread use of a new drug. 3) Known exposure to the environmental change early in pregnancies yielding characteristically defective infants. 4) Absence of other factors common to all pregnancies yielding infants with the characteristic defect(s). Since chemical response varies with dosage, route of administration, and particular agent, Wilson(1977) has established criteria and categories for classifying chem icals according to their embryotoxic (causing damage in early pregnancy) potential* in man: 1) Established as being embryotoxic a) Unquestionably produces a higher percentage of developmental defects or intrauterine death in infants of exposed women than otherwise similar, nonexposed women 2) Suspected of being embryotoxic.......... a) Apparent increase above background level of developmental defects or intrauterine death among infants of exposed women, based on large numbers of accumulated case reports b) Retrospective surveys indicate significant increase of defects or death among infants of exposed women, but "memory bias" of mothers .introduces uncertainty c) Prospective surveys indicate significant increase among infants of exposed women, but total number of exposed cases relatively small in consecutive series 3) Possibly embryotoxic, under usual conditions of dosage or in combination with other unidentified etiologic factors a) Questionable increase of defects or death among infants of exposed woman based on large number of accumulated cases or on extensive epidemiologic surveys b) Strong indication from studies in more than one animal species that drug has .definite embryotoxic potential, especially at high dosage *A8suming exposure to therapeutic or higher dose during 1st trimester. 4) Not embryotoxic under any known conditions of human usage a) No increase in defects or death among infants born to exposed women in well-controlled epidemi' ologic surveys b) Extensively used by pregnant women over many years without substantiation of cause effect relationship between use of the drug and adverse effects on the offspring Whatever the chemical of effect, however, experimental, teratologists generally assume that all embryotoxic agents do have a threshold below which no adverse response can be elicited-- a so-called, No-Effect level. From a No-Effect level, responses multiply as dosages increase. At teratogenic doses, increased malformations and embryolethality appear simultaneously. Beyond that point, these manifestations tend to increase in roughly parallel fashion for a time, although embryolethality eventually overtakes malformations and precludes any survivors at term. For the initiation of teratogenesis, as with other adverse chemical effects, the primary concern is one of exposure. In man, this translates as the capability of a parental organism to reduce concentration levels of foreign chemicals in the blood. This is accomplished in parental blood by excretion; catabolism and other detoxi cation in the liver; protein and tissue binding and storage. The rate at which these physical processes occur is all important. Numerous studies have been conducted detailing the teratogenic, embryotoxic and fetotoxic effects generated by 2,4,5-T and its contaminant dioxin. Researchers experimented with a variety of species and have demon strated both No-Effect and lethal levels in many cases. The prime target areas fpr teratogenic response from 2,4,5-T and dioxin are cleft palate and kidney anomalies (Tables 19 and 20). r- c.,? iI I 49 1DOM2155186 GO CD vH Table 19. Summary of Literature Involving the Teratogenicity, Embryotoxicity, and Fetotoxicity of 2,4,5-T Animal Form and TCDD Content Dose and Route of Administration (Gestational Age) Duration Effects Author Mouse acid 1 mg/kg TCDD 20 mg/kg oral daily days 6-15 increased frequency of cleft Bionetics 1968 palate, fetal growth retardation Mouse acid 30 mg/kg TCDD 113 mg/kg daily oral or l.o. days 6-14 increased mortality, cystic kidney, strain variations Courtney, et al. 1970 MouBe acid 30 mg/kg TCDD 50 mg/kg s.c. daily days 6-15 no effect Courtney, et al. 1970 Mouse acid 30 mg/kg TCDD 100,125,150 mg/kg daily s.c. days 6-15 embryotoxic effect Courtney, et al. acid 0.02 mg/kg TCDD 20 mg/kg daily, oral days 6-15 no effect Roll 1971 Mouse acid 0.05 mg/kg TCDD 35 mg/kg daily, oral days 6-15 cleft palate Roll 1971 Mouse acid 0.05 mg/kg TCDD 60,90,130 mg/kg daily oral days 6-15 marked increasing resorptions and 5 dead fetuses Roll 1971 Mouse acid ester 0.02 mg/kg TCDD 10-15 mg/kg oral, daily days 6-15 fetal wt reduction Neubert, Dillman 1972 Mouse acid 0.02 mg/kg TCDD 45,60,90,120 mg/kg daily oral days 6-15 embryotoxic effect Neubert, Dillman 1972 Mouse 150-300 mg/kg single dose acid 0.02 mg/kg TCDD . Mouse acid 1.5 mg/kg TCDD 30-60 m g / k g daily, oral mid gestation days 6-15 cleft palate, maximum terato genic effect day 12-13 gesta tion cleft palate Neubert, Dillman 1972 Neubert, Dillman 1972 Mouse acid 0.5 or 0.05 mg/kg Mouse butyl ester 0.02 mg/kg 100'mg/kg s.c. daily in DMSO solution lOOml/animal injection 12 mg/kg daily, oral days 6-15 days 6-15 clef palate, kidney malforma Neubert, Dillman tions some Btrains 1972 no effect Neubert, Dillman 1972 Mouse 74 mg/kg daily oral butyl ester 0.02 mg/kg days 6-15 embryotoxic effect Neubert, Dillman 1972 Mouse acid 1 mg/kg TCDD 50 mg/kg s.c., daily days 6-14 no effect Bage, et al. 1973 Mouse acid 1 mg/kg 50 110 mg/kg s.c., daily days 6-14 teratogenic, cleft palate,rib and vertebrae anomalies, fetotoxic n=ge, et al. 1973 Table 19. Summary of Literature Involving the Teratogenicity, Embryotoxicity, and Fetotoxicity of 2,4,5-T (continued) Animal Form and TCDD Content House butoxyethyl ester House acid House acid House acid 0.05 mg/kg TCDD House acid 0.1 mg/kg TCDD House acid 0.1 mg/kg TCDD House acid 0.05 mg/kg TCDD House butoxyethyl ester Dose and Route of Administration 50,110 mg/kg a.c., daily (Gestational Age) Duration days 6-14 Effects embryotoxic effect Author Bage, et a l . 1973 10 mg/kg s.c., daily days 6-15 no effect Hart 1972 100 mg/kg s.c., daily days ^-15 embryotoxic effect Hart 1972 gavage 60-120 mg/kg daily days 6-14 20,40 mg/kg oral, daily days 6-15 80-120 mg/kg oral, daily days 6-15 120 mg/kg oral, daily days 6-15 20,40,80 mg/kg daily oral days 6-15 retardation in renal A,P. in fetal kidney, reduced fetal wt, cleft palate no effect toxic to females, malformations and fetal death teratogenic, fetotoxic (80mg/kg no effect) no effect Highman, et al. 1976 Frohberg, at al. 1975 Frohberg, et al. 1975 Frohberg, et al. 1975 Frohberg, et a l , 1975 Rat acid 0.5 mg/kg TCDD Rat acid 1 mg/kg TCDD Rat acid "purified" Rat acid Rat acid TCDD not stated Rat acid TCDD not stated Hamster acid free of TCDD Hamster acid free of TCDD 1-24 mg/kg daily, oral 24 mg/kg daily, gavage 50-125 mg/kg single injection in utero 60-120 mg/kg daily, oral throughout pregnancy during pregnancy single injection on any day from days 12-16 days 12-16 20 mg/kg in diet 80 mg/kg in diet 20,40,80 mg/kg oral, daily throughout gestation throughout gestation days 6-10 100 mg/kg oral, daily day3 6-10 no effect no effect no effect no effect no effect embryotoxic effect no effect embryotoxic effect Emerson, et al. 1971 Emerson, et al. 1971 King, et a l . 1971 King, et al. 1971 Hall 1972 Hall 1972 Collins, et al. 1971 Collins, et al. 1971 51 ID0N2I 55 !88 CD 2> v"4 Table 19- Summary of Literature Involving the Teratogenicity, Embryotoxicity, and Fetotoxiclty of 2,4,5-T (continued) Animal Form and TCDD Content Hamster aicd with oil 0.5,2 .9 or 45 mg/kg TCDD Dose and Route of Administration 20-100 mg/kg oral, daily (Gestational Age) Duration days 6-10 Effects fetal death, teratogenic Author Collins, et al. 1971 Hamster acid TCDD not stated 2 mg/kg intravenous single day 8 no malformed embryos, 9% resorp- Gate, et al. 1973 tion-test, 6 % resorption- control Rabbit acid 0.5 mg/kg TCDD 10-40 mg/kg oral daily days 6-18 no effect Emerson, et al. 1971 Monkey acid 0.5 mg/kg TCDD Mouse butoxyethyl ester 0.1 mg/kg TCDD 0*05,1.0,10 mg/kg daily gavage 120 mg/kg daily, oral 216 mg/nr aerosol, inhalation days 22-38 10 exposures no effect slight maternal toxicity, fetotoxic, teratogenic Dougherty, et al. 1973 Frohberg, et al., 1975 Mouse butyl ester 0.1 mg/kg aerosol,-inhalation, 374 mg/ra 10 exposures 5-15 females died Frohberg, et al. 1975 Mouse butoxyethyl ester 0.1 mg/kg TCDD 392 mg/m^ aerosol inhalation 5 exposures toxic to females, fetal deaths Frohberg, et al. 1975 Rat acid 0.5 mg/kg TCDD 50 mg/kg oral daily days 6-15 minimal fetal effects Sparschu, et al. 1971 Rat acid 0.5 mg/kg TCDD 100 mg/kg oral, daily days 6-10 toxic to females, high maternal Sparschu, et al death, 4 to 25 survived, 3 had complete resorptions, 1 had litter of 13 live fetuses, toxic but no anomalies Rat acid 0.5 mg/kg TCDD 100-150 mg/kg oral, daily days 6-15 fetopathy and skeletal anomalies Khera, et al. 1972 Rat acid 0.4 mg/kg TCDD 25,50 mg/kg oral, daily days 6-15 no effect Khera, et al. 1972 Rat butyl ester 0.5 mg/kg TCDD 50-150 mg/kg oral daily days 6-15 no effect at 50 and 100 mg/kg, at 150 mg/kg, 3 of 8 females died Khera, et al. 1972 Rat acid 30 mg/kg TCDD Sprague-Dawley strain 4.6,10,46.4 mg/kg oral. days 10-15 kidney anomalies, embryotoxic, at 46.4 mg/kg, 60% fetal mortality, many abnormalities in survivors Courtney, et al. 1970 Rat acid, CD strain 10,22,46 mg/kg daily s.c. days 6-15 no effect Courtney, et al. li uu2I55I8S Table 19. Summary of Literature Involving the Teratogenicity, Embryotoxicity, and Fetotoxicity of 2,4,5-T (continued) Animal Form and TCDD Content Hat acid, CD strain Rat acid purity not stated Rat acid purity not stated Dose and Route of Administration 80,250 mg/kg daily s.c. 100 mg/kg daily, oral 400 mg/kg daily, oral (Gestational Age) Duration days 6-15 days 1-14 days 1-14 Effects embryotoxic effect many deformities many limb abnormalities Author Courtney, et al. 1971 Sokolik, Yu 1973 Sokolik, Yu 1973 Rat butyl ester purity not stated Rat butyl ester purity not stated Rat butyl ester purity not stated Rat butyl ester purity not stated 50 mg/kg daily, oral 200 mg/kg daily, oral 0.01 mg/kg daily, oral 0.1 mg/kg daily, oral days 1-16 days 1-16 throughout pregnancy throughout pregnancy embryo mortality, cleft palate Sokolik, Yu 1973 30% embryo mortality and many anomalies no effect threshold level Sokolik, Yu 1973 Konstantinova 1970 Russian Konstantinova 1970 Russian Rat butyl ester purity no stated 0.4 2 mg/kg daily,--oral throughout pregnancy toxic to female, irregular embryotoxic effect Konstantinova 1970 Russian Rat butyl ester purity not stated 4.2 mg/kg daily, oral throughout pregnancy toxic to females, nervous signs embryo deaths Konstantinova 1970 Russian Rat acid 0.1 mg/kg TCDD and free of TCDD Monkey acid 0.5 mg/kg TCDD Monkey acid TCDD content not stated 25-150 mg/kg daily, oral 5,10,20,40 mg/kg, 3 oral doses weekly, 4 weeks 5,10,20,40 mg/kg 3 times/ week throughout pregnancy days 20-48 days 20-48 no effect Roll 1973 no effect on 12 fetuses removed by hysterectomy 100 days gestation no effect Advisory Comm. 1971 Wilson 1971 Sheep acid TCDD content not stated 100 mg/kg daily, oral days 14-36 no effect Binns, Balls 1971 CpOO D0H2I 55 I9I cv 03 CD Table 20. Summary of Literature Involving the Tera'togenicity, Embryotoxicity, and Fetotoxicity Effects of TCDD (continued) Animal Dose and Route of Administration Duration (Gestational Age) Effects Author Mouse 3 ug/kg daily, s.c. days 6-15 varied by strain: Courtney, Moore 1971 CD-I: E.D. 50 for cleft palate, DBA/2J: E.D. 50 for cleft palate 9 E.D. 50 for kidney anomaly, C57B1/6J: E.D. 50 for cleft palate Mouse 25,50,100,200,400 ug/kg daily, oral *days 7-16 fetotoxic, teratogenic, increas Courtney 1976 ing with dosage, up to 971 at highest dose Mouse 25,50,100,200 ug/kg daily, s.c. days 7-16 fetotoxic, teratogenic 97% at highest dose Courtney 1976 Mouse 0 .0 0 1 ,0 .0 1 ,0.1 ug/kg daily days 6-15 no effect Smith, Schwetz, Nitschke 1976 Mouse 1.0 ug/kg daily oral, gavage days 6-15 increased fetal resorption, 21% cleft palate, 5% kidney anomaly Smith, Schwetz, Nitschke 1976 Mouse 3 ,ug/kg daily oral, gavage days 6-15 71% cleft palate, 28% kidney anomaly Smith, Schwetz, Nitschke 1976 Mouse / Mouse 1 ug/kg single, oral ' ug/kg daily, oral day 10 days 10-13 no effect, cleft palate, 34% kidney anomaly 1.9% cleft palate, 58.9% kidney anomaly Moore, et al. 1973 Moore, et al. 1973 Mouse 3 ug/kg daily, oral days 10-13 55.4% cleft palate, 95.1% kidney anomaly Moore, et al, 1973 Mouse Rat Rat Rat 1,3,10 ug/kg females, oral at parturition 0.03 ug/kg 0.125,2 ug/kg daily, oral 0.125,0.5,2 ug/kg daily, oral parturition days 6-15 days 6-15 days 6-15 renal hydronephrosis, 12,71 or 75% depending on dose no effect depressed fetal wt internal hemorrhages in fetuses Moore, et al. 1973 Sparschu, et al. 1971 Sparschu, et al. 1971 SparBChu, et al. 1971 Rat 8 ug/kg daily, oral days 6-15 Rat 0.125 ug/kg daily, oral days 6-15 Rat 0.25 ug/kg daily, oral days 6-15 fetal death all no effect Blight decrease in fetal wt Sparschu, et al. 1971 Khera, Rudick 1973 Khera, Rudick 1973 j 55 v Table 20. Summary of Literature Involving Animal Dose and Route of Administration Duration (Gestational Age) Rat 0 .5,1.0 ug/kg daily, oral days 6-15 Rat 1,2 ug/kg daily, oral days 6-15 Rat - 4 ug/kg daily, oral Rat 0.5 ug/kg daily, a.a. days 6-15 days 6-15 Monkey Monkey 0.011 ug/kg (estimated daily in diet) 0.0017 ug/kg (estimated daily intake) months 6-12 years 2 Monkey Animal Monkey Monkey 0.0095 ug/kg (estimated dietary equivalent) three times/wk during pregnancy Dose and Route of Administration 0.048 ug/kg (est. dietary equiv.) 0.24 ug/kg (est. dietary equiv.) early pregnancy Duration (Gestational Age) early pregnancy early pregnancy Embryoto. x. iUci. tr y, and Fetotoxicity Effects of TCDD (continued) Effects Author CZ..DO r v"-ri reduced fetal survival, lower body wt, lowered reproductive ability in progeny Khera, Rudick 1973 visceral lesions, reduced fetal wt, increased fetal death, maternal toxicity Khera, Rudick 1973 100V fetal death Khera, Rudick 1973 no effect on fetal mortality or cleft palate, 67% kidney anomaly Courtney, Moore 1971 spontaneous abortion, severe maternal toxicity Allen, et al. 1977 4 of 7 aborted, none of controls Schantz, et al^ 1979 (zero level TCDD) aborted, one ; stillborn, 2 normal deliveries maternal toxicity 1/4 aborted, no maternal toxicity McNulty 1978 Effects 3/4 aborted, 1 showed maternal toxicity 2/2 aborted, maternal toxicity proved fatal Author McNulty 1978 McNulty 1978 Teratogenicity Summary D0H2155193 MUTAGENICITY CO r*" Like many chemicals that have become part of our every Analysis of mutagenic effects permits an assessment of day lives, 2,4,5-T and its contaminant TCDD have produced the ability of a substance to induce genetic alterations. teratogenic responses in various animal species. The resulting information aids in estimating the genetic hazard man, animals, and even plants encounter from Establishment of a response and its severity depend on exposure to the substance. dose of the chemical, route of administration, species, and in some cases, sub-strains of species, and finally, Because of the similarities of basic molecular mechan period of ingestion during gestation. isms by which chemical mutagens and most chemical carcin ogens appear to induce genetic effects (i.e., molecular Teratologists generally agree that a level exists below laterations of DNA) researchers postulate that mutagenic which no teratogenic or embryotoxic response can be effects can be predictive of carcinogenicity (IRLG 1979). elicited. Research of 2,4,5-T and TCDD has supported this rationale in many animal species.by establishing Scientists use a battery of short term tests to indicate lo-Effect dose levels in test animals. the mutagenic potential a chemical possesses. These short term tests may include: Embryonic interference by 2,4,5-T and TCDD commonly manifests itself through cleft palate and kidney 1 ) tests for mutation in bacteria and eukaryotic micro anomalies at teratogenic doses and embryolethality at organisms; higher toxic doses of chemical. 2 ) tests for mutations in somatic mammalian cells; ,3) tests on chromosomal effects in higher eukaryotes, including mammals; 4) evaluation of DNA repair synthesis (IRLG 1979). Among the mutagenicity tests on micro-organisms, the one most widely used is the Ames reversion test in Salmonella. E. coli, Saccharomyces, Neurospora, and Aspergillus are also vehicles tor mutation induction. Mutagenicity tests alBo use. Drosophila (IRLG 1979). Tables 21 and 22 summarize the mutagenicity testing for 2,4,5-T and TCDD. 57 17685 ___________ 'DOW 2 1 5 5 1 94_____________________ Table 21. Summary of Literature Involving Mutagenic Effects of 2,4,5-T Species and Type of Test Results Microorganisms Salmonella typhlmurlum Negative Saccharomyces cerevesiae Negative Bacillus subtills Senatia marcesrens and Escherichia coll Drosophila Sex-linked recessive lethals Sex-linked recessive lethals Somatic cell mutations Mammalian Systems Mice, dominant lethal and Micronucleus Negative Negative Slight increase No increase No increase Negative Cytogenetic effects -- gerbils Cytogenetic effects -- mice human Data Cytogenetics -- workers Inconclusive Inconclusive Negative Reference Anderson, et al. 1972 Ercegovich and Rashid 1977 Siebert and Lamperle 1974 Fahrig 1974 Shirasu, et al. 1976 Fahrig 1974 Majamdur and Golia 1974 Vogel and Chandler 1974 Rasmusen and Svahlin 1978 Buselmaier, et al. 1972 Jenssen and Renberg 1976 Majamdur and Hall 1973 Davring and Hultgren 1977 Kilian 1975 Table 22. Summary of Literature Involving the Mutagenic Effects of TCDD Species and Type of Test Results Microorganisms Escherichia coll Salmonella typhlmurlum TA-1530 Salmonella typhlmurlum TA-1532 Salmonella typhlmurlum TA-1532 Salmonella Tester strains Increased mutation Negative Increased mutations Increased mutations Negative Mammalian Systems Dominant lethal, rats In vivo cytogenetics, rats Negative Negative Human Data Seveso plant workers, cytogenetics Seveso, fetal material, cytogenetics Inconclusive .Inconclusive 58 Author Hussain, et al. 1972 Hussain, et al. 1972 Hussain, et al. 1972 Seiler 1972 Communications of B. Ames to USUA 3/74 Khera and Ruddick 1973 Green 1975 unpublished report Rohrborn 1978 Heggiani 1978 All of the 2,4,5-T mutagenicity studies have drawn either negative or inconclusive results in tests covering primary DNA damage, gene mutations, and chromosome effects. We agree with the Scientific Dispute Resolution Conference, therefore, that reasonably adequate experi mental data has been generated regarding 2,4,5-T and that these data are not suggestive of 2,4,5-T induced mutagenic activity (Scientific Dispute Resolution Con ference on 2,4,5-T 1979). Results from several microbial studies have determined that TCDD increases the frequency of gene mutations. Microbial data suggest that DNA repair processes are involved in the mechanism of action since no mutagenic effects can be elicited in studies using- repair-defective bacteria strains (Scientific Dispute Resolution Conference on 2,4,5-T 1979). Mutagenicity Summary Short term mutagenicity studies have been routinely performed to assess the potential of a substance to cause genetic alteration. The resulting information can then be used as an aid in establishing the risk of a chemical agent's carcinogenic activity. All of the 2,4,5-T mutagenicity studies have shown either negative or inconclusive results in the various mutagenicity tests performed. In addition, the bacteria data suggest that TCDD acts as a direct initiator of malignant transformation since most mutagenic carcinogens are of the initiator class. Few promoters or co carcinogens show mutagenic activity. Mutagenesis studies performed on TCDD show that TCDD lias the ability to cause cells to undergo genetic changes. Human studies involving both 2,4,5-T and TCDD are insufficient and inconclusive. D0W2(55 195 CARCINOGENICITY The question of the carcinogenic potential of 2,4,5-T and its associated dioxin (TCDD) has accompanied the herbicide since issuance of the initial RPAR in 1978. Indeed, its possible carcinogenicity, coupled with its potential teratogenicity are the primary points of con flict within the scientific community. cp C> Animal model studies have long been used for predicting carcinogenic potential in man. The species of animals used in these studies must be as caiefully considered as the data that ensues from the experiment. As a class, rodents meet certain specifications that make them highly desirable for carcinogenicity experiments. Their life span is short which allows the fullest expression of a positive carcinogenic response (these primarily occur late in an animal's life). Rodents are small, relatively inexpensive, and easily bred, all of which encourage large study samples and confirmation of test results by other investigators. However, researchers may have problems of interpretation when using rodent species. Results obtained using rats or mice cannot be unequivocally adapted to man because of certain biological differences. Second, the SpragueDawley rat and several mouse strains noted for their high rate of spontaneous tumor incidence are often used in these experiments, so care must be taken to discriminate between spontaneous tumors and those caused by carcino genic mechanisms. Finally, a carcinogenic response can become apparent long after the original cancer causing stimulus has been removed. Manifestations of cellular alterations can take years to develop. This has been a recurring problem encountered with human epidemiologic studies resulting in a Catch-22 situation. By the time a carcinogenic effect expresses itself, many years have passed. Con versely, an immediate cancer response to a stimulus could be viewed with skepticism because that would not fit with the classic carcinogenic mechanism. All of these factors must be considered when analyzing a chemical for its possible carcinogenic properties. Animal research has been carried out using mice and rats as primary models for the possible carcinogenic effects of 2,4,5-T and TCDD. Tables 23 and 24 summarize these studies. . 59  17687 0 H2 155198 Table 23. Summary of Literature Involving t;he Carcino^pjLc and Tumorigenic effects of 2,4,5-T Animal Form of Herbicide and TCDD Content Dose and Route of Administration Effects Author Mouse acid TCDD not stated stomach tube 21.5 mg/kg/day days 7-21, 60 mg/kg in diet for 18 months (27 mg/day) no effect Bionetics I960 Inns 1969 Mouse acid 0.05 mg/kg TCDD XVII-G strain___ 100 mg/1 in drinking water for 60 days then 80 mg/kg of diet for remainder of life Bpan no effect* Muranyi-Kovacs 1976 Mouse acid 0.05 mg/kg TCDD C3HF strain at age. 6 weeks, 100 mg/1 in drinking water for 60 days, then.80 mg/kg of diet for life span males - no effect, females - increased incidence of tumors** Muranyi-Kovacs 1976 Mouse acid 93t pure in DMSO 215 mg/kg single s.c. injec tion no effect Bionetics 1968 Mouse acid 99% pure TCDD level not stated __. 62 mg/kg i/p injections daily for 6 days inhibited Ehrlich ascites tumor Walker, e_t al. 1972 Mouse acid 99% pure TCDD level not stated 80-85 mg/kg i.p. injections daily for 6 days doubled inhibition Walker, et_ al. 1972 Mouse acid 0.05 mg/kg TCDD 10 mg/kg, 4 single s.c. injections no effect Muranyi-Iiovacs 1977 Rat acid "pure" 3,10,30 mg/kg in diet for life span no effect Kociba, et al. 1979 Rat 0.05 mg/kg TCDD 3,10,30 mg/kg/day in diet present status: no evidence of carcinogenic response *XVII-G strain of mice has a known high spontaneous incidence of lung tumors **C3HF strain of mice has a known spontaneous incidence of hepatoma Leuschner, et al. (in progressT Research conducted on animal models for potential carcinogenic effects of 2,4,5-T have failed to yield positive results. The EPA's Carcinogen Assessment Group (CAG) acknowledged those conclusions in their February, 1979, report: "On the basis of the completed mice and rat studies, there is no significant evidence of carcino genicity for 2,4,5-T." They added, however, that testing ha3 not been done sufficiently in mice (EPA 1979a). Of the studies listed in this report, only one report (by Muranyi-Kovacs) produced positive results. However, 60 the CAG rejected findings of the Muranyi-Kovac3 report, saying, "CAG cannot regard the study as furnishing significant evidence for the carcinogenicity of 2,4,5-T." The CAG then listed their objections to the conduct of the study: 1) inadequate animal husbandry; 2) inadequate dosages; 3) arbitrary exclusion of some test animals from the calculation of tumor incidence; and 4) the unavail ability.of histology data on some animals. The authors of the report themselves suggest that further and more adequate studies be performed on a greater number of species. Table 24. Animal Mouse Mouse Mouse Mouse Summary of L ite ra tu re Involving C arcinogenic ADodsme iannidstrRa toiuotne o f n0tii.o0nn0g7 wa utegeak/kglyeg, 1fo0graws1etreyikces)airn t(ubbeagin t0(ib.o0en7ginwungei/enkkggly, a gft oar1s0tarwicyeeeikansr)tu b a a7titounagg/kewge,1e0kglwya,eset1kr isc)y e ainrtu(bbaeginning T2PAug foanr d 32prowmeeoktesd w ith 5 ug Rat a5fon00irm0 7a8nlg, wT2eCeuDkgsD.//kgg Wdbieoeedtkylyinwdt foosoed/ Rat a1fon00irm0 7a8nlg, wT0eC.e4DksDu./gg/kWdgieeetklyin d foosoed/ Rat Rat Animal Rat Wb5o0edeynkglwy/gedigionhset f/oaondimfaol,r 078.1 wuegek/ksg 05780.01wngeueTgkC/sk.DgD/Wbgoedfeoykoldyw ediingohsdet /iaentimfoarl ADodsme iannidstrRatoiuotne o f wd5inXoes1idge0_h/iae1tn2t igmfoTarCl,D7D80/g.0w0fe1oeokdusg. /(k5gWpebpeotk)dlyy and Tum origenic E ffe c ts o f TCDD in Anim als *0002155 197CaErcfifneocgtsenic Author Of. CO ntroe aetfmf eecntt e2ndmeodnths a f t e r Toth, e t a l . 1977 ntroe aetfmf eecntt e2ndmeodnths a f t e r Toth, e t a l. no e ffe c t a t end of treatm ent Toth, e t a l . wttuwemaoko-srttiuagmteeonressyiinsstiewtmi iathtoof Dr MmiBonAuseth esk in 442 ncsqheuooalpmalnoagusisioectuanmrocdoinursolems(alus(nl ig(vl)ie,vre)r,) 1211( pmagcenhlraigoioltilibooaglnsnnaaegasraintcoolot)cmmaharaic,sitni((oobs ckmr yaiantion)m,)( ,lai v s e r ) , 1111 casfiadcbrelrcenoironmocosaamirnca(igsnto(rssmeikamaitinen()odk,midma nue(styce)ls,et)e,s ) 111 asfqisbutrraoomcsoyaurtoscomcmaeal l(b(tmruamuinso)crle()s, k in ) , C aErcfifneocgtse1nic 111111( pmaaLeleyndaeramgeryilntidipoogdoihsgnncuaoaaecrcrcnctacyoetlitc--nmlicahloamrimcsaliteedani(uteosoankkc(smoeiyktmnmaati)odsa,iemna,s,e(atyen)so, tteesd)), DiGiovanni, e t a l . Van M ille r, e t a l . 1977 Van M ille r, e t a l . 1977 Van M ille r, e t aJU 1977 Van M ille r, e t a l . 1977 Author Van M ille r , e----t- -a---l--.-- 1977 , tI 61 ~UUHIJI3 Table 24. Rat Rat Animal Rat Rat Monkey Summary o f L ite r a tu r e In v o lv in g C arcin o g en ic and T um origenic E ffe c ts o f TCDD in Animals (continued) dwliXnoe1sid0ge~h/iae1tn2t igmf oTaCrl,D7D80/g.0w0fe3oeokdusg. /(k1gWpebpeotk)dlyy no e ffe c t Van M ille r, .et a l . 1977 ' 0in.1 duige t TCDD/kg/day r. for 2 years NOTE: , csFeaodmaMcshpkutDuipsitiseEhnunqhnndqudaelaateeAlvtoMauecucrceserccermralprLsecsaebemaeiiAirrasaemEtrmddimadmenunci,LintseiStieanetaenoeasiEaoses:cooortnnnsnacflyhS,utlsaulmocecic:ciiltsaiulsedxczdeelnecpenagdepyfeislahcciodlcefnlacanaepoioolcerriuenntgrorilcoctanrfffilollcteyecdceetlrialyatichluxeiabsnslsrsadrueqso,hcnniceoo,saoteietmlunaaeanhimelftmnlandragdrorgwiuedycccrmcdgaoepont.tlipryiheuncocnlaintoteiaeeyniyohrprforuoalsetrfcbiopaefDetmsaiomsmpcfaudnifeicremledesamlenadaacat,srdacecenonaeauratteorsdnoctndeydodocotetlrsttmiecoge,epufeslafifhnnecufisscceaeoonenso,her.nismmnqdec,naaf.euagairooasaddsa,dmeoldf K ociba, e t a l . 1978 ADodsme iannidstrRa toiuotne o f 02.0y1e aurgs TinCDdDie/ktg/day fo r 02.0y0e1a rsug inTCdDiDe t/kg/day fo r eb5x0o0dpyonswug/rtkegfoberintwndeineinee t m2t-o3onttauhslg/kg C aErcfifneocgtsen ic MhnFnffrrEooeAooMdpmmLseAEaisSLtgcc,:oEonoScnn:nieofttlirrlcoofuaulllsnsar trhi neh td ryapdlelirfpfnelearoespntlicacsem ifference s cnoo nstirgo nlsif ic a n t d iffe re n c e from ehnopy pintehereoplplialasalisath,icyapncednratrnmogpeehtsaypn,loatseida , Author Kociba, e t a l . 1978 Kociba, e t a l . 1978 A llen , e t a l. 1977 ' '> o 'O'* 62 , DOH2I55 j hck1thnay9oeTrd7wCc4rDnito)wnD.coocagaribssrTecotnhainainigcnsoe(gAeaeensHxcnyzHttysri)metvDemMeaimtcBeysAltyyo.i,vsftTpieCtFmomyDutoDerutniishnseites rpstimhnkaroedionpwuroerceasJtaeuektrdminot(uoaPfmrstohiholgeaareenpndppiaenrrtsoeaiiicsmntseid.aonattcGreoeyrlrol ooviffenr bctt(uiedevmeIirneontoalxrvysifie,nnosu)ahtnsriigdgahhwaat vt,teoiesollploncpensaarcogusidoseuenfstec.aretismhndaecl rddecotoauasssrereebc-sddii,nneoapaingteecnde-indidheeieactnnrtdcpcerooepntoseatafunlailtnlttiiesiavn.lgetuormATfCaotDnTrCdDrsDeDhillunaansg jJ I dVcce11fdtroShrccrtrhha0oaioefnaehaoiptep0nefrgssTstsmrrric0eesepwopctahnuhiM..clgtioineegnolnnepaeutitscowdsccoxaspiettlg.mTini-.HpsgteitlddhDav,eideusreeoemmeetnemoarrndwunViAd5,welisaiimodecyc0aacoaaltlrv0nyenpog,sesesenepypph,pesnrMpdostpte,ieotohughsortrpafectthaeeahditsrrteitelhnfeaeeesd,lltinlnoyineesegcsesivrttcolafts5erimiaefee0ascasbrtatieodheneayroplmlrdcdopxpnet,rnehkeeVaoafrpieocdcneddnbattfgatlrohd,oyhh,un.tawsdolTam7seeteaaMnCoKniil8pliuovinvpedKdDr-slnaodwnydnepeo,eiDatcolggscseeiel.tlicceusc5eabrxeefiemokwraettprbeuhpnpohTrileeeadmnoelopeeifyhrnl'unysiclretttotpmw.ctelyav2treeahdhbdg2aasreeidrcerer0trallenspheoOlmi0a..irtotwn'lnuncesiasnawioghpTipcnl((sgCygaaS1yafai1patDrnncnet9litpi9tolhciDgeaco7nytri7moewelraf8ratni7sdneecgin)nlsio)ceeluaodas5oti.-aahdvdes0ebcudyt-nee0eleoo5fssueeDerfeA0itnlsfaldenvseea0rliipdrtdonvmgwsectpuwheoplttclide,efpetlyoe.artdf,r ',; .deuPrssailiinenenuautfnorpTvfdtvsdlsaaedoipeuhieikictetrelecnseideststrtcotdeseei.liitgndyogvi.nsnchetahDopnlaI,toneihoavpuoopneaelcandenndatsuruoddtbdm.tummociededcaeolneoniaynuTnntltrtcyioshdloknadae2sunneobri/cn3dClwoe,vstyefheavttf1terrhhohnlstca9eueueeuial7rnmnvutsi9odcfceisco)gniiol.rlereniesisvtnpmdtghneittTlaicriisonbtAoSaitthewsilltpsedgemciresrataaoterehgssntttnfhooseuhtoitmhmeeaorrra-dsoestfeDawnpr,lnlsmeoVaoistnw1i,nlaatiG0hnitljsasa0eatoirhngy0bMoreeuhchhiopparsilieigghuialrspsltchhtosttt(eyuiCsllrnrdyytA.dt('cuoysEGooomgP)sfmAeTeonrihniicgs s ^dairdIetasniosot f a c ltousrmor eoirlna ttinee dr ewuscitttihino gnth eat ht ea xltopwwe ceittrehdd oontsaee r geraxenct geoepsrtgioaonnf s Tt hCdeDeDt e r 99 mined from the higher doses ( i .e ., lung and liv e r). nt(eu1mLs9t7ba5esgr)t.rloyreu,cpot.mhme TeenhxdisepdesrimbmyaeltlnhtenuomNn lbayetiroinni svaol blvCeelaodnwc1e0trh eaI nnmismitniaitmlusutmep er dhWcbctaaKfihsieooiyttoncefhTnpncafdisttchilemehfhb2ieletlrnureea1aeiepd0gcKttnlheieeh.2taosdcepTvitscgteoripiitinhedsbtaIitchnclape^aleadtinp.ehslnaosxtttlvnet.ofsiyuoedegtdshducaoletueynTsuuslnldaeeirhs(degEeceshseriPodgahnsataAmnCaasilyifnAdofribpinddGi1naficceingc9onaarertortt7tphhhgeetdnn9ielee-eetosaamesiti)snnhvcdhKfe.etaceoaexienopciorlrpptcdueemfeiaeddabbatrtinhitaholdomectcattydcedhhesrtelperteiinuealtsoTtttlidhrhtCufc(piyeD2aioil(lsDh1as2an0bm2n2ressy02sieptst00pcigauc0aetpiatdhnrcpitotcy)etpniapcihvtoprnethecdCeadto)leniAor,umlnd.auGsloneaell,idgass.vaer enri c cclilasonehnienpsoTlieoaoplhodungne,neglsaatdsnohptriiitsencoe(agaNnmgpflsarotocpoeetlortieltreoonemadntwtnotraeitobilnoinyuvatngCenls.etriahsfgxnyyeiupcnPeriNdierranerseraogstIltteendiaiincdrorespedinntpsrihiatntaeelugantlrainteCtvetdsiaineronep1artcnep9rteera7rrpoesft5hesIrf)erenae. rrntseaamRttdtstiaeittoauhnasntLoeuepmpri,evoaaeefrtndoirtcceflWvoaceftouarrkre Relceoms imoennsdedin c rl aa st ss:i f i c a t i o n o f s p e c if ic h e p a to c e llu la r 1) 23)) 4) CbddacHFabcN))))))))oheecoopWMMWCBPEilpaoaolaiioetolextonsosalhdefalroigscdelnrtpyiegrdciooahclccleilptfaifdeueelilhnfnblliillleyucifdaollrlfrorludieecadfffsulrnooocariilesafoerccct nfirsariiiaceatlitirntgneaeerdodtorn/emauotdntiariadsotpengadslpaisl s la fo ry ci fo -rm atio n TwapthvhlheaeaiycBsihtltaeadisrcbeaemdrsleenco,o"rnikndbntuehoetolwheepensthl"maeetesosxpmteiprbcbeeeenvrrniosimoiodnouduedfsulnuelltycestahe"ldeareastonwfbedyporrrrrebckoepasildhorliacfoleicoptnoergoahigtcaisineovavnelesctheraeevallcelnioedsdlmdiei,otnmenca"ersehtnadyttepuhdeerre . 63 Oa:-. o vH 1 I  D0M2155200 mdctclheooaeermancostpiwctnao,cooruframkirbnhsalhedie.noippctaocatoftoeetnchlteatarlontltulhoilnaaafcnrt rniemcsaauatascrulcehsrid,analonlptmyhreioano.bcccaiocdbAnueicrllnetrihcitnnyoesguugwoshhfaosetsfphuvaecetthhroyodcsneeelvooldelwauluotllapeansr,d ddddoTpblistttyhnhhteeiefuehasavtSaagttrepegneacesttetilrcauelciirnaovssrtcq,ttdeyepchthaaiuireeidmneeerbnlanindcssssertoteoiceeeienntnnmoecroabitongphniyntafmnhnaattrto,erehvennetHadoahdsgarnata,upianenaeestrllctdoisepgstoaivpespiriotosotwesmaslsrstinawuosrioaessecoaalgyriptmneepnohbtrgeisdnifrleornynosmeotostnhnosWffidteeieaaafotuvutoansnritdlaleptab.feocltuosisiretdtanltseocaneuamoasbanfI,iltmgneredcerseidcennpasotoihiafppthut(nhfaentn1lasteooaeni9erebongsnrde7aotloitmheee9crfptnanocm)aoysslanaortsprtbaascrteeayfiilmucigncnxc,tiniydgeodcavp.nopyrroanioeomcesec,intlssminvyeTouatntiioeatnhsaronghnnpir.eecfsmunasey,.lreuietfeneaooerddnAnaaec.pendedouou.stqldpgdstrahuolrsteusaohooerrltsweeinrtrmcssstth pathnrdeiss elunsantmgei.n reSLspopwroaegnrusede-.oDsaews lehyaver a ct so npsaisrtteicnutllya r lfya iliend thtoe elilvi ce rl ; chafi neatyiCpepoaaloenbnrc,tlfpheaulrwasacoithsiofntiniiloceptmhhonaaiess.otnhdoaeautnyrrlsiepsosieccbnaolsringersevaaigdet eaper srrrdiepociirnnategnc ocauetrrhrbsoeodeuner sciggolenacfnosemcsnroiadafntiliiitdcogiiaonnttinaion.nonotnt Saoolmtfeer seen (CJDO t> vH ccsituntaiumtTtridechnoyriorgnp.ssoer wetghtieinaetnhtiiislocnauincptkytpho.oeofrftThtwochyoaefpyrecytrhiefnpeuaolrragtKshettoeeniccsriicbt nasucpohcpedaorpuninologecrdestluooatshsiffoinsnnthsooerdnafu-aKtpliverooosocnoribatfoalteho ifsby., av1r9aeT7tih9opednr)seE. cPauAsr'ss otoorwsw,n hpSeectrhieesrneth,ifyoipcfe rAhpedlpavsaisttoiocrcye(lPnluaenloaeprllacasaltsricoci)nhonamsoadre(lEesPseAr C a rc in o g e n ic ity Summary ecs vtl raCearruti, refryee axnnttphyerirsact slt ep afaoenrsdeiclt imaortonhcui.asneto gfsuet unr dtihci e e srre shrpeaosveneas refcahit ol eids2 ,4ntoe,5e-ddTeemd. otnoH ow DhssInyyMyssTdBttCaAreeoDd,mmcDdTa,iCoritbDsiofooDnnnmpi,rtohsohuepiysnoaedosrewstothdhkxeeeiaynkarlpsachtsrueeaaamsnrecpdo(nAir,rnocHomeHii sng)ooeitaatfneicreapttshtoioioevsftr.ei tcknynaitnorwciinnintnhdoecuthgaceretewcnriorincoaosftgta.aeacgnrteyTi vlhiitsy . At high d o se s, TCDD does in c re a s e th e amount o f tum ors 64 HUMAN EXPERIENCES WITH 2 ,4 ,5 -T AND TCDD cmcoahsaaonunaremmedmnTnehcathpunceeiamartarnesbgpcaisneieeaepnsiTbnnnoChlctgeaDnleriasDelasaiboesllke,osfctehx.orth.paps.neotcrtmooTasiemrdTeehyduhniisoecntatifaionnaifngsrititgchmtuhettiaohmserleexscseeso,tinhcepntecatrthihrsirmosceiefgvhermaenaretehiyrsrrcsai,saysco,tlobsf naniriefnworactgddehiaatrvlhnsclredsehdrusoniseeneremoffagetingecccchho2fatefaselv,e4v,meec,tr5hiantc-snataThdtles oaecthofheeeiehfnrasafvfpesnUesacfiaidcemdatldtlnyiabooatceteoihfzrennttrcmoenaeibsscanrne..asrieeltgoeqocl,uslurrtlftnohaeetAwpeReaegoetlxnioseiitnanirnpcteocsqohtcaeiolsaenunuyosisildisnggbniru,nryheohhtislrceneeeia.tsllphyrgvufufuriee.fntisruloeTlsaiimtpnvolbn,cbhtuTeevgtiiesgednns,eh"aednoedgaaftsharbf.ctetaneeyiitsiecsnogndicsritnufdaouutocgsnatetptnlrehhhnrttldmoedsegaeetedb"w.faiisldarriteioniudoe2rmorppaRmivr,snno4a^buetaonf,e,olrrt5oenpasnhst-ershsliacueTrnmtcteuoreriaho,ratucaaatibenindtsioatfilattsyyooevferltrnipatramibheopac,orcducbafuitaeceporutariuletheffiossnylnmusfleiuygymceeu/uroacnarlnarlfitaiacnntcedhkd hdr2uei,mT4sfec,ah5nruer-rseTeesdx.ioapnrtooesususirnoemmmdteoiasrriceezupietssohsreittohsrne os2rf,4eola,f5ecv-htTauumnaoatln,r "eTuspCtsuDiudDdae.ilmleysioT"nlhomeognoyf-soqtlaulnooadfwntetiinnfgie d Dow Chemical P la n t Workers omMespip1nax9apeaipl5iTkreced0tosehhrhossaiiepwentsgtodusoaahp2nsrretef1s.,teu4oxi.9tlchd,7pr5ueyAo1o-OaslpTnaeea2neadxrpet,rl4mayeaoma,ttrzt5ahoiotpiion-ntenreeTudgs2ernf,Dsa,am4tototcihowa,tfota5hecrunn-eoCirTudehfvhrfmteeoeaowpdrammcorulhtoiotturrechhtencireaaneeaeelllgcssihocycPtstyarr:iepleecttaaewwusaenrrstr.x,taeedmptgaotioiehanorcfrrneerstiyueoMc,2nfrit,ani4lcardcyonoe,vlt5duapue-noirtesTndiedftrnvir,ageyow2ftrlalo0eooyv4rtrmreoskd,resrs wWbp(ecaoeiIorrtnnkehnmsitnogeanbfei natsnhveiiennerorvgraeatsldhcb,l eoliypsraasett twsrotetiiuhxftbdhapunytohtt,sah1iubsnar oelptepl mioacmdtfooTvni CtaeceDtlredhDslnee)tUsrumwea.Sxrtovoi.proe're;ntywrase,ihleniinmotvtycefi reoodmer2ntf,aam4bflley,eie5tcsny-t,ttThs. e have aconmd 201 CO poaTppearrBs neenanilroahnsdecsdtlbosoyigkpsfultrweeesulilee'drbsnchileahoeooat tmotft2oaeawac5tbpkhrsncloshayseaieoiinrmognsrresvedmhpsaiagdeahgllraaddweaa2eelcd6rerioteegdebcxtgledniaeaaplrnasenrtaeogennpawcprcpsieahimyepstertsihhxsurocteeudpdabinhdcontielsthshesaaitstceesya.,ftaodhtefr.noveecbstraetoocatIiiyonracTcntmesktcht(deiog2leuaOniorft,rguot4eodriftneeuhs,sar5ddmnettt -haddaatoTnodaiikssdm6saafaiJpn3pftLoagohrsaep. heyrrleetuocrs1earaepecubua9orliiusrl8iillngdcttltur0yogeshoir)ldcelt.ttdheontetfwirnyeo.xtoooTrefpmnehaeferrosi r- e cr> ty>M* 65 _________ __________ 3POHZI 5520?______________________________ T__a_b_l_e__2__5_.__ O19b5s0e-r1v9e7d6_a_n_d__E__x_p_e__c_te_d__*__D__e_a_t_h_s___A_m_o_n_g___2_0_4__E__m__p_lo__y_e_e_s__E_x__p_o_s_e_dD__u_tor_a_t_i2_o_,n4__,5_o_-f_T_,E__x_bp_yo_s_Cu__rae_u_s_e__a_n_d___D__u_r_a_t_io__n__o__f__E_x__p_o_s_u_r_e_, Cause of Death Category TO ob st ae lr v eEdx p o s eEdx pGe crot eudp O1bsYerevaerd T o tal EExxppoecsuterde O1+bsYerevaerd T o tal EExxppoescutreed* All causes 11 20.3 6 13.3 5 7.0 T o ta l m alig n an t neoplassw ........ 1 3.6 0 2.3 1 1.3 D iseases of cardiovascular system 4 9.1 1 5.6 3 3.5 External causes (accidents and suicides) 6 3.7 5 2.8 1 0.9 A ll other causes 0 3.9 0 2.6 0 J .3 *Expected numbers o f deaths based on U.S. w hite male m o rtality ra te s Source: O tt, H older, Olson 1980, T able 26. OE xbpseorsvuerde, an1d95E0-x1p9e7c6ted* D eaths Among 204 Employees Exposed to 2 ,4 ,5 -T , by Cause and In te r v a l Since F ir s t Cause of Death Category In terv al Since F irst Exposure Observ1e0d Y eaErsxpected O bs1e0rv-1e4d Y eEaxrspected Obs1e5rv-1ed9 Y eEaxrspected Obse2rv0+ed YeaErsxpecte* A ll causes 3 6.6 0 4.7 4 4.6 4 4.4 T otal m alignant neoplasms 0 1.0 0 0.9 0 0.8 1 0.9 D iseases of cardiovascular system 0 2.3 0 2.2 3 2.3 1 2.3. External causes (accidents and suicides) 3 2.0 0 0.8 1 0.5 2 0.4 A ll other causes 0 1.3 0 0.8 0 1.0 0 0.8 *Expected numbers of d eath s based on U.S.. w hite male m o rta lity ra te s Source: p tt, H older, Olson 1980. * 66 U0W2I55203 Monsanto P lant A ccident, N itrb , West V irginia - . oeasyxcfmTpcaiophdtsioecsumnoresrtheosoitrnoefta rcoNTcChfihDltoDMrorsaota,ucnsnsdWaeirneeetsdofftoleVlCtlchooitemwregpdicainnhngyirinaoaw,ntiohctirnrekihcem1hers9alo4olwtr9rht.ohaopleihdtfeyfenvoecexlltospppeeorrdoifecnecses cbomes ekxfyeCipsnthfoaht asebsll,otupoerrlasaemiptsiciuomecntstnoe.atdubcTiyolsCCoesl iDsnfhsuDa,dml o.ni ,arstcianktocdaiinonnn edna cd,bapiissuspoceseereapprsdsirhspeieymhbsryc.eiaahrrdaai cAlilrysuactntccuaaoternesmbuesrapraioznaictnectiiydaaesirst,nedgbdadyi n,ti hswcoopaiismrot hdcrepmehdrhraosoyynnreiisnc, caoacp(nnZhflleddaOlaoacntnhnkrnrtaee-Macusedunappbtisreseicucradhaiahs,leldyt.av8omirae,ngrn1lpyogdi9t1nop.98mgets40rdes9)avTE., CcaeimmDpartpeDApmlireofreeiiaytrndraereirietcreatoidstattiet.aothtiinhnnesoveystnemoa,arlcpvetsct-myeaohsimddmceoetapssidnpit,oonahtnmcienohstrhoceceelsf,cuuaudnedpbrxdirrisnezpeiddgzloiieni:smnedatdee,itnsersayistohkreyerin dAmqenasll ieiyuexflevgsAstrsatgnoeeviprdaoesorrnflrnycmuafeouesnats(huin;n;irt(tnne-leliaydieavssvrnesoaesegdewav,crredrartceemineesrrigeddeephrfeoonenoi g;lolplnituliarafaotlvrraa,sdiwgennintrerteddre-sfriaumosul bpaouiiimemnnntarininetl,rpvotiedoma)telvahf,iyeunraetmrhds;dtatfacehorlenlneeedarsencdaqdeestxenduesciseiroertxnhnoelotnfaodaenercyyswsiuyecescepfo)daoloxp:rotliilekeenlndpsroerdsra.trwoictslaohitnbniihbnnneydeOerigxf;nodoahorelmroominepfmgw;aeybphihnteiaeyinefatrtgsdooriutucoiehpamt ;a.pl dee.r oowepelthexxbfaoesIacsirnnisbemekoesrosenvi1strnheisssi9avnyd.5tmece.3iouxt,phnfItthoanea.Ifimnotnbieaulsvgiootreuewucfsdeeoosetwufrigaaaldnncetahddmaxtoebstaedrnerreskyssommei,snxdpo-aiecbndtmoueiseimeeatrpasori.plvngnoreeoaiydnonvBtehdueaeuemassltbenbgwsasnyoceattomknisreil,iekpnslxtreonaprmocstellhoafrsvmwnre.epoaiepgrhutrliAerasyoesnislnnksaleiescgisndiafsaoo,linnor f orwdrefaeepTatrieh1otoh2er1vt csfeomuiernrbirefmtjiJaieebfacldeinltrcusadolaitoferveyfai.,ttnhhtghes1eT9waJh8nooe0adus,rrirgen0i3n2isa.n6vulo9walol,tlevsfrewesdtOoiuvftcdhtechysruet3ipa2fcnaio2etdd9hidoae-orynarddetathi--ealzscreMe8d9aofeosbdemmlsldieoceormiwvnrbbete-yaeudrlpsity aoaTnhfsssfntyipaeicehobgdsopcmtemrtanupereoae4aallrimuat.crfr6oesahsiw,.mc4pdne1aowcoEhrsenevi,rixieseettctthw1xliriieisc7sovpeviu2catedhesdn05lyciurene..tt01eoeaot9gh1t5dcpm.lh0yeda..lBa4aenesxrt3cmeapeTTfp.e0rrxrrsehrhome2e.pcrimses,riteuneeeecmddwsexFtthuedd.piiaasved.eslbeete.alceayetttdhhseTxlueedsoNphnws.foeegofcriroeddnttoehOcefelmdywraanmtn0etehhlsi.cray8neesstel8mcakriconritpdneideiirhesnrsixecganteucpaitucialteicnhtecmnlceaa)sctdatloeaeollndpfriyrdgr.fyorni(ovtaamsendt '*** ZQ dwocli(onoTefendBanargmetibsehcicldoseaotaeetrbur2etdrssmae7ueeld)enri.vottsyhtcetuoeadodpe,nymxspcttpaluahoureldeefsirygniievTnrtnCeceaDceos.nDexuhtscolNnetersoefsteofsfvewepfrepsclaoarestmstsorhmssfeomsttlohnteaoonislsdrtslea,al calstnetatiurhdm.tcdiuoysothTlrnatcihilaystsaeolnirtpatn3yyh2noleatandodlbbyertiseaeseotishasftss e s Table 27. Observed and Expected Deaths Amoung 121 Males Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident Causes Observed Expected All causes of death ... __ _____ All malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Stomach Liver All other digestive organs Respiratory system Lung All other respiratory organa Skin Genitourinary organa Lymphatic and heaiatopoietic Other sites Diseases of the nervous system and Sanaa organs Diseases of the circulatory system Arteriosclerotic heart disease, lnoluding coronary heart disease All other disease of the circulatory system Diseases of the respiratory system Diseases of the digestive system All other diseases External causes of death 32 46.41 9 9.04 0 0.30 0 2.59 0 0.50 0 0.19 0 1.91 5 3.02 5 2.95 0 0.17 1 0.15 0 1.16 3 0.99 0 0.94 0 0.36 17 25.01 13 17.74 4 7.27 1 2.79 0 2.26 2 3.19 3 3.78 Source: Ott, Holder, Olson I960. 67 Arkansas C left P alate Study Aoyaterf3leutoohe2axxfegnrwetcaBkppdrryctraiiee-eeohaceielnrrcrsneeixiiltuasamenpavapfurlnkchetssttoseeeceu.ecelsnsenrledurtrttvidiabsoiurfpvgeattlfiroecaiailnnsooiruttfdghaovndtssr eebeettoreuecrte1tlhdevswogs9tlryeeoeie4ifamnnraxusf8agnnboptgti-htndnc1ioahonepeha9sstggct7uteaiehewsoht4rrlogeeanibn.ehnootiircaefcccitbrutnoiBi1o,irzdcwcr9errseeiie24iifrtedcddiffne3,rmee4eee2.ltnaaa,c.a,54cdnausttte-eAescy,seT5dehrR,tee-ot.tifeThagoocohlfsgeeuuht,fteemvaencP,addaa2lealermndencrl, 4fwoosuhifeonmot,eftdreu5iriffitrmandu-hpsf1alTmgyeyen,iia2nnxcai,lm0gwwnapi6tn1sotaotaaiheoarlstslyhowc,ur zsareeees7rdee s dbroyifsTfesheeeroxerv,neecsrraee castiermcw, heeterierm(sNdeeeflotpseuoecnnrtdeioceTdtth, Taaanltn. daf na1yec9x7i arp9alo)c.secu rl eoNe orfgt rssoeirguxapntegisgfroiecupnapreneirnstaeglnl.yte d C j g 2Q 2) 3) 4) dbdaDh^RI nvueaeieelrtatvrroateteibnietihnrehsglrivwagscmsibia,iedinnoaltnwheendaffaandesstdndifHorwwysteoonspceomtiioopaatt hhobannri soitfltghnasMarennet1fnheefoa9edieoCif7tnicufa4ocitdpsl-auveO1ralndeem9atrtgeC7bylanesmm8.oll)aa.firionnnootlteicsrfihocmy(enasrEraanpspsrtadedrri oroac1iilunynobn9i ssielre7nedOar4mgoosr-rb1cfrslyee9pc.f coaOh7uonea8rrrnrrrs.ldieoelnxaisafvgysonensr o . t lT> CD Spcati(((wnnRRuhpr edodReeil galdeesedwddpcpensrneoaaeie1n1ntnlanhIa99ttcraanct77ineweifh99neap,sebebconrrr))ouoeoset.. mnscvDebfcipoOaoauelumbr)ferann,rottidheetlrhdwdateniSht.iohdytit phannlaiOld,ttvihrbs,fpoeeooimewnrct hstbeerkhieeetimherst((tS1edqiahnI,fueiDospnfiS,nerteiehnm)ircoggecstvaseiahatxns7ttirot8t(uu)nta((wsd9g7,i)nyoei.,n7op hpnalseienpeyfervvdceepreeiecrtoonaconlsdebneltp)mne,fiardttdo)te8enih7nlaatisdhtsphe,s d bobsmcctmHcattstihonhhineueaallaoevaocedAexauayguwnneneigtfstgistudexlc,litaiaeoytvensdctstrihltswrewntua.ida"eotery"vcTcrrtl,tiormheheeeecehtsfhsuxcleseateo;aoHtaoonfptaltrlhueytenadlpdfoftoiivddc.streoswheeel,lttuittrnaheeeahohdsfrvsrnsAqseceeiforeieghfesssonueireoietacrsr,ntewpemnnta.tftsdtlhhn,pndctsotaihaeibtor2asyotofuoueniHemioc,trodn4ydftoibelttwanndyuse,erafl5cubsaeyciac-cerddtodiptelclTnheenoowodnelluaaiecwnfime,carenysaro2slcaseveuaercris"ue,trnerea4edependrrItcgegsne,ieutoa5nedamnucietrtttno-hetseiisloTrogsoaeeefiittsurnmnodhnateeumeeudiciaifexldmndtaoabs.'titiipsneacsrcfsepoyoutalittttoonhdaTw,oetsltrenceceeanexehttehnmdwiv.parel.dr"oeyabeaniooofenmnlcffottusruonyaeTctcautlalpshdactrsc'shrlomoeycoeeueeimweaonayt.vtehpiwrsgneaolaenoeeeisfrsctortdncou`satlueouuhlheilrlmendgpatisghsvsnsisheei r z e wchineaiaPsthsthhebednteihsoeenxinycaecsNhxaecerorervicbpeeamitdcinobinednooreu,totb1sf pe9in17rae96ys6t.hit2nae,gbT1lfhia9(sea7lhrll2eme,fdooo.afrsnetd,thaels1wp9yra7ay3eysa. irnwgSsiitpnhcrcaoey2ni,sn41ig,9s5t6-e1Tn,)t mOwaeoprfs(onaus8ieeirgdcAtttn/rllca8euecnoltob7aoserim.nwolnffn.idepisefisticr.rethaehsTsr7ffeugaoniethdndMpntecrted.geatasetfstnrljhhonapococenboeBarfrieincnrtunsieoctetttnha)xforc,ngaeeowpcnengsif1uehgso6sitcereoulrntttnhieeandslavedneibtc,eBteeocnaaaSem.bpotbtlhhbreoopmemitriurahscartarnaateiplelodhlsnnd7ifoancsotp.a7r,ttrtriguhomerreeeaewrpgsaet.ftnehtheleuiraieoepxccnloencOopecmsttftneniooetecethsot,9sttheea1fcdeoepm5lcinni.uteanapctpyrrroecaclraeTlaetstuegeadtchnteensgeeltmrieaoataonhnatfinhsnecrye,15or f Humboldt County eaabpreTnidaohe,remmwCailhoaillocoihufgotciirconnamcilaleuidnoDevfeseppsaartreitgmgpahneetaninntoocnxoiyef stohHieenarabslsttihhceeisdsceOatrrhsrliepeeardancylsaoiaCumrtaeslaaino.fof rn ia puanrnedTlgihkn2eae9rnl)eyc.fyotrhwea,atstthathge ee rineinvheOasstrilgbeeaaetnnosr."san c(Rounneecudlsuud1ae9l7ly9thb)haitg,(hT"aribatletesapop2fe8ars The methods of in v e stig a tio n in O rleans included: 1) mReavtiieown ocof nHceurmnbinogldtaCl loulnitvye vbi tiar tlh sre, c of redtsa l ^ oanrd ininf ofarn t <8 T able 28. HR eerlabtiicoidneshSippraoyf inAgbnNoremaral OOruletcaonmse, oCfa lPifroegrnnaiancy and -OOK2 ! 55205 .5(1MaG>tr00l1r cOH' ru>ai a Mona. HH II mm a cp 'r^ v"4 M 2n 3 1974 fS 12 3 1975 (N 23 1976 Tl 12 3 1977 12 3 1978 1 = January, February, March, A pril 2 = May, June Ju ly , August 3 = Septem ber, O ctober, November, December = Spontaneous Abortion = C o n g en ital M alform ation E3 = F e ta l o r In fa n t Death 03 Table 29. NRuemsibdeer notsf oNformOarlleLa nivse, CB airltihfos rnaniad A19b7n4o-r7m8al Outcome o f Pregnancy Among Year B irth s SApobnotratnioenous s FDeetaathl s IDnefaatnhst MCaolfnogremnaittaiol ns P reTg noatanlcies 1978 17 2 1 3 20 1977 13 2 15 1976 14 3 12 17 1975 16 1 16 1974 18 1 19 T o tal 78 8 1 1 6 87 Source : Reed, e t a l. 1979. 69 ^D0HZI5520B De^ny,' G alifcjirrtl JLl ocHafeuAapslferttehegornSfacenotrhcnveyciceheirnnse acDwlotaehnsndnpeyurx,coptbetrhldeeesmsaenCsdaoilnrfievfgoteharsenrtdiigawinaogmDtieoeanpnbanorottfmormDecnaelnltanooryiuf.ftcyomthee 1ttt hhi1oee4Dnesoapnrnteheayr saer oe.ir sn s lso)Hlaig.vagslemifnTawgohl,flei trmhert hui inearnarieptnleognc2p, o.5uammnlwamidotl ieunofnsrenaintnoycolf ihf(vtiponecowgshp.niuli.dnl abtCeiDoahenrniiennafygs, owocagcfhueip1lea9in76: stuMdeythiondcsluodfe dth e(Rfeieedl d1 9i7n9vae)is tig a tio n d u rin g t h i s one week 1) 2) mpomDDefeieersdntsacaitobucainnlalseonsldhrieomcalnqhzaouaalwfrerodtsisutstthhti,cooeonalfimonrndcefaikaivonarleenofmywopileniefrdnetdeigfgtcrheneavecalinoteiascfwoniyuxdsu, snoDuvudnresenuiutsrenaseeyrulvaianiswpleeaoawmertiptsneaenrvnrooinbwrfosleintmh s. 3) 4) 5) 6) FpwbpDaRRRrst eephboeoieeeerpreomrvrvvomttnioniiieerhoeeeontrtrtiwwwhdasxmitnoeneysfaidrneooaotnooisspohfffamoupuretnwisaaar1rroopab9tlllenhboaolll7illecpbfs3leoTieHHoo-md1apsDfoorsres9srtooieieiosdn7pntpogiani8afai(vnnnytou.tyeaeCCtnfshnaewsaellcdinpCriia3yennowrstoeanifiougccdaam,sennntseafatuadypoant1frdneidr9bnacyDmrvmf7seyye,3oeitdiittt-nevsnw1aaatenstge9doallriyo7miss. cnmdo8art i.ensa.uesidcastaconsdftaeohormotryddfrsrnipsi,vsamestsighpso1aieoeeob9fnnno7lseostsf3ltaitrr-nvau1feeta9ooe]7ru)8s. bptf(ho7eieruIrtnscprheetveesnreewctsn)ehotmanigdowte)anfoamtinho2eo1anfndinpi1ic5asrroeedixmvgliaenvpmaaletlneeiotcsdebticaeiacsrtlrhtlrheoeaiasnftfgdt edh2ed1alsuid,rppiinn.aargnedgmbTtnihiorahsetnnuchesacc,riooderifsuseai.rfxgsteheeceF,t(2oo9alfu(inTrvdsaetobuofldenye J0>` T ab le 30. COuatlciofmoer noiaf , P1re9g73n-a1n9c7i8e s and S p ray in g.o f- P-h.e.n.oxy .H..e.rb.i.c.id e s .n e a r Denny, co = Normal Live B irth E! = In fa n t w ith B irth D efect 3= M isc a rria g e o r F e ta l Death Source: Reed, e t a l . 1979. 70- :D0H2 155207 maboo ffoiAfusittsnghhirdnuoei agsurregsimhfei niosgafeflouosl rrt1fmie3nm.uaanmpat ietboeerenxcr ,opeofnetfcth.tteheedevrTee1inhns5tiecssaipdrcaecenornhdcrceereprenslota.otqtfeeunsmHet sioiwatwsilcoeealvnslreorriwtu,ahrigecbtehee asci ncayucoi uesft helrdae cs y diseTashtheims oifcloacrru rrttheonectheaereoaef xowpneeecretemdraelcsfoeovrrdmeenadtpiowenrictheininnt 15trhaeltiev.setu dbNyoir ttfhiemst ae.l pisrfnepirsdIesrhaneisdyeevudnaeencasedertexai ngapgi ndaosam.st oeddedrri isrpnetokocftietentlnghrttaeinclaoghol elcenyarfobli defi xcsetpsinrdpoet ersaae,tmydh ieanwtitogt ahttheatehernr esdeob/ yohr wiregporimebhnaieyacntsiitindiwcngeaeglrel ofrcoaml wpohatridhLtaheocnrctcaiutoiltinnroafignetueiecotnrthniisootaaurslliustmpgiedrgaosielsbsfewloteearemdmsreesast,thuiowpannatahwsricstaheiorcevruhemoalravafierlslRcykDuanerbopnrwenrilayonlagteraeeiossnss.uiotdbdcerSeienaofamittcikseoisennsocry . ddamm2n9oodiiIcussnpubcc1metaas,9rerruc7rrnmae8iitnaaen.mdggdtaeeromOy.t. hfneiefsoUaHcwufloasilroiwrgnmruegwpiavarnroegeemarger,leemsnlnptaahyesoinneoxrcbtupieeeqtredhcsureeiiaensailnnanDicctaeyeDacvndndueaoynrdinffaliaiyattveibrtoheew.l naeeom,ma dbleeaneadptutwiaepncneraadoemtlntexlaeyd'yinm1db9iaen7etd5e il ny einxTpthehecitsesdevsetrunadnygpee.r(coneen t cainsecidoefn ccel e of ft cliopn)g efnailtlasl wabinthoirnm athliety Hst(eoHomTuewherpedceoveres1iarn9,lov79rtfehease)hltai.egtpriabroetinocginrdsoaefnsctothwbneecomlsumieddnieesdrcetahptrheoriaraatteg,cdetus"oTa tlthoheserpetrhreaweyxaspsinpognrsaou."yrecinlegtoa. r Dboerwsttoeeofxpeap"xnpetTaontrieclhcyohtariehce.dfnhdeeiuacmaaurfctnTfpritieoicepiphsnvexcnouacgepts.rsasc,eosrptnlsrihuwbOiurftaroenelsrogeebhtmeeclptie'ghsarstamohenotshownusteor.fotrihacfttthheowetheTseuroeumhrthrrhooelbeeeehynffrialbceawmonhsiiacdcpduerikiier,sttrsdahb,sceyao.tiahwcmiflrnelisrhdgepitFieadeoprrlmogeaifsocmyeuspasusitspolnshcoulpriygehaugabomrlgriwdaaotlesssanieoisntmgsftyiwvsftienovhwoneeaooeiocslsdbmrf,liteailegepcataninasooodtiurnnitlodn mwmeaeynctaeanxl; iostont xlyiinncsot.h"nicsludaereth, aatnda hi te amltahy pberobrleelma teodf pt or e gennavni rcoyh^^i CD c l aThr ief ya utthh oi srs hoefa ltthh e mraetpteorr.t su g g e st f u r th e r s tu d ie s to fr- S t. Louis, M issouri, Horse Arena woBocdrthstttihohileehelfeeglaadoevvsInarpncane,e5uereattgC7lraleisotehtAatcoioerhspsahlrtinuntesede.healootgosd,relerxuiyvomsrzsiwoTweaefficetoonussfph,hiidurdnoiaotrtirthngeye1rshedexbvhf9t.adraygpDso7gieyodxro2riiiqmactesBsrst,sihhueaeksllepie.ddece,taitronhunadrsymeaegrittrscnoeeiprl,sanesednMCesnetsaodarttoihsiniatfortosnohdec,oigstnsnehuiosirnasaeasno,lulacrtar,ltrtouedreschehiuenruasaasao(nenaCecDfsttrudsafhDivstagniee,ehCecvhrryaasat)rtienheedsisildneeairfroeloinwMacdsdzndproaefieeereipormcoisdddeanolgrtmsanptsafhoyesbno,ualtugdamhyHe.fsroiaelogineiounhaaaalrtanndndwAs.etstleidse,mthvhr,rs,riieneolaTairlxpntvdaeahnundneeeeerdydyr5snisi4aetoss.adr wdpTw3tsruhu1hahaAebse.sac8ntstteafeodocqcttl(huo)aDutnueubeodaasan3nenc3tltnidkdtmehsluleeTatotlgohvCt/iDgeaolenDastflhdsea(ewwptnhpPoaaeameadfrhlser)yvtieeTtselnrCotlirohiDaossfpueDeisssblshwpoholo1uereieiwos9l,lraebe.e7lddctai4hnnob)iTv.tnolnheehtteaaefsikttfttnhoneciegoexbocwdaointcansttthoaar. emusraTusTniCCHbntDtdPsiaooDlitwtdai(oencl1tevnrnoc9evie7oncrews5,tth.lr.aolksonolorfIwot dBDrristfneioeiuoomevlBtsctlnteheutoaueerailwaldvohllttleeaseaifenddnorlgnweethphnosteeoietheurnhexaisyecgaypllsye.oabhoipu,lctnssneuaa(oogbax1rltrne,9puimdnge7ot n7otnsaiow)lruerltemilru'etssehtiraihs,weago:levs.shhlee.toiothsaxgedetrrtieeeexTecnncrcpvhaeeeaesalea,li.ntovdnsitaepdeaelmydnnelIynddmet trohecthhstothephtaehuedemoedTm7rroCgtfi,5ieeriDrtcrvodhseDahwexl,apwnpageaoyeienxcsnrerrdeeeaaocdecmrrextcmynhiaonsetamniatllltiieyinto.i.anss ndthoeTateahtrpemppaeianuoreeptdhnleot wrseshexeqpctoouhsneeerlcadluthdftroeeodmde, xiopt"hxOoeisunurtroeceaxxntpione.rrediecionoI xctveienrredmcienomaminothpsnelsestttroeealtybees w ith 71 PON2155208cthheilidrreonffswpirliln gr e."s u (lBt eianle abent oarmljjal pregnancies o r a f f e c t Seveso, Italy MmhbtstihheameeOeadrctbearneiterseiercSsrmiaooiodancfcaeclcoinoteurmhua2ttrhfmegr,ae4eocdoAm,nn5tfunto-d.iorsTnMeintnnimgiTbSpolahauuemp)envtbir.enlomhCsiacocehatTie,droezbhesmreeI,sidciht.caiI2eaCdlcxl,Mye4haEP,ec,5SamhlAnaa-litodncrrsati(omhcIlpndehahxaidlldoecalunccrsnohtietodol,prwoeithernanoenptpnCs4rhoo0ahedilninnmukteciiiineclroehce e n t dogrtfstttstheehhholtavlometeyeTyarierwpstco.harthsahrvoelcoypperehleowHarIaplCooatofstaeoMhedtvcorrrwodeuoeoEtaeliexvcSrtfbovuAeneafieeencdssttonnrhhof,ttzeywaaaa.2fenncltt,hehnadd4tsrtihnkoeueeT,t5eeeecrrashrywnFo-euotcrgs.nrlriuelumeiltttiodnyhia,cxbnuaadTcchspundyiaeoshtllneuoonooqelgddwdfbsrurai.cioseehuocahuotfpnmitonoreclluthevtTmhrrieaeodhreh,iminneecyncigwoatcsada(theWuclthtlreexipotertolmnb,lrhpxrlyeoyaiilaitddocbbctxetoeeeocescsitcoixcuiooiioanddmpopirlmnnneeeeellbodaernifdwpcpa,1ntonsera,rr9iarneodoedsl7mglaeetrcp,9ehiesctlee)odhceedb.stleuosyllsfoeneesrtlfwddeoaltyoencriinndheg AhEdac4t(oote3,esm0oaAs5tt0deail1,modm0m0r,soom70fpnapw00otghtlio0neernepstrahpoweag5tmeorinf,aoa0)fsa(m0nctdlh0ThstystihheCeseeDmDkmi(segdDoaisTec.dmccCorheaeaeDDeflnpvDbsmoieyercmidedoatcehaplianesp1carlidpo9rcttoidoe7do7cdtriuhnos)o1uciex9nctoi7pitt(onnaAp7rnmo)rtnaerdo(ikasoTnnu(neeyKCacfngnmOtfteceeioaDddecwfur)rnsi.aooaeftsmhry1floesBl9moe,t37aKa.tss75ee6ratbedna5)ap0ril. ne.oeeangdtsroctr1cuiae9tmrmonit7nharst3get)e. d Mwmoaar5ffranu0cfoieenBctrmatghpaTtiesihpdeCrrrumedDepadseraDenr.sl amcbf,trmcpneaoeonrsot(mneaesRntitaesbstesoraoa1bugennomfrgidditfitinoins4anggTa0t,narCr01iteoD5oa1iueoDnm1r,0nsdpn9e0dpwr.7tme0cte8eusht,rr)hirseBti.dnocewyuekasideneDet3fthhadn,lo0eeocbsg0noractsoo0ndftwoirevveivyemnleeildetrgroheelta(weetyaAnesetxdodiranrnoiskotnginodnfiogyelifinnlemMaledaalfoodsraitunoneoasduhrsttfaonr1yftiighdat9ahhwtli7nerser17aeage0arbve0dsals)eseru.esolaitfnf 72 pcboauCmnrnihpesildladainnrbeedynd breoaldnfidsntneeaasrsudsuecaloantmsdmanesoxdwnpeodilnseleivndeegxlo.tpopoesdStuhoremeskeditnoeesxcclpeeaensuridisoeitnnnigccseddmacucatsohttmeer-ia ^ ^ hpainneoAvrilmblseuisavtttlehoisdger.oausztosHocrniisaegennshbi,etmeisgfrtaeialcmnTsCaDwt(ioOnGoirnacmlgdroaapntdrtteoeeinssnuciittdenuwd1dee9aesgs7d,r7de)oas.ennstedratmhneedifnfeeSedcxevttseiennsoot nthaoefr ia , 5*1 - daniadPgenaoobposleevde c oaa msl lpclahalinoseeradrcionouefs, n rteharvesohuh-slailklsmeymarspkktoinmo fsl, edsmioiooxondin, c hpl aaotniesgorens , in g . ! o1siznoo0f 0Antuoettbhhhoet"eeuwAcatoa"stac1t rzc,0eoaoi0dssfn0eeatns(ha.hte.stars)iaGI.aCyriMso.gEZvSluoaeAnnldaeafrraAtdocai trionet(hacr1yel9u7cd6aoSen)veddvederdislenaoosngwcdarniarwbeplieoanpdcdroabatxteehiitndmegtahfstedoierliuyvsttiihtmd,eed ' '! T able 31. ESenvveirsoonmAreenatal C o n cen tratio n s o f TCDD R esidues in Zone Kin2A(rAeacres) ADvege.ragohgef/nC(iRonantagine),* No. inof ZPoneeople A 0.73 (180) 230 (0 to 5477) 736 B 2.25 (556) 3 (0 to 43.8) 4699 R 12 (2954) 0.0 to 0.5 (5, sporadic) 31800 *EB(Hxasoteerdnnbto,enrgaenmrd,eaCEs.uo.,rnesmeetqeunatesln.co,efs","Tsahmue npSpleeusvbelcsisoohleAledccct(ie1dd9en7Dt9:e)c).emI tbserN1a9t7u6re, S ource: Dow Chem ical Co. 1979. dagpertpReeraerotmpexoirirnmteetahddtainntshgoa0i1l.t000tlhe1pevppbeps.lmasmoe(1f aTpreCpDabD)r.ehgeLriesatteerrerevdeRaeTlgeCgdDiDarneliesvi(d1eu9les7s8) s taTghees :in hoanb iJtua nlyts 2o6f, Jthu liys a2r8e, a anwdereAuegvuasct u2a,ted197in6. th re e iDOH2I55209 waTdecr((CurvGRhieevDZrarieiaiaelDcoogddl.nuvgeraelaaeideasatnnerTsBnaedbshihra.eihadint1savtiwhw9di noa7R1eaing8errd9tehedn)7ceaero0.6teaesmr.)0osc.cmm0iolttdao1aveeurbTnegepdsrrlheeeepmaeddmtliaeupuos.lvcanrool bepsepiarRplluneswtrelhoslaegeecibxtrgdiveeeioimpteenawnmnonltaseeaitstoedriesnaeoflliyaalfbn4ft0ioedaT2,.l915grriu0t0aguy0nadturhnhee, edoweags xbfcaawa1srtuteinee0otbnxdnmseppsotedhwipnotvebsaeyautshnrf edoi sr hptipaoAb.n TthCOoDifcrDcdZaiosnzniooesnnRoea.lial ,prZeposcrniohedxaui"rmeRa ca"c,tteeodcrnioczv4eee0ndr,t0er0dtah0tiaiospnteoszootpaanlelel.l. o lfeTsahsbe optuhotapn1u,l4a03.10 deabtrtoneexeidArsgtp1etntoi1hrsassme,sbtudr,xoirynmetire.eps.tenitoodrstpihniTMicucveshaleetelasdmftmioihecoiwxredaenala-idttamliehnmtscrhiyuamnoalraravstbpbsauieiounnoriddnolvrpilvr,teuamyelilnomlaiaclnlatlaloiengaonndo-nncriuictanemtoencocrogolfsiunmpyerdgr2tseoaet1esegldo6,fmirf,fta0yerlm0aawpc, 0btrtaew.esaosngardosaons teffaoecntxrTascyCtnuiteDepcinDseldtlreod aSneRvaeelysgosgiisdaniosi fahshatseerac.lothmHpdelaecttaeodnfcralonumdd eptsh:ueb lpisehoepdle thinev mo lovsetd thinorotuhgeh ccanhaogdwbwTatoitt"pihmyoeTltrchbaiidteoexenpchtstapbnhhroseeiuicaecsipcgorrkilvnScaitrureeiemhemmeteylertsyddewdivfttpeapofaas.enailekohpasgitttfitnehionocfipr.eeonnedNrtrandnmsdaoctaorehe,.cehSlrtltaenheeocinilitncgocsanneiittodhyiocTnpreroanteesahfrohevncu,ufrnebtepdoonoem,nprtnueonufeticoalawosrshsh,tanrgophliiaastimnoagdoasssiht,vohynnsrlneaaoeonswosnasstlwatlbts.,ciloehvhntouencttmiieehdecarnueobmonhCrisorltcseuhrifr.ethloetvuneshabniyldornseaetneotadvveaTaicrrnncdpoeeaeailhtdnednnieacrefeoddsrannralanhcorttoeItnhimaathslush,ftogaopepiapmigneivlhssbittnudmdhhneaseltnoeireevseb,aeovendehetn-neenon.et"noortfaewolrif,mn g . wHaudenhddiwcrehearsrrhseneepsd,o--freht eoesdwpl see(vcReeiifret,ighcgeatihrlalanydti o ct1hne9eor7tt8ar)eie.npxriodsdte ufoiccrt ii veaner c e di edasteal mi biunesrt aa brt eee al ys o1n9A7a9tb, tohDretoibcDtnoisrsep'xuLpte.e rRSiedenisycoseltsyuitiifpooinllaonCwdoinnHfg.eretRhneechedeeoxrnpplo2res,4sioe,5nn-:tTe d ind a ta OCJ? r~ 1) dwrpnTfeooeaawprsttreeertedcmntirsattioeyelisrdn-lnopeytmhiewagodnfhialrycsotab.ggoyoiimncff Npeoettornhhonvteeemedadsuloeuf3cred5apttsfuthueiiroonsoitlnudnfogus.fgoceciecocsrdT.unmthcrhaeeeaebtpltofdtaoiRnrgoTrltneymioZanaatothnsbinodanenw,tosirenwwmrcweheoareimlecrihetpylete `vH . 2) womdadgtAasiitinnhinpbfebaeeoadncoistonrolnausdefctrlnrreoheiceitttrgoreueiaapac(amodxhwnsssroalone)eeeRieltanrmnydsssos.tsaai,eiuicnnwwmwasvssduncboFttlaeaiiredyrufslgrotiueaehnR.lthuaapcdTrtittrhnsbcbetteeeuweAeaZhotlreelesrtariouoilrhenenv.aitlnmwlnhaeealdelotaistnyhndpTbtarbt,fhha'eeehelrtonodeweeitt(rhognmebsr2theeeieectrii4eoynnopdt.r6anpcwecuotrt5ohbtoie7setrhadhmsptaltileheeemccttteipdhnoehotaraiyecmlBscfgrimeweseiehmimdmseoaZgnotaxocphiuoitlaaohltcft)frlntlomdsoo.afifed.cvvobsr.impbneeoeetsrhmdpeToennaedeTbonthctaexernithietoaxreweaspitennoaannspgseetnensetiecrrieoennsesactseowouetcttediurissleiondeasfrnee-ns I 73 iDOM2(552 10 'O Tabi 32. C hloracne Cases (No. and per 1000 In h a b ita n ts) by P o llu tio n Zones --------- ------- - P o llu tio n Zone Zone A Zone B Seveso Zone R Meda Zone R Cesano M Zone R Desio Zone R Seveso Zone non (A,B,R) Meda Zone (A,B,R) Cesano M Zone non (A,B,R) Desio Zone non (A,B,R) Other C ities (1) Chloracne Sept .-D ee. 1976 -E arly " No. per 1000 46 63.01 0-- 1 0.13 0-- 0-- 0-- 0-- 0-- 0, -- 0-- 3 (2) Chloracne Feb. -A pr. 1977 "Late" No. p er 1000 15 20.55 9 1.90 28 3.5? 20 4.98 13 0.87 2 0.43 13 1.68 14 0.90 8 0.50 5 0.18 10 Chloracne (1)+(2) No. per 1000 61 83.56 9 1.90 29 3.65 20 4.98 13 0.87 2 0.43 13 1.68 14 0.90 8 0.50 5 0.18 13 T o tal 50 137 187 Source: B isanti, et a l. 1979. 74 1DOW2I552 II ?] T able 33. B irth D e fe c ts /B irth s by P o llu tio n Zones and Year (1976 to 1978 (I-_V_I).) ii (mYoenathr s) Zone A Zone B Zone R 3(s- cA.s,B. ,zR.)* 1(9V7I6I-X II) 0/2 0/29 0/221 1(0/1.027880%) 1977 0/4 0/66 9(2/3.3796%) 2(19./224352%8 ) 1978 . 0/-- 1/-- 5/-- 16/-- (I-VII) A2d.m2 itmtianlgforamebdir tchh ildderfeenc to ruat teo f fo66r bzoirnteh sB ashs ofuoldr bzoe neex pRec(2te.3d%()p, 01..50+?)0. 7 o r 0.8 to `Refers to zones outside of contaminated area Source: B isanti, e t a l. 1979. Alsea I wqT21bfin00ouweegTcrreeweemahnlvuiseitniscestlesyeokco,sastrahtarfrureeeo1rda3nltfihayauAtegmmegledxesebdie1spesesa3aertcwwarlamsiBotrieeitfrraonhiwiessacnwicigen.trotahdheemresparemiarnoaewsrgiaplltesiieerrcmvadseoaiyfinroirtbrnegeOcyigdapcrgouieennsegrirgerutoseema,nthddhs.tbowieswnwfrhrS.ooiioc2mutmhhf,se4Iipnnwnn,t.i5hcioin-emtitThoyeiSeaennuwlsstblrafrosyeeiaimedar,rsetosinedst.de aslsthieltvavueTreehdmneliibeimncJdigoir)ivtnt,hesscailtbuoruamfsiartioeittashinncossiann.ero.xrAifpaelgWtscheetheaiedsrna(8otrthee6nepeoiondmfratit1tshad2cei-ad1wr3sraniisaxlogicteeoysmienfapowdrarirecepldeael vtreiwetooridyatnhthine cHoationfoodmTwnphpe2eravoi,ren4oeard,fu,5mt-howiTinorsi.strchsnuaofrotrnfhiif-acopgisrteehoenoisftfinrocerfmeoivdpirdenoneaerncatcerrbeedylwiadphtCreiennooconlrttuvhedeabeeladltAiwsslee,aseneanayOsormvenesgaaitollsauncbev.alsarisrrhiwiaamegreeesn t In his analysis of the Alsea I rep o rt, Nathan Mantel ccoHaae2onaxfre,m4duipsws,ame5eedror-edesdmiTnepeetndmtneohcdsroepatatrdhenoertaddnaypba.t"yi,srttnheugvegl"'(meMigiomaateiuansssnidsittcstseeacdssslaropparrmoo1itlrashinn9eaogat7tgaaoe9tnnep,-f)pee.ooorti"snhouutshcessniiebsedeaal1eebbpnwmoooctorrshiettmssiiacooievtbannner.isp"rrlsciiuautot(byogsMulelidabsttchhneituewtheysraleevnrceaue1mba9ol7blu9eetr)d. Alsea II be1ifnoev9tAvr7ew9encetbstheos)ten.i.ngtaEsinPpTtiAurhoaeanyStiiruonefsnguspuerootnlhtffsseiohtrhnoeeafrOnbAtairhcdllyiisedssereeadost2Ifut,dh4Fsyet,e5ub-dpprTyurooa,svarsynitidhdbe2ildesr8e, perthepr1oe9liad7d9tebuimacost(niEiioosPlnAo g ic pgmiinneoicTgnsrthhseeheitraebasAblleeAelldyslBear eamiencaliacIostobcrisnaroatescrunirlldnaiuaybtsgiaeioevtdrwneeea,.eisne.ccnbriiTudbTthteehehndeethcaeearhuyebtehorsrewvobuperilecsotrsiesrdotseeouuudgfgnsghapbtbethyrslaeattoeyntditinoncsgettluhapdwraaroynitofvdmyewtehneeiartere. 75 iD0H215521; (rltaoenlTgaehiotceiuaosElnnasvttbiuorodoryntthi"m*oetenonutdisaneel teoPthrfrmeo2itnee,4ecn,tt5iiio-rfTne .thAAeglseoenaccycbubarreseginnancea arenoaf epbspiodoreenm ainoy acaaattohnorrrweeeedTnaaanhticsIesgdwoouaooAfaohhffslouaistcCOsepabahlprowoerirmogsIrivIodxtohaineiunmli:rlnnt.iahtsvsat-epteiehnalasynesrtdtris--uga1e"dnA6aslyygt0tluo0bedpaa:rynsrsoey"qtph,acu:ueaoalaararlnneel"teeddaucdm,rbttienhiaweldnceeahl"ssiudcrtdeuhoaaerrrftndaeainOal cOt,frhrle"rouegwecmdogohenoinindnctthlhcrarooaonennilad"esst ogrs1ts(eape9ifeanTlol7scvp-hn2thheaert-aeaes1ottdnic9iiso,neoe7tponobfr7niodyu,.ttrasss'msptlt h)rToaaaeenrnbhtaedifteooatosEsrenniPeritddnAei oeocdtghnnlusiaaunetcsttudhaded.erhe.aaeydwrotbesaesodpa,Tcrp'roreehtiedgeiictonetatehndiislsvneusstthenmdva eoitiemnaiacfsogoarstnrmetnaliiugeazopdsaespssaydsi.teerxoesrdacrit, hoasCysmadateoonglfe,anioermcla2lfllirno0puioovtdfeswmeewirdoipszeon:bhieadpstkoithrsiseetcfpmhroniosdtm,e 1) 2) 3) "aJmwSswswautTct(hThEpmpubraahhhtoPbhaeorlsraoeoeenAeyanarnrrrrurtteyni;eeuettihnaasPiisststonpgnhewwastt2t,oognehhdineea,ascon4odasesisiaustst,tfriIa5oineenscappalon-dad2oieeeTnnseacaewsd,rrnoo4xxcbinioratougnDa,wr1orasn5sdemon0fflorat-yaaoo0ntrlsciTaainos0osfuirrotnbdieeamulicnsuockrbtsteahhenMaevsfrinoeondeaoetireitniawdntslsftgorhldu1wcnuscoenesctbhitrirwatuhnnx)eb1ousasdieaeaea9strnyinnsqsiedt7stfrdonhheedoeui,8enegeoaaler)xadAtn.brnnifhnemtdysiattipinehta(f2toourahieiact,nidnnch4sptroolthytaceehiA,pnsu5nerwbnlrptdlea-adoeosrsthiTyatrpltosexftiewyieasctnao.livuaemalJaenideuer2gtastzaeyneandtir,retun4neeauteedodea,att.rla5h"hyoiysatrtnhm-eneueatTghedasarttiwes.reoa owohbsttfhhueefifogemTnarht2rthtethheeane,4eenlittahgiu,alrv5itemohuvee-icttbTidnhicnenAodourgcuftrirlociosrssdeeeatifhennactthneecoisnecwpetnheedtoochemoxunilucoasfpteaendsaftentsterueeoptrsi,dheeopsofnyepuon"cTosn2tthameahtr,an4staaereinee,bts5deooAaoc-ouft.argTh"utstreoiestronhirai(acnneeEatbyghPsbo'AeewltsorahitarnrAiea1sstogixy9tgoneatps7enhnrasnt9eeescrrcmeypuii)enam.aonanw.rpautecyaieuscenarulesT,raaeashtlaiwuarerloyesenrhnovdapdiencarhyeoatabf ly 76 raff(relLcaoavcNwmmoeumsramdltehee1trdhde9oau7Alsst9ui)ltcct,sthherleai(etWfimlqIaIiiutagftejrsoasta1runn9idyott7yyf9ws.)ot,tehafiegt(iWthhsAtaetlgistcnoeseaacrltiheeIeIatnntEacsiPtfTluAi.ecdpyc1ico9do7ne(m9Mmc)lmaiuonuhsltniaoeoivltgnyeisc1h9a7al d9) mcheSr1oe2iootmgfSansehtmppttorhtoiorissntnep2tatldioy5aelcnifrzscpcetoaopeaetucrnlrielcsiitoengtenednoana,tbrthnra,oeac8frr2wytsteepil,ioqipottnhusfneeoosretramarnano1tete0sl1rtuyop0i5mr0omueopnsei.msctesamcrcnaucuaitenIersernobnrcreuiintaaknstirhngtrroyeaeaitwahsbtgeenUaoedarnmsmtftioiiitooneirtssnhdcsttsheitidyoeScaeopnttnmhmapascr.rrmtoeeoeeoteashnc,oelhylre. s aa bttAoernntiutoimonbnew.r iolTlf hrfeeasqec utoiinrrecs luhindofesl:upeitnacleiz awthioetnheor r arescpeoinvtaenemoeudsical 1) 2) 3) 4) 5) 67)) cwmdcwthtwtst hhhrooolehehhweieeimacsaeneelicttttpgsiasaahhhmacltnevleeeera;rexrrsrrtaneeisnitidaogaunttttlhhghau;teaupieereesspblodsa;oinwwttrlrhroolaiootyetemffmlyasaaatywwhtnnihgoseonietemfritaeghselamoacttnhrobpsffepihgiohanscotenyrthaantrmiseizrantioeacbeelcnnicisnoifaeoiautennontt(lsLhulicynateasteimyhsbpmelaaaetoeunabvbrsc1teoloieops9nromap7rtutnniot9metodova-)cnu.psaiidnntsaahideceattleyscaiie;usst hnehtr eeste;wr ;ho acautthaocntneTcnaeahutsotcreireeudoanaAsentdertleehalsryddoeboa.losarpreobItiiTIfrotolahrensesltstcitsuuo.stddntnuyystodhA,tyegctaoritenonnmnncduusdilpmisued.tcdbhdeaeeorrredsarsdeib,aiogneotrhevntietelohyirnnneetcsshfiosodtwirsuenephnd,iiyccctehadliwolniitezoninrecoeodkset,nitpsohpltaeocrne wphtshueohaSrpsictelepeecrioonvtGanbtisldseioi,ntznfeeegatrdprtatitelecharnisepPaotprninmraososcnixsteiiicnmtmxaiporuaterstnhiertaeeileygbrnsaeecr7. ei0gfnaaigvcpTeehehdnseropcswAoetponnliisttttahaetnhaolieeftzhoIeeuIptdhshessyaostasumenbidceloyywirapotnir1smoo0teabnnlt,.eemd mi s eAdt hi' fceua rl ct hhe eof fri ceeccot ombfpelisantiugndtymfervaeesqruusrueedsn tcliyso nvctoormoicmleodanr eiinna s .tthh e e Wglhieetnne ertarhatelu r e DON213521$:II1 I dovnawCcapceFsl oonftrpxooaouoimauactrprpnpathatgtiamrsrtruouabtsiretloomlhtbseo,cosanpioe,rsslliortlmarecyc.iitinoonisoAmaaaomnngaonurotlneeaeBslsnrsouseeaoslnu(ydmag:gsbcsaftwasetepaomdouctIinethnIaatlisttireuedoehehueertsven,ssesefitcetoenenrrusoodrsfloordpefaetfffttiheyaooebsf(cahaaclt,Wfnttnhe,ladttttocaoesmvmcitdtrohneairttrmaesehesoetndeovo21tsfaaihuasrs9tla,cgl4neeeesitt7aerthod,lsmil9i5aeeareae.st)e-tatpr.vsbeTnymeat,serotdoaArae.tnrebromsmctteapwahtfitoeosTcoritnihdacosccgihsneiynehoettcrsheoeof,aat,i)hdeneclgsr,leeceasi2oeocnogstiftn,nwin4reeeacatoteniw,slrqo5udoowttta(-uh-hsfsil2eeTeenoaerc,-ncme4naattoihhcidrigr,ndo5syeeeseoteua-rnhmnTcsethcsi)rce,,.p CS(NJouondartnymroaaall rreearaaarne age 15 p e11rc914e...430n t)pppeeerrr(Wccceeeannngtttner e t a l . HcphahilsonulaotrolmnAhasiewlaglaottgaenbtiesevestberpiedtereoriiencs,tscnpoapttaadr,irlnnoooltisbsditsfihsdcplatueoetedrodcmiernoadtcedAi,ttlioadaastilnintl,,tsoehee.adnoeacpt euurasettsIisrooItteftisaiffcce.qubsssuutculouctlerdhsaAastsyitrrstoueiloaoydnncafnyoaieharuilnnsexfpelogddosrtpeebrulxoantiilhccatnttteia,fnladyottacihecrtlokharyoniee2itslntpli,gse4soeircet,fn5otstttih-eeiifioTnsernsneattthponenoaaptshntrrudeeoday. '*" IN I I I I II I AcocaattohnoaflweAcssnneeotisdhnaaslteldw,aflellnie(hugtwsstgiixetccoeuehhprnddeootoaoywfoplw)pcllauyopsnhlyam,e,yanboetspdeaitpaioolxscrleweeCn.aptdnelseod.slryroFsiuveniirunnmaAiirnnvclstllgiiheaosimlsspeelavatrpprhea,l(irdeecctoiasropeuaisinrmtnsusciitmsamocruootmtiaeemhsflrse)emrtpeta(thsxmdWslioeootounhdrintdesautnttevyssoheao1s,tsna9t.rmdqpt7t a,u9aanCtt)eroihd.istnonweittcircanovueosi,nonnanlmedalhtlderraiolssy,l |jIi| ocs"tfaauIlradnhrriyemac,rgobinetnihgscse"iidwdeErehaPriAict2neh,g4.h,ha5sat-hvTTeechiitds"(eEacdPttohAane"yspd1irr9soaa7tdmte9utnearcit)telib.dcyu""tferoioncmcctoruetrhartehsedee Aasilnpst eraamayniiIsnI-g !| |i ii i ceaaTcadastpIttihhnnhnmnvpoeabhidrdeegaeHofrroeoonkfarrr,nruorueeeievtdtttnwarhgacriwatatdoogheeenwhtwlaiuevonuenoesostaadeguoseitftstusrooghrsuea,tihnsap2tvnspntcoawaroot,,epih4etcalratnhalhee,aptbcstetry5uhenesnopoeo-cuxyrernen(lrToeeWmirsopetattsmdoeienarriboamwaisesesriegnnntpewssecoranegesosrnaesslaenmaenaoxtnosraycddohaafrinasbynenmneillofdyloahcsttisiyosoeitttonsphhogoavihuiesnineenaeanspllemtd.mcetan:ihArpftelsttltehheaaieion.1nterlczreaelts9orfgtieaaescea7etzesnateWodrttb.9eihesnbfta)oohdeegy:tsiternanabnTrritetgnaeiasashaopepcracmltiettrhxhanahtkosrroreeeteotgsndrieeaaoryfpetbrdoasad.nrfeaunuaemulcaa(tntien1motttlrevdaohaedo0Osicbdetnou0erscietmnscmaeshurpbtts,rtlerlihuoyyetoJrersiueeudra.,frdtcnnnopsihedyeepceacdsna,ecra,ku,.t)ysr 77 opfi2(gaaH anify, M etcalf, Nobbs, and Worsley (1981). odohassrri anievrcteoameilceInsgalaneNurplsetserbiiiswart1ottheioria9nreneeaZf8ltsasct1heheNpr,aseodilelopecaoHufrrnsoiafrtaosdnmibrhnndddaeloigatstfl(wnhnyn1Hltadw9teehahnd6ea,olenyen0ninriadNe2fagy8aste2tonawhuea,mo4weselres,Z1etrie5edda9ee-dp7cakelaT7osetalloam2r.lt lnw,hifs,eoa4epdisealdd,,.1rtrf5gaae.eo9-uyblnr8TemciRu1tnosait)aagfmga.tyteerpeipeoxsa,papnnctIrlhndeoiflsiunecod,rdtabtrehwisitrindniaeprioigsctattehnehlcocuhnsmsiddttifuhinimoitesnhcdefcfogeyetanh,crteht s dmNa iloaeDlrtdituobhrsnliianrhsngt.ohdrstthhlIyeotocswascptufauitsrtdeayerilnsst;bpiNemir4erwt3iaho6ted,Zdo,eafant3lhadt7hna,7de5t5s11ew0h oewbhslaalepdbrioeitedvassielastrgiw.ln9leo9brseoeprdbenorm,crnea2nl6itfn4oorf The s ite of each spray job and the q u an tity and date oWmcNoc1thoh9fuoome5iotntr9eshptteaqhehainncnnlt,uaohyvanaatindhrnsr21oted9a,in4c6tirtynm5oe,i5nppre-dowternThesefreteia.sarocea2eldhpfn,4Aci2ptrh,stas,l5h4spoit-icentr,sTv5aeoareey-nhtTiaaaowpaa.pelnsfrepraesrilwaoiaTiroeec.flheddpoeresstnrhpeyisneoorseiadfbeaye1erntaisa92rtnicaa6,ngh4b1t0ei,9lsv5de7y,to-e2eTocvfakraotraool,sfrmeppina1itlrhandavt9icoy7aaoe6serirnneiaogcwyiunhw.ieensariertsh mowbar1ti hnan9faeaed7Tttbrtei7wetiiohoregtohvsenasrt aoossat keugshbl eeaapsorennwetiransnbsaergtaoitrtuneoebs,rdncerf"yictahadwbayttlehhgecellpnaceteroownconubnseudelpitaepr11arantotr..tdheaaJlida1at nimwgF.souSroeaoaaerrlunAeaprfypndoetsedacrmmcnesa1hh9op9rbao60rteitwi0osrieoppnefdnxa1aen9pstidrhnd7"ocoi2eeasueThn3stdca1.a,taondbmdActtloaeoImiunnl3ngoic123fupniit4,esddh4eA,rteee,su5nnmd,1g-cc9feuTaee6aifsl6rnetfsdcottr,s in o $>N T able 34 bb1In9ei7tcrwt2ihdeeseannncdi se13J1draaunAetiuuoatgosruysrfteo1g91r 69io07th7neaantlhdcoedmre3e1pmoowApneeuurrgleaumts9itoa6ln11f49.o6r6mb iawrttaihossn.1s.5,0T0Th0eo;tcahblaentnwgumeeebnienr1otoSf teabpltiermthbser T otal number 19169066 to 19179277 to drI anentcicioe C o(n9f0idepnecrec ebnot)unds Upper Lower AACASHTI spanylllolilelepnilnfopaahbtcsteeieepsbrlpadaitihrpdhftaiicladymmlsae, aaflletff oopprri mmsaplaaaattdtiioeoi nan sss* 14111486891885 161215134082067 05113111........5613964792370623 122172231........0239021757880939 00002112........6250462642768990 "Excludes s tillb ir th s , neonatal death, or d islo cated and d islo catab le hip. Source: Hanify e t a t., 1981. 78  DOKZI552 f5daws22ppe..e44rpInrane.e.s5y5aiitp-t-rnyhslgeoTTatt.otbarseeneodcdbtRohesenhatghodpagiwecooantrniseonnsiosistsnisnottv,sfeFpathlrrrhiyeaegaiyagutesaahrespvs, saeenoorrloadi4cfogw,iadea",t.acaesaraldonnl Tadsnwsbrhueeiaiinyrtlhtittehnehearceexrmixmpsdyp.oeeaeosdnluasficourraeserrtmeeor-taosafttoptieoranys Table II LiHoiyti to putative teratogem lot Individual ailloiMtiona. Us11vastloti All blftb aelfotaetiom** Test t f 1.00 T M* r* II .in 101 III .01 ? 04 T f* 11 ISS .0000444 411 4SI .01 Aca tosiBrosrinhneoalwarfyontirorinneagnTbreeenatsbcwseiieepoehnn3a5lwyi,n,adts*hsivepu risidnee du a wabtlaosi e f ixnidnopavo',isIeduscerteilngetaafi nftt eidal bimfpulaerlwtfhaoiesrthmsr oaotcthriieo n s . Anomcopbaly plea bifid A III 100 .10 III 111 .0000 MA f a1 1 .017 111 ISI .000011 I .00 ISI 111 .11 a 0 01 .0 111 1S4 .10 A i 101 .SI 110 111 .It M A ii 1 .0? ISI 1S1 .41 T a uii y .VS 00 .11 II ISI .11 111 U S .11 A 0 00 .SI lV 111 .11 M A SI 01 .0 IIS ISI .11 cift U p T IV .0 141 IS .11 a 10 III .00 SV SIS .00 A It 11 .SI >41 111 .000 M A 1 01 .IS 141 ISI .1 Isolated cleft V 00 0 .1 1TI 141 .0! plate a 1T0 10 .11 000 440 .044 A 110 SI .1 10 11 .11 M A 00 II .11 111 III .010 All beert f If 01 .04 IIS ISI .00411 malforoatloma a 00 100 .00 40V SIS .T4 A IIS 11 .10 40V 01 .4 M A 10 01 .10 1 l7 .00000 bypospedlee, T 10 00 .01 101 14 .00011 eplepedles a 111 IIS .40 04 11 . A 111 III .11 414 401 .40 M A 100 1 01T M l III .00004 Talipes T SI 1 .IS 101 111 .01 a 1 Its .11 4SI 11 .01 A 10 01 .1 401 110 .00! M A SI 1 .11 111 1ST .454 Ybe spectod veloe f T II espssvra valves re sealgood randomly to malformed babies, tbet 1, 11 tbere Is me correlation betvoea malforaatlee rata and ompooure. bait* of T and re kilograms P*r * 19* ko* par rear. tbe probability of a Mfber valve al T II tbe exposera velvet are aaalgned randomly to t M mal forced bablaa. **t*clvdee otillblrtbe, aaaaatal daatb, and dlaloeatad and dlaloeatabla bip. oureei tonify at ol., 1011. CO 'IoN s> Figure 4 E.po.ix* (Kt/kmhyin) eSaDKioalsonpsrrfowaicerrusoailan,1rttuyorscradi:yeiibnedab:seustp;eaaetlrrnroriasKHi,somwnyaiantatiawenenynridairngeodfkmiyccfaaloswfet(uhree1brdaodor9,t,iimewe5rast9sKaantphen1:loadD9t.ino,7mkiads2dhoare11ihglgcW9tt9efhoahao8,6yrvh1r5omaaait.)ulhnnvh,lagedgeeythawr,ipaorKvhoegnR1aaiitesc;9raehdhi7woeoda6.esunaau.nidsnrsreeP,in,nAhhuogafitoairgr=nselsehsdya1poase.in0tate0oards.lf Tauwerttgstfhooexr,rihribegeocetctaaahbuatnehnWp.eloplpicef,authubairttceaWrtofflimneeaaiorcrxgarthtnorlheneeaevftrdndsoiseefnog.odaritmeofsfrarmptmesfehrarcoiaoeaeicloclmtolaCtatirfiiNsaortionseietttroghysnim,loraeoatandrhtmfl(tieelpaioaasonsrftonnplaaoinvfpgdsotosriuernfnrolrmroti(saonefaapfitmimambiltocotiltiapaepnehowtinnuhenenhtlcesef3,saieodcm5tWhiwwro,oa0wafaaln0hale2sshm0abte,nh)4neco1gogeq,au0es5aaiult7tnrs-chale,Te0uhulliettn0laaahahtcit0lrloesethfoi)teaas,sdon0taat.phssgans.is2enweltuydd5waAahm.leenerde WTpTNrsifneoprehhhowscrDrueepadinsdriyudo,Zseecitnciefnhneftouasghdfeclisreeaebesnradril,neendearadgnaMustaMtfutteahottlhohamwortroeseoreiarssstfrilheeaisfnecolatmcanorrtfehmidicnlodnciaocspaeodnnltrtnmueiiorodncseainbdenemgl-idanMeisosoetr,nniadagftotohsttinhrectNafiiagsoesasetwl,rnliowrapiawabtufZeehcinttreiceesahetaahai.ollnyawncarenznstotadhdelsaryosnlrynseCfozoewholtaeaerithudgdtoiicpch2foahsre,tns4hiTerims,aaapa5lanbtaal-moslTrre.twoiahlntyee3ged5ly. . D0l#2 155rfSwedish O ccupational Epidem iologic S tudies Axelson and Sundell (1974); Axelson e t a l. (1979) r1sat9ui5Idln7ry-o11a9o9d77f24mwA(ooAxrrkxeteleasrllossiontynexanpandaondsdeSdSutunutndmodeolehrllelr,reibnp1icco9ii7rddt4eee)nds. ceodnu riainngreSttwrhoeedsipspheecritoivde occcvaat2tfrono9ooocfai3dFiuhtnntadia3orottzospc4tlrrurohn8oiiertbbel;amr)uunxswggpbodaprrtteiiiooiannootnnnhuunc-posaggpdpyoultteehsmerioewxc11aebnocp,,rri72iossmtootn84ohcfsna5b7acouttiwheotrhirnoexppienooabonpeersrrt>ubsborriktio4sssitsseci5oownatuerniinnnssrrndigdedv--tgehwcyyaa>cy2oeete4oieos,aanro95oxefrrns7nssptfiso8de.2soi>8aaatsssi4yapttuttnia5psmerngbeooergidsltbbr>toisooarsss4ooyonfeeh5nosfl-rreysvv1tdhda52eaa(n2:c0ae3attd7iiyorr-oospsannnocphemtn;;aotrereoseiirtnrbnosaabsonounwopiindcsh-tstbiihlsiettsn,dihnai2engreo,rgd4xsa y- wwdcacccanlit noanooouaceeicdtmTmmnailtredhclmetshbu>bhbnusoieeod5diiputlsrrnneaeaaeeetaadnntropyoteteddcttfeieipdhdhooioralneanneidcthrounososfseomdrew,blmaoraocasitotmihbtnrtsenoitrhenehdrisehnvnseotiohnaepcdgaartvrtdecnanuereitoiportsocrrdhcSvuie.nelttneaeihxipwersnnvgpi.p,reeoocsepFrodudegeehltosihysaH,e3suer. ehgc.0nrnroohaeeeo.wexdaa,stxrseectvoopayiuvhwsyeseif-tednh.,rscriyacoet3t, eghAe0otrrhdeTxpthxheawdoipeoendeaaorlrisisyagletttsoaohoecstaeuhdntctt-trehheaepost oonesaa1uelmnna9trtnosddaceam5etonxtom7idniScsp-pfhmt1oieshaeurot9eoeixsrcrnrn7newotlt-de2coostsleehdxiafptrdlheynwecale>eodneacmn3drnsiecmof eiotcsn dwkDeitrtl>hnoanixaa4esoieTpstlsw5ataawhopsmvnrefsiaaedioutbnyceoaeisirindeyxefterassttpneihapdt"otcerwniedm(smrtsdacruameissosilirdonuoserlrinnor,isjtmseuiostfotsodobtfriphgneeafutoeenaxctt"thnidgptotohiodmbahononegysirasacnneeenunegadwyt,drrnhsaewsaotowtiitsrionhlndsdtaroheeaauatoriahbbeykaowbaalelsedynesot.rriossbsttuehowatitoscTohrctoseoavihfcemrdpnpeelurkeedrborereyohsanirirctsfvststetueefppilirodddedowrbrwyaaeerafieeyycwsrnceiiipeatenndhoxteotthggeemnprpeohsooupdekasestslrenxSiouairenadfpebwtrhlsfiesxoieoeoec.og.sandnnrnoiucside)osritvehendl yest mf icoAarstnastlhiodtwyifnfienirnetnhTceaebcleboeht3ow6retethnexeprtheoesewdoabs tsoenorvpehsdet naoat xinsydt iaecxcaipdlelscyteadnsdig n i 80 cfthoouemnbdoitnhfaoetrrio nhthsee.r bai cmI ni di tecr soo lnatnardnadsct ,oc omsmbi gbi ninnaitafitoiiconans ns t c codohhioforftre.tr eanncde sfowr ere Tabla It Observed and aspactad number of total dgatbsi deaths dus to tumors (WHO chap. II) and lunf cancar fUMo A 50) during 1957*11 among herbicida sprayers with a total aspoaura 15 days. Espaciad number basad on Swedish average age and eea-epeeiflc death t a t a a . _____________ Eapoaurs Total PhamoNy acids and comb. Amitrol and comb. Other hacblcidaa and comb. Causa o( daath All eauaae Tumors lunf cancar All causas Tumor a lunf cancar All causas Tumora Lung canear All causas Tumora Lung cancar Obs. paca. >rs 7.979 1,747 1.215 291 vra Cap. 29.54 4.91 9.91 11.41 1.97 9.51 9.U 1.99 9.1) 1.14 9.29 9.04 Obs. 19 4 I 19 2 9 Jl ji 1 Latent period* 1 vra Obs. paca. yca t*p. Oba. Oba. para. 7 1,949 15.25 14 1,342 1.47 4 0.4) 2 1.129 9.23 2.2) 9.19 4 1 779 9)9 4 11 9 541 1.47 0.15 !> 209 1. 74 9.12 9.01 154 i* 5 vra bf. 11.59 2.91 9.59 4.99 1.41 4.29 4.12 MI 4.29 1 Oh 9.74 0.04 Obs 14 4 2 7 2 i i ,p<0.0) *p<0.6l ourcat Am s Isoa and tundell, 1974. O s> I I I occinoofcTmmifhdbboeeiiunnnaraacutteoitiohofnoninstsrhs. emthnieeogithgectdhobht etohcreaat xsteepsxtlhapeioinnseenddtohnbit-osys icpgthohneehinfooaircxdtaydntioatticoaeidnmxsaciletasrnosedxl ptuaomnsduorre|' wce4s1tx6o.iu6Aptndhwoxtyfsroeoouolrnasrrkloeessen.trhowpsoaraaAswnsremdticrtohoeeoSrxmelfuapmnpdtotoadihasrrveeyeeeleddslirthowatroaiaflissnntkohoeaxn4loe5pcfyoofosodunsiaus1rdry.r.u6emascgtoeewTctrodoehammesdpabahcatituyencasmnhsmelocdeoaxdutrloyhllaie(ntaacrecmcba1diis.idd5cietesif-rdnoycoecaroelen.andmrtsiren)on l !j>! dcdesiTthstrnhoixopeaiehcmvcrdpfmeaeIosliinoetcundubhwdsideegiebsfateoniddidhyi'amrnabwk1ttgheOtie9ttiahonohmds7scen9t1detoocpos9oufinohr7aurcbrtuoeit8lrpceanhcmn.cfrudlgouomoibraxtsb1lrhetoyaeyTieo9trornhte7hterhgeoapro8etdafsc.etfhehtapriienasdobnteeohsnybfsIrrannrei,sbtloahomesy4idcreac5fetsvuhsetiaiidelxsdts1iorthdaswepa9ilmnepyos5i(eeap.lAsrse7lyeoelr-elx1diwpgrfne9scTarrfoligo7oesosihttro2cohunepntnp,it-tothoayweahrreixoelemtetebhap,tftrrhueiSearbetsogtAawc3riicsoa4setolxeeea8uni-.ldenddmp,ailseaesasplpyhnonxsnt1elodzndouper9emsfsof7doaowsestt9bhnenaertae)ddoxs.srt al. who is-seoto-f 1 ' , DOH2I552I7 etixvpeeccteadlenmdoarrtayleitayr wanedreagtheens t rsaumt am. arized o ver the re sp e c echwyxaeeapAslracobrcutssieuca.l)narildcet-iyueoheslnaa.adtsre dbbl(aeIantesferneondtmchreyeoanthcephetaeherreidtloii/medwtiermhfiecawshtchuotedonsfoyrmm,f wioertatrhsiesmet etihnselaacxtnlpteuoondo4scek5uydredsepainyvteosreitrohoadefl wp1e9hTr5eih7toeh-d6e1sraw, mihotepnrleoltchawcetuaesrrhre.aedlrsbodicuiardnineaglyezxthepdeoswfuirierths ttoroefksivpepe-lcyatce eato,r ptih.eeeri.o,tidm, e omaaawlpanpgceoitFptriaedhdseooinoxsnsrrcnae.ecstydsxyteteps-.Tsapwftooniuesvimmutreheiaroooenxrdcdrptor,teeeaoemxacll1pttibaeh8taeiytdsnmceoetdeidob1ftrd2csrooeeecmxxrclu4v9pacreoretosudesers(mdsuTs pt.roauemhirbmneslontIoonowrtrhxt3aayecast7lhami)eatnst.yoiecotsditrtdeaoiDinsdwfllif,seeaatsrrhrnapeecemedgphneafiposepartluuderhfenbleisynddnguagosrboxaacmuystohpohesnogr t s , Tb)e 37 Observed end anticipated mortality among 341 herbicide-exposed railroad workers with respect to preparation and combination of preparation. No requifoments on induction-latency period. Population Doath causa Parson years obeervation Total cohort A (A+F) Total mortality 5541 Tumors Stomach Lunqs Amitrol (A) Total mortality 1945 Tumors Stomach Lunqs Phenoxy |P) Total sortality 22*5 Tumors Stomach Lunqs Amitrol 4 phenoxy fAP| Total mortality 17]l Tumors Stomach Lunqs p < 0.05 Sourest Axel son at at., It79. Anticipated 45.02 11.15 1.34 2.19 13.77 3.34 0.37 0.C2 23.03 5. 2 o.*s l.OS 12.22 2.99 0.32 0.52 Observed 45 1 3 1 y* 5 0 2 20 * 2 0 it j 1 1 quotient 0.9 1.5 2.2 1.4 0.5 1.5 0 3.2 0.9 1.1 3.1 0 1.5 2.4 3.1 1.9 I noWunhceend theex cleastse nocfy tupme roiro dm ovarBta' lfictoynsaipdpeereadre, da, me sopree cpiraolly mgpit hnhrioeexunet hpdoaexmyee ixxstucapr eobcoeiclsdduoesgrhderoo(rugTtthpraoewbuwlipeetahxs ap3msle8oc)iwwx.t eeeeddrlTl evthhxaeaasplnutooiesneutsax,r etlphweemtchotioepldehar tem.anmloiitoxtryyor tlaialnacintiyddt hs e in Tmwoantt hhnobhaooeTess ecserhtexromvleavepnraoleaweelilsdytrcitiydwtt ehenpaiadtxaoesymcrttrhees5aeowoeosnl. 4asgnsfote4i-rigmyptta)vhh,neereyoiralisslwfriryoetisfhacinsfnilaissftlindeomnt dyieertnaxixt. nlhgpepilgnoxoowsdiscsneeiueiasvdcssr eresi dexeqt hauoptauoesofraeelslsyeshittundiieomncer(nr1xaboe4aptfrihabcot seemcsiledeeradodens eu1srstsmi9at.ano6fblc2attieeeatHgrysrlaohotiwohatnf1uwmee9smvre6toeedn2org.,r I, j codaappareaeHemmxhuacriaaogoepTirtoowrrdhnaexannohtlesorgogliieisdv-ecnexgureeesysuetartrrxrhhdseesu,lpoos.aaaitounhhsaasctrtheesegps,aoisdeernpgirdgseusetedehxcxeannslopeiappnrttcineeilornoofeeoogddeisstrtrncaleesetoomdeoaddtwat hognnfiaineoadsitsntchbttruaahebaeiartrneiitxeiftlonhnacctitchnegeehractenueecusetsmdaowoissttrnhseembmroiencmestiirobhdnccrtsiheiyiymfgtndaecoiethanehsohhtrattoesepiirlrwogobtscetahndehirrsoanlsaiuli1rninmoysdewt9rtyanixte5rnuitagssp7atemghtrafg-lsodo1amfwortmeu9ioatronihc6pdumattneohm1tacigpebdhwit.tdoempttrehonpb.rtohriuteyzexeIelamnoee.nrldimT-oiiootthxrohydseyree- r ! t iI1[ . Table ) Observed and anticipated mortality la different subcoh o r n of herbicide-esposad railroad workers with requlreumnt for tan year Induction latency period. Population Deatk causa Pareen yoare sheer* vitlta MKOhett Amitrol total nortalitr ! > . Tumors teamen Lungs lu kcotw n phenosy Total nertallty ! . Tumors toneeh Lungs lubeohoit Amitrol phenosy Total mortality 92.S Twra Stomach IW Ifl p<.9.SSi y < M I | p<t.S2S. Source Asa Ison ot at. lilt. Anticipated .t I .H .IS . II 11.SI 1 .1 4 l.ll t.4l .a s l.a is S . is Obaarwod 4 ) ' 1 IT 4 ! IS 1 1 q u o t a out a.s t .s 2 .4 1 .4 1 . f.l 9 1 .1 J.9 S .4 2.9 81 ' D O M 2 1 5 5 2 1 8H a rd e ll (1977) ToopScwp1huwfr9ahieI7tltiehnntiitr7dunheto)iyenxrms.1-ehyt9tthasmw7leTara7iaoengwch,lgpdenieidpsuHi-satohesflnaapownttrmsi1aredeemie0lreanvne-sell2edhttlisn0rsgfeuoyonrnssewcyc,ratpphaereneiyyasosarttnmee.atrrrmdsstlayefleedwbdssmwitueeeuxonfrraomoncielnrwherokgeydaeremrasrrandetssawhdwe,ilaenehrgm5fitoueo5npfpmrswueoolworrosemioyirreowseesfrddaeoaes(rmexdIk1Ht nvope9maaedo7tlrniasse0tdae.lIt-weedn1pldo9almN,7atfto6itgioein8.rln7elisat s ooTphs nnwhei sAeeortntiolheopilnrexsayy.steatihervwameenTcanwisstdsroeosnpwtcfoauattetmatitrhegeloenvirvsrsatemesprngwiaoorietkoeufireepnoesrnos,r dtrtioasittmaehnn. gdedeens oorsi nednsumeeubdtrashaiitneniangninnoutgnttpihhsapemeple raoes1tkmxli9eeep5ragn;0ol,stsl ssumpaar nenieonddkl vtion1ttihhgs9er,6e0es . wmptcaatfyhrascrooeeepHriunmdcsteltaoediss.nrwnttidrnhoatjtoieheuevngtnlhdedoeslgS.ltnvmicntwehfdeaosyeaedHuetidles,vsioidg.lsfawiahutnalhtettraevhienrtnnoeheaatrcnell,ttaaymirortohieignpetsfosetaeenuwpntrldhsidcoaohyehaesidynvigpmbsitermeeeaeradxseabclpsgeauootouretmwusa,sufsmeeettiideapboonnohtlrhdeefsfonoeaoxrftfttthhorxpoeeycttomhhhdsergaeiruasamcterwherifnideeitcenuctarmdoceotaluixanolnmpsprcgehaoolsseugtrsynsurpoeiroxeeeny, s 82 H a r d e ll and San d stro m (1979) dwowoCmFp2sst1hateh9ffoaeeauray7aeIuurrlcdndnee9etretrsohyeo)eamsxepceaps1er.iyaxso9doaaiadco7rcfmsntteh9bTailfi.tnueemiceshrtcdnwnDHeoifotadeeoeCttlatfeadsssdscrsstaarehwt-.stdutwwemwhaeteeidodnhs;rseoaliydeDiltrsrthscedcarkueahaaccseicennndechehsroaeggedhedleltanioehgeo,ssasscrdasetusSitfiooohreodtosancepnn.ltfirrnotedornhc,adiomdgeoslflsmrenaitfainorfogcxohs2oomtmea,frrolmyhoilsanleeat2efl(pylhrsga1rHaioieecgehprtmahpwsacnalaridoNola(tedvbcnii2nrreai5ee6tdnaeftnletinsuoflirgdooeaytttmtruosai.rnlenmseenaaraaogddnee8rlodxscC0ttrh)icSpRsa1sorehyoo9s3a,eenoo1sen7efgdteasrr-a0dtrideendc,-or-ssntd1tseotstliirra9suutrnsoyod7peasinsmtocn7mfrlutadooi.,fidecuelrl eenr st*j^i'a* nwqLdeasslnsteemsttnoeuhoaaalsocLvwtieoesttrneiksipiu-eiwravengtinhosntisicarghocnoneg.basealdgndnmysunwehunsedeTmaccn.ioaenesrfoaaaridayitkxwtrssavoieveeTplalesrbissi,oehrnnyyweesrwyya,aaiuhfnnnotfetreiyheodeddceaftrlheeshrrteesceepcctphnmoaa.oiosehnebnlftrnnposrcseralttoynoleorElflrrueeyoecy,onoadssmesrscallepesseeshisilevnadsonnwet.dqawtenttehdnqxiuderaadmatpurevenogneaoesindintesstlhtoeicouiwtl'osenimnsporsone,ehmiipnsecwnntlpnisdoateoaiaroooasrxtyieyhxelorftehleynpcreyaaooahsunnnowarfelspdocctmciauvcokfisicmdnieeoiinucnnsxdstontpahuapdqritlaovepcrofsuutowsxoip,tsiesdeeoulplrestedurrnortmeeaiisaoesbluelsny,nr.ete, d TcpthohheFeninirtfsrtottyoylus-l-dss.tyiwxroepppopoeprraucttleeiadentnitoetsnxopf. aontshdTuerhe2ip0r8ttayot-cioeponnhneettsnroopxalasyntdiewanc9ei.trd2ses wpinoeecrrrlecuceddhneeltdocoreofain-sethde. wboaeifnoevcboeQdriatrdnakuluisu9esne7karteseetrdtepexipiexopetspb.fornocoesnweucrsauanRreieu2rrtreeee0spoeswlofjtieuoefsrrdeesethgcc5neeo0hjfturdrlooddsptmogtrmseuoerodpsdeefroyohmmenuerppsainnlnlciooocndicylyensdiueervvitrrrvaoissiadniiltndveuitnoeu;saadaalwnsdv.tlhdaemwiitrnasdIionfiilrywgtflkhscfreeoipiorrcsueahsnnpuetndgphrlowarrtaoxodpseyuvuttrop,einldp.oetd cptihosAlpsosuurolesaphtohiswoaernnnc.ooilmns FawTsoraaasbtflhect eoasr3lce9ue, exlaxpthtpoeeosduserrdeaeslattoot5i.v7poehheefnnorooirsxxkyytheaafocceiirddnssstoiroafennt-dlys/ot,urdy 5D0H21552 19 afthoser 6rt.6heolas(etTiavebexlepor i4sse1kd). wtoasch5l.3o ro(pThaebnleo ls4 0o)n. ly Twheas r ec alalctiuvlea terdis k Table 39 cEhxlpoorsouprehentoolsphiennotxhyeacteottica l amc ida tse raianld /o r Exp. Non-exp. T otal CC aosnet r o l 113998 21283073 . 22505862 RxP2<el0=a.t0i20v41e. 6r. is k : 5.7 (95% confidence in te r v a l 2 .9 -1 1 .3 ). Source: H ardell and Sandstrom, 1979 Table 40 ___________ PEc hxalptoioersonuptrseh eantonodlps chaoernneotrxeoyxlasccluewtdiiectdh_a_ec_xi_dp_so__s_ou_nr_el_y_._to_ Exp. Non-exp. T otal CC aosnet r o l 121473 12823703 22044176 xRP2<el0=a.t0i10v71e. 4.r is k : 5.3 (2 .4 -1 1 .5 ). Source: H ardell and Sandstrom, 1979. Table 41 ___________ Eaa nXr edpWcerxoocinUlturdot oelds _c_eh_xl_op_ro_o_s_pe_dh_e_tn_o_o_l_ps_h_oe__nn_ol_yx_._y_a_cP_e_at_it_ci_e_na__ct _si d s Exp. Non-exp. Total CCaosnetro l 1376 12823703 12934330 PRR< 0- .060.16 .. Source: R ardell and Sandstrom, 1979. H oeeeTs xxurihtppHbuhoaossaess,treaecrdddontehpmclehitelbnoyesinda,nnocsiavduxhitmyigildooSgpnuaraeuicnasnoridtldeaisfstdtstierecbodsootomhurt hdailndcn.ti ohobxttlthhoeeideenr ocspac,ti nhouh cmsiaenerntmedcoalaelusbsrledcyl diiwanttlehghrreoiepss2rkepae,3ulp,sae7raomex,r8poa-conltTihgiskoCeeednmDlsyDi,tco.a l I 83 Eriksson e t a l. (1979) j DOMZI 55220 poSctfoohwrfeerIencvmsdooetiihomn1cfeu9tap-7sl(lt9etElihymssrru.Eiseekbnuresistekstoasansnnsooacsrnreteichmstoeemiraitlnnaalmasr. ,tloh.issnet1tud9dStfe7hyiws9voc)eesb.rdieybisseohTeHdxuhaptsirhsoatdeaseretcrnledealmspsaetooond-rsdcett ovswScsanrtarataiinsrbootdeeuilsndsstrtsoetomnufdd y ed mddmmbdrf2eo5eeieeaaesecZrasttdinaeccnetdhnhhan1edeeseci9tnnhemhddo7cdy7f7ipsem51if.lnocto9ahywray7rleDs'eeet8yieedpta,tieruhesrrocmmcasuermwporstaotww,snreaooeostrttiodcceffrthhooacecdsufsfoldiseehosenvexstainthedwcs,trtehtaioreonyaosi.rlncgleesselolse..oaugcFtrfdhhwsoit(eecDored5bpasreeeatelachmnlynferyooaeaetasnsflrsalrseeec.yorodobssmentii)hntrDcsf,weeidd.aorqaeseimtvneheruaeendsEitidhdrtlaieiuwpctrvdhhmerlaeiaeemlrnaccscetglooeeaaiwggrsnadehoaenlhtsnsaosfaovdowneortasf cacdcterseenuhooetlgcpLclnneopa.eidiptnrvarlrihoedosditmnopeiiSliondgvnhepngseeinedsctcn.tcaeupaaoidtssiraaluneTeesllvsbsshwy.waitiohsaathautennoasedwdsnwoasaetcvcascaicnosoocoodfuinnnnodupttdlecnrralddaoouotw.tiilwlreorssraeleenrecdeQwanaptnlteheudobrodeyoeefnsntctheatvitciohneoiuwreminipontnananaitrreateaimedixliroslrtveplenqpnyioho,uetenr,fweenecdssoxkostepmxcipinnonoyoototnnans'koascunsdinectfruaeegcsiciddarteeswshdebaeyorboebriyrts , beyerntiexxoeuopAppaarnoroorsddsrssedotuuremipfrritdeeeireoossimoww.ncblrcaaoeesulrrsItskponssiiannofatognfautiohordgmarntihmunnoatamtlathoaifotoreneigroonxerrmnsdpidwcioaaottusaohgynuslentrueeaahonerslessdemttirooas,bpbeilwxcbsfloiooipiyesdouorreheeecgsrsuihsddaatrtrenoeiyssdufsfrr,.noelptimghefoeoaosLrsrrssaomtdeiigwecntrh-diewigda.vcthrneraoauedlleueftuiavrea l bccEyaoxTsnpe2hotse2rsou.7asrlnetsudp.dteoy2rc19ppehnocetpnouoonlxfatyrtitoohalnecs .idtines cTslothurdicrecatdyhsel-oes3ri2og9apnhhditnedon5f.oi9vlstihdpewue raaccsleas r,sneetps1o1o0dfrtieetdhde. mtoeAspeshnecshhnoyowmxynalainctuimdTsaobrosler ocf4h2lt,oh ertoh peshorefent loapltsairvwtesas rfoiaslakllocwuoiflnagtme daelxiagpsnoasu5nr.t1e . 84 Wwthahesen6r ei.8nl adti(ivTviaedbulerailss4k3)exf.opor Isneedxap toosseucprehalroatortoe pphha eennnaoolxylyss iswa cetirodes e c xal alcorl uni fdeye d , T able 42 wExitphoisnuret r itpo l epht seno(xtye sat ccidasse oar ndchtlwo roo pchoenntroolsls) Cot ora secp hhwel oniortohxpy he xae pcn oiodslssu r e pNhoe.n2ooxfycaocnitdr3o lso r wI cihthlo reoxpphoesnuore5ls to Yes 0 4 21 No 0 9 76 R95e%lactiovnefidreisnkce =in5t.1e r vxa^l(l)= =2 .52-01.10 .4 Source: Eriksson et a l., 1979. Table 43 ___________ wcEoxe nrpeot rsoeuxlrsec l uwt doheednp haet hnndoo xs eym aeatxccphidoinssgedinwtaosteceshltilmocraionspaehtseedannodls Exposed M30orde a yt hs a n o30r dleasyss Unexpos' Test cases 7 7 85 C o n tro ls 2 3 206 Relative risk 8.5 5.7 (1.0) oF95bo%rtaecinxospnofirsdeeedlna ctcioevmeipnartreiesdrkv ato=l u=6n.82ex;.6p-xo1s2e7(d.l3) in=d 1iv6i.d2u. a ls , one Sour'pe: E riksson e t a l ., 1979. DOH Z 1 5 5 2 2 1 mepcbaNrRrinnxheyhioeesdaeeplclkadnmrpoaooietlsotpsiioxqiufcrlvkvwyouyoraeeeplarc-cagt,heprrcaterloaiidxiloessddcnpisrkkceuucsiotnslmi,hlsoceaafulbrioxoogttrdepiepearfrroredovsoonsep1ostposouhd.t6)hoafriebewpetnheewarhroenexneteralodpenplzrssaooh,otox4e1strdiheeneyr..iv29dagpooxenxaoaxcycwnlcir(unaptrTiieecddishsaarsdeiesecbknnsosilgdoewcofrxooasalinyv4dftrlthdchi4e(boMuaoi3n)necsc.lu.Ct3naedoisPtdzt,iAnevosAec,(tdxioTrrndepbo2fnaauusoef,tbll4aposcasryl-meaea.rlesDdnucii4ssh,sntei5,tiavogo)t.eohiftohlf-yne . mcanocoamEitldepirdsgioknusmtanshndaoyastntwmceothehmtsiecephanrcrlih.cissayeknmcoaawcnlorcaitlsnsuutkmdnaeioondftras PctlhiCotmoDaf DrtittseheidneaxnpdostohonsePulfyCtredDpetFovtasoe.rlttohpspoh.mseeneoTnxphtyheyeonfoxy T able 44 ___________ mmE2 ,xea4pct,coo5hps-iurTnorgpe anwatondadscthdehelliiocmhrpohliopnernhapoteerxnodyop_l_sa_wc_wih_d_easn_s__Mee_xxC_cp_Pl_oAu_s,d_u_e2r_de,_4_-a_tDon__d, Exposed Cases 7 C o n tro ls 4 9R5%e lactoivnefidreisnkce =in4t.e2r;v axl2 (l) 1*.3 -51.93 .4 Source: Eriksson e t a l., 1979. Unexposed 85 206 Table 45 weExhxcepnlousdiunerded ivatonidducmhallaostrcoehpxinhpgoesnewodalss toeinlipmhceainnsoeaxsteydanadc idcso nwtreorels Exposed Cases 11 C o n tro ls 8 R95%elactoivnefidreisnkce =in3t.e3r;v ax2l == 61..83 -8 .1 Source: Eriksson et a l., 1979. Unexposed 85 206 ! acmwvtraaalhHfyooennsogaoemaasddserIrnrtsrunipectsutpodhhhereLrliueeeoaoeouxt1etlmdscsaspl9fnlhselt,8loanhaodaf2s0seemocs5gb,Efu,rwaetr,erureatasaHsnhiswaknejBlo1ttmoasdsc.est9eorobwhseeax8donaa8s,0eemvFpmh5ncer)leaehe1o.,o-loagwc9nlertsdbeg7acaamois4dhnneCdtniiheddcbeem(bcatndyacarasii5neoshLhellteeedasfitliieemtaosssyssnydecuts1rienpondhtac9belauncolyfot7srrdoodolcycet8lsuayleagara.)(edndcsa1sri,aeeoccoe9ogdoueaT8Scasfnunpw0si,fcwltnd)lemmoureydddtsop(daoapceeiHlaillvccsorsleaitaeahgeo,fisitndocihrpannvtdedsnubr.ofareeeeieeoaanrrdlgotctlmlltlweys.eIif,odneceaeelydxsnerwoEameenopartnerdhssmporlirtikedhetrsd/ahoopsueelemsrrlrinosegiaocntnsoert,aon t <p 4 ,ddesrnitenohxiiavgvcopIiialnpriorduserhftsddei-oseuotdeenrernmddoseruximsanywap.itnspiaoesalsenxAilctmomhmpniwdeooeaisendsln-axauegterpetrnroedaixoandftpslaatbteuyooosly.rssihetuinaihstrogelEo.eiilgnsfxneh.lppgeFwa-ohgsotasorslusraenmrdseecotoheshbsatlittoonnaathnrotinoeaodnornpeenrvdghleoiowaeewndnnbeweayeoi-cykgslmm.raosewoadoxrneieElpltrvhreoxeeqpspwnnuuoeotaerssasetustsrtewei,dosanas crtuermgiItnaoerrrdoidinoneinga gawennxaoasplsyoiusss.suiesrde, s.Ina l eal as tsseencthoc ynand pafeinrviaoeldyyswei saa,sr s ni nopcrlsiuoudcr ehdt ol abtyae d is ncy aap3thnnh6ddTee.1hnie1r3op03l95scsetoru.ccchrdoreoaeymdnnstpptnpraorooorenenplpdds-uHo.ilntraoogttdeiOodgc9fnko.6ietnnhxct'eppsoroeonclrslsyscuaimessrewptneehstedot,romoeof6apd0f. htehehc5enS0aeo4daixxcsymteHoydneo-a.nttdcw,rgiodokO1lsi5sfn9c.'oasthcsreedascsiscehewsalaosisertheos ,- 'j wcpcslltyoihhiahmmgAelleocncnnpsirouhhtiosxofstllhohpamiycoetrhfaewoaoaesdpnnscnr thaitoudeitsfldnoodsssnyortooawaTclssplltiaaeohasob-newtieplesxe6efeudp,f.rl04eegoa:a6r.cswtoieut,loiuxlrtnephTrtchespoluewleteaidwaxramtsenrpsaioedaseoond.llssnyas.4iusvzt.rih8ieewTvdihipeeeftt(dohoTcrrraioewhpbseuhlilikgaexetlhdhtnpi4oo-ovgdxb7fsereyui)afm.rdfeeraeaeiscslrtNtiikaeodgeobnxsnlptaioonsrsht uerde ! \ 1 cehxAplomorsoounpgrhe ethngoaovslee aneadxpr epohlsaeedntiovxteoy acr ihcslikodrsoo,pfhhe9ign.3ho}-lg rotahrdeea r eccohlamlotibrvoinepahterioinsnokl o f }; 85 itJUH2155222 c(aTlacbulela t4e8d). fo r low -grade ch lo ro p h en o l exposure was 2.5 _T_a_b__le___4_6__ wExitphoisnuret r itpo l epht seno(xcyasea caidnds otwrochc olonrtorpohlse)n o ls Cotoraspcehshelonworioxthpyheaexcnpiodolsssure Nphoe.n2ooxfycdocnitdrso lso rw1cihthlo reoxpphoesnuore0ls to Yes 2 10 49 No 1 16 91 xR952e%(lla)ctoiv-nef i5dr3ei.sn3kc. e 6 in .0 te . r v a l 3 .7 -9 .7 . Source: H ardell, Eriksson, and Lenner, 1980. II T able 47 ___________ cwEoxenpreot rsoeuxlrsec luatodfet dephr aennthodoxysthe a e ec xmi dpasotsceihndi n gct oa ws ecashs lodarniosdspohlevneodls ________ E x p o s e d ________ 90 days <90 days Unexposed CCaosnetsro ls 104 2301 130083 Relative risk 7.0 4.3 (1.0) Fx4952,o%8r( l )ecwxoapnsof i3sode5ebd.n3t aca. iesn eodp.p o s e d in te rv a l to = unexposed, 2 .9 -8 .1 . re la tiv e risk = S ource: H a rd e ll, E rik sso n , and L enner, 1980.________ 86 Table 48 ___________ wEc oxenpreotrsoeuxlrsecluatdofetdechr alonthrdoopstheheeenxmoplasotscehIndingctoawsepashs endanoisdxsyo lavceidd s Exposed Unexposed Low-grade High-grade Total CCaosnetsro ls 27873 1149 259 2398 xR9i n55%et(lela)rctviovanelf i drei snkc e (1.0) - - 62..15 1.2-5 .0 399..73 344..16 4.6-18 .5 2.8 Source : H ardell, Eriksson, and Lenner, 1980. b(TeRnazbeellenaeti4,v9et)r.ircihs lkosrofeotrh yelxepnoes,uroesr stoty roetnhee r woerrgeaanlisco soinlvcreenatsse, d daHciofWidfdehgserk,neinnct'chhseelodrcciosoaepusaheldsseenwboealensrd,ee s dont aoirvbniol-diHrseghodaedndgii nk c itfnoos'osr tlwvelyxoempnpgothsrsoo.umurepas, t ownoipthahepnpoaxryent dmpcealyhxaicomoeBpriddncxpoeaoihsisssnnxoeuomydopregcfraaoeoe. annsctnoectieadTnttsmihohstioseer.ingysrneiaiassmnnnkroiticseugtefsnhodasutcoc,rllbetltovaeshao,rredsiwnmatitehnrismvnede,eucrncast,thouhulemgtltohohggudroaeitocertaspvstgeehstehdlucenoeopnipcntpomhmcrleleaseeu,sfntcdsfhteeiocaodoconrnifntsptcmhobhmeyeafaivnltfoioarxgbnyleant Table 49 demrE(expixavg)pptaoicosorshsiduriuonirrnneghegigwitnowhat-shogoenrdragIidssasei=nmoilcltuvoolewtsadco-nghlevarlooanedudrnoestpsthahenoxeindspneoocIslIseuaxsre=ep(Cso)heseaxigdwnihdset-treogecdroae.pndxhteecrnColuosladxostyeelvgdaeo,afnrtcyeditdriss Exposed_______________________________________ _ Cases Une6x0posed 10I II O t3h0er bSt ret yni1,0zr ee n n e e , tIo50+t aIIl Pt o2, 3taCl C ontrols . 222 33 40 8 81 7 RRieslkativ e (1.0) 1.1 2.8 4.6 2.3 12.2 (1) 0.1 13.7 11.1 13.0 42.5 i9n5t%ervcoanl fidence - 0.5-2.4 1.6-4.8 1.9-11.4 1.5-3.6 5.7-25.8 Source: H ardell, Eriksson, and Lenner, 1980. Summary qomdbeceHAanppshttohonxtefesoureroluaeotTdpetpmrenwwnhdshmev,bchoestoueeoxeeiieisitrciveudsfceinhcunoriaoeegsneipsefebrialrcdnmheitnsrs,linrteesgsrlcl,cucaidiyecctzeteoirtkoheedismeeeorr,nnneedoxeeethesmhglopaisapoclt-roynihueehsrrarofasargeteeestlsittlainnsdeclutls2(olaoeaorettnsnOri,nyuxtee4pbattntoteytuypmibtde,,titt5rdsaandeoaoioem-tenasdsaefsiuiTitsned,socstltthcipsobrinctoadhaeioaafetttacedhucnshlmenoncnuliolmedmdtftte.tpyplli,adaooilvaaynTcccUlorriglteedCofhyosip1i.igfosDnSecil9scmirenognsdctonsfoD8.auraorphtcnm0las,eonuduwiat;pallinhdptpyodnpftre;ohcaaheiradcdZricrcornoeenedebpaiakitanasbspsnficcriioebvegslfkdncleohrpileeeeios.btelteemunyarevs,efnfelosdttisrtisaaownuenoetnogS.trtulhvdaeliftwiesidoaeoaetnai.nleiyyentnnTmblc.ovediv,sdastlhoseieeeoW.srtsuitndhehesfaphs1ssshepus,ep.o9,rhisAviwoppdi8lneoeiaitorep0ohpdmntrla)oeroeed.trkordhygntreyeceres 00H2155223 87 H istory AGENT ORANGE I5S224 ac2j2uso..n44Tndg..th55aelieis--fnsoedTTldoie..affn4oVO.Otl2sinit1aeehwtnenpgtreao,armuehlw:ln,eodrencsblolioocnkfifsdnio2Aesw,tg4snfe-oDnobrtmef aOcuneardlquaansute4gaioe.l4on1pfsthapiwertotohssurinceu2dhtss,i4ecwo-ae0filrnleyantuhdseed AAggeenntt PBulurep:le : Agent W hite: Agent Pink: Agent Green: 83 .. 16 0 .54 8.16 8.16 lllae5ll2bbbbbs:,4/3//1tyggen2,::54d2ara-,4-bsllTmm,cu5pniatiin-ylic-xxTcsbolttlo;u6uudoe:rrtyr4eenbysalt-umliecbmtry2ui2a,lxt4oyc.t0-u2iflDd0r,4ea2, nl,,5b4dn--,-52Tbi,s-u4Toit-nbyOulxaty in l goaAAupmlur2f9ieno0ssfr,egnu9iedpeaTrrsege6ddpitiohsnuhmns2naeiertsoeAsftorleteonO.chNl,(ngtdBhesreere-ah1anelrrnetawnt9btserttifchhgob,6firkicoeOeeba5ntimhccif,ctiairdwaicraatldencAaitfnahderhosAsglgorneeemelecemouaslta.nuiegAdsspstgeecaAairspgmdthnOTatilelueiod.syihnrvgesnFisaetuned,1naoslsesiOeg9.bflktweSel7,r(ref2uaSoo4afTnau1,uauc)t9epceg.h9srtit6hceryceeel6w2anoos,t5s2V)nurcufa,e,me1snyt.im4soeea9fttshi-ednto,7sa(nDdrsB1trsiaouobanii,lmunocnaairfftngcnhodonaockgdhVarasrlrmoarcdeiopos2eeFta6aslwumetnc,i,ten42ngoradcbma3id,odhfeer5mc7puuutets-epb.enntafTrmpaalriotrucaeocsyellaiwednFcer.,irstacrtntiseooisstei11frtomioneeon99onend7r7tnds4f1), ov faRryceo.pnocrTtesanbtorlefa tit5oh0ne suocmof nmvcaaerrniizoterusastiroehnseeraobrficchTidCOeoDsn atihnnde ATrgeCepDnOot .rOterdangraenge 88 T able 50. OCroanncgeentarnadtioPnu,rpplpem8, of TCOD in Samples of Herbicides SSoaumrcpeleos f ONuramnbgeer of SPamurppleles RaTn(CpgpDemD)of CoMnecaen(npptTrmCaD)tiDo,n JInohvnensttoonry,Isl1a9n7d2^D 200 (4) 0.05-47 1.91 JIonhvnesnttoonry,Ins1l9a7n4d NInCvBeCn, tGoruyl,fp1o9r7t2d NInCvBeCn, tGoruyl,fp1o9r7t5 10 42 238 0.07-5.3 0.05-13.3 0.02-15 1.68 1.77 jif~>-*i 2.11 * AE grclhiniveAdFBSample Ie 45 EIngvleinntAoFrBy, 1972 2 - 0.04 The Weighted Mean Concentration of TCDD in Orange * 1.98 ppm aWADraonwrtaioglCryhistheeesSsm,tiafcoWtaerlriUUTgC.hnDStDi.-vAPepa.re,tsrtifeMtoyrrsi,mdolneaDndadAybFtMyoBn,iI,cOnhOthieghioraipn;o;.raenAtidvereTohsAepancBaerelyhRmtiecsLaelaarbcSoherraLvtoaicrbyeo,s , ''StounrpIluslsanHderfboicr idsetorOargaengeinwAasprsihlip1p9e7d2. from South Vietnam to Johns cFour of 200 samples may have been Herbicide Purple. `'Ts1ih9p6e9pNi taosvear1lv9eC7d7o.nasstraucstitoonragBeatstaitleionfoCr eSnuterpr lu(NsCHBCe)rbGicuidlfepoOrtr,anMgeisfsroism evBHapetrriaboyince,idqueFilpoPmruierdpnalte,-own1a9Ts62ee-s1xt9tAe6n4re.saivCel-y52u, seEdgliinn Athier FevoarcleuaBtiaosne oRfesaeerrial Source; Young, e t a l . 1978. uun l Hw(0ieTt.r0hhb2eicinwpidpdemeiiv)gOihdctreuoadnanglcmeelenosatpntrsraactyicooeonndncsteainnoitnfriSanTotgiCuoDtnhDh igVf(oYhiereotrunanagl(m1l 5ewTtCpaDpasmDi *)1. i.9no189r 7pl8op)wm. ,er gs1pr9o6rHav5eyeretbhdfirocooirudnegesh2tOs.9.1ra9mn7g0ie.lliwoNansinasepctyrraeyspeedorcf oeninntl3ao.n5fd mAfgioellrnietosnOtsraanacngredes wmfaarsnom dTwGcast imioihorhxsOneiosinseltfueea,pnnmiat,etnhmctriehenocoPodeeafniun1nttneaTka0rttdeC7ip,,nmDopeDam4ifrandn1oididnaxlpVaiililnsminPleiosgerueanect2rmtnsefep,ao4tnplilmiynue,omt5.aur, -o4atnTe0pt4dfed4Tesdwptrhhcmioeeanee3srsfice6nl8Veahtlt oilnte^ioatcettrprnatotboinotlbuniaepcfnmusrhoidtdtt.useiehehtnrudeobdetafsriecbetedoiwTsirdctCieieiHaADmrdeDlgeelaa.eyrst2pnbe,ptid4NclO,iii5dcnr-eaaeTsnt y.g e , atomtIoafulnotnesxeopcfoosmTuCrpDeaD,retsshpeVreiaefodtnlalpomewritnoagcSreaenvoeafsloya,sriesIat aclaayns , baefommreaatdsoue.trae l o f VSeievtensaom (h(ig3h58anlbd omned3ianm ielxlipoonsuarec)res=) 1=.3 0g.0m5/agcmre/acre wueitnhxsaeeEpsVveoeSecixnefetetpvndhoteahssemooeirnudbgwpihcbtohoioopdttuhehmalneairasgtepiorhoerrtnaadi sysheaisrnvo.aeof vtfhbeaexemrepianhaogibsngeuiihxtlrupietdao,ynesdei dmtinmowtreoetodhuieTDalCndiDcoDeaoxxpinnptpchoeeafasnrnurotrrmeptahetitaaoohrtpneelaes AE gffeenct tsOrange and th e P re se n t C om plaints ab o u t I t s A lleg ed OdVhVbpwathrtheweeoaaeariiretWlpepsatcaawmaetenretlntddi,saietgriematheinehmdtncdhtr.asiuhnoei,liianeAsrmlwieltecIItgaliphanVnocaronreeeesntrtn.nenAeeg1hlctssa,9rar.aleasOteanav7nrtineRr8,ssiaorioedaaz,uttenncnPeliaultoogaxtftathtwioeegtnuffpooorooortlnrasunecaefrihlgenzryRts.ahdhwseAhemeedsteiauoghdsiHisiruteseweloreslnacrdlec,nvavtsoVxosileihnyvnhAOpinraengdceoacemrmtfocraeiselaovirneunhrrlrnenrVgtiafvrlmihdgaoceenci.drnAruaasmacnVthrtba'.hoceeoeeloinrdAdlVehfuoaetwetotnduehtAxttaaestgmhheapstemgpdhehsaoreiiadstnesntmnvaapuaueitinshsrelorffatsUeOftoisrleeshopPaasrlrrhtaofiIetidaoiiabcnaornionvangnbetlrnghesnAeeesitwce..cgiosetlfsedoirerfnnoeTHttmkoe I0 0 LLD puprobAlgement f Ou rrtahngeer . sc re e n in g c l i n i c s to in v e s tig a te th is Agent Orange--Future Plana menxoinpRteoeosswunerlahyeracthct,oooinfntthineathunedye ,,eefbrfoefulesitiacdwntusti.aloll f ea tlfhsfoee c ubtsese hinoavtfeeAnrsgeiefsniuteldtOerdatongfredoemwteirl-l I S . 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MaHy o1w5e,ve1r9, 79. meharBsteanpgeuennvaeatdgsIirciriniitneaionvhfltsnageeieJtemnuddonrEhleey,roonPv,iltAtnidosiec'au1irswnecst9bhghos7sweoofa9tontfcr,ahddrinaeSttesthhtsa,ciceeeeailid'sslleiudBhnowhPgteanhtAaaatiieazrtfrhdipia,nccnorudgawtocbhAnsuneletiem-dsosa.f,vhuueitniensshaspddetnuotsehmdr.ny"oniiadstontfhsePdeeh2taivin,emn4uniead,toesll5eeet.nh-nnsr-Tecctceoor"oooAtfrmopnofmt2ftoruie,es4iasnrcsne,tdu5heese-eedx,iTm .a opsunlas'TpcMeehane.rdcehcdo1nu4s,soels1id9oa8t0fe,d2 ,4Ah,e5lao-rTninggcoscmoomunretntchbeeda tistnul espWeinsadsheeidxnpgaetnocdnte,dnDotn.oC- . ta k e mep2rr.oi4ennOc.gi5nitso-iJhrouTennfaoe.aroinndd2g4sf,roea1rlan9d7tTe4CdDi DtthsceoreomsEtphipodAeuurnecdspas nrowbcceeiectlhelaeduditsnhegethsoenf ienicinteisftsoisaraimtnreyaadtbiaoianlngiatalygyinat ittsocht a l CmmaTridnCeooedDtenenrODnfitmineiettnrorivoJfeegryunnasisnciill,dtygeaouitrnhTe2tpionCe5srDgt-eh2DaE.ifen6dPeA,dirnOaserefr1ofnoest9ithrasp7ilmesa,4aet,lrhdopwteatifpahctnttheupaeaerrnrlloaAayabnDargtllgniyeeicdceonmtoa.cixcybnlinaocimoAhlef Irestemnamdltdh.aapeowttladraheaesmoaDfsdeoaunoinroalltomtxladgyitenoiyestohtf,ienosPrdttlmhoaaPnexnfilandsoniceniirnno g log gto y ActFpciIorrgoFeineRnOstntAeuincnmAyr uiAtpgaheftpaoeiioruprninneerlsdenltaagd2ntR1tiiinhds,negtaggr1ptai9ousn7uttbthoBttrlcesa,iocat mithhcohauheenev.tereebaE(irRPcoitAnhPirdAge eRsics)ohshmpruaoaapedgynodairceeitxannuctssnoReutiexteeyd2.ibce,ud4t ot,e2t5caf, -4fbreTee,lr5eb.tc-autTisPtnT.r euthhsresueieUms nkmpdaeyr EPA R eg u lato ry H isto ry Summary Tmht rCaaoDsnnTDibth,tseeoetrhnoEinePfgAaAthocsgetofeounrhtcmrhyseeyerhbhoafiocsneirerdob. erfietc.egWinduielthba, etiepionnrncimareotaafrsoiidtlnhydges f owhrereigtrhbiutilscathitdiecoeonrne2taag,m4nid,si5n-aTnt MWncbtsIhuIereaeaisnrtspqrcItihnehceuciphnaiincsF1sneogkmi4eactrool,btleyns.ntrlh1,uloaa9faonADht8rriddry0a.oltCtez,,hhnrra.coet1rohudphf9mgeoTsu7ehrh9aidncbe,ricgitaaanhrste.nthgeieircodsesstenaAuloihBrllneanbalPtosAvpytinuetoohgotisrnhseneftsecsouhhrtotheeosaeudecbscfarseertiemei2aennnbn,nteg4hlattys,sieit5mwtfato-lirfrmiTepceiitnnphle,egdaeciasoiscdslaslmc.ityetweeimidxeniObuepnlgmAennletgiciletanfisytrmneieog,cadmet in.inc y aspthniaodesnOtonuInOrrnFetreasedmn,bertreufnoat(toruarysel eCst2tausp8n,r,rcofe.h1hlo9imub7Ee9site,xesgedmtahorpedpfteeEnn2frPds,oA4,imn,5gais-qtTsiouululaesotctdniocbmaarpinewigehoEweftmdessrehe,roegdafaenpriiwtcpncyalghyi)Sc, abuwatsipnoiketnhnss >00M2155230 . \T i 21 CONCLUSION kocast aneovf iolnaneAwsticsapllamteteehbdtcihdoglnioereeaouwsnusab.otgac,ornhckuudTdsnmsahidomenuaoxaurlbfiailsneyittbesr,sedbliifsoeioesofgrncorehnffanoitophncstthheeei ynetpse,sooeutsowsffbsftihjueb2reiedcclc, e4hptitse.,r5esur -essTeqifnonugrrtier esatthhes aees retchbplheoar dect ycst e o nnnut ml yb er of cappopps..n.rclarua.ae.inptitIyeetieitheetcnr.hddehbsitesuaimdwafttshnoiahcsenntibacieeemhdersveeoxinepsrmhreroeeartoorcacvhctsutroeaeitecrsnnldheoeptcpssaflustapurserodsgaspneweilpaooedveaisnqnsorepu.i,tsneteotthdaetoeepttrhhdtpseoeorrmeeabovlnc2.jpeidoe,ecr4ucwitrI,atr5nestte-edofahTenefodrcoe.srodsfeemhc,daItmirhvfeteheeetnpnoeattwrs2sieepfi,isn4tihaehc,pap5nsvmaet-teaproaTatneottyhariadcsdavccoseiokstmh e r oEaagcpltehndabeofvdavnlfsssTeeeteiicdtcrlrhisvdsaiteooepoatrnexsblsoeheheiltnevposiifegsf.auenheehplltdscaafeivdTfartseweaboloneacsexdocahetaikapafsclnvhcp.ftihoeceeaetyweseaitopHa,rllheebftloededelttwedhgearernnebaiavnai2etmetsetf,orh4onat,aghue,fll5eeasnael-enndcrsTecet.itacsesarebeotqitaneaTpelrubirghfoasclTafeohrlihenClstreyysDhcaideouDmtssnati.tomheunbanofsaprnbiortloondseytmrghostoatfairswt2fnuhct,thhe4eoatihes,crff5eshcaNi-esitcoTnh-ncteooheism i awweattsfftithhouhvufigloireeteflerscrmueeleaniclsrccsjdlleenoaatat,ussminhbaaplsvsldtet.eritfeeinouwnuvnremdUrrhlneeeAealtui.ayduascSslcnhsltrcsu.eayinwhuargvlonmas,etbehesdagmtrisihnwchgatihdecachahhiicvoctnrooetauscheeusrlsocstbisrtlteedoeehtn-ivoceaboenltyediiwsorrfnddoufbtmouheeoefafruseeovanibcdlcdsypiirtlavlioebtaelvhemmat2arsldoyesfni,eade4smltaknyhdawn,tirua5onye.uhnae-o.hpleeuTpnatidtraegcde.lblsrayhDrd,timbfowceeeoodsoiT2recrdrehft,am4hedoceeue,mofx,ts5omepsita-noc2tcneaT3oocoay,nn4crnfpsase,ccsagefte5auaooeir.g-nfstmmmerTrosefieerpdocOfmnrlefuu,tituscchtlhpboiltefoesrtrth woobphseaffeoenqrslubttIilhhfate.iieecnloiltcdnhEheeeuPesAp,saeAua,rsnpisdneioenmgo,rt fsimob,tnhn2uaiesytl,thy4trec,rfa5eouftm-odirrTvrreaee,tcihnntihesCttheiaooeAcEunaPpmrAdirtnweeinfmrocoiicafclirainclmpn.tchh-aaecealtlosivWlonaeEsnhPtiuinAafomtvapendorrivn-eleervgshcreeeieaddnptacheturheesiibndnilngoiigncusint,ccafoaosttmovhneoisr eaaitIfnonnanfcdfrteomsHichcocnuaoiaumntcpwsnytlanauncutaocseemeiafrdvdvsbedaeiiednbrsiroedeya, wxnct rbtcithhnebeiaeslr,etietosnhaogirtksnr.acdp2hnbste,h4oeRefwet,ierwe5nscs-o.keteTensttahhno,rweeecexthrnhxdp.eephaorsaotsaAntuswhdurneoar,raevelmmehsiysaaasvrtiiioenesnnpionobeetthgefafeefsteneosltooedcnneltygscbxehegteoetfaeanmfftrtiiismevillicelnveeadeldos. r meengtcashuaqopfraeuferrupneesmHsaialeevcitgoaeettoewlossdhrmlceyoeavepdclealneiaslrialkrtyoent,,rehxnnstliaulitooiacnhnehtltcudtafoikbrlfltnoeeaeefgdrvors2colceuf,tmy4osofllrs.e,fnto5wvtsmo-waiiihTdnddIaieeSttscvhnracheeeenccav,irdsdesoneeustcnhodastiesomehegiriodareapnxoedoeaiodfnifrirlnssoatshspbVbtrtihreelbiioyeex,retlvhettpfnheehfhtoahesteismogeedcutrhhrb,rteeeeseaeifc.wdrseiowetvchdaxtreteohebsirruaseas.llntnediiesnytnhhTbhthceeolehaeoutainhsesanldexoethprf o im pTohretanf cine aol f c 2o ,n4s,i5d-eTr.a tioFnormadudlraetesdsedas isan thhaetrboicfi.dthee wehciocnhomd iidc 94 oCPCDBVWMds5aPBaBoBBBTaSPB1NBBBnVrtnn09cafularalrooiotuurajua.aaaocd1e6aoaaYrelilvtvsgEnssCctcswditeni,gtm6fsrtteeeelnrkfhkfc.eneukdaAia.tenyay,roloammibcerm,ov1eSsmsl,,rm,,nmnrsurlss9o,ifa1apegensnrainssHT4HUEnRtR,n9t,,oetdo,iiiowh5dBoh,,7.rcean..ay.ec..WWPnWia,Rfee8,rtimVir.noGGArHtn,ra.rJab.DLDho..o.NDNob,set,,.rC.i.gemead,PeEp.lEecneti..i.r.rondcpRhYpCREitts,o..lbedadeA,iBta,aeh.aaloe..t3dhilesnarnBP,rty,rimpcsu,tcteoeWsydEeohppcmlmniAyaeasrEkP,dxetxo.eghr1rpoceisecna.,yp,enr,nall9enrsosnCnnoaoi,os.ss.ekr7enemtSCtBAxeev,,htrsils8SAnlySY,oi,ee(.sopi.o..enUAgtoUpcmomr,,LCnt.afrfcaKWaH.ASfseilro.oetTPetSomhDI..,i.Fc.ieTessnpA.dnu,hs,aAvR.pooiadro--tCeZR2eripe-agbelohn.caATPfals,en)eholbdreieanDaER,iro,seciertfsohlcsrAss.sSsl.eiixfmsi.nAyptptefpId,b,ftPai,eniAErsB-rerliicoecencaosdccaeba79ocotsnnrdtqy1nanuyiesaTP:i1rtt,lzigddr91cgtsyta.Worlh:leloAiiii73e9litatJues.gconrd-.oai6Vo1soCd9at,sg,opiiot.nei.ehncH1S-dfj,iidenr-onru2ssnNMda8l.ydicetman,t,1ivco.H1l8niieatocpeo1WuPaPf25dtnyReInlNSSne.,lxnb,:lrlunrcai1ticSeaoocctittbalusfeunns8Aegeor1a1nodutioirsyi2dJktuo9n9uctculebg,aosot-7i7irinadl.c,o1egdnsaeha48d2fg,(s.tDftsrtd8,,Pne.i..9i,tiroioRon6rdsCc2o1t7Owreound7S1o,e1amO:,,yd34pf:5tSt9iiWtflcD3huin;sh8oo1,571ooi56ac)Pew9r,4:s9f.n2.n54pets,bhtS6.7sauu0-ype9U-12,7oy3Idb0n.9.e,u,n4y-4oT65tai9hx,7tr505ey.d,-23ACCCCD8CaCCPcCCCCbCTHP2Tb-SPT211n9o9ehhe,2c.rrh,orc9eooooolaorroD3d40ooneeta7annyieaxals(uuuuuxrl,edo,s,s.6rcs4zmzstifflinrrrr57bkbieencsPsi.oicitttottto)ccconm,1Kynnnnyis,so,shcm:h-8-si.7i9l,,a,,eseee-lteel,papitlodoen7c6iDB,rnyyyyou,--tgygeDAd6-ADroT16f,f,,,addre.ymyos.PxTo-1En:i.ri...57TDyGaAGoKKKKiorkSS6patr..nC5n6FaaS,nxexe8h..e......sdnnD9A,4H,,,,DytDDDl.si:igseoXedd8nnmPsD-,sor.n...ge5yhHWMex6H2,,,,,,s,aa.pcro6reOBd,4.1,ildoe.oboe4imceNSxa7MTeM,29-sancsirdcrip8noWoB,7yitcbg.,.tboceeucouoY4d.i61l-I,cirairixiuuoumlooennc6ai,a,.cd.h1tcsipln5rAlAnnigDuLi,e9c,ecleelelddaidaJW.c7.,comirs..at.teneac.T,ai-aS1eIs1i,,imeSnndccidonAaJE.9,lee.sdpAeM,.TBTdln2a7s.tntrpAm,ehLr1,nSta0aavteenpihyMeCEdor9ct.ito.lacihr.lgnoelcC,Rmfi.n5atnioaoeedoeloMfCAEdtd:v.veoilno1nePdHhTePfo,teoidmisghe3cwtgrceanoahsrnei..roydeone3dceHFe,,,em,trtaroinadsrio7funastrlcilmehsm,rTa1sS-Rmtc1Riaai,intonr1Acn,a9n92.le.teebae.p3ldnJo,u6U7e,r,rptonci3N3o.aT4e,,5,atbdcottgnhT8Cs.s.2vt,a1isioi.r7oyeioAipeWBY,pd0l9eeatoxvtg,psnec7ie:rlnqu..8.eo3uDBvehP1,s0,#c,sfrrl/n9wtn9.na27.a,telliseusV.6a,P.7-1o7t7ritigiiciedLDt7n-,l.t76oooryCoh4noF.EIti-tea.l(nnngeec0,2fAJos..rd6nceyssot8.oC3tavu)hrudoK3H22fi,:tahgminoodA6i,,wfr,(euocle4nnoCCaC71iouasinrhneT,pn24I9thArtdrb5anhpslnh.7-oe,uSiol64oeem11cd(siTr8y8-fwC,,.fe29ii.5)od.,13,-7d,,oi4Te-e5,t8n.hds-,.)-t5... CHaosres,esA, .VA e.,t. anCdlinC.ofNfmoarnth, AJ .mR.,., 3W:2a7s3te-27O7i,l: 19T73o.xic fo r hCs1h9ele7areb5rpk.ic, aidnDed.sEc.a,antdet ltet h,a elJ.i.,r ApRheg--esr-i-ni-d.-o-u-lFe-i-cos--o--dmo--f-eC--tc-ha-he-b-lm-oo-.rl,oitpe2hs3e(n3ion)x:5yt7is1as-cu5ide7 s8 , of CTT rioinnsbWWy, aattDeerr.G,, .JJ, .. WAAoggngrr.., FAFoo.ooSdd., CCPhhheemmot..o,, d22e11co((66m))::p11o00s55ti22t--i1o100n554o4;f, 2219,,447,,055. 96 1U0R2 I233 OCf1o9ufr6mfti0tci-nem1g,9a6,lW9es,Ra.sDaThno.id,ncugemstotteninl,atl blND.i,o.rC.tCh.,9os0n13g9i.n2e7n30i3.tth,aelGMRoveaeplrfunobmrlmiecnattoioPf nrVisn,ietithnnyagdma,tid Davring and H ultgren, H ereditas, 85:123, 1977. ES1P9eA7c9tiF(oIdFn)R.A6 (Sb )c2ieAnctitifoicn Aondv2is,4o,r5y P- aTn ealn, d RSevilivewe xo, f SFeIpFtRemA ber 2 7 i s WEPAashHinegrbtoinc,id eD .RC e.,p o1r9t7, 4D. ocument EPA-SAB-74-001 US EPA, DRRoiampDapoopmr.tein1iI0cS1oT,,ISA1A9.N7, 7V19(a7Iltu7at.4al i,zaienInn)e.s tditeultloa TSCuDpDe rnioerle tedrereSnaon,it , EPA - 1979 J e llin e k C o stle News R e le a s e (e ). EPA - M other's M ilk S tu d y , U npublished, 1980. AcD21a9i,r37roGc7,c7i.hin,ol8oovgra-en1nn2teie5,s4tirTsa.ic.n,hDletouhtrleola.dtlwiE.bn,oev-nT.szutoamCt-ooopnr-tadsimynios.itxteiTimanot ixon(iTfcgC.Dm, aDo1)bu8sieal:5ni td5syk2i-n5o5f 7, cDoonntnamelli,naHte.dD .s, oPilh i-llMip iss,soPu.r,i, IMllnorebs. s Ma os srot.c, ia2t3e(d34)w:i2th99T, CD1D974 . D7 3o(s7t,) :r41. 0, -ieTt27a~lT. 9, 75S.tatem en t on 2 , 4 , 5 - T and TCDD, J . Pox. TDtrooicxuhigclhoeArroptypp,hl.eWnP.ohHxa.r,ymaeact.e,taic2l 5. a:,4c4Nid2o, nin-1t9em7r3ao.ntokegyesn i(cmitaycaocaf m2 ,4u ,l5a tta ), oD.oiw2C,4h,e5mi-caTl Canod., SRilevpeoxrtAtuoguFsItFR6A, S19c7i9e.n tif ic A dvisory Panel oDthfoewanCEdnhveRmirooicunatmel seCnfoto,.r, 1T9th7rea8c. ee nCtrhyemo fistCrihelso roinf aFteidre D-ioAxinsos uirnceto Dow Chemical C o., M idland, Mi. ADarecrrpceihotl.ilrc,t InVoandc.A.idt.hH, aeynHgidr,irOa2act,cz4uck,ut5eap,. a-nMTdt.re,idcc.hT,hrlooo7xn:ri6oicc1pi-thy6teo7no,xofixc129iyt5,ay43c.editniicchdloaocgrisod,p:h ean o x y CEinodnwltyaamrsdi.sm, TeWotex.rM.,.p, 6eGr(cll)oa:s3las1,t-io31n34.L, a.n,1d9M7r1ue.tnhoofxfycwhlaotre ra, ndB u2l,l4. ,5En-v. T JEoidseymEanisne,mJaondny. , War Shadows produced w ritte n d ire c te d by owaEPcraAdiyde, -r a(nOs2du,f4sfpp,i5ceanesd-tuoinTrfge)P, ureepsspegtsiics1eot-dr9fa4tP2,iro,4o2ng,/5s2ra8m-f/o7str,9r(iDtcchh)ee.lcoifrsooioprnehseatnn, odxr ieygmahcetresgt-eiocncfy- EAP2P1egA,sati-1inc9siO7td8feR.f iecPger iosodtfruacPttiseo snct oi canintddaei nc iPonnrgot ignr2ua,me4 d,s5, RR-eegTbi,suttPrtaaatbritloenI PI o,ref sum ptio A pril n ! FEsiniPexAb-R,ryueeRalaraeyrtpioo2Srn7pt ,ootno1fta9nAF7eo9sosr(ueebsss)s.tmA2eb,no4tr,t5oiofn- aTRFaSiteepslrdayinInPtvrhaercsetteiicgeOastri:eognon(oAAflsraeeas I I ) , j E1P9A79-. 2 ,4 ,5 - T P o s itio n Document, P a rt 1, 1978; P a rts 2 -5 , EoAfmrceSerg.alomCvhiocenmhe,.llaCSo.Dtcy..p,hNiRmtlau.srhiMuidme,etbKiyn.gAp,.,eAsMtuigcuutiasdtgees3n,0e,sPis1re9si7ne7n, mteuudntapanuttb ls1ist7rh4aetihdn. s Ep24hrn0een-2,o5xK6y,.a,c1eD9t6iic6s.taricbidustioinn aanndimeallism, inAactliao.n Voeft. c Sh lcoarnidn.a, te7d: Eh ernreb,icKid.e, s S, tuAdciteas. oVnett.h eS caannidm.,al 7m(3e)t:a2b6o4li-s2m7 1o, f 1p96h6e.n o x y acetic FP auhbrliigc,a tiIonnte, r n1a1t0i-o1n6a1,l A19g7e4n.cy fo r R esearch on C ancer F231a,4n8g,,5, 1S-97.CT2;.,in2e4ft:5em5a5la-.l5e. 6Tr3ah, et s1m,97eT3t.oabx.oliAsmppla. ndPhdarims t.r,ib2u2t(i2o )n:31o7f - EFtromiocedhr.slooCnro,ospmJh..eLnT.o,oxxey.,ta ca9e:lt3i.c9, 5Ta-4ce0ird4a,toing1e9nt7h1iec. sr atut daiends or anb2b,i4t,,5 - FS1y6am6n,npoiOss,iruemgJ.oMnP r.oS, ctaPeetreedcinoUgmnsmivae.n,rcdiladVl(>et7gh.eintantiinogn Mw iatnhagcehmeemnti,caplps, 161- EPA - C arcinogen A ssessm ent Group, R eport 2/23/79 ( a ) . 97 DOH2I5523% 1*7724 h2ctFieo,eo4andn,rce5iernfragon-l,rinTRgc1ee2agntr/h1idtsae3tie/sn7rirle9vbu,-esux0ePt0staaarb7ont d2lfeV3p1np-6eor-ste7Eitsc2iPuce3Ami4,d1opeF.ftiionpinnraolteaddgnueact ttiesntrosmct ohirnnoeatldagtiiionasnitnrga Fpp85h-idr-ee9inos2otx,olsinn1, e9sJ,7, o1aD:unr.d.,eArteslasaoltc.e'.,d ODcefotfmeicrpmoiauilnndaAstinoiannl. cooCfmhpemomelyricsctihasl,lo rc5oh5d(l1oib)reo:n-zo VAF iegsgrh.e,etraF,tiooJrn.eRsMt.,aSnleaegrtvetmieceren,,t wp19iG7th7-1. h2,e rIbnicFidine sa,l EUI.SS., VDoeiptI, , o f Finornd,a tuRr.eE,., I lelti naoli.s, MR eusceoatrocxhi,nsW, Einntevrir,on1m97e8n,tapl pC1o0n-t1am1.inants Fanradn hk ,y dPr.oAs o.,ile. t Waele.d,s, H1e5r(b3ic):i2d1a0l -2re1s3i.d u e s in pond w ater Fe19frof7eh5c.bterog ,f H2 ,.4, ,5e t - aTl . i,n InNMv eRIs tMigiactei,o nTse roanto ltohqe ye, m1b0ry(3o)to:3x0ic9, Ga1n7ad5le(P,2y)Tr:5a.z0Fo3.n,. oent eaml .b,ryEofgfeencetssis oifn ththee Hhearmb isctiedre, A2 ,n4a,t5. R- eTe., G28a-2r a9,t t i1n9i7,S7.. , TCDD P o iso n in g a t Seveso, B iom edicine, 26: Go36rea1h,lrina1gd9,7m3P.in.iJs.t,raetito na lt.o, mThaen, FTaotex. oAf p2p,i4. ,5Ph-armT .f, o l2l6o:w35in2gAGcDouienogltlvuaaasmtnLia1nor8amd,tieb, da1Ar9da7.ir6,ae,, aDMMseicmioonf.nistS1at7eemrvopien.saoDtieoalnnlad PMSroaegndraiiatm, , GfMoiruihlatthane, RIDetgiaoiloxynin,ale GafRonerdraptokhRroeatw,nrgbsePikNciE,iWdx-Hap3.l,., dS1a9rtn7aid3f.,t. ScUteSoDwnAtarrFot,ol,rRePs.t,a cASifeeirrcviaiNlc eoS.r,pthrawGyeensA.t dTFjueocvrhea.sntts Gonre2en,4, ,5U n-puTb,lis1h9e7d5. re p o rt from D ispute R eso lu tio n Conferenci GR5:ra1ut3n, o0wF, f,J1. W9C7.1o, s.me t. aT ol .x,icR, e9n(a5l) e:6x6c7re-6ti7o0n, oHfea2lt,h4 ,5A s-peTctsin Ptehset., oFHtrfeiadcla.hld,lPoeSqrroo.uMpacth..e,,e noFEoerfxdfe.ylocawAtcsmep.toircnSooteapccir.neidgEdnxapi(en2. tt,s4Br,5iacootls-n.,tTaan)3ind1oi(nrt2gh)Pe:72i,6rP,42'p-.,5roDg-DeTn,y HT airnt, MEic.Re,., TVo xailce.rioA,ppMl..GP.,h aTrmeraactoogl.e, n2ic2 (e2f):f3e1c7ts, o19f 722.,4 ,5 HR19ae7ws4pf.o, nLse.Ro. f anpdla nBteshrteons2, ,4R .-, DSBe,leWc etievd itSycieFnacceto, rs22i:n245th-2e 49, Hanedllpinlga n, tCs ,.SJ.., eEtnva. lQ. ,u aClh.,lo2ro:1d7i1o-x1in78s , in19p73e.s tic id e s , s o i l s , H4tptoe8hicgl4eohh,nmgno1iiaxcc9ny7a,aa6lcnB.eda.tn,icdbeloaatocdpaidulc,.rh,iJfeiS.meediTqsotuprxeyrinectcp.ihaaaElrnanhgtvie.iossnt&oinpHodafeutach2leo,td4hl,,o5ign1i-(cm3at)ilr:c,4iec6hh9ebmly-oarao CHRaaitrrcoLitnaiov, geeNrn. NWEexoiplploilsaaumsrteisc,, NGJ ..oMdNu.,CleIPs, eF6r3os il(sl5ot)ew:n1i2nc5ge7-Ca1ne2ds6s5Ga,trioow1n9th7o9o.f f MHreiompnoo4rrtpo.ft,fo, 1I9th7. e,3. CDoonwsnu'ms eSry, n1dr1o1m(5e.0 ):lI-t4 C, aSnhHerampapnenOHakesr,e, CAel. GR2 ,eo3sl.,d7sC,t8oemin-m,utneJ.t.rACa hc.,ehmle.t,roaPdali.bth,e.nHzPeohp-aaprtm-idc.i,oPx6oi:rn9p1h9iyn-r9ia2th8ei,ndm1u9oc7ue3sd.e, by GExoopd. mSanta, . VC.Hi .r,. , 2-148D5, in1j9u5r3y. to c o tto n , M is s is s ip p i A g ric. FHdoo&k, Ceots. aTl o. x, . T, he14r:e1n9a-2l 3h, a1n9d7li6n.g o f 2 ,4 ,5 - T in th e Dog, eHI nxotsuetsniets,uivteeet oaPrrl o. r,jeepAcetsaste1es3ds1m0ue3sn-eBt .oo, ff Dehececo.rblo1ic9gi6idc7ea. sl , eMf fiedcwtesstoRf esearch GFES19qoer7aurrv5tiekp.ismcoteweansnGtkdei,fnoR. HraTn.mg,eecuHhtE.aextriRpbo.eincpSiodatrnaatdl.P, NDs uUWrSp-i1fe4DtrveC1ip9sot7i,no6tnorafson.ldA: PgGarAc.r,aietfrkFiicoaowlrNesSskoptir,rthayw est H ussain, e t a l . , Amblo, 1:32, 1972. JcI.nhNenCmIsi.c,.aJl.sR .fMo r, etutmaolr,ig, eBniiocaitsysayin omf iPcee:s ticaidperseliamndin aiyn dnuostter,ia l 'DON2155235 oPI6nn,otet1Rer9nais7gtk9iea.nAlcsyCseaRsrscemigneuonlgate,tnosSrycainLedinatsEiofsnitcimGBarotaiusnpegs (TIfRohLreGiIr)d, ReWnistoikrfksy,iGnFrgoeubpruary oTKpnhohxee2.nra,o4A,x,py5Kpal.c-.Se.tP,tirchiMcaarhcmclKio.di,rnola2peny2hd,(eln)Wt:ho1.xeP4yi.-r,a2c8dPe,reteirc1iva9na7ad2cti.ivdPe,oss2t i,4nN ar-taadtlsic,s htulod rieos- ' C\i |> s fS^ DInitbeernnzaotdioionxailnsA, gveoncl y 1f5o, r WRoersldeaHrcehalothn OC arngcaenri,z aCtiholno.rin a te d K19i7li5a. n , New York Academy o f S cien ce Workshop, March 28, EItesnetrvna'stce.helS,ocrAol..dRiTb.,eecnJhzonono-elps. ,-, d Gi9o(.xE7i).n,:66Din8i-s6at7qri2ub,aut1tiic9o7nm2.oodfel 2e,3co,7sy,8stem , qK20uim7a:bt5ilt9ea,-6ti0Bo,n.JJ.a,innG. srt4oa,scsk1, 9Mc8o0..lLl.e,c tTeedtriccohallo rPoldyibAesnhz, oS-pc-ide niocxei,n Jg2er,4na si,5nen ,-froDTm,.JDr. eoetxat:iCnahels.mt,oicrAaelnsaClayons,di(sCfrofoonmrf idTfCiieDelDndtsiraelst)ri,de ua1te9es7d8.inw iRthice FKinoimrFemsoitnrresy,stJS.EePcr.voisFcyesrat,ekmVesri,,c tPPo .arNica.i.,ficB iFb loiroegsrtapRheyseoarfchH eCrbe nictiedre, s Can. JcCeoonn.ss,uemn(,cinogDn f.2Ji,d.3,e,n7et,t.8iaal-)l, T,C1AD97DR8, .eusnidpuueb lSistuhdeyd , onDowBeCefheCmaictatlle Ka4n:i2dn3g32, ,,4C,1.T9-7.G1D.., f oe rt ca lle. ,f t Spcraeleantein gp roo df utchteio nh .e rTb iecriadteoslo g2y,4, ,5 - T J2e,n3s,7en,8, D- .JT.C,DDe,t uanlp.u, bAlisrheesdid, uDeowstCu dhyemoincalshCeoep., c(ocnosunmf iidnge n tia l)Klin*gPmraanc, tiGc e.Cs.,, WA silhetoyn-I,n Fte.rMsc.,ieWn ceeed,P uSbcileisnhceersP, r iNn .cYip.,le1s975. Jufeonnlplsouewbnli,insghDe.dtJh,.e, DeoflewiedCa ihln.eg,m ioScfealcTrCCeDtoiDo.,nto(oclfoancTCftiaDdDtiennigntiamdla)i,likry1a9nc7do8w. csr,eam KTuConDcdDhaetiren,d ,Cb e.fWerof.m, f eaEttP,AaRIlPnA,Rp.Aire se sB a rbcuhl l .f o Er nt hv e't . p Cr eos ne ntrcoel oTfo x2.,,3 ,7 ,8 Jenssen and Renberg, Chem. B io l. I n te r a c t., 14:29, 1976. Ju8os9eh9n-9os0of 5np,, hJe1n.9Eo7x1.y,. ThheerbPicuibdleics aHnedalpthiclIomrapmli,c aBtiioon. s Socfi. ,w i2de1s(p1r)e: ad MJPino.ehsDntthiseceotcinkdm,eerasNnIa.nigEnec.m,.t,ehanen1td9oE7L7fn.avAwirmroenenrmciceea,nntW, f.VoHro.e,l sT3tsh, ,epprRo.W1le3. 5*oS-ft2e5vp5e,ensNsti.cY(ied.,de.s) , K2f a7et3ae-r,2n7eay7n,, d P1d9.Ce7c3.,o. netat mailn.a,tioTCnD, DEinnv 'tth. e HeenavlitrhonPme re3npt:., s5o. u rc e s, Kc1h0e1lao9rr,noed1y9i,o7xP2.i.nCs., ine t s ao li l. s, , P-Ee--rn-s-v-i-s-'t-t.-e--n-S-c-c-e-i-.--a--nT--de--c-m-h--.e,ta6b(o1li2s)m:1 0o1f7 - Ks30tea(n3ba)gi:al1i,t9y-E2.5Ein.., th2e,4 ,a5q u-a tTic anednvdireornimv aetnitv, e -Ds-.-o-w--Tn--o--t-xo--i-c-E-i-ta-y-r--t-ha-n, d Kpr aehtresirn,a,aAtaKdlv.Saen.,f. f eCRchuetdmsic. aknS, deJr.tA.h,e.,1d2Po0mo:7li0yn-ac8nh4tl,olre1ot9dh7ia3bl.e ntzeos-tp -idnioWx iinssta: r K2st,uo4cd,i5ybaa-, ndTR,.oJFn.,dc.oegCteonasmilc..s,tTuRodxeys.,uol1fts7r:2ao0ft s52-2i-n2yg1e,ae rs1tic9nh7g9ro. dn iice tsto cxoicnittayin in g dKanioodcxioibnna,cionRg e.rJna.i,tcsie,tyt TaBoxtlu..d, aynRdoefsAu2pl,tp3sl.,7o,Pf8haa-rm2t-.ey,ter4aa6rc:h2cl7ho9rro-o3nd0iic3b,etno1zx9o7i-c8p.it-y dKinioocxriaibntas, ,(TRTC.DoJ .xD,i)c:e. t Ar eapslpu.l.,ltsP2h,3oanf,7a,813-3 5wt(e3eter)ka:5co5h3rla-o5lr7ot4do,ixb1ie9cn7izt6yo. -pst-u d y Ka1c9oi7hd4l,. inJ .Dma.,n, eAt rachl.. , I An tb.soPrhpatimonacoanddyne. xTc rheetri.o,n 2o1f0:225,40,-5255- , T Kbthuoetnyisrlteaosnfttefinsrpo vorinan,gpT,re.gKGni.g,anSEt xaapnneiirtmi.m,ales3n9tas(n8do)n:1o0nth1e-t1h0ee2f df, eecv(eRtsloupsosmfiae2nn),t4. o,5f - T LI IamRm,epSo.rHt,., TAanbeErsphiadwemAioslsoogciica tAe ss,seAssumgeunstt o6,f 1th9e79A. lsae LFSineaentpeagtn,.oi,mMf 1a.P9Lls?e.,,7s.tCpicpoimd5ep3sa-7ra6itn,iveGL.aWmrg.eetIavAbioneliimsamanldso, Hf A.Wpcha. ednDeomoxriycouhPgehrre, bseosd,c BidN.e,.sY ., 99 :t UUH2 I55236 CLSinpeour.at,BhgcueKheGn-RDeDre-a,p6w5rFol0e7d.y.fuceRtitaotnas,lS.ut,undCpyhurbcoloinsvihceerdOinrgdaal tthaTroeoxeficCgiteeynlaemorfaertci2ok,n4sG,5mob-fh T oLrinnanm, eMn t.aBl., pelat natsl, , 1P11re. vAengtri2. ,4E x-teDn siionnq uCiryi r .t,o 8c0r8o, p s19a5n9d. LMCooibnsestsroo,ulrLiA,.AtUl.a,.Sne.tat O, auGlb.ei,iocrTgHoiaxe,iacl1thi9l7lS2n,eersCvsDic,Ce LNCoin.ecnEotelPnr7-Cf7oo2ru-1nD3ty-i2,se. ase M16a:j4am65d,ur1a9n7d4. G o lia , C anadian Jo u rn a l o f G en etic C y to l, Majamdur and H all, Jo u rn al H ered ity , 64:213, 1973. AMsi1inni9lxa7sn-aRE9yet.PeeeAllaI,a'IrstiNoSrR.ne,pepopAtonoontrrattnFe)oe,voofarGuelAsusetotsAarsg2etbies,oo4smnrW,t5ieoaonsn-fthiToRtnhfgaeSttoaepnssraFtyaUiinetniPldsitrvhtaierIccerntsaeiviclteyeOssm,rteiegMg(toTahanothriedcohAsnru2eo6asesf, d M arigold, D.B., Schulz, J .E ., P est Monit J . , 3:124, 1969. dMa ni aodtxsmai nmi,currEoa ,bn ivFa'lt.., dHBe geernaaledtzhaettiP,oenHr s.oJ.f,. , 52S:,23t5u, 73d,-i82e s 5 8- o, nte1t9trh7ee3c.hbliooraocdciubme nu zlaot-iopn- Mc2h9c9iCc, klus1r9e,f6e2dE. .cLh.,loeritn aatle.d, hHyydpreorcpaerrbicoanr,diPumo u latnryd aSsccieintecse, in41:>295- MoSfcciCethnoecnenHse,lal,l.1o3gE8e-n.1Ea4t.e9, d, MA1o9ro7or9em., aJti.cAs,., ATnonxaliscoopfathNo.Ylo.gyAccadheamrya cotfe r is tic s Mda icbsCeinnognznloee-lplo,-drEaiol.xEdi.n,o sXee,nt TaRohlx.e.,suTAs opmpxoli.nckiPteyyhsaormf(m.2,a,c34a,3c7a:1,87m5u--1la8tte7tat,r)a1c9fho7ll8ol.orwo in g MA19bc7No8ru.tlitoyn, s Win.P.P, rPimrealtiems,in La reytteLrabtooraFtoerdye rRa le sRu eltgs isotfe rS, pJounltyane2o7u, s MD19ci7vQ7ius.eieonn, oEf.GP.,u beltic aHl .e,al2th,4, ,5D e-ptT, oanf dHHeuamltahn, BNierwth ZDeaelfaencdt,s, MPU19SoeD7ss8Ase.,ilbsoElePnA, HMSeya.m,ltphOos'KHiuemazeafoernd, s Pthf.re,omUBasTeuCgDohDmf aHinn,e rtRbhi.ec, idEEenvsvailriuonantmiFooennreto,sftry , MAWpcormeaenssescehreeilicsnrnnoagtnniatno,tgiAnoM,snts.hsD,oe.ceaCiHtta.,teiatorhMblne.iicn, fi1.doB9e7r4a70cAtkhpagsenrs.o,neuAsusn1admd9lv7eamm1nn.cteaeeCtmteioernmnigatml ooisrffseiloStehncveiaefnnoAcAtreASttoh--e MHtoeoao2lrte,h3, ,7'JP.,eA8r.s,-p .et,ett5ra:a8lc.1h-,l8o5Pr,oods1tin9b7ae3tna.zlo -epf-fde icotxs ino f (TmCaDteDr)n, aEl nevx'pt.osurt Ma2n7od1r,tdoi1nc9,a6mH7b..aL .,in e rtanagle. , f oPreerss its tgernacses eos ,f W2,4eed-sD, ;1 52(,34),:5268- -T Min uhlalibsiotna ,n tWs , .RW.,eeEd fSfeccietsn coef, H18e:r7b3i8c-id75es0, on19w70a.ter and i t s MR eusreaanrycih-K, o1v9a7c7s., I . , e t a l . , European A ssoc. Cancer MCphauenrncayenroy,xi-yK3a3oc:ve6at2icc6s-, 6a3cI 3i.d,, e1fo9t 7r a6c.la. r,c iBnioogasesnaiyc iotyf 2in,4m,5ic-e, trBicr.h lJo. r o MoTfouxrRriacayots,l. FInA.gJpe.p,slt.ienPtghaa2rlm.,3,.,,7T,3h85re(e-1):Gt1ee3trn9ae-cr1ah4tl0ioo,rno1dR9i7be7pe.rnozdou-cpt-iodnio xSitund, y oMaE1gf9na7rvso28hie.r,,o3cnoR,7ms.y,G8es.nt,et-amBl TseCQ,aDulDFla,ilaniJptayrpl .liRIeMnedsp.Ltowir.t,tiuthtEEePn,sAvii-lUr1voSAenPGxAm-DeBtno6te-a0ltl0tus5Dr4vf,iilsAlitnergi,brmiuMcitcudiro.lo,tn. VNHiaeetrtibnoiancmaid,l esAP caiarndtemVAy,ieWtonfaamsSh,cinieTgnhtoecneE,s,fDfCe.Ccotm.s, mo1it9ft7eeH4.eornb itchide esE fifne cStsouothf NS9taahfteioe Dnd a.r,linMAkicenargdcekmWaynatdoefrCCSoco.,miemnI ncitectes.,e, NaDtr.iJn5.,0k0inpgp(1W8927a87t3e),r,93Man3ed1r,ckH1e9Ian7ld6the. x, , WNP eaaststihoiCnnagoltnotAnr,coaldD, e.mCVy.oio 2f , SWcieeendcCeso,n tProrlinPc iupblelis., o f19P75la, nNt AaSn, d Anim VNWa loataltesihroIniInn,aagtltiPovAnee,csatdDteCem.cCoyhn.,ntorofo1ll9o:S7gc5ii.eAesnn,caeNsss,aetsiCosomnraneln/StAocoyabfdeepamnryes soePfnetsStcainCedon n c trol es, 100 iOOH2155237 NssmearatiileolsnraoNl doCe. na1nts,c,eGrFuIeinbdrseutlaiintruyetse19foC76ra.rCcianrocigneongeesnis BTioeacshsnaiycailn R eport NR eastieoanraclh-, C3a5n:c3e2r14I n-3s2t2i t3u, t eN,ovRematbeLr iv19e7r 5W. orkshop, C ancer PHiepaeltrh, AWs.Npe.,ctse t Paels.t,i cM. ,et6a(b5o)l:is2m7 2o, f 1927,43,.5 - T in R ats, KPDlaeiumgfmrmaadenra,ti(oJenrd.s,a.n)dV, oMVlooadltei2lo,itfyMA, acrpctieo9l n1D-, 9eP4k,.kCeH.r eKIrnbecaicr.n,ideyeNs.aYn-.d, CD1h9.eD7m6. i.stry bONecetwclsueorenrne, nACceg.Jri.in,c ueAlttrukaraanl l.s,aUsR,seeTtoreofrsa2pto,e4lco,t5givye-, TS1 t9ua(dn3dy):3Co7fl7e-tf3ht e 8 3PR,a lea1l9tae7ti9o. n s h ip oN5f:e6uT7bC-eD6rD9t,, inD19.m7, 3ae.mtmaallia.n, As pseucriveesy, oEfn vth'te. Heme ablrtyhotPoxeiros pe.f, f e c t APldimvamnceers, Jin.RC.,heemt isatrly, SP heor itoe cs h, e1m2i0s:t4ry4, o1f 9d73ib. e n z o -p -d io x in s. MccPahoorllbloaeonrcond. b, PheAnyhdza.,orrmo-Gpxa-ylcdoloaivlose.x,er,,in1wE,0:.i3a,th4p9C3-oo3mt5-ep9nma,trie1isnto9hdn7yu4lo.ccefhro2loa,3fn,t7ah,rr8eynl -eh, yt edtrroa - ANt2r,ree3cuah,b7t.ee, 8drPt ,hw-mDiatt.rhe,ktorD2al.,ci4lhlE,m5lxoaprn-.o, dPt rlIaib.cte,hhnloEzolomr.o,-bppr2-hyd7eoi2ntoo(ox3xx)ii cn(y2,a4ec3fNef-ta2eiuc6cn4tysa, nc-ii1Snd9c7hma2mn.idci ee d e b e r g 'a Ns iemwtpolni,ficMa.,tioFnosr,e sJt . RFeohraebsitlriyta, ti7o1n:15in9-1N6o3r,th 1A97m3e. rica. Some NP aocrirfiisc, NL .oArt.h, weetsta Fl .o,r eTshte,WPeeedrsSisctieennccee , o2f 52(,54),:541-7, T19in77a. JN.o rFroisr,esLt ,.A6.,9 (C1 0he):m7i1c5a-l72b0ru, sh19c7o1.n tr o l: a s s e s s in g th e h azard , oNPtluhatmnertanpG, lraoPnw.Stth.g, broyTwh2toh,r4nstouDnbi,cs thaHlno.cGr oe.p,s ,hQeNnuoaaxtsuyt eraelc,,e tJ1ic.5H5a:.4,c9id8I n-5ahn0id0b,i t ion 1945. O6sfou(mlr8iaee)n,:4Ms 5Kua5. nr, eeic1tit9pra7aa7llc..eI,nCccoihnnletoarrmaotdionirbasenntsiznoo-tfph-eFdliyoNxeAitnshhse raalannndd dcFsh,luloeCrhogedamisboesopnfhzeore, OaEcntget ,at igcMed.aGic.n,i d et, ht:eJ a . MlO.a,cncuA. faMmcetoudrr.te,a lo2i tf2y(2l A), :44n, 57a l-y5-s0ist,rio1c 9hf 8loE0r.mopplhoyeeneosx y PPraorck.erS, oWut.hBe.r,n WWeeededanCdonBtrruoslhCCoonnf.t,ro1l 8o:3n4R6-a3i4lr9o, a d19s ,65. OPP arfnefiescliedoenonftH'sSecrSibecinicecinedceeasn,AdEdTxveeicscohurntyiovleoCgoOym,fmfMiictateerceoh, f A1t9hR7e1e.pPorret soidf etnhte, ' Rasmusen and S vahlin, E col. B u ll. , 27:190, 1978. oERfpeeiPdde,remgDino.a,lonCgciiacelsifIoninrvneDisaetingDnayet,pioaCrntam, oe3fn/t2Ro1e/fp7o9Hr.tesalothf AS ebrnvoircmeasl MOuetmcoomraendt FoR27fue,erPdth1,re9egD7r n9.I.,annCvceiaeslstiifgoinarntiHioaunmsDbeoipnldattortamnRdeenpTto'orrfitsnHioteyfalCAthbonuSonretmriveaslic, eoAus tpcMormielmeorandi !j aBRiitjeegrttlhghinieeanl2(iiW0,gthhGest.tC,)o,oTfnJhguetrhneeeEsss2Stio5emfv-2eat8sthoi,oena1E9co7cu8firdo. pteheneatn. TCSDPoDacpiteeotryxpicorefspeTonottexenidctoialol gy, JRst.ereiFganmoersr.i,,d e6I .6Cv(1e.,g2 )ee:t9at1ti4ao-ln9.1, c8Wo, n1itla9lm6t8ih.neateu spe uobflic2 ,4w,a5te-r Ts utpop lcieosn?t,ro l JhR.eiprAb, igcJr.iiWdce.., F2. Co,4ohd,e5rCry-h,etmrJi..c.Hh2l.4o, r(oL2p)l(vh2ae4rn5oe-x2ny5la0ra,gce1em9ti7ec6n.ta icnidduc(e2d,4b,5y t-h eT) , I\i Rohrborn, e t a l . , M utation Research, 1978. APPinelqanuPnnaetstsniyc:nlvsWayAnelveiaGdanuWIiiddaae,etne1trto9ifR7iT1ec.hsaoetuiirorcnIeds aenCndotioCfridocinanttariootilnn, g AanCd-omACmoqinuttatertoeic,l AP egtreircsuolnt,u rGa l.EH.,isTtoheryD, 4i1sc:2ov-1e3ry. o25f 3D. evelopment o f 2,4 - D, cRhollol,rinRa.t,e dT ocxoimc opolougndics,a l EEnvv.a lQu autailo.n SoaffeStyp,e c2i:a1l17O-r1g2a4n,o- 1973. Rino lml,icRe,., FSootudd. ieCsosmo f. Tthoex .t,e r9a(t5o)g:6e7n1ic-6 7e6f f, e c19t 7o1.f 2 ,4 ,5 - T bRyosree, fuHg.eAe.s, fRroomse, SSou.Pth.RV.,ieCtnhaemm, icSalc iSe npcraey, in1g77a:7s 1r0e-p71o2rt,e d1972. \ 101 , * 00 215523 17728' JWRuonassesh,i1nR5g,t.oTn1..9, 7O26,4.C5J/.u,dniepo.x2in35.,s, 1A97n6a, lyMtiecmaolraCndoumllaobfo rtahteo rsUSMEPeAe,ting SC2op,3sam,r7s. c,8hTuo,-x .G,t e.9Ltr:.a4,c0R5e -tI4o1ar2l,d, ,ib1Se9n7tu1zd.oy-po-df iothxein teinr a ttohge e rnaict ,ityFooofd oAoRffomwet2erh.,,4e JV.h-.a, VDzHaearytdn.mdsaRs2t,eo,s4T.l,,.5iAv1.e5-,s(tTS5ou7cmt)ky:m6pa2ear2ys-hs6ooe2cfr9biat,iocteix1dd9iec5swo4.lioathngdict haanle ierinvfuaoslruem,a taitoionn pSinraourfeairltheso,fofT,f oM2x.,.4WA,5.,ppe-lt. TPa'flhofal,lro.Tw, hi3en6gd:4o9isn1et--rd5ae0vp1ee,nne1do9eu7ns6t . pa dh ma rminaisctorka tiiroe tnic SS ttaann ffoo rrdd RR eesseeaarrcchh II nn ss ttiittuu ttee ,, MCheenmloicPalarkE,coCnoamliifcos r nHiaan,dbo1o9k7,6. AHoSUSfFteaBrAtr,bhkrimeU,cyitdUHaeDh..ES,uO.g. wFrAeaainnyiqar aePl Fjrl;oRo.Mv,recipnieScogorrLoitG,lborigTioanEiulsCcntOaodiMcn,rdspDPoCBurrooagamwtjsiemeaocylanin,tnd/beUNiTotoea.edchse5o,tg-lCo1Rra9Oga7dni-5ca2gat1eil,3o-n0lsit0iu-old0lf1y5, AmSnocbenhes-athtinrunatmgzca,tnoSof Pf.Ltrhip.me,a paeSetetroscapicerleht.ys,reonTontfooexldToi ocgaoxitcilcoatoglhlliyoecgaeeylxi,gpeMhof fstaeeeredccnhtsttho1p1a5r-o0n1dn5upu, cape1ltd.9 TinCDi), 79. CoSfcohnFuiofbererersst,trinyG,.CHS.a,alciArfaodmranmeinsa,t,oR, C.1Sa9.l,7i1f .R. eDfeopr.e sotfa tiCoonn sPerravc.,ticDeisv. fo r dSicohxwientsz,, EBn.Av'.t,.~fefet ala<lE.h, PT eorxsipc i.t,y 5o:8f 7c-8h9lo, ri1n9a7t3e.d debenzo-p- AS cugieunstt,if i1c97D9.isp u te R e so lu tio n C onference on 2 ,4 ,5 - T, S eiler, E xperientia, 29:622, 1962. SBthhuealdle.onfEvfi,nrovLn't.mA. e.C,not enettaxrapno.ls.eT,doAxa.ns, ena1ur8ac(lhl4y)f:4oto7r 822-4,,438,5,57, ,8-19T-77eT. sTteCDr Dh ienrb ic id e s , Saphcraoiwdps,e.rWtWie.Cese.,dosGf, e5sne:t7vn5ee-rr9a, 2lW, v.1aA9r.i5,o7uT. hs ley sseulebcsttiivtue tehde rpbhiceindoaxlycarboxylic Shirasu, e t a l . , M utation Research, 40:19, 1976. mSc uteelnwttuarfreot,r FhRoer.Eerbs.,ticGSideraarvltoiwcders,ikfiGt, eHrne..dGTu.,ecctAhio.enrR,iapUlt..aSPp. NpDWlie-c5pa4tt,,ioo1n9f 76Ae qguriip SuRsteeopuoitrn,t AB16.gA8r,.i,c1uA9l7tlut7m.rea.n, NJ row. aLn.dB .,fo Br atrhneesf, uKtu.Kr e.,, CeAt STa lr.e, p Er innertcj) Tbt1e3aht2icrg4atp,ecerhn1ila9,ol7rJ4o.i.dEnif.be,ecnteiztoon-apl-a.ds, ioaInxcsinereq, ausIeenldafeoscfut.secxIemppomtsuiubnr.ie,lit1tyo2:12to3,319,7- ,8 dTrima imnoangse, Fsy.Lst.e,mWs,eeAdRSc oTnetrcoh.l Pinu bwl.e,ste1r4n-34ir,r i1g9a6t0i.o n and cT1a7imu-2sme8o,ncso1, 9nF5c9e.L.rn.,, rKelsinegamrcahn, anDd.La.,c tiAoqnusa.ticR eacnldamBaatniokn wEePeAds, 1; PBST22 w,e,oa43rtsi,hs,se57sp,l ,,e8mK-cKti.it,-cavrelree,ctgeshtetIirrnooa,anrcloAI.hCnp,.lGhtaoeCrer.rc,roani.rdnoa1coix9tibgniy7oeeoe6nnngt. hzsaeoalnna-ipncCod-lodBnCi(ifoToeaxCarnePiscnnsEeac)rye(wCdooioinoftnhxtEtirnhdoc)eiolf,lfhcoeCoegrrnrieebctmneai clntointdae,in S iebert and Lamperle, M utation Research, 22:111, 1974. eSa1o9tmu7iAs9tNh. A,ZSbAEoR.rHCtHi.o,,nASs enaannsudoanl 2aCl,4oA,n5fnea-rleynTsciesS poNraf.ZyO.inrBgeg,roannPcahDpeaDrtaupnoreendsieSnn,ptoeAndutagnust WT ereidc hSeclile, nDc e.W, .1, 61e7t ) a:4l4. 7, -4L4o9ss, o19f 6h8.e rb ic id e s in ru n o ff w ater, wTRoseocpdhoyrltrpleNlyaon,. tsFCR.St-o1.,3c-hR6e7em,spi1oc9na6sl e8.troefa ttmr oepnitcsa, l AaRnSd, Us uSDbA-trRoepseicaarclh Sd52imb3ei,tnhz1, o9F-7p6.-A.d.i,o xeTtn a iln. , CTF-e1ramtoigcee,n iTc oitxyico. f A2p,p3l,.7 ,P8ha-rmt.e, tr3a8c:h5l1o7r-o ESa ckoiskdpo.lainkBd,ioilI't..s MYbueu.d,t.y, El 7fe6fes(7tcet)r:9o0of n-922e,4m, ,b5(rRytourgsicseihnalenos)riso1po9h7fe3nr. oa xt sy,a cBe tuilcl. TNaumng, , CTh.lTru.,rgelte , a yl^9,:42L7e-4c3a6n,cer(Fprernimcha)ire19d7u3e. fo ie au V iet TcVouinnetgtni,naumToe.uTsse., uSettituldiaziela,st,,i oC2n9li:no5f3ic-d8a 1le,feof1lfi9ae7nc1tt.ss oonf mc iavsisliivaen san, il .w w n l \ o u l UEScoDnAo/EmPiAc A2 ,s4s,e5ssm- eTn,t UESnDvAiroFnomreesnttaSl eSrvtaitceem, Ao fss2es,s4m,5en-t eVn te gPeat ac tiifoi nc TTe,am5-2B8i,o loFgebic. MN oanrtahgwemesetntRwe gi.aItihSnodn, H, '1eV19Jr97b79i7.c.i d e s , UC19Sa7Dl4Aif,. o rFn oiar,e sUt .SR.eeFsotarbelsitshSmeernv ticoe ,f NE navtiioronnaml eFnotarle sSt taLtaenmdsenitn, CoUDneSaDtlerAiarf,nioogPrrenlaaliatnaent,dd CUGeo.nSrnh.atasrFnoslcloaernmaednsedtnStSR,iteee1rvs9ve7igco4ene. t,aNtEiaontnivoionronanl mSFaegonertbaelrsut sshtLaatanendmd einn t UUS.DSA. , FGo vu i'td ePlirnienstinfgo r Owfefeicde c, oWn tarsohli,ngAtognr,i. DH.Can.,dbo1o9k734. 47, UUWNSona.isTthe4aid7nr9giS,ftoftan2C6t,e2osDmp.mPCpri..s,o,sdiU1ou9nc.S7,ti0.oS. nGyonavtnhedrentmSicaenlOet srP,garlin9ni7ctiunC,ghTeCOmfpifcuiacblesln,t . WUUNSona.isTthe2ai9dnr5gi^Sftfotan2C1t,e2osDmp.mPCpr.i.os,,sdiU1ou9nc.S6,ti7.oS.nGy-onavtnhedrentmSicaenlOet sr,Pgar1inn9ict6i7nC,ghTeCOmfPifciuacblesl,n: . VbineannrzaHot-sipll-eedxriop, oxJsien.d,, Cetothealmolwo,s,plheIenvrceerl,es a9so:e5fd372-i,n53c4,7i4d,,8e n1c-9e7t7eo. tfr anceholpolarsomdsi- V20i4et:8s 1a7n, dMVayets25F, e1a9r 7H9.erb icid e H ealth E ffe c ts , S c ie n c e , Vst1ey:it1snrt2aoe2cmp-ha1sll3,o2arnJ,od.dH1i9ib.n,7e3nCl.izvaosi-inpdga-d, mioJix.cEien.. , AinMrcemht.aambEomnlaivcli'atnS. tClaiobvnietlarimtym. iTocrfooxs2.o,,m3 ,a7l,8 Vogel end Chaudler, E x p erien tia, 30:621, 1974. Vp24-od1si,,o xJ1.i9Gn74.,.(TCeDt Dal lI.n, CT5o7xBi1c/i6ty moifce2, ,3T,o7x,.8 A-pptle.trPahc ahrlmo r.o, d2i9b:e2n2z9o- VHteoetsra,altchJh.GlPoe.r,orsdGpi.bu,petnsaz:,1o2B-p5.-N-1d.4i,o0xP. ianStheiopnlto. gla1ibc9o7E3ra.ftfoercyts aonfim2a,l3s,,7 ,E8n v 't. oo WACO elcastngaotnebeeerr,I,rI OS2s5.rtLe,ug.do,1yn9e7aS9tn.tdaa tler.e, UpAonristv,ceirEesnnitvtyii,froi cnCmocerrnvittaailqlliuHse,eaOolftrhegthSoenc,ieEnPAces CG\\,O? WmAceaatidnae,bmoRliic.sLmP.,,reaCsnshd,. SN9 m.Yinit.h, L, 1.M9J .7.6SA..,udSuse,leHc teirvbiitcyidiens , r eVloalt.io2n, to WorRefoalyiacnate,liroSRtnao.iLcnt..o,, WWLt.hoisengudihrobtmnsB,atin.tB-,uo1xtF4ei.2dd,:a5tTai2ohl5kne-5ywg3l r6ioc,twha1ritnbh9 o5 rt4xhe.yegl ui cpl al aat icnnitgd, s aPicrnot iv c. i t y W71a:l1k3e6r,-1C37.N, .1, 9R73e.h a b ilita tio n o f f o r e s t la n d s , J . F o re s try , Tbhlea sWt aaltl SI ttarleieatn J oUunrint ailn, R*7o6ch, eMAagrcrhee2s 6t,o 1P9a8y0. Damages Over WWeeeedd SS oo cc iiee ttyy oo ff AA mm eerriiccaa,, CHhearmb ipcaiidgen, H1a1nd1b.,oo1k9, 734.rd e d ., Wv aeriisoeu, s Aa.mF o.,unDtsavoifs, wRa.tGe r.,, WH eerebdsic, id1e2 (M2 )o:v1e0m1e-n1t03in, s1o96il4. w ith WCNeowhuirtHseeasviodenef , aDnTidohxoLisn,onTCdhooenn,tPa1emn9di7nu5al.utimo na,ndY atlhee UTnoixviecrsCitlyouPd.re sTs ,he WPPlreiinlnsuocmnip, PleJrs.eGsas.n,, dNHEeawntidoYbloooorgkkyoa,nfdJatmeLroeasntdoWolnoi,glsyo19nV7, 7oC.l.larIk eG efnrrearasle re d s, WP rielssos,n, NJew.GY.,orkEnavnidronLmonednot ne,nd19B73i.rth D e fe c ts , Academic Wi1n6i6lns:o2on6n-1,h-uJ2m.9Ga2n,.', p1A9ri7bm1n.aotrems ,a lIitnieAs ootaf Einntdr aouc rtienroinloeg ideesv, elsouppmpleenmtentum , - MWh eairnnbasitgcoeinmd, eenAst,.Ww4h.e,(n1J)a:r1p.2,p-l1Rie4id,ttyt1o,97fa2..lwi .a,teWrshhaetd haapr epaen, s Intod . pVheengo. xy Wanditt,th eJ . ,EPAA Ad ilsscaue s sI iIo nstuodfy t,h eOresguosnp eSn staioten oUfn i2v,e4r,s5ity- , T1979. 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UFFo.noiMdv.eTrCesicltyhydneooslfdoagMliesa,ts, sPaNhc.hDuut. rsiettitos n is t UEP phniiidlvieepmrsCiiotoylolego,ifsMt A.Dla.b,amDar.Pa .tHB. irmingham JJPeuhflafireumrssaoMcno. loMCgoeiosdnti,,caMTl o.CDxo.i,clloePlghoe.gDi.s t / ACUhgneirvsicteeurrsltiEuty.raoCl frToMsesca,hsnsPaohcl.ohDgu.issettts DOM 2 1 5 5 2 1 2 , ...u 0 ACT.nailmJi.faolCrnNuinauhtarS,ittPaiothe.nDiP.s to,lyLteicvhenstiocckU nSipv ee rcsiiatylis t UPRlonabinvetretrPsMhit.yysDiooeflvolMignia,sstsPahc.hDu. setts JSE.anntGoJmoorodseolongSiEtsatdtwearUdsn, ivPehr.sDit.y MNSepweerrcYiiloarlkEisisUtenninibvueEdr,nsviStiyrco.DnMm.eednictaall CHeenatlethr WCNDaeuaansntchreiiCrnti.goRtoFnenlsieseSttac,rthcaThteeero,rxUiPcnhoi.vlDoe.grsisitty FEUo.noidMv.eMrFsiioctrysoteborif,o lWPohgi.siDsct.onsin FFUo.noidJv. eTrFesrcitahynncooilfso,gMiPsahts.Dsa.ch u setts ERUonngtioevrme rEos.liotyGg iosoltdf' , NPehb.rDas. ka UWP l.naiGnvtreirPesrhistyoysnio,oflPoFhg.liDos.rt id a BAU ilnofircvehedermsEiit.syt Hoafr pWe ri,s cPohn.sDin. WUR enislileviaaermrcshiRtyB. ioHocfahvCeemnadliiseftro, rnPhia.Da. t B erkeley MWB uaAinltltbaieaagtmeeCrm,oReuE.nntntHyvD,airziCosenatlrmtliiincfeoetnr,tnaPilaihs.tDM, . osquito Entomo lo g ist VABSI nrttioMatctonetteerxorndrneiVUciyHsaenlttei,evrCrbeaHeernnsrestitm,teyAraMtdoo.mflDoi.gN,nieiswJst.t,DrYa.Ntoirokuntr itio n is t WCLoominlalsiuamLmienrdTaH. eJUaalnrthivviesSr,psiePtychi.Da l.is t MTBUhinoooimlcvehaceseurmslHaiitr.sytJE, uovNkfoeulCsu,tatriliPoitfihnoo.iDrnsn.tiisat a t B erkeley JTRooehsxneiacGroc.lhoKgTiesrltil,aenCrg,olnePshuP.Dlata.rkn,t -North C aro lin a FOPoaroeudglonTE.eScKthanitfoeelroU, gniPsihtv,.De rN.siutytr itio n is t JUNamnuitevrseitriRso.itnyKisiotrkf , FPloHr.Did.a NSEmteuoptrrhyietnUionNni.ivseKtrsreitiytzm an, Ph.D. MFPoeaonndnfrseSydlcviKaennriotaigseStr,taPteh.DU.n iv e rsity JUE.cnoiCnvoleamrysibistutyrn oLf aCFoarlcifeo, rnPiha.Da. t Los Angeles AORrogebrgeiocrntu lMStutaarcatVel icUBairno,icvPheehrm.sDiit.syt PPRhuoSargdrepmureeaccPyiU.a nlMaiinsvdateicrPkshietaly,rmPahc.aDl . S ciences EHEmceonornryyomUGi.nstiH,vaeAnrnstteiot,yrnLeLy.M., J.S .D . y 106 *QQCKhriicsategno, MIclNliuntto, isPh.D. n 2_ l. 5_ r5 oZ*t vn JNPoehwsyespHihcaimaMpn.t,oMnH, ielNlaeelwtrh, HMCamo.Dnp.ssuhilrtea n t JOA.rneigmEo.anl OSSl tpdafetieceiladUl,insiPtvhe.Dr s.i t y SCRtol.ibneLircotauElis. NOUulnstriovinte,irosMniti.ysDt.M, ePdhi.cDa.l School CSRyliacnrhtkahsreodtnicEC. aonPldlaergPtcehhy,s P ic h.D. al O rga nic C hem ist ASPhemerveioraidcRaonnaptDaolepnoDtrate,lnADtis.sDts,o.ScC.ioantisounmer A dvisor DUManevidivdiceirRnsaiotlyllC, ohPfehmU.Ditsa.th PUBainuoilcvheSeramslititmsyt aonf, CPha.Dlif. o rn ia a t San Diego FUBo.noidSv.eSrScsciitehywn toeiifsgteCrta,lifPohr.Dn .ia a t D avis STS hipdaeenn cdeMyi aeOdlSicishcctaui nlpidanCet ioloPll,nlreeagMvl ee.EDnopt.if,ivd eeWLmLMi.isBocel.oodngicsyiinn e SNSSyatMuarraatteehrcdiuitaUHsieo.nSniUSpivshenetorci,vsritiaeE,trlydisPsiuotthcyf.aDtNi.o,ewnEaYld.oDarnk. d HUI nendniruvyes rtFrs.iiatySl mToyfothxP,iicJtotrsl.ob,gu irPsghth.D. AMR ogilbwreiacrutuklRetue. rSSa lcphiTotzoeelcrho,nfoPlEho.ngDgi.sitn eerin g FHP rhaerydvsariirccdika nSJ,c.hNoSoult tarorieft , i oPMnu ib.sDlti.c, HPhe.aDl.th JUNunuditivrteihtrisoSitn.yiSsottef rnC,a lSifco.Drn. ia a t D avis CMPSataeentmphcheooerrlinoaClgSeiS.ns tlteoSratenr-nKbeetrtge,rinMg.Di JTMohhoenleCcAau.tlhaTroolBidchiouUlnontegirvi,setrP,shiBt.Dyio. ocfheAmmisetrica '0N3 SUFotnaoindvleeTryesciEthy.n oWolfoaglNlieesnbt,,raFPskohao.Dd . S c ie n tis t APEumlibzelariicbcaenHtheCaMolt.uhnWcSihlpeeloacnni,aSlScisicet.nDc.e, Man.dP.KH.ealth APNmhuitelrriiipctiaonLn.MWEeddhuiiccteaa,ltoASr cs.sDo.c ia tio n WBU.inoiLcvh.eerWmsiiitslytliaomf sG, ePohr.gDia. ERHniacerhrvgaayrrddanUWdniliEsvonenvr,isrioPtynhm.De.ntal S p e c ia lis t WUP hnayrirvseiencrisaWinty,in koEefplisCdteeamilnifi,oolJronrgi.ia,stMa t.DB. erkeley JSEamomcoeriysa l UHH.n iiYsvoteourrnsigiat,yn Ph.D. , Me d ic in e JTKooehnxnni ceAot tlSoSagpqipus,ta,rJe Ir, . n ,Pd euPnshnt.srDiya.lvl aHn iyag i e n ist ;i fij SBA.utCtsoJohornnhnsenue lmylB,,eryGFiPonarrggmoet od,enur R,cCteJih.zSaDeianr.fme a&t yn BCyoi nmgmt oisns,io nP .C Policy Advisors MJTohahennaDgDeimeiebebonoltdldCGornosuupl,ta nInt c o rp o ra te d -v JALoetsBteooprenhuefyP, . LMamubr,phLy,eibLyL.Band MacRae I jI 107 American Council on Science and Health 1995 Broadway (near 081h Street) New York. New York 10023 Telephone: 212-362-7044 Dr. Elizabeth M. Whelan Executive Director 1DOM2 I 5 5 24 4 ^r ' 'fit I I American Council on Science and Health 1995 Broadway (near 681h Street) New York. New York 10023 Telephone: 212-362-7044 Dr. Elizabeth M. Whelan Executive Director  oA>O I I I f 1 'd S e*ssi2no(n DOW CONFIDENTIAL INFOR "" " R & D REPORT D O W C H E M IC A L U .S .A . OCPARTMENT/CITY Mammalian and Environmental Toxicology Research Laboratory TITLE 2,4-D ACID: ACUTE TOXICOLOGIC PROPERTIES" CRI NUMBER LABORATORY REPORT CODE DHAETETISKSU-E0D02372-043 f February 26, 1986 LAB, NO. PROBLEM NO. -J -1__ 1 P A G E S' IN F U L L REPORT a u t h o r {s ) / m a s t e r n u m b e r ( s ) J. M. Wall/077592 a u t h o r (s ) s ig n a t u r e (s ) M bu)?SIGJ NJATUREJ > 0 rL K. S. Rao This report is: IN TERIM FIN A L and mainly: m NEW REVIEW D ESCRIPTIVE SU M M A RY W ITH C O N C L U S IO N S : A sample of 2,4-D Acid, id e n tifie d as batch number- 850914/20865/1, was submitted for acute toxicologic evaluation. The source of th is buff-colored solid was Ivon Watkins, Dow L td ., New Plymouth, New Zealand. The te s t m a te ria l, which is in commer cial production, contains 2 ,4-dichlorophenoxyacetic acid and 2,4-dichlorophenol. Acute oral to x ic ity testing was conducted with Fischer 344 rats (Charles River Breeding Laboratories, In c ., Kingston, NY). Eye and skin ir r it a t io n tests were conducted with New Zealand White rabbits (Hazleton-Dutchland, In c ., Denver, PA). The acute oral to x ic ity of the te s t m aterial was low. Range-finding tests in d ic a t ed the single dose oral LD50 fo r female rats was greater than 1000 mg/kg. Three rats/dose group received the te s t material as a 10% suspension in corn o i l , by oral gavage, at dose levels of 250, 500, or 1000 mg/kg. Lethargy, the only i n - l i f e sign of to x ic ity , was observed in the 1000 mg/kg dose group. A ll rats survived and stead ily gained weight during the two week observation period. --- Test material was in s t ille d into the conjunctival sacs (eyes) of a male rab b it at a dosage of 0.1 g/eye. The single exposure resulted in s lig h t to moderate discomfort, severe conjunctival redness and sw elling, severe reddening of the i r i s , and severe corneal opacity. Ocular e ffe c ts , which were s t i l l present in both eyes 21 days a fte r exposure, were more pronounced in the eye where washing was not conducted immediately a fter treatment. - Test m aterial was applied to p ic a lly to in ta c t and abraded skin of two male rabbits under dry or moistened conditions. The m aterial was applied to the abraded sites fo r three applications and to the in ta c t sites fo r eight applications a t a dosage of 0.5 g /a p p lic a tio n . E ssen tially no ir r it a t io n was observed a fte r prolonged (24 hours) or repeated contact with the te s t m a te ria l. Results of the skin ir r it a t io n tests indicated the te s t m aterial is u n likely to be absorbed in acutely toxic amounts. A R E M A T E R IA L S D E S C R IB E D IN T H IS R E P O R T O N T S C A IN V E N T O R Y ? IF N O . L IS T M A T E R IA L S O N R E V E R S E S ID E O F T H IS P A G E T H A T WE W IL L U S E O R PR O D U CE C O M M E R C IA L LY TH AT W ILL R E Q U IR E A PMN. D ISTRIBU TIO N : . D EPARTM EN T FILES R & D A D M IN ISTR A TIO N CE N T R A L REPO RT IN D EX (566 Bldg. -- Midland) FO RM C-4J01 PR IN T ED R -2-14 yesEJ "D 17736 D is trib u tio n list is c o n tin u e d on attached page. DOW CHEMICAL U.SJL 1803BLDG. M A M M A LIA N A ENVIRONM ENT A L TOXICOLOGY RESEARCH LABO RATO RY MIDLAND. MICHIGAN 2, AL - 3 > fcid -002372-043 MOLKCUIrAO formula 3 / N ^5o<fi^./so?re>S/i STRUCTURAL FORMULA -OK COMPOSITION 29m, 4eh-.is~--te rS'EeO'icic.hhlloerrac pphhee nno&lxyact' h'c. fe.i d Inerts graf f i / /T o_1 C ^V. jUc * SS? S r c ? i? / jc ii j7 / 13 ' 2 S' balance. 01< OQiUNCPOINT c mhHo, (E%XPOLVOSVIVOOI. LINIMAITio) COOOOOIVSNSSS (TOCOMMONMSTala) Alone. OdMCAt, MKACnVTTT l i AioT H/9l?7?OLiS (ra pH olansb, w a t , uq ht) fiifiT H f i P r t T Z V O U S ITAOKOF O f FLASHPOINT t o n a i tomo. MSLT1NOFT. VAPOOPOKSSUOS mmHo. MC f c c pH PHYSICALfTATB COLON PUNITT (%) Set-li? (tMCUJOK CONCSNTNATIOMin ain) ajuwumrTV frC./H ~ T'tfEr^j Ox. r' 7*&CE>uC : )N*>OLttBc "0 H.'Brz.JZ research . f bench POOFOOD AND POTKNT1AI. USB.' P K oPu c t ts P ILO T PLANT SEMI PLANT 0PLANT im com m E pc/ L . PKozouctioaI. R E G ISTRATIO N LIU.: (. S a t i h -- Leise p r c d u c tion. S o / n e Potential f o r &yc./sHctn c o n t a c t manual h a n d l i n g in pilant, and ungosi/on /thha/ation user a n d AMOUNTS TO OK HHOLID: to leaser e x t e n t b y m a n u t h ctttcnng p e r s o n n e / . 4 r g e q u a iih liC S . Pactare. c o n ta in e rs MUHAN KXPSOltlB#MNC0KR INU NMANUROIUIMNAOCS lie Problem, Has been handled dor PUNPOSK(s ) FOO TOXICOLOGICAL tbits: SDATA SHKKT FON I AFB MANDUNO B 'mATKNIAL IAFBTV SATA SMKST/LAOSb O il TOXtCITV 80MPATIOL8 WITH INT8NOBO USB e^rNiBAOULTIOOACTLIOANSSIFICATION FOO SHIPPfNO QpOK MANUFA6TUOK NOTIFICATION (pmn| Q oTNBO --PLOAIS EXPLAIN o d 3 0 0 Kgs, many yeans CIA ITU OIK A CMCHICAk ANALYSIS CTIVB INOOKOIBNT (*T THC MINIMUM) TINO ON THI TICA IN TCs[Zl Charge Ita3?, Aleta 'Zealand O cla. , i acRisH roa t. xicitt ( 0QTOLTH1BIOIA ROA AA.I.TAATIOU POOM C*l|lll R-INI 4-o q _Miu.ii.irso C d ''V/f3 K.ta, tnoFFftT ItiorJ uTKthS - foui aPjFe iiou nra SC, Pt-ttnoura AIEta 2.t)UfAjj>. LTP, - (IIONATUOB) / ^39^'r7i. LO. NO. 1 7 7 3 7__t_o__/_f__c_/__S__S_____k_'_c_/_i___iJ__f_fc/iIrt''uS 1- -pi' ll L '`\.nr.tr+ . r d ACUTE ORAL TOXICITY TOXICOLOGY RESEARCH LABORATORY T HE DOW CHEM ICAL COMPANY MIDLAND, MICHIGAN c,l t M n 7J-OK3 METHODOLOGY k -*3 7 ? -^ i> Animals used for acute oral toxicity tests are fed by single-dose gavage using a cal ibrated syringe and a blunt feeding needle. The animals are fasted overnight (except rabbits and mice) and are weighed before dosing, the day after dosing, and at I and 2 weeks after dosing. The animals are observed closely the day of treatment, then, daily* for the 2 week observation period. Unless otherwise noted, 7-10 week old Fischer 344 rats, 6-8 week old CFj mice, 6-8 week old Hartley guinea pigs, or young adult New Zealand albino rabbits are used. A minimum of 3 animals of one sex per dose level are used. Non-corrosive liquids are dosed as received, corrosive liquids are diluted in water or com oil. Pastes and solids are pre pared as solutions or suspensions in water, corn oil, or 0.5% methocel. DATE I . *4, 1?-'oo -&.h adjust* rJisf-- L i\OC> -/Ltd? e.'jlfm u Q" L-O'.CQ -jicLti c,Jyk*s.^ c JL -? u V.Oo iedhi cJih zjL i Q _2__-_S_-_f_S4T' - 3 0 Ccjt S~ sLjdzvS~ '/ii t&'jcbL te f f l u x ' *L/***~,^ c Jp .* iL * _________ L _________ -- . o-,htih.isi i <l.@s ,x/~ $> y / w '& M x f a iA * j u j - >. t i i u h -- -fijih &*J- Q. U-jr* J^ L Cyft-J g j 1^ i h j j f f T & s & o J? K H / J )$AU <gp U k - .^ 2 (ir. ^ t - J L * j f ( x L . COMMENTS e Jtz f- C-v_____ oo _tsa -ao ir fcSn3 /Anim als were: Euthanitized Sent to necropsy Dai(i : w h r k r - pQ , ^ ` except weekends & holidays A C K O F FORM C-40M I R -M R $4*1 iVtt-'U MCXxtXtJM+ uJtL J J07eJ J CO CMJiUl. ifz?fr r 77 t'O TOXICOLOGY RESEARCH LABORATORY EYE IRRITATION TEST MATERIAL ' 'Z - 3 ) --$ e r g __________ 00*2 DOW METHOD- CO N CEN TR A TIO N %W/V U N D ILU TED S S t 2 i ILENO. 0Qei-3%3. -O Y J RABBIT NO. ISS E X M ALE CAGE NO. g o o -r FEM ALE l(- 2 3 7 2 - ( 43) 82 SSIZHOQi METHODOLOGY Tw enty-four hours prior to use, the eyes o f the rabbits were examined and established as being w ith o u t defects or irrita tio n . The test procedure consisted o f instillation o f approxim ately 0.1 m illilite r or 0.1 gram o f the test material in to the conjunctival sac o f the right eye o f a rabbit. Follow ing a 30 second exposure period the eye was washed fo r 2 minutes w ith tepid, flow ing tap water. The test material was then instilled in a similar manner in the le ft eye which was le ft unwashed. A t various time intervals both eyes were examined fo r conjunctival irrita tio n , comeal in ju ry and irrita tio n o f the iris. The behavior o f the animal was observed fo r indications o f pain or discom fort. Both eyes were examined at intervals to 7 days post-instillation. If in ju ry o rjrrjta tio n persisted, examinations were conducted at 14 and 21 days post-instillation. A drop o f 5% aqueous fluorescein was used to help assess comeal in ju ry at the 1-hour reading and at all subsequent readings. - _ i 1 \ Grading of Responw : s A . Im m ediate Response (Pain) 1. No responsa. 2. V ary slight -- N o m ore than a fe w b lin k s -- N orm al in a m in u te o r so . 3 . Slight -- blinks -- tries to open but ca n 't. R aflaxes close eye. 4 . Moderate. Holds aye shut and puts pressure on lids, m ay rub eye with paw. 5. Severe. Holds aye shut vigorously, rubs eye with paw -- m ay squeal. 6. V e ry severe. H olds ay e shut v ig o ro u sly . M ay sq u ea l, claw s a t e y e , ju m p s, tries to escape. B . Conjunctive! Response 1. None. 2. V ery slig h t. Capillaries p ro m in en t. V e r y slight sw elling & /or redness. '3. Slight. Conjunctival membranes som ew hat inflam ed. M ay be som e sclero-com eal inflam m ation. Similar to response from a m ild soap. 4 . M oderate. Conjunctival membranes inflam ed and tore, lids swollen and reddened. 5. Severe. Conjunctival membranes red and sw ollen. N ictitating mem brane sore and inflam ed. 6. V e ry severe. C on ju n ctiv al m em branes m ark edly reddened an d sw o lle n . N ictitatin g m em bran e ed em a to u s. Pussy ex u d a te -- e y e m ay be stuck shut. Corneal Response (Before staining) E . Irritation o f th e Iris 1. No response. 1. N o response. 2. V e ry slight haziness. 2. V e r y slig h t. 3. Slight. C lo u d y in part. 3. Slight. Ju st perceptible. 4 . M oderate, Cloudy over whole but not opaque. 4 . M oderate. Definitely perceptible. 5. Severe. Cornea up to 50% opaque. 5. Severe. Marked change. 6. V e ry severe. C o rn e a co m p lete ly o p a q u e . 6. V e ry severe. C o m p le te lo ts o f fu n c tio n . Corneal Response (A fter staining) 1. N o n e. 2. V e ry slig h t. F e w d iffu se areas o f epithelial in ju r y . P ro b ab ly heal in 24-48 h o u rs. " -- _________ 3 . Slight. U p to 50% o f aye covered with shallow epithelial injury. Probably heals. 4 . M oderate. 50-100% o f eye injured but lesions are shallow . D ou b tfu l if vision will be im paired. 5 . Severe. M arked injury over w ho le area w hich m ay result in loss o f e y e . 6. V e ry severe. E y e lost. Com m ents O bservations recorded in this space m a y in clu d e unusual ty p e s o f severity o f responses n o t fu lly c o w r e d b y th e de scrip tio n s u n d er G ra d in g o f .ponse. Particular remarks m ay be m ade concerning the lids, nictitating m em brane, iris, pupil, lent, or anterior cham ber. SKIN IRRITATION -- DOW METHOD RATERIAL ^ V- j ) 4 ; TEST BY REPEATED APPLICATION UNDILUTED; m WET PATCH Q DRY PATCH D}ATE **--> .Jays on exposure % H 0 1 - yL '7 -APPLICATION NO. CAR HYPEREMIA D0N2155429TOXICOLOGY RESEARCH LABORATORY file n o . RABBIT NO. CACE NO. ? s r 4 9 W .3 O o r -i a* n% 1 I* .i METHOD A EDEMA NECROSIS EXFOLIATION HAIR LOSS SCAB SCAR ABOOONMEH APPLICATION NO. INTACT 1 X ys r 7(/ / \ HYPEREMIA 1a /i / \ EDEMA NECROSIS EXFOLIATION l // i ti // 1 // / /i // 1 /i/ i i / / Y\ SCAB / 1/ i ii // SCAR /1/ ! ii /J * -- AABBOROOAHMOEEHD APPLICATION NO. 1 1J \ HYPEREMIA J 1 ! /! i i /I EOEMA 1 i / 1 i i /f METHOD C NECROSIS (i /1 ii /J EXFOLIATION SCAB SCAR WEIGHT IN KG OBSERVATION BY M 1 1 1 Vlfil i f / / / / b 1 / 1 rnj / i e?.i7' 1ii / / / b -a/ (2a Pi.*1<i1 _____________ v\V \ \ ____ VA \ \ ) METHOD B !__ UCHCO S fo c h ili} , ^ 7 , DATE / z / ih r k-37a-fM3) -S K IN CONTACT-IRRITATION METHODOLOGY New Zealand albino rabbits are prepared lor this test by shaving the hair from the entire abdom en with a straight razor and barber soap. Anim als are then rested lor several days 10 allow any abrasions to heal com pletely and lo b e sure skin is suitable lor use. Applications are m ade accordin g to the m ethods described below and reactions and observations are recorded daily during the application period^nd at 2 weeks from initial exposure. Applications are usually discontinued and the animal humanely euthanatized upon production ol an irreversible skin burn. METHOO A (EAR) Liquids and pastes (no solids) are applied to the ear. Ten ~ 0.1 ml applications are m ade over a period o l 14 days. Th ese applications are lelt uncovered. METHOD 8 (INTACT ABDOMEN) Liquids (0.5 ml) or solids (0.5 g) are applied under an 1 by 1 inch cotton pad held in place by a cloth bandage taped to the marginal hair. Ten applications are made over a period ol 14 days. This allow s con tin uous, intimate contact with the skin lor a 2-week period. II sulticiant solid sam ple is available, another rabbit is treated in the sam e m anner except the cotton p a d s are m oistened w itt^disiilled water. METHOO C (ABRADED ABDOMEN) / nU W y % > j - An area o l skin about 1 by 1 inch is cro ss-h alch ed with a sharp hypoderm ic needle to penetrate the stratum com eu m but to produce no more than a very slight trace o l bleeding. Liquids and solids are applied as in method B . Three con secu tive daily applications only are made, which allows lor 3 days ol intimate, confined contact with the abraded skin. DOH2IS5UI GRADE f l eHbYiPtEiRsEfMiIlA}, NONE VERY SLIGHT SLIGHT MODERATE MARKED VERY RED EDEMA NONE VERT SLIGHT SLIGHT MOOERATE MARKED SEVERE NECROSIS NONE VERY SLIGHT SUPERFICIAL MODERATE OEEP VERY DEEP EXFOLIATION HAIR LOSS NONE VERY SLIGHT SLIGHT MODERATE MARKED SEVERE NONE VERY SLIGHT SLIGHT MOOERATE MARKED SEVERE SCAB SCAR NONE VERY SLIGHT SCLRIUGSHTTATION MCROUOSETRAATTIEON MARKED SCAB DEEP SCAB NONE VERY SLIGHT SLIGHT MOOERATE MARKED SEVERE DATE: COMMENTS: __''U2/2&IU- ,, u v 7Z . t .. . / z .jc fS 'S ' f i a M c f a fl& U L iJ a Jj/ f~ .y _______ ;________________ SKIN IRRITATION -- DOW METHOD V- & * ; :DOH2!55t3l TOXICOLOGY RESEARCH LABORATORY FILE NO. YS-ABASAIT HO. 9V3 <r CAGE NO. o r-i TEST BY REPEATED APPLICATION OUNDILUTED; Q ET PATCH K DRY PATCH OATE days on exposure % 0 1 METHOD A . EAR -APPLICATION NO. HYPEREMIA EOEMA NECROSIS EXFOLIATION HAIR LOSS SCAB SCAR X AU H r ? v ( : A* s 4 ' 1 % r1 14 ON ABDOMEN INTACT APPLICATION NO. C* r'3 {-He**'*) hyperemia EDEMA NECROSIS 1 AJ iJ 1/ i/ yr // /i /i )* METHOD B EXFOLIATION SCAB // i1 /i /i SCAR i1 / i V0 1 1v-- ' ON ABDOMEN application n o . ABRAOED O0k* 3 HYPEREMIA 1 i // EDEMA 1 i // METHOD C NECROSIS 1 i/ / EXFOLIATION SCAB SCAR 1 i/ / 1 i/ i / i/ i 1 WEIGHT IN KG y.ti OBSERVATION BY M l i QmJ ft*) SlCNCO &7 /1 /1 /1 /i /1 y/ /i /i /; /1 // /1 (L \ /i /1 /1 /1 /1 /1 l 1i t 1 1 1 /1 /1 & ilb j DATE \ _ _--_______ \ X \ \ \ V A 1.7Y44 k> 3V73 - (ni) SKIN CONTACT-IRRITATION METHODOLOGY New Zealand albino rabbits are prepared (or this test by shaving Ihe hair from the entire abdom en with a straight razor and barber soap. Anim als are then rested for several days to allow any abrasions to heal com pletely and to be sure skin is suitable tor u se. Applications are m ade according to the m ethods described below and reactions and observationa are recorded daily during the application period and at 2 w eeks Irom initial exposure. A pplications are usually discontinued and the animal hum anely euthanatized upon production of an irreversible skin burn. METHOD A (EAR) Liquids and pastes (no solids) are applied to the ear. Ten - 0.1 ml ap plication s are m ade over a period of 14 days. These applications are left uncovered. METHOD B (INTACT ABDOMEN) Liquids (O S ml) or solids (0.5 g) are applied under an - 1 by 1 inch cotton pad held in place by a d o th ba n d a ge taped to the marginal hair. Ten applications are made over a period of 14 days. This allow s con tin uou s, intimate con tact with the skin lor a 2-week period. It sufficient solid sam ple is available, another rabbit is treated in the sam e m anner ex cep t the cotton pads are m oistened with distilled water. METHOD C (ABRADED ABDOMEN) An area of skin ab out 1 by t inch is cross-h atch ed with a sharp hypoderm ic needle to penetrate the stratum corneum but to produce no more than a very slight trace o f bleeding. Liquids and solids are applied as in m ethod B . Three con secu tive daily applications only are made, which allows lor 3 days ol intimate, confined contact with the abraded skin. COJ ro cn c_n -CvO is) crade l HYPEREMIA I f *1 EDEMA NONE NONE 2 VERY SLIGHT VERY SLIGHT 3 SUGHT SLIGHT 4 MODERATE MODERATE 5 MARKED marked 6 VERY RED SEVERE NECROSIS NONE VERY SLIGHT SUPERFICIAL MODERATE DEEP VERY DEEP EXFOLIATION HAIR LOSS NONE VERY SLIGHT SLIGHT MOOERATE MARKED SEVERE NONE VERY SLIGHT SLIGHT MODERATE MARKED SEVERE SCAB SCAR NONE VERY SLIGHT SLIGHT CRUSTATION MOOERATE CRUSTATION MARKED SCAB DEEP SCAB NONE VERY SLIGHT SLIGHT MODERATE MARKED SEVERE DATE: -t /7U /s-----r--- <2 TT J L l / Z/ V ^ r & S It / ' t * _L..L COMMENTS: M gy 'yt y^ umiaX A u / h u x _Je - ex to VV' .li.Irli!it-cjfifijaiMff*-*' . k v-'" ' ' : ***s?^\"i>?-rjS_.TM./R*WjaAIm.T,N,H'>GE-2--,4FiI>.'DN-'IDVCI,HN.,LGORT'"TOOHXPBEHIioCtEctODhnNeLOtOmAOWXiGWcYaIClCAaHA/RCvELeEmsMTeTaIIOCrEcAShALTmLSCCaIbODOsoNMraPtCoArHNyIYCrKVE-"N. S. V^;'rVu'- ^-.F. aO6*.'*. - v ;. T1/12213^9_.1- 407i> 2-1 1.v>-,1 \'*-.x'K ~-1'*,"* ! isWUr. . "tv' ***"' - File report '*' > -- CW k ; , .:'vv Work By D * R * MMuu asell i --l .; : l r: lU pt By *&: ' : j. : . . ^ V '> , r^^r :g g i,:r Problem:. : ^ :'c'";-r vv:;- ^ : v > K* '.f - v-: " Some Information regarding the toxicity, of Dow 2,4-D on *; fowls was desired. ... -,! '` J '.V1. . .4 . <> - ; :v Vf' Experimental: Four groups of 3 chickens eaoh were set upland, fed diets containing given amounts of 2,4-dlohlorophenoxyaoetlo.acid. ` These groups were maintained on these diets for a week and then dls- ..:j_ J carded. At the end of the. experiment, all of-^ttie Jblrds -looked arid acted In an entirely normal fashion. 'The setup and data obtained atlT are summarised in Table I. -..I.'. ' - .. V^^-VX!.-' Conclusions: .. . 'v.-^V/ . ",,,4 . - 2,4-Dlohlorophenoxyaoetlo acid can be tolerated better :-"'cr*cnnI\ .-V*.i-''i _ by ohlokens than by rats and there is no danger of ohlakens, and presumably other birds, obtaining lethal quantities of 2,4-D from r. forage treated In the manner reoommended for.weed oontrol. _' - - rl-2 :>r*; j ir/i I ivu.: - , 1219 25 25C 945 4*^..1 .I*<F1> ` - -- .< r. Jiil 1 ;7 t- ' ate ' : - o r vt ' <> ! - Reeulte f .v;- -.ii ,:;., FFeeeeding ... of . 1 2,4 -Dt o . Ohlokne .. . with Their Diet . .. . '/'Weight'ln Crema v; ; r* C o n tro la 0.09C 2 . U>P In Diet 0 .V i, 2.4-P In Diet 0. 2.U-D In Diet White ;..Creen Blue Are. White Creen Blue Ave. White .Creen Blue Ave. White C r e e n Blue !.Ave." r, V--? ... . ____ ____ ^ 25`5 ./;.385 :\r^o ^ ! 3 5 ' ' 330.; 370 .. ': 2 75 `**i,.i*. t/,w'-i/- f 1 i7: .. ** .w; ... J ... l.^ ;32o k , 360 370 - 330 .;' 2 go` a- . .- ..;. .; .; ;^ v . Biochemical Research Laboratory ' V , THE DOW CHEMICAL COMPANY . -v;. . 7,4L* '. * -:tv - ;fc Subject . ) . >= . 7A -v: V. : .- .r 'cFha.* T12231.91A1V-1 1 - 1 - W' - 3 v PRELIMINARY . THE TOX ACETIC ICITY ACID INF -( KOF2 O3R27M2, A4- 3-T-)IDO-INC.HR.L.E0LRA0TPIHVEEwN.0TXuOY; -__ L -c- ; /.; lo-iq-lUl. ."i ^V.' :By. ,,H; A * _*_y s e / ' ToTechnical Service & Deve'nent Div. V: W. R(W. . V W. ea .Allen) sey -- ' Organic Research Laboratory % v -;; V : ^ Rapt. By ' Z f . / C . Q x S Y X i -%5:;y 7 i'0> * : Y r ?. Preliminary tests have Indicated that y^-dlchloro- . phenoxyacetlc acid has a moderate acute oral toxicity and that ./,-7 -': it does not produce marked skin irritation. i.Yt^SrY l Y ^ : We would not expect serious difficulties to result from handling this material in a reasonable manner. Y `.CSr>DE0| '..:.. Similar tests will' be made on 2,4-, 5 "t1:.r..Jli ck l oroP k enoxy**7 ' acetic acid when a sample is available. \.v" V'i'J' cn cn '. .7 ia-4- copies i -f/.-V. *** ; '* ' * '.l : ; ;; i/'': ^ I - -'jf `fc ' , i- . - :! -.*v--'-''-'-:''-:' .1 ] :.;..v"y' -V ' Yr:? i ' *i' v*v' r. '.v.- .;* . : . .`Y*-Y-d "*v* C *v-v ; 1JVV'-.' : ! >'`v ' > ,v ' '#1* : -,' - : -. ;*. ' ' /^ *' "*** r:. .^>1 : 2 U1219 25 25C A'S&l^ ------------------ -- - -- ' --- ;l: T H IS REPORT IS T H E PROPESi^TfVy T H E DOW CHEMICAL COMPANY D O H 2 1551(07 \ 742 ' ACUTE ORAL TOXICITY OP 2,^-DICHLOROPHENOXYACETIC ACID TO RATS, MICE, GUINEA PIGS AND CHICKS V. K. Rowe D. D. McColllster and H. Cr Spencer Biochemical Research Laboratory The Dow Chemical Company Midland, Michigan 17749 -1- The 2 ,4 -dichlorophenoxyacetlc acid was administered by oral Intubation to rats, mice, guinea pigs and chicks as a solution in olive oil emulsified with 5-10# gum arable solution. For comparison, the sodium salt of 2.,4-dichlorophenoxyacetic acid was fed in aqueous solution to rats and guinea pigs. The guinea pigs and the white rats were mature, young adult animals selected from the stock colonies of this laboratory. Young adult white mice were obtained from the Carworth Farms, Rbckland, New York. The chicks (New Hampshire Red) were purchased from a commercial hatchery and used when about three weeks of age. Mixed sex groups of each species were used In these tests. Table I summarizes the concentrations and volumes of olive oil solutions of 2,4-dlchlorophenoxyacetic acid administered to each species. TABLE I SINGLE ORAL ADMINISTRATION OF 2,4-DICHL0R0PHEN0XYACETIC ACID Species Per cent Material in Olive Oil Volume Given by Stomach Tube Minimum (cc.) Maximum (c c .) Rats Guinea Mice Chicks Pigs 5, 10 10 . 5, 10 3 0.4 0.9 0.1 0.3 4.0 2.9 0.22 5.2 amssizHOd Mortalities resulting from the various single oral dosages of 2,4-dlchlorophenoxyacetlc acid and its sodium salt are given in 17750 -2- Tables II and III. All surviving dnimals were observed until It was certain that they had fully recovered (usually about two weeks). Symptoms of poisoning, particularly with the higher doses, were ataxia and myotonia. TABLE II MORTALITIES RESULTING PROM ADMINISTRATION OP SINGLE ORAL DOSES OP 2, 4 -DICHLOROPHENOXYACETIC ACID Dosage (gm./ kgm. ) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 1.0 Rats No. No. Fed Died 10 . 10 10 10 10 10 3 0 :o 3 6 7 10 3 Guinea Pigs No. No. Fed Died 60 64 66 Ml N o ... No. Fed Died 60 51 64 66 66 Chicks No. No. Fed Died 60 61 66 64 66 ; D0 M2 155%09 ' TABLE III MORTALITIES RESULTING PROM ADMINISTRATION OP SINGLE ORAL DOSES OP 2,4-DICHLOROPHENOXYACETIC ACID, SODIUM SALT Dosage (g m ./kgm.) .0.3 0.5 0.7 1.0 Rats No. Fed No. Died 10 0 10 2 10 4 14 144 Guinea Pigs No. Fed No. Died 60 64 66 The acute oral LD^o values with their 19/20 confidence limits were/determined for each according to the method described by Litchfield a and /Wllcoxon . yhe results of the statistical treatment of the dosageregponse data are presented In Table IV. 1. Litchfield, J. T., Jr. and Wllcoxon, F.: J. Pharm. and E x p t . T h e r . 177516:99, 1949. -3 TABLE IV THE ACUTE ORAL LD50 VALUES FOR 2,4-DICHLOROPHENOXYACETIC ACID WHEN ADMINISTERED TO RATS, MICE, GUINEA PIGS AND CHICKS Species Form LD 50 (19/20 Confidence Limits) gm./kgm. Slope Function* Rats Mice Guinea Pigs Chicks 011-acid Oil-acid 011-acid Oil-acid - U:375 (0.302-0.465) O .368 (O.3 I2 -O.434) 0.469 0.397-0.553) \ " 0.541 j,0.358-0.817) Rats Guinea Pigs Aq.-Na salt Aq.-Na salt O .805 ('O.6IO-I.O6 3 ) O .5 5 1 j,0.417-0.727) The fold change in dosage required to produce one unit standard deviation in response along the line. 1 .6 2 " 1 .2 3 S 1 I7 SE 1.811*0 l-77 I .5 5 Or> DOMZI5SUO The Litchfield and Wilcoxon test for parallelism of two lines revealed that the dosage-response line for the rats (oil-acid) deviated significantly (19/20 probability) from those for the mice and the guinea pigs receiving the 2,4-dichlorophenoxyacetic acid in olive oil. The line for the chicks also deviated significantly in parallelism from 4 those for the guinea pigs and mice. The tests for parallelism of two lines and estimate of relative potency indicated no statistically significant differences in comparison of rats versus chicks and mice versus guinea pigs. The dosage-response curves for guinea pigs (oil-acid) and guinea pigs (aqueous-sodium salt) did not deviate significantly in parallelism or relative potency. A comparison of the rats (oil-acid) versus rats (aq.-Na salt) revealed no significant difference in parallelism of the two lines,but the test for relative potency indi cated that the free acid was significantly more toxic to rats than was the sodium salt. 17753 I I ISS I 31100 i i"T f i. :'*-lV.-*v .*-wr*-`t*:' pT '.- V `?AV un '1*0. .*' Biochemical Research Laboratory TH E DOW CH EM ICA L COM PAN Y , Subject THE TOXICOLOGICAL PROPERTIES OF 2 #4-DICHLORQ- -- PHENOXYACETIC ACID, AND ITS SODIUM AND ALKANOLAMINE SALTS, AS REVEALED BY EXPERIMENTS UPON LABORATORY ANIMALS 743 Fa. T2 3.14-11-1 a*. 1219-02 R.e.d nn.d 6-12-4-7 Work ByV. K. Rowe L. F. Ney H. C. Spencer To W. R. Veazey Check Rept. By SUMMARY The acute systemic toxicity, as shown by the administra tion of single doses to rats and carries, was the same for the free acid and the sodium salt, and was of the same order as that of phenol. The studies on chronic systemic toxioity, using repeated oral administration to rats, showed but very little' evidenoe of summation (or accumulation) of injury. The LDQ for single oral doses was 0 .3 g./kg., whereas the largest daily dose without de tectable effect was less than 0 .1 g./kg. but greater than 0.03 0 0 ac p*o g*Ag. The outstanding pathological effect was seen in the gastro-intestinal traot, consisting of inflammation, sloughing, and hemorrhage; but minor changes were found in the liver and cn <_n CO CO cm kidney. The free acid and its salts are but slightly irritating to the skin. Only strong solutions were capable of causing irritation. / ' >>- cr cOQLc;.J r* Cl C CJ. There was no evidence of absorption through the skin. CONCLUSIONS 1. 2,4-Dlchlorophenoxyacetic acid and its salts are moderately toxic by single and repeated oral administration. 2. The principal toxic action on repeated administration waa exerted upon the gastro-intestinal tract. 3. The acid and its salts are but very slightly irritating to the ' skin, and are not absorbed to an appreciable degree. 4-,This m aterial presents but l i t t l e hazard when used as a weed k i l l e r . The use con cen tration s are s t if flc le n t ly low to o ffe r no hazard of systemic toxic effects and of skin irritation to man or animals. Concentrated solutions and powdery solids might 1219 25 25C 945 .. 17735 Biochemical Research Laboratory T2 3 .llk.ll- 1 Page 2 o Materials tested: 2,4-Dichlorophenoxyacetio acid: The regular plant produot contain-" ing at least 9&$ of the acid and less than 1$ of c od i c h l o r o ^ n phenol. Fusion point at least 1320c. co 2,lk.Dlchlorophenoxyacetio acid, 'sodium salt with one molecule of water of crystallization: The regular plant product con taining at least 93$ of the salt. 40# Liquid Weed Killer Concentrate: A kOj, solution of the acid in water as a mixture of alkanol amine salts. Acute oral toxicity lbr rats and guinea p i g s : The 2 |lk-dichlorophenoxyacetic acid was administered as a water solution of the sodium salt (pH 7*2), one ml. of the solution containing 50 mg. of the acid. This solution was administered by stomach tube to young adults of both sexes, the rats receiving volumes of solution up to 5*9 ml* and the guinea pigs receiving volumes up to l4. 8 ml. The largest single dose given to guinea pigs was 8.9 ml., larger amounts being given in 2 doses at a 2hour Interval. All deaths oocurred within ^8 hours, most of them within 24-. The survivors were gaining in weight and of normal appearance within 7 days after feeding. The results given in Table I, may be summarized as follows: Animal Rat Guinea pig LDq 0.3 g. pe* tg. 0*3 g* per kg* LD100 1 .0 g. per kg. 1 .0 g. per kg. Table I Acute Oral Toxloity of 2 4-Dichlorophenoxyaoetio Acid for Rats and Guinea Pigs when Fed as the Sodium Salt Dose in gjjfcg- ,, 0.3 0 .5 0.7 l.c Rat s Nof Fed No. Died 10 0 10 2 10 IfU m- Guinea Pigs No. Fed No. Died 10 0 10 6 10 5 10 10 17756 T 2 3 :i4 -ll-l Page 2 w- w Table I Results of Feeding of 2,4-D to Chickens with Their Diet 'ate -13-47 _____________________________________________ Weight In Crams______________________________________ ________ Controls_______ 0.05# 2.4-D In Diet 0.1# 2,tj) In Diet 0.3# 2,lup ln Diet White Green Blue Ave. White Green Blue Ave. White Green Blue Ave. White Green Blue 215 290 3^0 , 325 262 260 290 210 292 230 260 275 222 300 230 Ave. 265 -17-47 265 360 400 2i,2 375 320 355 255 250 295 330 330 221 320 260 291 -19-!+7 255 335 410 , 385 36o 330 370 275 62 320 360 370 15 350 250 333 ve. wt. gain 21 2 9 . #2 3 . otal food onsumed 500 520 785 675 Z 6 8 G 9 ) ZMOQi .m- 4 Biochemical Research Laboratory T2 3,1^11-1 Page 3 A preliminary or range-finding aoute oral attidy was con ducted on the 40$ Liquid Weed Siller Concentrate using rats. The *10$ concentrate was diluted with an equal volume of water for feeding. The results are shown, below: 1D0HZ155393 Dose in g./kg. (of the 40% concentrate) 01003.....07503 Rats No. fed 2 2 2 2 2 No. died 000 2 2 From these data, it appears that this liquid concentrate may be slightly more toxic than the 2,4-dichlorophenoxyacetic acid content would account for.- This is not at all surprising. Irritating action upon the skin of rabbits: Tests were madd with albino rabbits using daily appli cations upon the ear and shaven belly. The applications on the ear consisted of a thorough wetting of the inner surface once a day, 5 days a week. The applications on the belly were made by a small cotton pad, wet with the test solution, which was held in place by a cloth bandage. Tests made with 5$ and 1$ water solutions of the aoid as the sodium salt and with a 5$ solution of the aoid in butyl oarbltol aoetate and in 50$ ethanol resulted in no significant re sponse. The ear usually showed nothing; the belly showed very slight hyperemia and soaliness, a reaction frequently seen in oontrol experiments. A 40$ concentrate of the acid, present as a mixture of alfcanolarolne salts, seemed to be strongly Irritating when bandaged ^on the skin of the rabbit, producing a severe inflammation and edema with sloughing. After this reaction subsided, however, daily applications were made with but a very slight irritation 17758 D0H2155394 BTi2o3c.1he4m- 1ic1a- 1l Research Laboratory Page Ij- resulting. Dally applications of this concentrate upon the un covered ear resulted in no response. When diluted to the concen tration recommended for use, this mixture of alkanolamine salts produced no response in the rabbits1 skin. In none of the tests on skin irritation was there any evidence of systemio toxic effects. Repeated oral administration to rats; Experiment I Experiment design: Olive oil solutions of 2,4-diohlorophenoxyaoetlc aoidf suspended in 2 to 3 oc. of gum acacia solution, were administered by stomach tube 3 days a week until death or serious intoxication occurred, or until 20 doses had been given. The concentration of the olive oil solution varied according to dosage of the acid so that each experimental rat received not more than 1 ml. of the oil daily; the control rats reoeived 1*5 ml. of oil daily. Groups of 5 female rats received each of the following doses in g. of acid per kg. of body weight: 0.003, 0.01, 0 .03, 0.1, and 0.3. The control group consisted of 6 rats. The rats were weighed for 2l days prior to the beginning of the experi ment, then matohed according to body weight and started on the experiment, the ages being 60 to SO days. The various groups had average weights of 17^ to 176 g. All animals were weighed twice a week during the period of feeding and were observed for evidence of ill effect. The examination of the animals consisted of gross obser vation of organs, determination of starved body weight, and weights of liver, kidney, heart, and spleen, determination of blood urea concentration, and microscopic examination of tissue sections from heart, liver, kidney, spleen, adrenal, pancreas, and stomaoh. ''Rats on doses of 0 9 0.01, and 0.03 g* per kg. were also examined f i ^ blood hemoglobin, total red cell count, total white and differ ential cell count. FIGURE I Biochemical Research Laboratory T2 3.14-11-1 Page 5 00H2155396 ' Results! Three rats receiving 0.3 g per kg. died after two feedings, so that the two survivors were killed and autopsled. Of the 5 rats receiving 0.1 g. per kg. two maintained their weight, three lost weight to a marked degree and had diarrhea. All 3 were killed and autopsled after-receiving 13 doses. The rats on doses of 0 .03, 0.01 and 0.003 g. per kg. showed a slight depression of growth at first, but recovered, so that at the end of the feeding period the greatest difference In average weight from that of the controls was 6$. This was not considered significant. Hematologloal examination of the rats receiving 0.01 and 0.03 g. per kg. revealed no differences from the control group. See Table II. The measurements of organ weights revealed an Increase In liver weight In the two rats that maintained their body weight on 0 .1 g. per kg., and possibly a slight Increase In kidney weights. See Figure III. Table II Summary of Hematological Studies on Female Rats that Had Received 20 Doses In 2/ Days of 2,4-Diohlorophenosyacetic Acid Dose, g./kg. No. of rats in group Erythrocytes per eumm. Hemoglobin, g./100 00. Leucocytes per cu. mm. Differential count: Neutrophils - Filamented Lymphocytes small ~ large Mean cell diameter (microns) Controls 6 1 1 ,1*0 0 ,0 0 0 13.9 IS, BOO 10 66 k 6A 0.03 5 10,500,000 13-3 i s , 300 15 32 7.0 0.01 5 10,000,000 12.9 1 7 , too 9 *74 6.S *7D- Bioohemlcal Research LaboratorT23.1H--11-1 Page 6 tJrea-nitrogen determinations were made on ozalated blood obtained at autopsy from the control and experimental animals The results are presented graphically in Figure II. It is evident that, exoept for 3 animals, the urea-nitrogen concentration was essentially"~th~e same in the animals that had received repeated oral doses of 2,4-dichlorophenoxyaoetic aoid as in the controls. The three high values (2 in animals that received 0.01 g./kg. and one in an animal that received 0 .0 3 g./kg.) may indicate slight impairment of kidney function in these animals. It is impossible to evaluate properly these findings without more corroborative work, but at least they should serve as an indication that repeated ingestion of 2,4>-dichlorophenoxyaoetie acid might lead to kidney dysfunction in some instances. Gross examination of the two rats killed after 2 doses o 0.3 g* per kg. revealed a severe irritation in the stomach and gut. There was a great deal of blood throughout the gastro intestinal tract, with inflammation and ulceration of the mucosa. This irritant effect was probably the cause of the 3 early deaths at this dosage. The 3 rats that showed diarrhea and marked weight loss at 0.1 g. per kg. had a moderate irritation in the gastro intestinal tract. The two rats that maintained their weight showed no irritation. The control rats and those receiving 0.03, 0.01, and 0.003 g* per kg. showed no gross evidence of ill effect. Hlstopathologyt Sections of the heart, liver, kidney, spleen, adrenal, pancreas, and stomach were prepared for mloroscopio examination. The results of this work are presented in Table III. No histopathologloal changes were observed in the tissues from the control animals or in those that received 20 doses in 2S days of 0.003, 0.01 or 0 .0 3 g./kg. 2,4-diohlorophenoxyaoetlo aoid. JD0H215539? i i fv':-.f<jr*, >77 J. a / o U y ^ a FIGURE II D0H2I 55398 FIGURE III 00*iS51 3M0Q Biochemical Research Laboratory 7T23#l4-ll-l Page Except for the gastrointestinal irritation, the only significant change found in the rata that received 15 doses in 2l days of 0 .1 g./kg. was slight cloudy swelling of the liver. Such a reaotion is not severe and is commonly believed to be reversible.,., The same type of chng'ln the liver was also found in the rat s that received 2 doses of 0*3 g./kg. These rats also showed slight kidney involvement. Summary of Experiment 1 : The results of repeated administration by stomach tube are summarized in Table IV. The only toxic effeot of importance was local irritation of the gastro-intestinal traot. This action was produced by doses of 0.1 g. per kg. or larger but not by doses of 0 .0 3 g. per kg. or less. The injury to liver and kidney at doses of 0.1 and 0*3 g. per kg. seemed to be of a minor nature. f'7 ` i o Killed or Died Heart It Spleen I Pancreas Stomach Species: R&c Sex: female Table III BIOCHEMICAL RESEARCH LABORATORY Summary of Pathological Findings Repeated oral doses: .g ./lcG . Repeated vaoor exposures: ra g ./l. rc-dl Dose Ht i 0 zz r, < g*/ kg. No. doeee No. of dava 3506 0 20 28 3508 0 20 28 3681 0 20 28 3^9 0 20 28 25I7 0 20 28 3^93 0 20 28 K K K K K K Condition Normal R * R 3cbn Al N N N N N N w OJ >H 0) c. rdH Al NN NN NN NN NN NN N N N N N N -Ol1-- 1 cti <D ud < N N N N N N N N N N N N Problem No. T 2 3 . 1 U - H 1 Exot. Ho. 2 9Run No. K5372-3 Material: , -diohlorophenoxyacetlc acid 03 t-- 0 fH O rHj m a: N) N ) 1.5 oo. olive ) oil dally N ) controls N N ) ) 3195]>.003 20 28 K N 5^91 C>.C03 20 28 K R 1516 i>.003 20 28 K 511 i>.003 20 28 K H l706 >.003 20 28 K j N NN N NN K NN N NN NN N N N N NN N N NN 519 0.C1 20 28 K 520 0.01 20 28 K W 0.01 20 28 K 499 0.01 20 28 K 4-92 0.01 20 28 K a H a a a K NN N NN NN N N N N NN N N N N NN N NN N NN N NN 1 2 1 9 - 9 7 - 5 N0 - 1=2 N%ormal tissues as comoared wit .1 tissues for control animals N N 1-1FU c c 1i i'i17 nfl ;----- Page 8 r) n Species: Sex: female Table III (cont. ) BIOCHEMICAL RESEARCH LABORATORY Problem No. T 23.lL.ll.-l Expt. No. Summary of Pathological Findings Run No. Material: K2 3 7 2 -3 2t^ D i chlorophenoxyacetic aoid Repeated oral doses: ,g.Ag. Repeated vapor exposures: .m g . / l <rdnH: t-oA Dose kg g* ./ N o . xPes No. (fiTye WHHOHO-UOoH> Condition OfGGcl) -ucCPdD Liver Splee Mk s iKCLs0HAD)3I. C -- 1--fC0c0nt31i1 < aGGC0Oc,dO3 cB0d5{S8e n |q , mCGOD^fGbc-d, Orose Exam. tomach Intestin e 351 0.G3 20 3^90 3.O3 20 3665 3.03 20 3^95 3.03 20 39 3.O3 20 26 26 25 25 25 K Noraal KR KR nK K NN NN NN ..1L 1 N NN NN NN . .N __N. NN J LN N N NN 1_JL . N N N ....N . NN 1 3*^9 0.1 15 3303 0.1 15 3902 0.1 15 O J L369^ 1*) 355 0.1 15 O3521 . 3 2 O35B^ . 3 2 21 21 21 21 21 2 2 i_ + J LK Marked loss ir wt. 'Diarrhea. ~.th . N IL . + J IK R K + +*fR K +K Normal app. + IK R H N N N NN ...N _.N. .._N.. N NN nN _..N._ N _ . N N NN K Moribund KR + + +N sl.o 1 N N N N NNN ++ +fr +4 +N NN NN ++++ ++ ++ Page 9 11 1 N = Normal tissues as comonred wit i tissues for control animals i 219_97_e c -i h 46 "O ' CO -3 -- ?- 0 Ci-C-i 7 M n a - i - Table IV Summary of ExperimentalofRes2u,lUt-sDiOcbhltoarionpehdenonoxyFaecmeatliecRaatcsidth(aKt237R2e-ce3i)ved Repeated Oral Doses Dose g./kg. 0 0.003 0.C1 0.03 Percent in olive oil sol *n 0 0.0$ 0.2 0.6 No.of doses 20 20 20 20 No. of days 23 23 23 23 Growth and Survival Normal Normal In appearance; 3-e# below controls In final weight 0.1 2.0 0 .3 6.0 15 21 3 lost wt. rapidly; had di iarrhea 2 maintained weight; no diarrhea 2 2 3 out of 5 died; others moribund Hema Blood tology urea Gross Organ Hlstopathology appearance weights of viscera Normal Normal Normal Normal Normal -- Normal Normal Normal 3 nor Normal mal-; 2 si.high Normal Normal Normal Normal t Normal ^ nor Normal mal; 1 si.high Normal Normal -- Normal Gastro Livers- Llveri intestinal Kidney-f Kidney: normal irritation -- Normal Normal Llvenf Liver i Kldney+ Kidney: normal Gastro Normal Liver + intestinal Kidney! irritation PTBa2igo3ec.1h1e^0m1ic1a-1l Researoh Laboratory m s s u n o a j. V<*1 TB2io3c.hllekm.ilcla-1l Research Laboratory Pag1 db M2155^04 Experiment 2 Design of experiment: Diohlorophenoxyacetio acid was incorpor ated in the rat food in an attempt to avoid the aoute irritation in the gastro-intestinal tract. The normal rat food was a finely ground powder of fresh ground whole- whe'aty 55$; dried whole milk, 25$; dried meat residue (liver), 12#j dried brewer's yeast, 5# oaloium carbonate, 1 and iodized salt, 2$. Weighed amounts of dry, ground dlchlorophenoxyaoetlo acid were added to this diet to give concen trations of 0.01, 0.03, 0.10, 0.30, and 1.0# by weight. Groups of 5 female rats were started on these concentrations, and on the normal diet, when $6 to 1 0 8 days of age. The rats were selected and put in matched groups according to growth made over a period of about 3 weeks Just prior to the experiment. Whenever possible during the oourse of the experiment, rats that were ob viously quite siok and losing weight were killed and autopsled in order to determine the cause of the ill condition. All animals found to have ear infections were promptly killed in an attempt to minimize the spread of this infection. The examination of animals at autopsy was the same as that made in Experiment 1 . Growth and survival; The rats on diets containing l.C and 0.3$ 2,lk-dichlorophenoxyacetio acid lost weight at a very rapid rate so that they were killed and autopsled after 1& days (on rat died on the 0.3# diet). Rats receiving a diet containing 0 .1$ of the 2 ,1k.diohloro- phenoxyacetic acid grew poorly. Only one rat survived for the duration of the experiment (10S days) and two deaths were unex plained except as the result of the experimental procedure. Rats receiving doneentrationa of 0 .0 3 and 0 .01$ grew as well as did the controls, the maximum difference between group average weights being less than 5$. All deaths in these and the control group were due to ear infections or pneumonia. Food consumption was extremely low at concentrations of 0.3 and 1.0$, the exact amount eaten being uncertain because of the large amount wasted by the rats. The amount of food eates at the lower concentrations was essentially normal. < ~ X Biochemical Research Laboratory T 23. Page l1l M2 .l-l DOM2155405 - ~ Blood urea concentrations, made at autopsy of the sur vivals, were somewhat lower in the experimental animals than in the controls. This difference is of questionable significance; however, since all values were in the normal range, the control values being grouped at the_.hlgh- end. Table V UreeuBlood Concentrations at Autopsy of Diet Animals Concentration of Dlchlorophenoxyacetlo Aoid in Diet 0$ 0.1 $ 0.03$ 0.01$ No. of Animals 1 3 Blood urea mg./100 ml. 23.2,21^.7 ,2 6 .9 ,37.1 12.5 16.0 ,1 7 .2 ,1 3 -3 14-.3 ,1 8 .6 ,20.5,22.1 Results of autopevF The rats killed after 1 6 days on diets containing 1.0 and 0.3$ diohlorophenoxyacetio acid were thin and poor, with depleted fat depots. The results of organ weight determinations in rats on the 1.0, 0.3 and 0.1$ diets are uncertain because of the decreased body weights. The weights of heart, liver, kidney, and spleen of rats on 0.03 and 0.01$ diets were normal. Microscopic examination of the tissues revealed, only a slight parenchymatous degeneration of the liver cells, in the rats on the 1$ diet. Two of the ^ rats on the 0 .3$ diet showed a slight cloudy swelling in the liver and in the proximal convoluted tubules of the kidney. The one rat surviving on the 0 .1$ diet showed a very slight cloudy swelling in the liver. None of the other animals showed any pathological changes referable to the treatment. 90HSIZMOQt PTBa2ig3oe.c1h41e-3m1ic1a-1l Research Laboratory Conclusion on Experiment 2 t When 2 ,h-dichlorophenoxyacetio acid was Incorporated in the diet of rata over a period of 1 0 3 days, adverse effects were observed at concentrations of 0.1$ and higher but not at concentra tions of 0.03$ and lower. _The--pathological changes, found only in the liver and kidney, were of a minor nature and were insufficient to explain the marked gross response observed. Extreme weight loss at concentrations of 03 and 1.0$ were associated with an almost negligible intake of food. rl- 4 - i i THBEiocDheOmWicaCl HREeMseIaCrcAhLLCabOoMraPtoArNyY Subjact RANGE-FINDING- TOXICOLOGICAL TESTS ON CHICKENS ---- W!TH 2,ikiDICHLOROPHENOXYACETIC ACID 744 fu. T 2 3 . l l L - I l ~ l chg. 1 2 1 9 - 0 2 Rac'd WFWodrk B66y---12D.35---4?4.--.77 MUSSell To File report Probiem O Some Information regarding the toxicity of Dow 2,4-D on fowls was desired. <_n cn Experimental Four groups of 3 chickens each were set up and fed diets Co Oo co containing given amounts of 2 Jli--dichlorophenoxyaoatlc acid. These groups were maintained on these diets for a week and then dis carded. At the end of the. experiment, all of the birds looked and acted in an entirely normal fashion. The setup and data obtained are summarized in Table I. ConclusIons: 2 ,4-Dichlorophenoxyacetic acid can be tolerated better by chickens than by rats and there is no danger of chickens, and presumably other birds, obtaining lethal quantities of 2,^-D from forage treated in the manner recommended for weed control. rl-2 1219 25 25C 945 6dGI2M0i Li ti W*4. Biochemical. Research Department THE DOW CHEMICAL COMPANY 745 . W 1?.?!? RESULTS OP SEMICHRONIC ORAL TOXICITY STUDIES ON 2.4-DICHLOROPHENOXYACETIC ACID. Pile T23.14-11-1 Chg. 1219-02 Rec'd 9-27-44 Pin'd 8-3 1-5 0 WorkBy V.K.Rowe To Agricultural Projects Committee Att'n: W. C. Dutton W. W. Allen D. D. Irish J. F.. Kagy - G. E. Lynn Executive Research Committee Britton's Division Att'n: J. W. Britton R. C. Dosser Legal Department Att'n: W; W. Sunderland' Check UNIT INDEX 8 -3J-S - k: oo cc_nn GO CO CT3 The effects of feeding 2,4-D repeatedly to rats either by stomach tube or as a part of their diet are described. INDEX HEADINGS 2,4-Dichlorophenoxyacetic acid Acetic Acid: 2,4-dichlorophenoxyPhenoxyacetic Acid: 2,4-dichloro- MATERIAL The samples of material used in these tests were designated as K2372-3 and K2372-4. They were regular production samples obtained from 267 Building in 1944 and 1945 ^essizHOQ; Biochemical Research Department T23.14-11-1 Page 2 PROBLEM The toxicological work reported in the attached summary was carried out some time ago. The purpose of doing the work was to acq toxicological information upon which to base conclusions with regard to the health hazards encountered in manufacture and handling. The attached summary of thi3 work was submitted as exhibit in evidence on August 2, 1950 to the P.D.A. Hearing for the establishment of residue tolerances on fresh fruits and vegetables. CONCLUSIONS It appears from these experiments that 2,4-D is moderately toxic when fed repeatedly to rats. Doses of 30 mg./leg. by stomach tube were well tolerated and a dietary concentration of jJOO p.p.m. was well toler ated. This information together with the other information available led us to suggest that a residue tolerance of 20 p.p.m. 2,4~D on fresh fruits and vegetables v/ould provide a wide margin of safety. ia (ID ) U 9 f* )< v J1 > I M a . 1 0 / J | W 3? C A S S A *. u . 4 K O K M A N .1 f . l L L Y aral i HIM N I '.dm.-Ma,. si<hrsis m H r v t r u r U -n>: J fc llu s e m l i h u | t | l t <* ,io*l *! 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U K l.U T hy ir*rarhiw m v a n n o ass*!.. pckici> A llC ll M ALU CH O ? 33*4* 2 6 1 -2 7 0 . 1 9 1 J .- - 6 .i l rent hypotheses pgi io r w a n i t* ex p la in ib* o rig in of r a m m u c r n ir p o te n tia litie s <4 a n h -m n a r r exa m in ed Ifr s u if * **l term inatio ns *4 p ly r y r lt r h t d r o r a r ts u i* i-a r n is i . sji tn 12 Miiiplri 4 m a i r n a U r o m ^ i * r 4 4 i'h r\m *4il` a r v r-por-d ln 1 3 in** **'sam ple a n a ly x rd . rarrm o o *m * i'omp*amdn a n * < J > rrrv H |7u ro ntpiM m ia p r i la W y p r n r t r a ir thi* a n i r p i d u rin g t i a i v ' f t **l iid u n * tria l irr a tm r n t. as ra rh rv u m lH l i m n*4 o i.o n |s 4 w vi-lu* h u ir**- hr a r h i M T h n r p r w r n r r mav i * I r r a i*arrtm <i*ni* p * ii n i ia i i h to ih r fthrrm whu a lr r a d v rHam Mi and C r T h r w m r ta U ra n mhilMt b r n n p v r r n r *h d r tu \1 a s r in hi- luma and Ihtis r r t a r d th- m r ia la ^ ir u n ta nd<>t(radailon <4 ra r n a o ^ rn n * h\-dri' arb*ta F u r t V r n s r a n h ti-nds to d r t r r m m r (h r *4 ta rrim ^ n nu- hvdnx-arbons in onte r i.. s u p p rn a this forra i4 --C M U 424 0 M A R T IN E T . P . Wrtem< in n * n s r . a p ro g ra m lo r thi* pros-. Hun of h e a rin g faru lli -. a iud>rtsis d tsirtlsiiu n 4 pn*tN* 4 n-aw-t prisurr to n<Hf is nret a ry AHCH M A I. PRQ4 3a * " i ^ * 2 0 l 3 7 j -A d in -r a r r r l a u i Sound I r r r l . ih r *vp*Mirr lo kirinc ih r w hole worfcitpc p r r tiu t **n ia iU a u s k i* ih- h r a n n t; a r u .lv ih r o r k n irn . W hen p r n d s i4 mra**vp<*surr l o m u s r a r r in <rr*p rr?w 'l. its* (Hal expomare lentrth n*m aininu ih r vam**. m uwr *4 hudv*r m o-nsiiv ra n n r h ea rd w idu m i in r re a s r d ris k A |ira iii*a i m rth ie i. iiasrd <ai Ihe w orks i4 K r y ir r . v a n rsiald islu sl shirt alH m s thr d rtrrim n a lto n n | the Irn a lh and d iM rth u lti i <4 iru* p r r d s rturtm i a hi* h it is ^dvis.tM * In w ith d raw ih r v o rfc rrs fr'*ra m u s r .ic u r c s M i In m m v r.i-s. this m rdwuj would he U` SS s lr tn ^ rm than ih* o n r lum -d u|>>4i llw- mus ra tin a n u m b e r" and thus m on* r a v ilv a m - p t o l hv ih*sr rrs|4isii|fo r the orcanixatifft *4 w ork S i v r r t h r l m . *t s<*ulil in cem -ral ! m o re s irra u e n l m ih r ram * 4 s h r ill m uses 'r r n t r . i l lrv^iuam v r.ir-^v ^^ZO Q Q N xi.-C M . M 4241. ASaOLLY. Mt .e0 nSKrXs'^xoort A CAV1C.NKAI X l-'-nn. urni. ra u s rd by n -h e s a n r A R C H M A L P R U E 3J><4.: J O O O I'V 1-J2 -- T s n w*w r a s r s >4 p *4 y a e riilh 4 ih r vrniu*rv*rao<i*r n p r o n - *4*- s e n rrd in y*^na le a th e r fa rtitry w o rk rrs usuti: d u e s <th a (s-tiot uni U*)C hade having a hudl rin d e n t i4 h -h r s a n r T e s ts * th*- ia t**rv a ir showed a so lrrn t te v rl U ic V r than ppra OnaJumum li v rls .t Its ppm and 300 ppm w e r e hvt in Japan and Ih r 1*SA r r s |n r t u * It Although the r m a U t r - h P l d i t * 4 t h d e te rm in e d , ih r ik u tc rr *4 petroleum C and n h r r -- ih r e f ta in and p rrri-n u v i* nteasur* s in vo lving a t m * p h r n r r m i m l s should h r iahen <> thiard acainsi this new s o u rr e 4 Ios t r p o ly n e u ritis L . II. 4242 T O P P IN G , l . and J M PfTHK f V i r r m t n a t o n 4 tn ununt* t n r fr u r y in n a t u f jl w ate rs A N A L t 'H IM \ C T A 2l 200*203 ( V i i - - A f r r r n l t v rtrvH^u*d prs -durt* m r o r p o r jU n a a K M nO ^* H 2 -H4 s*4u (|ii and N a m e le s s ro id vap*r Jtmir jlis<*r|itt< ^ r i tr* -- ttp h o to m etry w as used fo r th* drti-rm m utH n 4 Hs in s ra s a i r r s *-n rtrh e d w ith Hu at le v e ls *4 0 1 . 1 0 and lO.O 1*1 as p u t *4 studi s 4n the rf| t*ts <4 iuM*thol aniunts ol trj- m etals o r m ari.w f* d rh ain s. The technique m*si-rthed l e i " * p erttu itis l s a l* r samples to he analy<ed fo r Hu down to 0 002 u I " I . - u h a 4 - 1 sam ple S* al* expansion w as not r t q u t r H . so t h jt r s ir e n w lv st*adv lias* lim* ui the c h a rt re c o rd was ensured *-*<' M M H4243 51E G E L . J . and T -I .S P A C K h U S r h r * a to hvTs r i i i.imm . 2 l i ^ j H i^ ij 1 t r r ^ i i j | <2 t2 irtM sM n>j d J * w ^ e ir H r ^ s jM n iH ^ l w i J j 4wi* /?7& 771 , 4 3 M I ........ I. . i j . i . J . m I | IS l - H X A I I ! -1 -H IIA i I IM O ): 1A0-',4 21*7? An iitMisoalU hii'h *lo i.M v m * a le i*.m lead . * v ita m in A i i i I oj io n Its I o id ien li.wl *`lini**.l a*d radi#.|oUir eviitertres 4 Ih* i* , i *l on.i* i.im a l |ir* s'.**# im i |r.- e*r<4#ospinal flu id pritein it* # o ti I'Uat** fjiOt**i 4li*at *4 llo-se sitilinun induced by udrai; ^-- A r n 3 i r MH u ll 4i <4 I I.* immts 4 vita m in A lv a health faddist m other . --C / 4244 A .M iN Y M lII.S f o v o i iy 4 ihlt.un 1 I R M K 0 J 3 t 3 h 2 * i : _ -*>11 .o e n nuaiv*i*ttr and -umulatltre pmssi fi rra- B hI h u o -s he tn.iin iia/.ii to the ta.eft*ril p u M ir Ih the fo rm <4 r b n ii* iil*-s omI ms* in nii-s `I t .Its ra n *aftt r r Ihe b d y by tn h a la iiis i as t ihi*i ov oil' stoat uh ' i * e i <-*atlan*inald f . / d s *r fro m ihe hands !t iis**r|i|>4i ilw .* v j i >Ih* skm S everal pla*4irau r a s e s , the im - |s*tI,in * ou lodine 11 m he i|ttei*fU taM iau iv m is when e a r ly lo /.i r a r *i*.|*s't al s;5s . utsTr-d and 'he therapy 4 th is kind +-4 !*! tiv ar* d*ossi| M \| 424' H H K V U lN t H I H4 H 1 .'H )IJ )N and H (ilR A R O , t t - r n u * in s i H i s d i*v |dt-*e^H..s*t fens ARCH M A L h l O F 3 3M 5r l 'K - i o i |**7.* ! Iv- * as*s .4 d e r m itis w e re i4senred ver a 4 y r l*rt*al ! all l.ik lit la* i**rv *>rk*-rs usmu p h e m p la s lie re s in s Th# (.ns e*asisied *4 **rvih*nt.i**>os jM pules lcai*d n exposed rtiw r t s .4 ihe lelv Manv * * n a*oi||i aled lv .veraiehinU. No tfeiteraJ i/ l i*s.*is *a iK M -iio i im is mav hav*a he*h a re s u lt 4 the fa rt thai .iJf*rtcd w **rk e is * r *fu-klv fn*<v>-d to aher )hs in (Im fa c to ry lite l*s.ais ,i|i|* aari-1 tr**ni ten w eeks :* a few months a f te r Ihe Is ctnninu *4 V|swr* in m**si ra s e s -rx re p f in 2 m o re slo w ly *d rv e in ) *.is*s .<| ia /i*n M in *>oio*'t<k is a .H*tve|v m am pulaunc ihe resins. S i * is -Iuiiu infoi fiu ta te li p.u 1. r4Hu-id P re v e n tiv e m easu re s laJu iih luf*d the ir.in s o r .4 rk*ar * w ith htsi*rtes *4 a llr r c y p ro b lem s and w o k e r s or* s e n ili s<jll*rifni lr**n \|r>Mire in o th er p o s it. Ihe n-<hii I i *h i >4 h.opllm c i * m in im u m rei**imm*ndatuids f o r c a re fu l I is.oal hie.:**** Im armi* -4 |ir*4#eefive dm ev and rrdttrfl<a 4 -i|euuir Iwsi* amt ia|e*s |H I 2 IL t t l M M I I U K O N : aiV K .U N M K S I O l'K R A T IO N S . 31 W X M - M ll U K ON K X M I IIV K H IO lftiA M Z A IKJN AND G O VERN M ENT I f i S i 'A I N 'I I H K A H IM i'' f l u m ir a i* .od the lu iu rv <4 man tr it - * * U nI I I M I I I M SA t K - /M l 1ST SK-S. 4-Htl. A - i. 1071. 1 - O T st f nirk* *4 th s a li'iv *a >vels*in and n a tu ra l -hew cals tn fm d . Iitiu s o r and drinknw* h Af-rap<s w ere raadr > le a rn v ita l U t i l ih*-s4 i.mp'Oimls ha *4 urhaalfh and vi 1 . health 4 futu re - : -f.iii*4 ts IM Iu i.u t is . in *-*ens. m u iau ifls and Ceratocene w e re .Its* uss* d I le * tl*. tis re ss a Kt*-rj| * lt*ri in fe s e a r r h . re y u ta U util esito* m th is ar* a 't*r* ass*ssed * ( ! M M Jer^ r i >-Hrrl . - i : IK K UN (Y i .VMKRCK:. S l'n C O M .M IT T C E o s k n e r g N \ I l H M . H K M II IM f.s A M I I N V IIN IS M K N T Th^ I > 2 t . i - .' r i . h l i * i. / i i i i ' - x . n > i | - n i.f n , . i i l i l i ^ f n -f ln H * .-\ m ill inft m u - m i nl l > I IN .. H .K SA I k 'l |> T . i.M > SKSS 'll-.2 1 1*471 l 1!?! **S**m *w ni'.il data 'W i'r-rm iu the synthesis and r e ti I us i h o m .io si |th**ft>4 .utd pft****v p es tirtd e s and de(.ltaiion tu li* * < itu Iw Ih I ti 'hi i | e .i t Rec**ranM*ndat|ons a r e vjiven fo r Jh* iii.iie 'lla susfw nsi 4 a 1 >*.islrai|*l *4 rc*n*mC p*4Suis r m - lan ito u 4 ,* i- ir o hl*r*i4e*ii***ia'i'it` a id *< ' M M L*S424s l.o c iS ID N I K a id | 1. RO BINSON R a dnw ctive w aste Its. h a i c i s in *!) ;rm m e -ie a r pwrer fa c ilitie s o> iiAfiii i-iMx.axu'i r 'hvkllanck.cnsp div i;i<ikch lK I- i i r l - - > l l - T l - I I -2'> 1-iYI i i i w i i a r t f r * ihrrM idi I M i " f ti<|oot aiut .-j s . - js i.uii atu- *asf*w lr*m 9 n u r le a r pow er faat lttle s a i* * u in m a ii/ *d m Kit r |i* A cen erai d ts e u u tn n ni Ihe wurres, ll| - s n*l a* mi *4 I u iu h I arai cas**au w a s le s , Ihe a d m u u s ira fiv e m e i i- - | s ,uwt t i r ^ r i.iiim ; *\|s rH *m e ir he 9 m ic lr a r pow er stali*ras a# a ls .. iie-ludi*d V a n - a tatHew arai 1 h a rts s u n tu a r ia * th c h a ra t-te riM 4 he f.in lii*s ami th 11 ili.scharue* Ths oddend*ni In th >p ort up laies ihe t.(M s ind e t u i ls Ihnratdk I9 7 u Hke r e p o n in rlu d e s an I* t**r a h f u , i n \ . -abuh U-- :tiw*s ihe r h a r a r t e n s t t r s <4 th p lan i arai iis rtM ha re* im it i .a d p r u rte a b rte f h ia to ry >4 its y r r a l i u s . Ih * jpti teites a l v * im iu d e a r.i|4 i 4 dira h a r u n . > r f pr^skaruras .osi m arni* i u m > *^ara li-4 i a a lum iii< i U l im e . - - C . M . M 4249 l S IM n U C H K A L 1 H C E R V IC E The rK-a. * i s i c q w * m 4 sm.Ounu. A n -r u c i I* he Sur^isra (**ierjl. 1971. f i i T l ' i l L I C >iTk 'a i TTh JiKHV f i n i . - 1971 OHEW H S M * . l 74131: 1 - 4 M 1971 -- H.I . i n M .a ICJIVIM- ,, l a la ria d ta t ra n U .ira a ru U r d iM -o ..* , , h r '. i r i4 i.ln i.-lin ' b n rk .9 iii(M u r]i *4*a<*a. r w r r r . prp iir u lrrr .ual i i- t u a i. i j i u M n v t a a r r d i t n m n la t i a i l . T h r d o n arra > amlr4 "C M. M. ' "* 4^, jn -rn a t annduaal Min pn -a m ar y o * m * l ir." a r r ala., p n - 4430 M A R TIN . ( B-. KW ' P tR S a iN G and E R tH K A f Ktle* i 4 fu ri additives imi a t r pnllufa rm iss o vis (rum d is iilla le C.Hi f . r . a lu rn a c ra i Cn V I M M l> R O f A O E N cV t>l`h L A P -S F R a lp j r n x p n r m * . 1 9 7 l. - - 1 > O H I A i r P m r w i id d ir I S I n n r . n n i r n t a l 1` r .H r r lla a Atardry a liid lr * Ar a n - al ( u r i a d r t u iv r . u . _ r .H iir ! a i r poi l u t t i * fn w a d>illa* m i tauniiAd l . m T h r a v a lla ti IH . r a iu r r w aunrrywd. 0d a o n p lra id all koutra otkhiiT ra p r-n u rrd . ei k i u t-'V ; K - W </0^ <?7 7 2 IV . 1 % I | U H 1i.tth- Gcwcv u t H l-- i U k tw C m a n ia p 'i l I* * jf i. i' i 1:*_____ n s T 3 ^ TF5r ^ i n g j s > i a c n c it o w n a a g t t x ir a Y snnrsciO T iT C T m r e iiT r a e r - r a f ln r ie e . ii. i w k w i. lin i. T h r viia mi i.. U IS rmu d e ni >ti dit M aIIi'Il fIrwo mw U fcXCi iMm w (Iru m fJuuna lu Nu*. 19*0. ua M l. STEIIBINGS. R . E. 'SMiaKtarna Cmm mwarviakae|y,. (f -m amtai BCat ul. Ha a annriru-. * .. %.rvie. FjmiI i, l/K .l Rw*MW f| ody arilt nrnuanrvihti tia HIv.-imt uawny i uta nnwihH o fir r hravy by ti. R ^VlBO N S iu J ' T K f l ! * T 9 'T 75 .--T w n m u paralad by 14 m u. w r nuda in a u l d vicn u in e d . C om |a ratle maazmmnaant ra re dima na Natalia La*. An and a ih in c la ip n in B ritta n y , w here ' I waa .ira n d a d ta lha p ria * >d m e m a M Him M am embasta fe M a r sam ples u( La Gnv. in flu 1994, in a n n i n ia rro c h a n .ro la flo ra l ro m p o .Mion and lha o v e ra ll a t. enced by vrkau vaste am ar pn llta taa. han Iba th re a t id cau.ui ib * jn fz - fa r i, id heavy n u ita m in a tiia i by vaalharad o il. M a t a a ll m arsh plani \-uraula d a re fo p a tr u t a le a r tu c k aa aaa 'h a caaa fo r Lab Mantua. The proie lu rv iv c d a ll but Ih r hca viro l rtuM aium alloa. 0 l appeared to in rra a M d lavala in deep m ia r u a y ln t d h d m tn the a c tird v 1 II 12. producan b a r itr u p ro se is Uta ;ad,B, s w a c ic a r m ia r . Surface cuorenvdeiinHlinyaiuw.hMich. i nterrhaog lie v lad lu c h lo ro tic r o i am i and aymptama in a ir . yieldin g re p la n i . Aa lha U m jrin lw . at ii 12 lavai in la n a r la aaauanf. Tha reducn o f Una v ita m in in ' ra p id ly denatured a ll m arsh-- can ha im portant fo r re ta in in g m l'ii i\ mm. .aim- w -.'irr liv an appenprtata treutmewt may ha a rnatady ut tha ra w >! la i Cimava and m bar la n a . p o M d ln g tha .am a p ro *ta rn .--A . B . C. th is p r o m , and preventing p illu lio n al.aerhara. 99 4. S IIC IIOLONOVA. I. P ,, and V . P. DYKOVA. (Im i. M irrH i-.| y y V iro la Acad. 9 n . U kr. SOL K iev. USSR.l Dryzhdzhnva flo ra vr *.m r , 942. B..- aid .' V . MORRIS. (M ar. S el. Lah Manat VV Brtdaa. Anglesey. M. W ales. OK.) Tha vaa ad H rs-roo let ahaorpllon m es- uramant fn r lha -- lm a nos e t ornant p o llu tio n la Iaora an w a tro j. W A T titt rtJ jT M llr t 19-27. U lus. lV ll.. - S u w w la Ibe UY absorption ip a e tra c i im T a ta ra ! aa u is h a n tu tin a w ar monitocad w a r an an aabrudnanyfek naflaprodidium T . fY ra .t flo ra id re u a rrn in rm iia ro u u i . w ilh iw t-p rn d a c ls .) M K ftO B IO L IH U W T V T 'J 1 W 4 4 I-H C R ?8 |R u. and Engi. u m .J-iT ha yaast llu ra waa aludlad in cunfam tnsied e-vt unrontam inatad rro a ry o lra . V a sa i, o f Iha genera Candida. T - m l- p ii Bhiabdorula. Trtehnaporon. S acchernm rrra and llanenula v a re im la u -i nual pa rlad. '.n o s * chaagei ara la la rp ra la d la la m a od Tmnabla tu p p iv at o rn w tr .-naoadffm n Ota m .|o r aourcaa o f land d ra in .c a and auto* chihoauo. fo n jn g q s i a c ltv iiy . D ifferences In ih * maIn c u la r am ura id lha a rm a le m anar dacia ad (rem thaca m u re r ra a n ll la aaaaoanl varui>nn la hmh tha degrew of alm ur p tlon pa r u n ii ad dtssohrsd urcanlc C and th r ra la llv a ahaorpC M d ittila d iffe re n t avalanclh ra tta n s . Masca, only a pnnr ro rra liila a hctwaa tha UY absorption and tha d u solved o rm a te C TJnrontam inataii m a r v o ln g g iu rtm i ip a c te . w h irb did noi ) m iiu iU iv n-alhun ei m ora a fta. H IP tra in a ad y n a t fro m Iha rro a rv o tr rtm tam inatad w iih m l-p rtid u rt aa stm ilaia o il hvdnm arbM ts m ore thanntratim <d tha lu n e pcclcs laola lcd f r it t i the O neper w ater and fre rn la b ro . O il-p ro d u c i indlnencw tha aafarfnm od a r ile * t i r i >d hvdrora rbnn im id in n g i n t l . - , 1 . T . G. roo!am la n tiu lasd . A ppreciable abort la rm rartaU oas in ap a rlra v a ra a lio recordad. These v a rlillo a a aavaraly lim it Iba aaa ad UY absorPanca 99 1. PARSONS, A U C X and PATR IC K R . OVCAN. fra c . M lc n maaauram aata to r tha Ind ication nd m anna orm ate p o llu tio n . W M a l and C e li. O loL. O bla S a le L' n iv ., e c h in iboa, Ohio , USA.) P ro n te - ito n u t ro fra c e U u h r polysaccharide m a iri by Zoo.lue ram nera. 944. STtRN. n n . (M c d tie rr. M a r. S a n io . C am .. Salammb, A PtPpLj ^MOICCRltOq bBiIQOL 121M(41: S1 -744441. IRf rTt I..-- zfc. ra m lg cra H1Tay'na~* uu Tunta.I F u rthe r c o n trib u tio n . ! lha atudy od tha b lo p ro d u ctlvily in p o l- thaalzad la rca a m o u n t o f m a id s p o lym er (w hich m ight ha s s p h id rd luled m arine coayalem . AkTv IM T CEN0R HEP id / lt . j l - f f . I7 3 (r e d . IS U |. |F r. tu m m .|-*A T a ta r m a.a Which la uodar influence id mm mate untante aawade choatau its cham tcal cum puaittoa and alvo na c n .lu .ic a l i iinditto na w ith raspaci tu norm al m arine ecoavatem *. It m u la in a h i.h a r danaity at p rim a ry production w ith pradum inaaca id .-ro ta ia p tn u y ta n *a m ir apaeiaa. Soma nb aerraim m la iba Lake at T u m i m ru m p a ra ilva ty highl7 poUalad and is lig h tly poilu tad a m how aa aaaaaa od polka anta fro m v a lo ri fro m f ro cin as, (a la d osa, ( b r in a , la d o s , mannoae, ohabla a rc h aad suerose bata Ihas# carbohydrates v e ro usad aa supplem e ta (o a che m ically d iiload m edium . A ll u t D a a supported p u lym cr ayalbeaia to (ha a s in i Ifu l c u ta ra s thickened I lo a e *!- C uocentratina od carbuhydraia aum enta la lb * ra n e * 0.9 lo | U < n waa a d a c r itic a i la c la r la d m rrm 'n ia g eventual lu ta i Ihtefccolao 4 lo a g e i, caccpt la r M in a lo Iha Inraballon ilo * m iu lrc d . G htcow | a buth rata ud M antm chlorla oculata la h igh ly polluted a ra ta .--A. B . M . disappeared (ro m tha fro e d h aw dhim ra p id ly aad ro rro bead w eb la - * crca a la g c e ll craw th am i p o ly -J -h y d rtu y b ig y ra le (PUB) accum ulaiio n . 949. BOURC1ZR. M ICHCL. (S in. M a r. tndeum . M a rom lla . P O Cctmlt mam d a . bnusa-rnucM d in a I r C im a i da la C aaaidaim a IDocem - PHB coocaalraUaa dar r ei aad aa a s tra c a lk tlir pol yaw i w u* aywlbad a ad. a u (t ln g a lin k bdw aaa PHB aad a d raes lh ila r productio n. bra. 19*nl. IRunning rad nsd I . lha L iv o a <d C a a .ld a ic w 'D ecem ber. 19941.1 TICTHYS I d i: * -7 U ..U a p . IM d frc r : l I T l t [E n ti. u n n i. |- 993. UCXfTGOMERY, MARVW L , m i LOGAN A . NOfUUS. Siac* M arch 1947 alum inum w o rt, bava haaa d l.c h a ra w s m u tu o Im o ita a u b n u riw camma ad C u .td a lg a s inaa r Man e iIIagl ha m atita id a pipa tndiim at a depth nd 39(1 m . Up In B a r. 1994 ih m e tte 'a fin a rad colored m udi spread i . iha canyon and ra c h a d a depth nd I H00 m. Two differw nt mona caa nuw b# d ta tu i.u i.h a d ; a ra m n i aa utr io n e m*ar lha mouth id tha pipa W ith a UUch la y e r ut rad mod, and a tata la y e r pe> rip h a ra i una w ilh tu r m a i bay.k lc IU .--A . B. M . d n d . P u m L S uad oda dara dk. Hocbach. De d inhaBa r. Vlaaaa, A n o tr.i _ L in e y u rU ra fig - B .w artim e d a r Geb a rra , d b a d r r Aawaaduag run " 2 ,4 ,9 -T Un W aid ro rbun dm atad. I p ro ttm ta a zr alady od ih dancers S involved la lib a u a a .J 2 ,4 ,'9-T la Ih fo ro d .l rio flfK U L 'T U N 11f l i t : 4 -4 . 970. -~Th it a . 2 ,4 , i-lric h lS rc ia w auayacatl a cid 12, 4, 9- T ) causas a UkM la m p o ra ry c a la r p o lita la a . T h a n Is so s ig n ific a i. O a o g rr io Bah u r d h r r antam la. Tha ralaaalT o ahaorplltm aad dg rada/ () a lo . od 2 ,4 , 9-T ut (ore a l a u la S tadrra da fa ta r dispiace m a d fro m 94. eooPEU. JAMES M. aad JERRY L . W ILHM . (Z tm l. O rp - yy O kla. M aia Um v.. S tillw a la r. C kla .. USA.) LnngUudina) v a ru lto n n i P panpbyltm prod u c liv ltr In ahalaton C ree *, dklahnnta. p n o c q K l a nCAJJ SCl 5 - ih - 22. tlkua. IjiS fra i'S . f tpbytna bMmaan waa ampiad using a r tific ia l rabatra ta w a r a a ria s a t m rrsam m r n r- f tro a ia d a rra s lo upaa w ater and su b a c i s o la r. Balada11. d ii Ita by grow th and dagratfaibm rudero th r residua a l ih r h e rbicida la Iha vaga ta llo w ith in s rv rra l weeks. 2 ,4 ,9 -T haa a law t u lr it y ; I l la ata -- -- K.pannane ta lha s e ti u r la pfama ad la qu ickly e tlm lu te d by anim ata. in a u ro Unum in aa anricbad atream . A grow th c a rra was plotted and analyzed by a dincaauauoua lim a r rc g re w lo a a n d a i. Tha o a s imum in s ia n tin a urnw th ra ta waa uard lo r o lio u lt p ro d u c irritv . P r<alurim iy d rcrrzjm d down.Iroam fro m Uta p U lu iu m o u tfa ll.-- H. f . C. 993. ENVIRONM ENTAL POLLUTION. V u l. 1. So. 1. 1970. 2 O u a m -rlv . K n a n l M ciU abv (E d ltu r). K ls a v i-r PubU sttag C o.. C T O : Casez, England. P r. 2IS .4 0.--Thta IM riK M Ia ia l tou rna i I . coarorm -d m atalv w ith Ih r bh ikartr a i (fre t, o f p u llu tlo a and taclu dr 9 4 7 . K R 1P P IL0V A . T E R E S A . A b ru ta lavs. Czech.) LMVIR0M P O U .U T * Chenopodiatum d a u c i is s a r. _ M ita Potygomaa vtculana B r.-i Koea ta asiani H n a ik ll Il dawdops hero w ith (raaapllag a u area tu ffan o from a ir poli Acad. S ci.. . lauro aaaoc. nova. awmm-I-- A u ccia a ilio - a new p ia cnm m um ly nd B arsa fin n ohaarvad la d a ta rm iw iha p ia m a , ' a ta lIna P taaia gian-LoiiM iu a B ta eb aracia rlsad by tram pled re a rarch papen un Iba ecological effects o f a il tv p so l eavucnm cntal po lita io n and p n llw iu a ro m ro L The jo u rn a l p ru n dea a vehicle (o r the w ta c it d lz arm b u tKM of u r h ltiu l papara dtacaaataa ih r y(1.lo . le a l im p lic a ilona o l piiU uiiuu problem a Iru m manv puiais uf view a clu d ln a lha Ita rra a tk in a L p n llU ca l, ecunum lc. socta l, a rd te a L m anagerial. planalng and an glm -rrlng aap-ets. R rw a rc h papare m e ha (actual and o rig in a l, and m u nut baro broa published rlse w h e rv, thum b papers de scribing w ork whona chem ical uparla b a r* a in u d e broa pubUahrd may h r sterpe Od U provkm aty iinpu hlU hrd b lu k a ilc a l in tu r- amia w ith high Mg coocsairattdas w hich com * fro m ow a o rta l tdriuaw ot lha m agnaaiia w orks la Tkhaaoeca. ntaikm and roncluabina aro Included. Types ut tu a irih o , luna ill includ . ; ro a ro rca papers; re vie w a rtle Ira ; abort cum m ualcathm a; bung ro v trw a ; cu a frrv n c ra aad m rrtta g s ; aad le ttrrc lo Ihc ib llu r . 944. BAKER. JE N IFE R M . (U n i*. C u ll- fw aa oac W sl*a. t'K .) Svrauu onal affaci ut m l p o llu tio n on a ll marh v a .a u iio n . 01X09 2 2 'It . TSa-110. lllu a . M aps. | M . . - I i l i m arsh frana acta near p*m brnkc. 1W 5 W ales, w a r* ro p a rim a o b llr aprayad u h fro c h Kuwait e n d * o tl at d if r k r p rin c ip i* faiuaiacr u t ih * to u rn a i ta E nglish, bw papera " Fronch and Germ an w ill atan be U icludrd. C n rrrg p uata-u cr should h r addevised tu lb * E ls e v ie r P ublish tag C o. LTD , R u p ie Ruad, B arking. Eases, E :la a d .--A . J .9 . ferent lim aa od te a r, aad racovary m easured gala a pm nia fra m e . Throe was lu lls lo o t ir o n vegetative damage lo m o ti p a ra w ita l apactes. bui SUA. GLOYNA, EARNEST F . and W . WESLEY FC K E M FE U lE R . in ih case ud iha annual duaada m arm m a damage was a ve rt, aad was y y J r . |E d U -il b y|. W ater Itrc u u ro ra ym pnuhua, N u. 2. W ater q u a liry fu rth e r lavaatigatcd using drnaTiy aad d ry w aighl m a a w n m a n la . P luw ar _ l B ro v *n iim be p R a lc a l and rh ro jta a i pro rr a I* z v .d d lp , lim a . daaa-ty m aasurar-anl fo r Junena ea ra rti-. Fcaiuca rub ra . Pta a yu in a n " i.n lv c ra U i u l T esa. P rr.u ; Ausiin , f r ie . t^ A ; bnntam . Eagland. 1970. im a . and S cartina a lownaandii. noad lb m arked rm hctloou ^ (low cruw P r. Z19.00.-rhl volum e cor.halos the pipa re prepared ta a sp re ta i raa occu r id pU aia a ra otie d artico (ha flu w s r buds a re dacatoping. Plow - lecta ro serb-a h -r the 3rd W ater R esum es Sympuamm, spenaun-d by arc. g oiled , ra re ly produce scada. O ilin g nd sip d u rta g w lm er may the UotrroaM V <d Teaau C rta a r fo r R asaarcb ta W a irr R aaourros ta raduta iro m ln a tlo a ta Inc aprtag^ JR-L*"ki.-- :<? " ' A p rii 1999 at A ustin, Tesas. Em pha*ta la on th r m u ro ro ta develop er -- 0X O T M0P le t Ita . O aT ud wy h>r. %r. / s j Gcm-ral :ll> uudci- lave IIUIIX It. IIUMICU- 'a lls sUllCI kIfnjf. ScaIItlsC, |k.-CICX. In i ullfilili Inul ti: m alaria. Cal U|1SCIS. In Control adcquatclv : ad m e ni m g litgidy : otherwise nihalances. I all m a j o r . l uded lhal ilici led h y uiiy mlicr evcls could m e imput ili u r g a i m - couiilik-s ie\ h i (lire lI iaddceagmuianlie leilung can .nodes. M ercury: An n has been -laics since I m e rcury review s the . p u ilu iiu n c p rn h le m . inn in llle ic ol ilic idings ate uw ncss ul a mercury ' w hal had 1 mercury Kcsidual :: tlie new result ul ic recall ul :h c market am m alim i d ia l Itine, uii r|gl iel isp uainnd! ;ury in the ud in liud eiilraliuns. liculty ul analysing b io lo g k a l inalvM ais hy saruius inelltnds is discussed and th e b io lo g ica l iik -th y la lio ii m u le s u l m ercury m ilnciiV iiu jim ciii aie presem ed and illustrated hy sch cn ia ik s. h i fo.c O71if-i2n0.7A0./ifA. nAoi-nvyom4o0u(2s.01H: eISru. i1ci0d7e1i.: " S e e m " ' " --2 .4 .5 -T repnrt. The rcgtxlialm n u l 2.4-5-1 lur use nn crops Ini liim iaii consum ption and lit granular lurm around hom es and iccrvaliu n al areas was eaiieeilvd o n M ay I . I ` 7(). Its use a iu o u d water an d in liq uid fo rm arou n d houses an d le e ic a tio iu l aieas liad already been suspended m i A pril IS . Under the I cdcial In s e ctic id e , F u n g k t d c . and K o d e n lk 'id c A c t . (he Dow ('h cn ik a l C o . and Hercules, lu c .. I'euinm ed lur rvlei'al ol die cancellalH uis In an advisory c u m in iilc c . T h e coiiim iitc-.-'s iv p o r t, su b m itted lt> (lie l.n v iro n in e iila i P io ic c lio n A c c ik y II.P A l lor aelim t on M ay 7.1*171. recom m ends dial all u e i ..i 2 .4 .5 -T ill e ffe ct h elore A pril I '>70 be allow ed w iili die pro n sitnts d ia l perm issible residual levels in lo o u lie estab lished and that residues o l the eo n iam in an l. 2 .1 .7 .b -leirachlom dihen/iH/r-dioxm I T C U U I . be k ep i al a q ie c ilic low level. The icp o it was critD cd by several prom inent scicu ti.is. The report tlsell cm itauis a dissenting optniun by l.l'A advisory em runittee member Hr. Hiei/dur H . S lc ilin g . Sterling said that th e data cm isidered by the c u tn m itlc c a iled n> ju s tily i u ju d g m e n t that there is a level a t w h ich H D D is m u Icralngcnu.'. H e also said lh al ih e repurl did not consider liic consequences ol ihc adm itted uneerlainiy aboul the late ol 1 C H U in fund chains and anim al tissue. U r. Sam uel S . h p sicin . speaking fur the C u m u u tlce lor knviruim ienlal lu torm ation. said that "th ere are recent exp erim en ts, inexplicab le discounted by the b P A co m n iitle e . that show even low doses ul 2 .4 .5 -T d o cause leralogerik' effects in n ifip r m g ." H e said dial the report em itatned "clearly teeluik'al errors and unsubstantiated statem ents" and that the fcPA com m ittee had not sltuwn a com pelling need lur the continued use o f 2 .4 .5 -T . 71-2071. M arvehal. C .; D em o/ay. D . (Biologic O icn n-giup pc. I'a. Peehiney-Progtl iP U ' K O l. L yon s. France). M oegiichc R u c tk s ia c n d c von lin d a n in M ilc h uud M ilch p ru d u lcien sind uhre p n k lis c h e B cu eu iu ng. | T he pusnibie residues o f lindane in m ilk and milk products are w ithout practical significance. | /X n r. Mikhunrl. 2IUJI: 1420-1. 1070. (4 lelctenees) are( C e n iu iii Argum ents g n s u m ^ In show that lindane la i least '>*'.5'* pure tinmw-mijmt u t h ex a c h lo ro cy c lo lic x a ik -). on e ol tile ehlotinated h y w H h p h lfj insecticides, should uol he cm idem ncd along. u n e etk 'id e s ut tin.- grou p . hasK e c e n l pu blk'ity a b M fJ g lA l* M sniucs 1 ch lo tm a ie d h yd ro- caihon uisectk-idei brought about mass condeninaiiou oi (his entire group u f in veen cu ks. II D D T were ..sed as the only u id k a lo r , this cundem nathm m igln be ju s i. H U T is slowly degraded and is easily stored in lip ids. D D T residues are readily found in the fa tly tissues and m ilk o f cuw s that lu v e eaten Iced c o n ta in in g D D T . L u id a n e . w h ich is In itially ap plied in m u ch low er co n ce n tra tio n s (8 0 lo J 5 0 g/ha lin d a n e as com pared In 1200 lo 2500 g 'h a D D T ) , b m ore rapidly degraded and is q u w k ly exp elled irm n th e bodies o l iiu n n u a ls . Tests w ith m ilk showed litat residues o l D D T s -'te still 548 fOOH2l55l39A (> 'e lv s ta lile A w eeks j lt e r llic i " s w cie Ir c a lc T w iil. U H I il'ljlio f ii. l'ifiii). w iicicas no icsidiies ol lim laiic w cie dvlvcls-d .in th m ilk a lle i 1 wc-c-k (K a d e le tt r f u l . t'1 '2 1 A s Itndanv is la p n lly degradvd m i ih c surlaic* ! plan is llln d d lc s lo ii i l ul. l'X it) and lia e e and tta re . l 'iir S l and il is taptdly e s c ic ie d In au im a ls. m ie ca n assum e iliat lu m ie us>* n i lin d a iic i l i resuli in rcsiducs hvlow l.'ie lo lcra u tc levcls. 7sTy1om-x2ip0coo7sl2iou.gmCy'n. ibx(Ilr.eidyog,leIs)(.'a(plie.l.soStiiecniiibdaee.si.UJc.aovNims..miDCueAnpicl'.a>ut5ilo<nillns(vi|i.groaCnpai.tliHfIo.-turinmt.iiail an ni. U4IS.I: J \ /k/-. ; 1071. I h e S y m p o s iu m m i A g r ic u lim a i ( T ic in i-ais H a rm o n s or D iscoid lo i I-ihnI . Peop le, l'iivu n iiiik 'lil was held February I ii* 17. I " 7 | . a l S a e iJin e iilo . I .ililm m a . T h e n ie e tin g . s|Minsofed hy lite l'n isersils o l Calilottira Disim i ni o l A gn elli- lin ai Scien ces, was allvm led hx ah oul .'5 0 participants lim u m d u s K s , 'ncetim tettt an d lite f ir s e ls ils . T w e n ty -tour p-apets weu* presented m i the them es the need lot agricultural vhem icals. piohlvins associated with llicir use and solutions io Illese p ro b lem s. O tk- pafk-r p m n le d m il lh a l the p io h ie tn ! using ch en ik als m agrieulliiie involves lond su p p ly, ihe dLsplaecmenl o l agricultural w oikers. incrcated u th an u altm i. d e clca se d n et la m i in co m e and iiic q u ita M i d is llih u tn iu < ! fo o d . A noliter particqiaul staled lh al despite increasing Inod p ro d u ctio n , o u tp u t is only o'- above national needs and that chem icals must he supplem ented w ith les'stanl plants and the use o l p red ato rs and p liero in m ies iii >>rjcr to increase (lie ntaigin between m upui and cm isuiiq nioii. O ne paper noted lh a l losses in C a lilo r m a o l w ild lile an d listi in l')7 (l w ere the low est o f an y y ear m the prc-cc-cdmg ten . The view was exp ressed lh a l th e greatest danger o l pesticid e use lie-, in direct exposure o l agricultural w orkers. K cm cdics such as mandatory protective clo th in g, respirators and periodic checks o l blood cholinesterase levels were m en tio n ed . Ih e idea was p u l lo rth that the most serious problem associated with placing sole relian ce on c h e m ica l c o n tr o l o l p csis is pesi icsu rge n ee and cincreeiice. D on hl was casi on the belici dial synthetic \-ouqkiun-Js c o u ld he d escliq k-d lh a l w o u ld m>l in du ce resislauce ur pesls. A s lot the n u m e , the participants concluded that ilteie will be m oie alieiilm n paid lo environ- m enial side eltects. m o ie icsiiictio n s o l cm uim ied scrutiny and e x p a n d e d use* o l j g i u u l l u i a l ch em ica ls. 71-2074. Sh ep ard . II. II. IA u th r address nor given I. N A S sy n ip o siu in e x a m in es pesi e o n lr o i strateg ics. harm (7n-/r. i.U!Hr 4h, 4S. I0?l. S m ite o l ih e pa|k-s presenled al Ihe s> m p o su iiti m i |\-M c m ilio l sirategies lm the l u l u i c " aie h n e lly revk-w ed iii Mils a in c le . Ih e sy m p o s iiiiu . al ten ded by ab o u t >14) d e le g a te s, was o ig a m / v d h y tlie A g ricu ltu ra l Hoard 1 th e N a tio n al K csca isli I'o u iisii N atio n al A cadem y o l Sciences and held lit W a sh iu g lo n . I). -Several governm en t and private in s titu tio n s co o |k -ijlv d in sponsoring the m eeting. T l.c papers dealt w ith such lopk-s as "l'e st co n tro l in health and agiieuliure inter- n a tiiiii.il c h a lle n g e s ." " F c d o g y I agriculture in the w orld o l today and lo tiio iio w ." " tinplem eiiting l'est control sirategies. '* H usk p n ik ip le s o l v e o sysie iiis an alysis, llo in to iia l iii  WA.1-X-- .fc^lrA,.' 7 / 315007 V vi.TlC ^^ P (i134 ^.00X2155138solubilizationin DETERG CRiacal1ec5nt0i*o7,n0Eaa.. 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T9T 55185 >f Environmental Volume 5, #3 M een reached raaHswpcui2stiietttigpqitmeinnhhnhntncaufv-rsx-bouieoasgedgaioenig6ei2scplevrlsapdgimnivhce.lme7dhasmaougepheoeeg2pt7naruex0rreilniefdiopoc0u1ntiasolir.6iseidlite1scot29mmrnbambmnosyjsimrau7innr,.bii,nn2ape4aeaaolca2sltolgrlop,natnnln-i,n,enMot4eus5/TfddlmUmttdAt.fikafs,re-oemehhAo5oatbu3gNneiTaeg[whsfeTinc-80rEIliiagHerZT-eantEpvaaMahfilatnpsihwrsnlnetsp.henpRnedigSeB,efraje.dairnppaiogeo-llcCrlmRmXrmtiB,?rgdoitrfpdafefTHos]ed-ftpotseeOauaaltsulfdhrh2gAdpha,lylunerrsouooroDuaese,ieerateevo.Eewfmt4omnnicarcEtse,evDn,ntoityaiLifttdTm5r,ilionefedohs0uLanoisio-H2slnnthe.fdo.e-nl.IntTye1tor]tdeN,Cgstexa.deho4--rehr2fThsrniaaGlodyefs,eoftwnpoebi5hmtgfomT(enteSgwfpwo#iPsee-eicofUcacaKhhcmegeaTt,hin5hrterirrholcenSplnBDe3iaivypaer.sllcin.Atg,enonsleraiaRauahsBtthirmrwnidiPvlletaernsoncsDFlooioookFegcrndceyrinaanguxaoalnsemoo-LtitsektmaihotlBitnarean.nofnAtdoco1eneexophfdsi/fcuedg9lndbesnfhNRiepo.eunnoin2T62eteccurcfnriZhsgtdIt9ctn,,oteharcnmaho3e4dn.aEce,coiivgea,itefesxc,o,orosniuasmNote65dorWodirniennftrimsrdpc-.,fatSneeeecdt7seT2ortReenxssC2fufa,aaoc-aol,sfnura[tth,nnl4oHhtbetoirtanl4dettnsftndehau,genuacmrlpUtaG,o5iiWwymarnii5fbtirmnNcerm-cbacaTteeol-eTtnn,woaeycauceMTdaorZtmcesslflslh.tFtailirosy)-)iuneitfoshaRalno,prtnme22odor,xsniiiGwdnswIrTde,cg4,eptrif4-m4efunra5iohehihdftmeuieor,cps,sots<toir5-eeeeeC5rhfreacmca1idirnra--2-chdtttcr)esta2TeiboTehdcs:eah,abphnp.s4;dei,hen4teetee^-t-iad,aahs.no5cy5rt,a.izn-;-ta:ToTsIlI?-- _tcspp_hoou_u_olvrr_usaii,eb_ffl_iieic_eml_nadi_ztetrilemoy-dbnbyraima.ntuntaeaedt1.chusr%hooewedcriedpusptuomtiiodotaarnoiiyuisemwSbtwhoeeeopdrsheaeaeaopnrbgxpdoliylyosicccelh.eoalopbau4lrclsaeBotitiotveentioitni(esI(fts9)rhto0aenm3ra6e[pt-36ru0cc1eroo2t-ian7-uf9i)iiccn5c.aar-en4tdcia]ovanTaafhtnlenoi; 779 MWB2 155132 4--TOX irNA_rY/_fjc_\/PPSccdcdsatIU*dGA2rE1oWscchnhoyyanb9oieht,hhx-1.n1s3iuResEmo1fcc(lndoiaa1uey5c51iie1t,l5ldluvn5ntsrrE60uth.at05tao)pa0,aezsum0m.lyy7,es7.0cseV(mhpd7aemv775adsI47el1a2FnpareaIi1mC-inDsrt3tefa3inocp1tEicxnilr,liansqebs-ynt9nourcsaoetyWc1oaRetSe7ui-.piglddarntnal7bUsnn.C2gotaaelTweyj.cgufG,tEwsaaFrmefnssycmn,l(ihrisantevaTdmVGhicioteigiiCtve4ahf1iatslnR]rolrsosh,eneeisaM.o5.9rll.tam.nx,tfri)aueFpe(7cireo1sfi1)M.voa1chsaosh2arercaFq1.ae9ofsn)sf,nra,otddBittculr,earlAytodeuiltbdsic.vaveynoereoioobd2PnanaelifetfesssPnR,ngebneias-ar2fdfmgrtrnnh6me.,tsnecEusH-a1ocsbT1e.,nBtaatazwUr(irVto9iyr.mypeinor4x.ffgnotocr(7oainrrIemh)-.ioG/GsdG.na1Eo,aBtnpftitafsagVevo,yonn.tmo.te.e-Wpg,r;rhe,uo.4gdorcir.r,i.pmfntgeH,)5ast.eIiMaa)1.rsowIieiiMr4nmp.aW.neco,2clPtnxcu^u-oliirr,tcpGgA6-tiiaicea(ssnoeonpatnhoeArP3sreenteartdgefoJiloq2s.Rn3prVa6of.m1stnfguubl,uU"e.10oetaefg9E4y)eeucesacaed7rl.$f7[.yr,ncn(rVttlr15ntcrmW-1,Eiu,yesSig3de7t-26Itd,vf,lcsEnKTscaoErh14stae,efea&l,4h.kx,go6v,irsiWnsri.nlLci,aon)n-ucrePs,(c5d1d0.FHl2ieilPai(,go.-.t6as1eeFtCd,twgeTe!a.4(h-Inbrt.;,rtl-h6e6facn)h.,ioioie(tIA)o)5st.)]rorngAs.inem.thrx,,tr-.fWntm-gei-dtoiib(.PUntUsta,csc9rRp22lTutErohratgks3oitn0.6rsEFoomojcsugiye.-xSliu,0cte7hcIlxEosnrVvsntrprsP.-s.6diehilegee.xic6tcthIseeo-ef.fgEraylhE5pnatodnlsTray.-Gmata]u,.e.(nl.oWHrtnGd.1MtnfsroiipioTieiRras(a(ceem.iArsmzfnL.Gnhaso1sechrsshoteSpilstf9aiietaacua-eeTnntlnoocetep7n^naoblhrrlaphOictaronscgs2slnn)d..~yneeees-.,,l.,,,f., DOW215 5054 K-4568-(100) OUNM 5bUbb iflTgirT'm ti ii~T 'i'iiV ''r i ------7 -7 -- r"i Va ~i ~"; < fcj... ETlosxevicioerloBgyiomLettdtitcnal, P14re(s1s982) 175--181 . 17J IBNILTIAHREYREAXTCRETION OF 2,4,5-TRICHLOROPHENOXYACETIC ACID (HPLC; hepatic transport; phenoxyadd herbicides) -35= DAVID L. EATON Department of Environmental Health. Institutefor Environmental Studies. University of Washington. Seattle. WA 99195IU.S.AJ i: ((AReccceeipvteedd JJuunnee 91t1ht.h,1918928)2) I if SUMMARY TxbacrbmeopiyohloanUpadeebrcd.yaserseeri.cRottetiitdrhnocehpaatvnaaltntcsyinadoercs-ndodwco8efd3a(mem2-9niipp.btdmo4hhrn,ofpat3oTshmia-fteuiTirTirsas)ehcrtedoeireidginnm.htttrbhrepm-eyaparonvoateautlehhrlenbfneedioSopflruiuuapamrentsrreixlaycacytcgnth.irecucoaexi6eenntreec-.ehlDdmuiaqlSaaainuifiowtnnetiindeosclretebnchcyiaaehlm2densrr,aimoa4abwtym,,si3enaos-awisaTinstgoetlnrusrygialeinsorft4acaiwi9cophedbalamhnbinnmyo.tuiglnf1tiy(eni3tHssdhap.ti7tPegere9o2rnLddel.iC4odofoi,nls)c3a2fegar-3agTntwnthemth.aaeleylrsgSyod/hrsiluoaeneiatssscgcleefoeo-2tvolwhf,ierf4feaereb,esen3iudloal-rientlemfifccnii2ihfconn,uuhavd4anrniei,tioc3cgirnorate-eeoiTtndodepindniuhinnane6tdwndhtthhdoheaaee,sr-.t . INTRODUCTION poianthfAte2dhno,le4tosh,rex5oasy-utTagaa.bhdnoSddvnafeuuhomee5urr0nehbrdoimodftudfghsee/akststgtasu[,al1d.ta-iu[e1n9rs0da])thei,boaxinvnalioemaonriefyenxtehhaedmxaevctrihreneeenetediauxolranttihmrneabainnertcyseopadxamoindcredtiitryserbye,cilstlafltiyeaatimtrveytehflaeeyoxnrbcdmSrileoidiltarviisreoeypnxiomeoosxicfptccioSrouerinrlttvraioeenodnxtf ainndtheotthoetralpelalismmianaetiloimnionaftSioilnvedxaatas,thCeolrbenuarnl s[y1s0t]emdewvealsopsaedturaattewdo. -Bcoasmedpaortnmtehnist pharmacokinetic model of chiorophenoxy acid herbicides which suggested that 2A,4b,b3r-eTv,ia2ti,4o,n3:-t2r.i4ch-0lo,2r.o4p-hdeicnholxoyroacpehteicnoaxdyda.cetic acid; HPLC, high-performance liquid chromatography; 0378-4274/82/0000--0000/S02.75 Elsevier Biomedical Press 17783 tWR.W7: dBBMk 176 aetntheirgohheerpadtoicserse. cSiricnucelatnioonneoof fththeseesecocommppoouunndds swiosualpdpbreeceiaxbpleyctbediottroanbsefoerxmteendsivine etphvreoenllotiuvnaeglrltyh(2ee,xp5cl1ar,esmtreedaabhisnaoltfrh-pletiifoeunroinfoetfh. tehsee cfroamctpioonunedxscrweitethdouint rtehdeubciilnegmthaeytositganliafimcaonutnlyt aerexnlTcarihte.iviotsi.nossnithnuijdpeoycfbtiienottvhnweisesoetifngpaap[tUrletaCdiscm]ud2lia,ra4era,c5nt-lpdyThebthtnioleoexbdcyieoltineaacrrcymeindietnxreachtrieetorhtbnieoiscneiodxofetfe,2n2,4t,a4,n5a,5d-nT-dT.tonfoartdue6rteehromfofilnlboeiwliiatnhrgye MATERIALS AND METHODS Animals Adult male Sprague--Dawley rats (200-250 g) were anesthetized by intra- evopneefidfrnijtuoowsfnetetrhpaelreciaoabdnrilmnteouicniiao.itvslelt.erdaacwtdtiimooitnnhinopPisefEtrru-ia1ort0deiot.ahnnadnoefP2(E1,4-5g,50/k-tTgu)bt,oinafgna,dcrieltihstpaeetebcticilveoeldlleyuc.ctTitohanenodpfeluneirfsitnwfeeamastottirehadel crIenoccTmr.ey,bcsiShtnatne.lidlciLzawoaltuiitigohsrn,audMfnreioOfmo2)r,m4sbu,e5lcny-hzTMetnhC(ea9-.tr2iT%nahgn,e-liasnSobjieegdc!mieutidamon2Cs,ao4hl,fet5m5-fTo.i0cra(im1l.v3lC../3kiongmmjebpCcoatidin/omyyn)mwwwoeailasg,shpMtrpeapuplrrloaiinrfveicieddkderadonbddyat drHaodPsieLoCcohfeaumnaCilcy-alsalibsp.eulerditysoodfiutmhissaslotloutfio2n,4,w5-aTs o>f9810%/iCasi/kdge,te2r5mminegd/kgby. Crehveemrsiec-aplhaansde cscbBaooyimllAueltenhpcctl1eiteo5nestl-dgalme(i.1iclin-t0nBcit0oloipilnperpdemr)s-eaiw-enmwtjeheperoceiltgedicshooaenlwndledbegcirllateaeesd2wss5aete-mevpisgelpthralyeteludi3qba0uneasodnmtdfi1oon2l5floi0cpnowl>nahidssnemegpacaaliui.rqtviwinu.vaioeizsntes3jcde0oco-lmtmlfieoiiccbnntrielobodehiflefwe2om,esr4ara,estm5co-ipcpTnrlltae.iitcslBletauwldtobieooerindnes scintillation minivials containing 100 d of 30% HiOi to reduce color quenching from bile pigments. HPLC analysis 2P0aRcckemvarecdrosle1u-0mp8hn4aB.seT,ahuHetoPtwmLoCatseoadlnvaeHlnyPtssLisuCsoefedqbwuilieeprpesea0dm.0pw5leiMtsh wpaehroBesrpcohowonnrdliuececatecCdid-1w8(siotmhlvieacnroHt bAeow)nldaenettddmeBthilaensoalm(psloelsvewnetrBe)d.iluted 1:3 with acidified methanol, centrifuged at 10000 x g . >.*$1 00H2155057 177 ofonrEto2lumtthioienn,coofilflutsemarmend.ptloesrewmasovineitrieamteadinaitng30p%artsioculvleantetsB, a, nwditah 50-^1 aliquot was injected a flow rate of 3 ml/min. wAreassptweicnotc-islvuteedlpye,dgwrtaoadseiuennsseutdrce.hAealnfutgetiironng10osmoflinvneoanntplionBleaatror bg6irl0ae%dcioenmattpf3oronmmenint7s5a%fnrodtmo795th8%e%cBoBlauatmt 81n5.mmUiniVn, ambastorrixb.anFcreacatito2n3s5ofnmeffwluaesntmwoenrietocroeldlecfoterddeevteercytio3n0 so(f1.25,-4m,5l-Tfraicntitohnes)c,oamnpdle1x.0b-milel alilqiquuidotsscoinftielalacthioonf cthoeusnetifnragctoiof n1s4Cwerarediaodadcetidvittoy.10.0 mi of scintillation cocktail for RESULTS [l4C]2,4,5-T-derived radioactivity appeared in the bile within 10 min after i.v. cinojnetcitniuoanllyofthrthoeugchoomutptohuen6d-.h Tbhilee ceoxllcercettiioonn preartieodo(fFig2.,41,5A-)T. Biinle bfliolew dreecmreaainseedd relatively constant throughout the 6-h collection period, indicating that liver if(nlu4jnCecc]tt2ieo,d4n,5d-roTesm-edaewirnaievsderdeacrdoaedvqieoureaadctetiivnditubyriilwnegaisntah6sissohc.pieaTrtheioeddwd. eiActhlinateodteiancllitonhfee ib1ni5lti.ha7eryc1oe.n3xc%cerenttoirofantitohonef owfas2,n4o,5t-Ta riensublitleo(fFeigli.mIBin)a.tiHoonwoefv2er,4, .t5h-eTdfercolminepilnascmona,cesnintrcaetitohne ocof n2c,4e,n5t-rTatiionnbiolef 2Ab,u4bt,i5tlh-eTetocionpnlpcalesanmstmraaartiadoteinocoroefaf2s2,e4.d2,5bw-yTasoinnolbbyitlae2i5nd%eedcloidnvueerdrinttgohetthh6ee hpfilroasfstmb3ai0l-e2m,c4ion,5lls-eTacmticoponlninc(geFnipgtre.artiIioBod)n,. banyTd3hcehovnaotfaltiuenmredeinoj3ef.c9utiroinn1.e.6o%btoaifntehdebiynjbeclatedddedropseunocftu2r.e4,a5t-Tk.illing was 1.23 0.32 ml, ccappoolhriollTequugnuommrooadxnntmseyatamaoetctrfeim7dbd1.s9ii0lnge.2a1er,anw4tddmhe-i0erei1enn1caa,thn.0nuedaasmmnl2eydidi,czn4aei,,wn5ldra-netstbhsarypiitcscuerohcrsemelttvouivepordreolfyselpye,tterh-.aopleyBupht2iiahlors,eee4nesns,i5oaHcti-lmcvaTPcepL2iddld,eCe4sr(f,.5iSrcvoW-ioelTmvldileteshxrctta)ahttednwhedideohsafaistrrccorodhutlmivceveetlliunuutayrtttnaeeisliddmynlysffattrrhleoossmeimmmpbraittiilnhhloaedeerr, t2bforAuoti)mn.mjePorcaesttatisoklnisrkeeoecllefyui2vtri,ien4npgg,5re-f2sTr5eonpmmtrogvtdh/akureigcoceuo[dlsl4ucCcmho1ann2rj,au4bc,get5eat-wrtTiesedtweincbaisal5en.s2duacbarijednepsdcrtaoe7ndd.d0utcobmiibliHelnePpwHLigeCPmreLeaCnnntoasstl.pyieWsdciseth,rneatani(fFnibeeiidgwle,. asppremneeciaaaomkklvlaealaarstetm,d8oa1.nuf02rd.no1tmmdoimidnftihnrnaeaopdcwtpiooeaalasapurcpmetoeidnbvasirqtweyturaoviswteebdaaessvs(raeoFervcliieagiaartb.etleade2dsBstioow)nc.ititmhahAteeaptdgh2pne.r4wiot,pxi5ute.-dhaTek8tha5weid%sliumthtpiienonabgfikislteatr(htaFetfii1rgoo0r.n.ma1,2dBimados)iai.fnocf.tenirlTvyeihntyeat -a r? *7 Q K 17J IV5 c_n eo n eCOn IP f!i:! Ii1 1 F ig . 1. (A ) Bile flow (o-- o) and biliary excretion rate o f 2 .4 ,J - T (------- ) . Bile sam ples were collected at 30-rain intervals for 6 h follow ing i.v . adm inistration o f 23 m g/kg [>'` C ] 2 .4 .3 -T . (B) C on cen tratio n o f 2 .4 ,5 -T in bile (o-------o) and plasm a (o-- o). Plasm a samples were collected at the end o f each 30-rain collection period. Each value represents the mean r SE o f 3 rats. D ISCU SSIO N unTdehregoreessuslitsgnoiffictahnits bsitluiadryy deexmcroetniostnraitne tthheatratth;e15p.h7^e1noxoyfatchied ahdemrbiniciisdteere2d,4d,5o-sTe i QiA U* f- 1? rpFaeitgr.iwo2hd.i.cRSheerpreircaeelsi0vene.5dta2mti5vlemfrrgae/cvkteigrosn|eWs-pCwh]ae2sr.ee4.cH5o-PlTleL(cCBte)d.anBaainllyedssiaasnmoaplfylebseiilnde Bffrowormarsaatdanikoeuacnnttifrvreioatmyted(tBhre.adtfior(sAitte>3da0n-lmidneinb).icleolflreocmtiona was recovered in the bile in 6 h. Other studies in the rat have demonstrated that 7wp5rie--ths8e0na%tpsltoausfdmyo,araehllliaymlfo-inrliafiet.vio.onfadfarmobmoinuittsht5eerhpedlaas2tm,d4ao,5sc-eoTsmilsepsausrltttmihmaenantte5lw0yameslisgml/okiwngaet[re5td,ha6inn, t8eh]x.epIuenraienthdee;, i <- * the plasma concentration of 2,4,5-T 6 h following administration was apt 7eu5lrie^mtohinaonaftee-tdahneeinsitnhtihetiteaizl euvdrainlueraet.ssu.TghgSeeesvtleorwtshauetrtirneaenl.aolu(1tfp1u)untcrteaiocnendntwslymasarlelcpopomerrtpercdoemnttihsaoetdf utihrneet ambmniealeisxaseitrmnhyteaeesrlxiiaccbrielsvietaiavorseyncreueollxyfact2ruie,mr4teo,p5ray-aiTfrcteeaidnrpatrhiceneinttayrualrpfefoeturhrniattchnotieniso-eancanolemsseatpcdhoomenutiidnznadeirsd,itlrsyraianttitcooepnotashsoeitfboplxyruiecrrfeeeetprhfrrfaeeensdceetnr.otou1r cebraoliitoTrmerthreioaensnfpasotbrifanoioltdnieramrwmyoaiaftteiyholidnmhtehacoievnlfieanm2tebi,uo4ecni,eh5nn-dTsiibldm,oilswpinianaoericrtyreerdedbcel.iocallentiencfeeltoonwitnreaidpttehilocaenlsrimnaeoaddfecoco2nrn,el4yca,es5sne-lTitgirnahtwtibloyiilnt,eh.afnTltodihmwemeodoersdctilrdooe 2,4S,i5n-cTe ceoxncrceetnedtraitniobniloefw2a,4s,5n-oTt biniobtirlaenwsfaosrimnietdia.lly greater than that in plasm; cafooctrnivsrieednetraraalnbesllypimolreitnsssaytiesotfefnmicoieffonrt2,2t4h,,45a,-n5T-Th[e1mp2aa-ty1o4bb]ei.lipaHrreyoswetnreatvniensrp,thoierftlsipuvrceohr,ceaassssheysasstrebemsepeonenxdsieisbtsslce,: bawppililaptishaemraytraism.etxTehc,hareset ittbnihoicoenecmhboeieflmcioahitrachynaelicrsmomonesrccgrehaenanstniprciaostnmaisoniinrboelnsoepsffo,on2crs,a4ibtb,ii5ollei-naTsrfyo, draeetnlchidlmiisninenpedahuteituonrnanotlmiolcefointm2o,r4pne,oa5ruce-hnTmedad*sfinat[tsh1i elucidated. ackn ow ledgem en t This work was supported by a PMA Foundation Starter Grant. REFERENCES 1 V .a . Drill and T . H iratzka. Toxicity o f 2.3-dichlorophenoxyacetic acid and 2.4.5-ir phenoxyacetic acid . A report on their acute and chronic toxicity in d ogs. In d u . H yg. Occu 7 (1953) 6 1 -6 7 . v.2 V .K . Rowe and T .A . H ym as; Sum m ary o f toxicological in form ation o f 2 ,4 -D and 2 .4 ,: herbicides and an evaluation o f the hazards to live-stock associated with their use. A m . J . IS (1954) 622-629. 3 S . K h an n a and S . C . F an g . M etabolism o f C u -labeled. 2 .4 -dich loroph enoxyacetic acid in rats F o o d C h e m .. 14 (1966) 500-503. 4 K . E m e, Distribution and elimination o f chlorinated phenoxyacetic acids in anim als. A S c a n d .. 7 (1966) 240-256. 5 S . C . F a n g . E . F a llin . M .L . M ontgom ery an d V . H . F reed . T h e m etabolism and distrtb 2 ,4,5-trichlorop henoxyacetic acid in fem ale rats. T o x ic o l. A p p l. P h a r m a c o l.. 24 (1973) 55 6 W .N . Piper. J .Q . R ose. M .L . Leng and P .J . G eh rin g. T h e fate o f 2.4.5-trichlorophenoxyac (2.4,3-T) follow ing oral administration to rats and dogs, T oxicol. A p p l. P harm acol.. 2 339-351. 181 7 H .- C . C h an g. J .W . Rip and J .H . Cherry, E ffect o f phenoxyacetic acids on rat liver tissues. J . A gr. F o o d C h e m .. ' 2 (1974) 6 2 - 6 i. 8 M .W . Sauerhoff, W .H . Braun. C .E . Blau and P .J . Gehring. The dose dependent pharmacokinetic profile o f 2.4.5-trichlorophenoxyacetic acid follow ing intravenous administration to rats. Toxicol. A p p l. P h a rm a c o l.. 36 (1976) 491-501. 9 M .W . Sauerhoff, W .H . Braun and J .E . LeBeau. Dose-dependent pharmacokinetic profile o f Silvex follow ing intravenous adm inistration in rats. J . T o xico l. Environ. H ealth . 2 (1977) 605-618. 10 W .A . C o lb u rn , A m odel fo r the dose-dependent pharm acokinetics o f chlorophenoxyacetic acid herbicides in the rat: The effect o f enterohepatic recycling, J . P h arm aco k in . B io p h a r m ., 6 (1978) 417-426. 11 W .B . Severs. L .C . K c il, P .A . Klase and K .C . D ee n . Urethane anesthesia in rats. Altered ability to regulate hydration. P h arm aco lo gy , 22 (1981) 201-209. 12 W .O . Berndt and F . K oschier. In vitro uptake o f 2.4-dichlorophenoxyacetic (2.4-D ) and 2.4,5-trichlorophenoxvacetic acid (2 .4 ,5-T) by renal cortical tissue o f rabbits and rats. T oxicol. A p p l. P h arm aco l.. 26 (1973) 559 -5 7 9 . 13 J . B . H o o k . R . C a rd o n a . J . L . O sb o rn . M .D . Bailie and P . J . G e h rin g . T h e-re n a l handling o f 2 .4,5-trichiorophenoxyacetic acid (2 .4,5-T) in the d o g . Food C o sm e t. T o x ic o l.. 14 (1976) 19-23. 14 F . J . Koschier and W .O . Berndt. R elationship between 2.4.5-trichlorop henoxyacetatc an d (he renal organic base transport system , B io ch cm . P h a r m a c o l.. 26 (1977), 1709-1713. 15 C . D . K laassen, D .L . E aton and S .Z . C a g e n , H epatobiliary disposition o f x e ro b io tic s . in J . w . Bridges and L .E . Ch asseau d . (E d s.). Progress in Drug M etabolism . V o l. 6. ch . I . W ile y. L o n d o n , 1981, pp. 1-75. o o 1X3 cC__Tn7 <=> CD -- jrga Volume 20 Number 6 C o n ten ts o f V olum e 20 (1982) included loose in this issue -L, *ly y v * * \ v y ^ __ *. \ ** . .1l;w ^ &*:V. .;7 ':Ji:\\>; An In-te"r*'n"7ati,or;n-'a.'].-rJv*oriurnal &*//'* pubrl^irshfSeid^Vf/o^r.-vthe ']- ? : i:' V-- * Effect o f dietary butylated hydroxyanisole on tnsthylazoxym cthanol aceU te -induced 1 * 7 :7 * toxicity in mice (B;;. S. Reddy, K. Furuya, D. H-:anson,J. D-tBce. lloan'd.:3, V. B,,er,k',e-)i vC*'-' 853 Lack o f carcinogenicity o f butylated hydroxytoluene on long-term adm inistration to . ~ 7 . B 6 C 3 F , mice (T. Shirai, A. Hagiwara, Y. Kurasa, id. Shibata, S. FukushimaandS. /raTTM 36P) .A n investigation o f the genetic toxicology o f irradiated foodstuffs using short-term test system s. I l l --In vivo tests in sm all rodents and in Drosophila melanogaster (H. fY. Renner, U. Graf, F. E. fYrgler, H. Altmann, J. C. Asquith andP. S. Elias) 867 N o volatile N-nitrosam incs detected in blood and urine from patients ingesting daily large _ . am ounts o f am m onium nitrate (G. Ellen, P. L. Schuller, P. G. A. id. Froeiingand .. . Bruijns) : ' `' - - ' 879 ' T he influence o f food flavonoids on the activity o f some hepatic m icrosom al m onooxy- -- genases in rats (;W. H. Siessand if. F. Yemevaut) _ . ' -..M 3 . Inactivation o f aflatoxin B t m utagenicity by thiols (if. Friedman, C.id. Wehr.J. Schade andJ. T. idacGregor) .~ .. 887 ' T h e effects o f patulin and patulin-cysteine mixtures on D N A synthesis an d the frequency . o f sister-chrom atid exchanges in hum an lym phocytes (R. Cooray, K.-H. Kiessling and : K. UndaU-Kiessting) - _ 893 v - - V . The subchronic toxicity and teratogenicity o f aitem ario! monotnethyl ether produced by Altemariasolani (G. A. Pollock. C. DiSabatino, R. C. Heimsch andD. R HUbelink) 899 ' ' IS S N QX7S-69I5 F C T O D 7 20(6) 853-994 (1982) Abstracts and comments--Fd Cium. Toxic. Voi. 20. no. 6 973 socamtt1ehtihf9n.roa,oocrstoll^9t^elrjtaIaos>htmntRpneVedpcvrmclrqteecaoax^ivrtdpbceciamrorliqientlahaoatipettaklfegelteiesstgnece(ifhngenaWfTsaeljiot^ncfsyhltngef:necgeotda-7eslnjdeai5MJrdrw9ljsgitikeSmfiqteJftrithSCuo^ibtRtmtIfeocfiuder<tfwotdutcyMleudtrhlotytr#mihhem,ereedatDraaPiyiteygrnivefgyvproin.bnoefrosDesyealtttSluciiy(sgpdihKbus^aieojgeent1jilgsy9oocte7hnrsoose4ee-stfir.l: Another look at the carcinogenicity o iAEtnordxi.ecklhsMsseooemndn.i..cO3a.l8(,s12u9H7b8.a1str)a.dneSclole.fstI:-t_iassBcuaeesrgesa-.rreNcfo.emrOean.s,t aMsntuoddilyee.xr.pBoTrs..ur&Je. 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<ubminium and impaired breeding in wild birds saNbhliureydmlhlsso.imWEawimtujNKtir.i~onBEf.c.caism1u..s2p(a61at9,iiro83en06d13o.bfErdveeiefddeeicnntcigveeionfforiwmni^valdotilovpneamsqsefeineruginoge-f jJjJ^aSvfcibtplfwwwdniunileajursokrorderemdeSscTecelotnreiuyrmheuhleecanhgdyyecvbeelameiisseheseirtuantibmeturgloctbigmheodintfbmpnoopaerrd,bjwitoaiuuiaaeeeeinenlmsicficcdtdgorateuhbpahtchugmntedrtorteraeslfoedgettolrreuhdlhhadadeieymnsdoeerdusttclatydtrdhtobaiiarllhnueys.ieiOntwpanfhcgmfmdoTethatTghasoiet.crcs,ehihushnerOfttmstntSeehiilorecochurvtsOcysri.ripitoreeerttoV-eelsashEpes(.telitllsesFpatxrnofaehtnearymne.tifkmfcteeanoiorobhenloen-.daretlf(stehngnisnlIcsiuutdahtltvsceeirphlamnenieaaedahedkaudremdlaeaeveanagSurib\ssInynkoongiwwtec.iiaylsen)rrnyeelpuTe(sdmgbysdrwMdoicsmeii^saehisnrrbhoi^sctdAeslomictaheasalrsrtdlSlriucoidicsastmduaptqusfsLbciDrn'shr-snirhaivaniyi'luneecfDPpnaateiecixgrelrnebmsbdsTwhahitdtliioieiniletrzeertnnaaeudonhedndarassggnsssee-rss.sslt ?V I ;'* * > ti**** 8 -J) > 161V'' RCepRorpienPyptErreiidSgnThtfetIrdCo1mIb9D8yJA2EapcCbekRrySmERrSSi.imYtIePDkMlAUimmPmEOioSnerfSeiArItcUh.aNenEMDcdCoiStEphoEyeXrmrRPigIiOcEhaStSlU,oSRwNoEncoie.ert1y82 Review of Studies with a o 2,4,5-Trichlorophenoxyacetic Acid in Humans ^ Including Applicators Under Field Conditions <_-i c_n M. L. LEO, J. C RAMSEY, and W. H. BRAUN <=> The Dow Chemical Company, Health and Environmental Science, Midland, Ml 48dd T. L. LAVY 00 Univcnity of Arkansas, AUheimer Laboratory, Fayetteville. AR 72701 Studlea la animals and humus have shown that oral V doses of phenoxy hsrhleldss are. rapidly absorbed 1 and are excreted virtually cosrpletely as phenoxy acids In urine with a half-life of lose than 1 day. TOie rate of absorption of 2,fc,5-T Into the body appeared to be slower after external exposure than { after oral administration In hunans. Pharmaco kinetic modeling Indicated 97% of the 2,k,5-T absorbed through the skin would be cleared within 1 week. Measurement of 2,b,5-T excreted In urine of spray crews demonstrated that the maximum absorbsd dose Is not llksly to exceed 0.1 mg per kg of body weight per vork day. Urinary excretion provided a more reliable measure of dose than analysis of patches worn ty tbs workers. Exposure was highest In mixers who handled the spray concen trate and In sprayers using backpack equipment. Some absorption of 2,fc,3-T was apparently due to wearing contaminated clothing bgr field workers. The herbicide 2,b,5-trlchlorophenoxyacetlc acid (2,b,5 ,T) has received considerable public attention In recent -years. Concern that It night cause birth defects, or miscarriages, or even cancer, resulted In numerous investigations during the poet decode (Table I). In April 1978 the U.8. Environmental Pro tection Agency (EPA) Issued s Rebuttati* Presumption Against Registration (RPAB) fbr all uses of 2,h,5-T (l). In February 19T9 C M issued a temporary suapansioa of uses In forestry, rlgfats-of-way sod pastures (2). Uses In rice and rangeland w r i not affected. Bearings began in March 1980 to evaluate all available data pa potential risks, end to balance these,risks against benefits from each use. lo decision bad been reached when this review woe coexisted la August 1981.  01 osi ' ....u 'n i M u a i 'n g i i u u t u i rrcsuMjrti.ua ngai.ua>> n c g i .. . for all uses of 2,1,5-T. 1979 - EPA temporarily suspends uses In forestry, rights-of\ way, and pastures* 1980 - Cancellation bearings begin In March, to review all available evidence on risk, than to weigh benefits vs. risks fbr each use of 2,1,ST. 1981 - Decision It should be noted that hasard dr risk Is a function of exposure as well as of toxicity. Thus, an Important aspect of this continued debate on 2,1,S T Is the need fbr representative data on real exposure In huaus, not only fbr applicators of the herbicide but fbr the populace at large* EPA1s RPAR Position Docuaent 1 (l) Included estlsntes of exposure to 2,1, S T based on direct measurements of external contanlnation bgr other pesti cides applied vith equipment slallar to that used fbr 2,9,5-T. However, In nost cases, application conditions were quite dif ferent fTon those used fbr 2,1,ST. The response submitted hr Tbs Dow Chealeal Company Included a aore realistic evaluation of Isnssn exposure to 2,4,S T (3,). This evaluation relied on data frca several studies la huaans which showed that 2,1,S T was rapidly excreted In the urine with nearly complete clearance frca the body within less then a week after exposure. Based cn these data, the dose received by a person using a backpack sprayer was estlaated to be leea than 0,1 allllgraa per kilogram of body weight per day of exposure spraying brush. This estimte was subsequently confirmed by an extanslve study conducted la fbrest workers applying 2,1,S T under field conditions la Arkansas. The fbLIovIng review summarises the findings In all reported studies co excretion of 2,1,5-T ly humans given oral doses, or exposed to the herbicide under noraal field conditions. Including careless work habits. Tr OH?155012 '"'After' Ingestion Im i (v) 0-12 12-2% 1 2%-36 36-18 2 %8-60 60-72 3 72-6% 8%-96 % . f"itlift'r $ of Dose Excreted 26.8 1%.1 VffT* % of Dose Excre*ted 38.11 20.7 8.7 67-5 9%..%9 81.8 %.8 1.8 88.% Daytlsw Collection? 0.70 0.70 O .69 0.72 av. 0.70 *One subject pooled tha 0-12 sad 12-2% speelaena ao tha assn excretion for dijr I 1 not the r a of the asaa excretions tor 0-12 and 12-2% boors* ^Calculated fro 26.8/35.1 0.70; 20.7/29% 0.70; 99/l%.3 0.69; %.8/6.6 - 0.72. Although considerable variation saa noted among Individuals la each study, particularly la thosa conducted ty Kohll, tha overall agrswmant la vary good. Aa auanarlzed la Table HI, 26 to 57$ of tha 2,%,5-T uas recoverad la urlaa collected the first day after administration of a single oral doee, compared to tbs 50$ predicted by phamarolrl netic aodellag (6). Dermal Application Studies In a study by ftldaana sad Malhach (13). only about 6$ of the 2,%-0 applied to tha fbreani of human volunteers use recov ered la urine collected during a seek after exposure. Also, the rate of excretion saa closer after deraal expostoe than after Intravenous Injection (13). or after oral administration (8) of 2,%-0 la humans. Reported bv After Administration of Single Ormi Dome Dosage ng/kg Humber of Subjects Mean % of Dose in Urine 5 S L Pr 2 Per 3 Bs l . c_n cn CD Gehrlng (6) 5 5 38 29 1U 7 CO Hatsumura (10) 1-5 1.9 1 1 15 30 1*5 30 5 5 fCohli (12) 2 3 5 1 26 22 18 7 1 57 16 3 3 6 2T 23 10 k Calculated1 50 25 13 6 ^-Approximate valu assuming lnataot absorption of tbs total | do and a half-life of 1 day* Similarly, a lower rata of axeration was noted aftar appli cation of 2,1*,5-T aster to tbs sbavad skin of rats than after oral administration In this species (Ramsay, unpublished data). The rata controlling step was shown to be absorption of tbs ester through tbs skin. Once inside tbs body, tbs stars war rapidly hydrolyzed to the acid, and tbs acid was excreted at the same rate as following oral administration of 2,1,5-T In rats.(29) A controlled dermal exposure study **es conducted recently at Oregon State University In which 2,b,5-T ester formulation was applied to the skin of humans (lb). your concentrations of 2,U,5-T ester emulsion were applied to tbs point of runoff on bleached denim patches, 900 square centimeters In area. The patches were then held In close contact with tbs skin on the upper thigh of four volunteers, including one unman. The patches were removed after 2 hours and total urine was collected for 5 days. As shown in A b l e IT, leas than 0.5% of the applied 2,1,5-T was absorbed frae the cloth, even whan soaked with con centrated spray solutions. Studies in 2,1.5-T Applicators All available studies on exposure to 2,1,5-T in applicators are reviewed herein, with special emphasis on the "state of the art" studies by Levy in fbrest workers under normal work condi tions in Arkansas. I77S5 2 1 55014 *-- excreted' in " 2 ^ ,5 - r - per kg bv* 5 Day2 Absorbed3 per c* per 2 0.38 O.kk 0.000003 k 0.72 0.8k 0.000007 16 0.66 1.1k 0.000009 32 1.38 2.3k 0.000011 Patches soaked with kQ al of solution containing 2.k, k.8, 19*2, and 38.k g r a m of 2,k,5-T acid equivalent per liter. Mounting to about 100, 300, 800 and 1600 ng per patch. ^Urine collection began 2k hours before application of treated patch and continued tor a total of 5 days. ^Corrected for lnconplete excretion In k days after exposure. kfor 70 kg person. Dow Study. In a review of direct and Indirect aeesureaeots of exposure in applicators, Lang reported an unpublished early study bf Dow In which 2,k,5-T exposure sea censured in eight field personnel and two observers. Direct aeasurenents of exposure were based on analyses of air saaples and of patches sianlating akin exposure. Indirect aeesureaents of actual dose received were based on analyses of blood saaples end 2k-hour urine collections from thsee Individuals. Tbs workers were applying a low-volatile 2,k,5-T txrtoxy- etfaanol eater foraulatlon diluted with fuel oil at 3 ga1/100 gal (2% 2,k,5-T acid equivalent). The spray was applied selectively to the lower 3 to k feet of .trees and brush in a utility right- of-way using hand-pressurised backpack sprayers (2.5 gal capa city). The applicators wore short-sleeved shirts open at the neck, long pants, no gloves end no hat. One of the backpacks leaked as evidenced by soaking of the applicator's clothing at tha lower back. ^a P<Ji d QO'. C .. ... -.....-- -- -- ----- -- -- "V have prevented the relatively high exposure experienced by this ro I ndMiivghitd. ual, estimated as a dose of about 0.2 ng/kg of body Table V CJl CD C3 ; * 2,k ,S-1'1 la Urine of Spray Applicators: Backpack Crew, 2k Hour Collection (3). Subject Occupation 2,k ,5-T In Urine 8 2,k,5-T kg bw1 mtU2k hr per kg bv4 s 1 Applicator 2 Applicator 73 0.85 l.k5 73 k.30 7.06 0.02 0.10 3 Applicator 59 3.00 3.58 0.06 k Applicator 68 17.00 13.18 0.203 % 5 Foreaan 77 0.75 1.25 0.02 6 Foreman 87 3.80 >.79 0.06 7 foreaan 70 0.07 0.09 0.001 8 Sen. Foreaan 78 0.03 0.06 0.001 r. 9 Ind. Hygienist 75 0.02 0.03 0.000k 10 Clin. Cheadst 73 <0.01 <0.03 O.OOOk ^Kllograas of body weight for each subject. V-5 Calculated froa the urinary levels using the pharmacokinetic aodel developed from an oral study In buaans (6), asaualng .,1ji that repeated dally exposure bad resulted in a~steady state body burden of 2,k,5-T. Subject k wore a leaking backpack sprayer which soaked his shirt and the aeall of his back. SPA Study. The first published report of studies on 2,k,5-T applicators was by Shafik et al. of EPA In 1971 () They analyzed urine aaaplea collected from people occupationally exposed to 2,k-D and 2,k,5-T, and reported higher exposure In li spray operators than In those vfao had less direct contact with the herbicides. 1 j 17737 2! 550I 6 taken to avoid akin contact, A total of eight urine saoplea vere collected, one froa each individual on the afternoon after praying since 7 a.a. that norning, aod one in the early horning the following day. The 2,k,5-T found in the urine aaaples ranged froa 0.5 ppm to 3.6 ppa. Asauaing a steady state body burden and an average 2.0 ppa 2,k,5-T in 1500 al of urine per; day, the estlasted daily excretion in these applicators aa 3 eg of 2,k,5-T. for workers weighing 75 kg, this corresponds to an effective dose of about 0.0k ng/kg which la similar to the doses observed in the Dow study. I>tt Studies The first study was in Arkansas in 1978 using 2,,5-T under field conditions for forestry applications in that area. Ccaplete details of the study were reported to EPA in February 1979 (15) along with kinetic analyses of the data fay Baasay et al. (lo). The study involved monitoring a total of 21 crew members applying 2,k,5T with four types of equipaaut (Table VI). Two applications were aade 1 or 2 weeks apart, and exposures were reported separately. One backpack sprayer did not taka part in the second phase, asking a total of kl exposures. Table VI 2,k ,5-T Study in Forest Workers, 1978: Total Urine Collection ftor One Week (levy, 15, 19) Type of Application lo. of Subject Backpack spraying Tractor driven alstblower Helicopter using - microfoil boom - raindrop nosales Total: 21 subjects, kl exposures1. 7 k 5 5 lOne member of the backpack crew did not take part during the second spray period.  .A' s V.V. , ?!' \ : p. 4. ' *1}\- '* { i \-l *1. -:.-14 -jii i <; 7 H r**"lenS ht aLT 2,4j-T in Humans 141 Monitoring during the application Included measuring the 2,k,5-T level In air and on patches fastened to the clothing of ' the workers. Total urine collections were cade over 12-haur ^ periods before, during, and for up to 5 days after each e x p o - O sure, and each aeaple was analyzed separately for 2,1,5-T. 3E The product used was a low-volatile 2,k,5-T propylene r-O glycol butyl ether ester formulation containing 0.0k ppa 2,3,7,8--- tetrachlorodlbenzo-p-dloxin (TCDO). It was applied as an emul- c_n slon in water at a rate of 1.6 pounds of 2,k ,5-T acid equivalent cj-j per acre (Ib/A) in the backpack study, and 2 lb/A in the other Q studies. These were low-values applications at 10 gal/A In the __ ground studies and 5 gal/A by air. .Thus, the workers in the aerial studies were exposed to about-'55 *,k,5-T spray solutions compared to the 2 or 3% used in the earlier studies by Dow and EPA described above (3, X)* The four crews were selected from a group who noreally did this type of work in that area of Arkansas. They were instructed to perform their routine duties la their usual sanner with as little influence as possible free tbs test situations. Prior to the spray program each worker filled out a fora which provided personal infonation regarding his or her vital statistics and history of any previous involvements with 2,k,5-T. Workers were selected who indicated they had not worked with 2,k,5-T fbr 2 weeks prior to the study (15). For the nost part, the workers did not wear gloves or special protective clothing, typical attire fbr numbers of the spray crews Included long trousers, long or short sleeved shirt, and d o t h sneakers, leather shoes or field boots. All wore bats except four members of the backpack crew. Each crew member wore six patches consisting of 10 cm x 10 cm squares of gauze, backed hr filter paper, fastened to clothing on the chest, back, upper ana, and upper thighs. In addition, each worker wore a portable air puap which drew a known volume of air through a column of XAD-2 resin which trapped the 2,k,5-T from the air. Total urine collection began the day prior to spraying (day 0), and was continued the day of spraying (day l), and fbr at least k or 5 days following each of two spray operations 1 or 2 weeks apart. The total urine excreted by each worker through out the entire test period m i collected for 12-hour periods and kept refrigerated until analysed. Analyses were conducted at lorthrop Services, Inc- in Little Bock , Arkansas, using a modifi cation of the gas chromatographic method of Sony at al. (IT). The urine samples were hydrolyzed to release possible conjugates although 2,k,5-T has been shown to occur as the free acid la human urine (6, 17). For most*workers, the highest concentration of 2,k,5-T was in urine collected ths first day after spraying, ty the end of the second day, all but two workers had excreted more than 50% of ths total amount tbay excreted la the k to 5 day post-spray v r 8I 0SS11 f x ^ t u r 'tjd"'arcer"bri"MBininrmvioa;'`'proDM^'`cni`!'\i;'xoiMr`Mi absorption of tbs 2,*,5-T star frai tbs kin than 2,kt5-T acid fro* tha gut. This is la agreement with observations aade by Feldnann and Maibech for 2,*-D and other pesticides applied to tha forear* of human volunteers'(13)' Calculations by Ransey et al. using three methods, shoved that 97? of the 2,K,5-T absorbed by forest vorkers vould be excreted in urine within 7 days following deraal exposure under typical field conditions (16). The study demonstrated the variability In exposure of tbs 21 crew aenbers depending on tbs Job being performed and on tbs care taken by. some individuals to avoid exposure. Tables VII through X report tbs apparent total doss absorbed by each test subject, based on tbs total 2,k,5-T recovered In urine during each test period divided Iqr tbs person's body weight F i g u r e d through * illustrate tbs excretion pattern for those with tbs highest apparent exposure. Tbs backpack crew * i aads up of seven aaabers, Including two couples working as pairs la which tbs fsaale sprayers weighed about 30 kg (110 lb). Tha total absorbed doaa of 2,*,5-T ranged h i * 0.01 ag/kg la tha sixer-supervisor to around 0.09 ./kg for tbs first exposure In each of three sprayers (Table VII). Table VII Total 2,*,5-T Excreted la Urine per txposurs la a Backpack Crew (adapted fro* Levy, 1J., 19).* Subject Sex ksjw Job 8 2,J,5-T per kg bw1 1 M 72.6 Jtixer/Supervlsor 0.011, 0.012 2 M 68.1 Sprayer 0.086, 0.0T* 3 F *9.9 Sprayer k H 95.3 Sprayer 0.087, 0.053 0.030, 0.033 5 F 52.2 Sprayer 6 N 65.8 Sprayer 0.031, 0.01T 0.038, ---- 7 M 7**9 Sprayer 0.093, 0.037 ^Based o* excretion on day 1 of exposure and 3 days after tbs first exposure and for k days after tbs second exposure, excluding excretion on day 0 before each exposure. might account for* the increased excretion observed in these tv male workers (Nos. 2 and 4) at the end of the first spray perlod> Figure 2 gives the excretion pattern for the other two sale- backpack sprayers, one of whom did not take part in the study during the second test period. Exposure in the mlstblower study was somewhat less than la the backpack study. The highest apparent dose was about 0.q3 mg/kg in the mixer (No. 11) during the first test period (Table. VIII). The values shown in calculated by Ramsey et al. (1t6he), last and column of Table VIII represent the maximum were dose absorbed by each worker in the two ;sprayings 2 weeks apart. Figure 3 reveals that the mlstblower driver (No. 10) was being exposed at a constant rate throughout the test period, possibly from wearing contaminated clothing. Table VIII Total 2,4,5-T Excreted In Urine, and Calculated Dose per-; * Exposure in a Crew Using a Tractor Mounted Mlstblower (adapted from Lavy 15, 19. and Ramsey et al. 16). Qj Sub.1ect Sex hg fa* Job "g gi1.,5-T ner kg bw Measured Calculated1 8 M 95-3 Supervisor 00..000289 0.032 0.012 rs> c_rj cn CD 9 M 84.0 Driver 0.042 0.032 0.046 0.037 CO 10 M 106.T Driver 0.033 O.OUO 0.041 0.054 11 M T9.5 Mixer 0.078 0.043 0.086 0.053 1Maximum value for total absorbed dose for each individual calculated by three methods based on the pharmacokinetic model for clearance after dermal exposure to 2,4,5-T (lb). 17801 :\ i Ju, *i PESTICIDE RESIDUES AND EXPOSURE * First Exposure (Days) Second Exposure (Days) r oe CD tO rFoigwusreinid.icaEtexcarpeptiloicnatoiof n2,4d.a5le-Ts)-.-in--K-t-we--yo-:.cmCoauolpuelpe(ls4ea);pl-p:--ly----i--n-.g-fe-,tmhmealahelee(r3b()i2.c)id;.ewit-h, fbeamcakpleac(k3)s;prCaoyuerpsle(a2r: OZOSSIZHOO i i ! I C i i r'' i ' i f ' i l 'i Figure 2. Excretiionndicoafte2,a4p,p5l-iTcaitniotnwdoatmese)n. aKpepyl:y--ing thtetrhwejrtb(i6c)id;-e--w--i-th, mbaaclekp(7a)c.k sprayers (arrows I ZOSSIZMOQ 5 I LENG ET al. 2,4J-T in Humcms ) Iii I <OGsD j 1 I 4.0 Figure (3s.ecoEnxdcraeptpiolincaotfio2n,4w,5a-s-T-2-i-n-w---Ieoeu.kdrsrmilvaeetnerr()a.p0pK)l;ye-i-ny-g-:--t--h.-e-m--hi,exresburip(ceIidr]ve)i.swoirth(3a):tra ctor ddrraivwenr m(9is);lblower 7 7 n c c 7Mnn PESTICIDE RESIDUES AND EXPOSURE OON2I55023 11. LENG ET AL. 2.4 J -T in Humans 147 Values obtained for helicopter creva are presented in Tables IX and X for applications with a microfoil boom and rain drop nozzles, respectively. Flagmen in both studies excreted only 0.001-0.003 mg/kg indicating they received very little exposure even though they were standing under the spray path during repeated passes ty the helicopter. The pilot in the raindrop nozzle study (Mo. 17, Thble X) received a higher dose than the pilot in the microfoil study (Mo. 12, Table IX), possi bly because he routinely checked and unplugged nozzles with his fingers at each fill-up time, and also helped to change the spray boom on the helicopter before and after each spray period. Table IX Total 2,I*,5-T Excreted in Weekly Urine per Exposure In a Helicopter Crew Using a Microfoil Boom (adapted from Lavy, ii. Sub.lect 12 13 lb 15 16 Sex M M M M M kg bv 95-3 109.0 81.0 61.3 7**.9 Job Pilot Mixer Supervisor Flagman Flagman ng 2,b,5-T . per kg bw > 0.001, 0.011 0.075, 0.061 o.oob, 0.00b 0.001, 0.001 0.002, 0.001 Table X Total 2,b,5-T Excreted in Meekly Urine per Exposure in Helicopter Crew Using Raindrop Mozzles (adapted from Lavy, 1, 19). Subject 17 18 19 20 21 Sex M M M M M kg bw 72.6 86.3 81.7 86.3 95.3 Job Pilot Mixer Supervisor Flagman Flagman mg 2,b,5-T per kg bw 0.03b, 0.039 0.068, 0.127 0.007, 0.001 0.003, 0.001 0.001, 0.001 i D0H2155024 148 PESTICIDB RESIDUES AND EXPOSURE figure U illustrates the discrepancy in doses received by mixers. Mixer So. 1 (backpack crew) had very low levels of 2,k,5-T in his urine, possibly due to the fact that he wore gloves and was cautious in his work habits. Mixer Ho. 13 (microfoil study) had relatively high levels of 2.U.5-T in his urine on day 0 before each spraying, indicating he might have been wearing contaminated clothing. Mixer Ho. 18 (raindrop nozsle study) exhibited a natch higher peak urinary level in the second test, and also received almost twice the dose (0.127 mg/kg) No* 13 These than he did in the first test (0.68 mg/kg) , in both microfoil boom tests (0.075 and data support an observation made years ago 0o.r0 by 6Wt1ohlafnmeg/mki(gx1)e8.r) chat the likelihood of serious contamination is greatest during handling of the pesticide concentrate and could be largely avoided A b3"y"wwi<eaar*ryingiSimppreersmeenatbelde gloves during in Table XI mixing. showing the total 2,I,5-T excreted by the 21 forest wrkers in two exposures under typical field conditions. The highest dose was received by mixers who handled the herbicide concentrate, followed by appli cators using backpack sprayers, spray tractor drivers, helicopter Table XI Summary of Total 2,1*,5-T Measured in Urine of Sprsy Crews per Exposure Under field Conditions in Forests in Arkansas (adapted froa Lavy, 15, 19). Job Description Mixers Backpack Sprayers Sprsy Tractor Drivers Helicopter Pilots Supervisors Flagman Humber of Subjects U 6 2 2 3 U Range of mg 2.U.5-T per kg bv1 0.012 - 0.138 0.019 - 0.10U 0.033 - 0.0U9 <0.001 - 0.041* 0.002 - 0.030 <0.001 - 0.003 ^Includes 2.U.5-T excreted on day 0 before each spraying due to wearing contaminated clothing or exposure of fingers during mixing of spray, and 2.U.5-T excreted on day 6 after first spraying (i.e. on day 0 of second spraying). Jl (io v.>^ CO 2,4,5-T in Urine (mg/Dey) :u -t-- Fig-u-er-q-eu--i4,p.mraeiEnntxd.crroMeptiionxneoruoNlfeo2.(,I4IS,)5(;---T---b-y),wmmoixirbceearrocsgfklooi-nipvlaebfscookuaoernrmd(c1r(w)e1.aw3ss)c;aa--pu-pt-i-lo-y-ui-ns-g,Inmthhiesitshbwelroobrwikceirdhea(b1wit1si)t.h;-K-d-e-ify-f-:e,rent SZOSSIZMOO J0H2IS5026 long sleeves, and gloves, and had practiced good work habits' like sixer Bo. 1. A subsequent study by Levy at al. (20) denonstrated the effectiveness of wearing protective clothing In decreasing exposure to 2,b-D In spray crews during aerial applications In forests In the Pacific Northwest. Eachof three crews, made up of six members per crew, were engaged In two helicopter applica tions of low volatile ester formulations. i During one treatment the workers wore normal clothing and followed their own indivi dual work habits and precautions during the spray operation. In the second treatment the same crews wore protective clothing and were supervised in their work to maintain more stringent protec tion from exposure to the herbicide. Comparisons of the two treatments indicated that, although low levels of exposure did occur, less exposure was evident when precautions were taken. Data from analyses of air samples In Levy's 2,*,5-T study (15. 19) and 2,k-0 study (20) indicate that exposure via Inhala tion was Insignificant during application of low volatile ester formulations of these herbicides. Data obtained by direct measurements of contamination of patches worn by workers have been used for estimating exposure to pesticide sprays (1). However, such data are of limited value for emulsions p( r2e)d.ictFionrg exposure example, to phenoxy in Levy's herbicides' applied study on 2.U.5-T as in forest workers (l, lg.), the total exposed skin area was esti mated for each worker according to the method of Wolfe (21), using photographs taken at the spray site. Total dermal expo sure was based on the average amount of 2,U,5-T detected on the six patches worn by each crew member multiplied by the total estimated exposed skin area for that worker. As shown in Table XII, the observed dose (l.e. amount excreted in urine) was generally natch lower than the estimated external dose. Also, patch data would not predict exposure from contamination of fingers while handling the concentrate during mixing of sprays. The potential for exposure in bystanders has also been investigated. In ing gauze patches a study by Lavy stood directly et al. (22) an under the spray ipnadtihviodfuaal wear heli copter during application of 2,U,5-T at a rate of 2 lb/A. Based on finding an average 2 mg per 100 square centimeters of patch area, the external exposure calculated by Wolfe's method was 0.86 mg/kg for a person weighing 76 kg who was waring shoes, short sleeves, long pants, and no hat. Although the urinary excretion of 2,U,5-T was not measured in this individual, flag men exposed repeatedly during field applications of 2,U,5-T 173GS f Z O S S I7 * 0 " II. LENG ET AL. 2.4.5-T in Humans 151 Table XII Apparent External Exposure Compared to Actual Dose of 2,1,5-T Absorbed by Forest Workers (adapted from Lavy et al. 19. 22). Job Description Mixers Number of Exposures 7 mg 2.1,5-T per kg body weight gauze patches* excreted in urine^ 0.01 - 1.62 0.011 - 0.127 Backpack sprayers U 0.20 - 2.5l* 0.017 - 0.093 Mistblover crew Helicopter crews 53 V 0.20 - 1.58 nd - 0.02 0.029 - 0.0U2 <0.001 - 0.00U Pilots U nd - 0.11 <0.001 - 0.039 1Baaed on average 2,1,5-T found an six patches per subject for each exposure, and estimated total skin area exposed on each subject as calculated by method of Wolfe et al. (21). ^Excluding amount found in urine on day 0 before spraying, possibly due to wearing contaminated clothing. 3Excluding mixer listed separately. 'Excluding mixers and pilots, listed separately. excreted only <0.001 to 0.003 mg/kg (Table XI). This is a frac tion of a percent of the exposure predicted by patch data, despite the fact that the flagmen were under the spray path for several passes of the helicopter. Lavy also reported that no 2,U,5-T as detected on patches worn by an individual who walked through an area sprayed 2 hours eaasrlifeorund(2w2i)t.hinAl8s0o,fe8etk%ofofthtehesp2r,aUy,5p-aTthapapnldie9d9% by of helicopter the spray was delivered within 160 feet of the spray path (22). Thus persona near or entering sprayed areas shortly after application are not likely to receive measurable exposure to 2,1,5-T. qi-iQ C- X /O ^ 152 PESTIClOe RESIDUES AND EXPOSURE Swedish Study Occupational exposure to 2,I-D and 2,1*,5-T was also studied In a forest situation In Sweden (23_). The materials used were butoxy ethyl ester formulations of 2,U-D or of a 2:1 2,1*-D/2,I*,5-T mixture applied as a 2% emulsion in water using tractor drawn equipment. The spray was applied at a rate of 2 to 3 kilograms total active Ingredient per hectare (1.8 to C 2.7 lb/A) to a distance of about 20 meters from both sides cf c the tractor. Two areas of about 70 to 80 hectares were sprayed during the test week. The temperature was*, about 20*C from Monday through Thursday with little wind, and was 10-15*C on 10 J ULd Friday with sporadic wind. Four spraymen took part In the study, working In pairs of two, one driving the tractor and the other walking ahead to mark the areas to be sprayed.Onetractor bad a cab with awindshield but was open on the leftside. The other tractor wascompletely open and both men got sprayed when the tractor turned. Three of the four own took part In preparing the sprays from the herbicide concentrates. They wore Jeans and shirts, with rubber boots or leather shoes and leggings. However, they had bad work habits, contrary to advice and recommendations out lined In the publication "Pesticides'* published by the Council of Europe (2U). They wore the same clothes all week as they had worn the week before doing the aasm work. Two of them lived In a house trailer In the spray area and took their rest periods In the trailer where the odor of the herbicide was noted. All were smokers and smoked during the day without washing their hands. Monitoring consisted of measuring the 2.U-D and 2.U.5-T In the air during spraying, and In blood and urine of the workers during the 5-day work week and for 36 hours afterwards. The levels found In urine are shown In Table XIII, compiled from data given In the Swedish paper. In the first pair, urinary levels ranged from 1.0 to 6.3 ppm 2,I*-D, and from 0.1* to 1.2 ppm 2,^-5-T during the whole week, with little difference between the two workers. Generally higher levels were found In the second teem, peaking at 11.1 ppm 2,I*,5-T In the urine of one worker on Tuesday morning, and lb.0 ppm 2,^-D In the urine of the other worker on Saturday evening. The estimated mean 2b-bour excretion in the Swedish study was 12 mg 2,b-D and 7 mg 2,1,5-T, amounting to 0.l6 and 0.09 mg/kg In workers authors calculated weighing 75 kg* In that exposure ranged afrloamte0r.1 0expteori0m.e6n0t,mg/thher for 2,1*-D and ers, based on 03.0t3o t1o* 0.07 hours mg/hr spent for 2,I,5-T in spraying each the day four work during the week. The highest levels found in urlns wers lower then the 17.0 ppm found In the early Dow study In which one of the workers had a leaking backpack sprayer and whose estimated expo sure was only about 0.2 mg/kg of body weight (Table V). Thus, despite received poor In work habits, the the Swedish study (2d3o.)sesweroef 2.U-D and comparable 2,1*,5-T to those received by the backpack sprayers In the studies done by Dow (3) and by Lavy in Arkansas (!, 19). 11. LENG ET AL. 2,4,5-T in Humans 153 DUH2I55029 Table XIII Levels of 2,I*-D and 2,1*,5-T Found in Urine of Swedisb Forest Workers (adapted from Kolmodln-Hedman _et al. 23). WHoerrbkiecride1 Mon. pm 'Aies, am pm Test l KK LJ D" T DT 1.0 0.5 1.9 0.5. 2.b 1.0 1.6 0.1 Test 2 JG LEO DT D' T >.5 3.1 1.0 1.3 3.1 11.1* 3.0 U.9 Thurs. pm Frl. am pm Sat. pm Sun. am pm 6.3 1.2 3.6 0-9 2.1 0.1 1.5 0.7 3.0 1.2 3.1 0.9 31..11 1.0 0.7 3-1 6.5 1.9 3-7 l.l l*.2 5-6 3.0 21..20 2.3 3-3 6.1 2.7 llt.O b.3 31-.16 22..12 15*..23 3-5 2.5 iD - 2,4-D; T * 2,1,5-T, as ppm ;found in urinee Toxicological Significance of Exposure to 2.U.5-T Sprays Sporadic exposure resulting in doses of less than 0.1 mg/kg of body weight per day spent spraying 2,1,5-T would not appear to pose a significant riak to applicators of the herbicide, even if the 2,1,5-T contains trace amounts of the impurity 2,3,7,8- tetrachlorodibenzo-p-dioxln (TCDO). Perspective on the poten tial risk can be gained by comparison of this estimated maximum dose (0.1 mg/kg) with doses which caused no effect in animals treated daily for extended periods. Numerous studies have demonstrated that the no-effect-level for 2,U,5-T in pregnant rats and mice is about 20 mg/kg of body weight when given dally for 10 days during the critical stage of development of the fetuses (l). In Dow studies with specially purified 2,b,5-T, no effect was body weight per day continuously observed in for 2 years r(a2t5s.),feodr 3 mg/kg of over three generations of reproduction (26). In studies in Germany with ./.'.'ill iiiiA. 134 PESTICIDE RESIDUES AND EXPOSURE technical 2,U,5-T containing 0.05 ppn TCDO, the no-observed- effect level was 30 mg/leg/day in rats which received this dosage prior birth t(o2J_c)o,ncoerptidounr,ingthrtohurgehe pregnancy, and generations of for 30 months reproduction a(2ft8e)r. Thus, all no-effect doaage levels are considerably higher than the estimated maximum dose from exposure to 2,1*,5-T in humans, Including applicators and mixers. Conclusions 1. The maximum exposure expected under relatively careless. field conditions for use of 2,*t,5-T would be leas thai. 0.1 mg/kg of body weight per day spent spraying. 2. In tbs study in forest workers, tbs highest exposure was in mixers who bandied the herbicide concentrate, followed by applicators using backpack sprayers, spray tractor drivers, helicopter pilots, and flagmen. (See Table XI.) 3* Exposure would be considerably reduced if the workers wore gloves, particularly for tbs mixers during preparation of tbs spray. (See figure U, mixer Ho. 1, solid line.) b. Measurement of contamination of patches worn by field' workers is of limited use for estimating actual exposure to* herbicides such as 2,*,5-T. (See Thble XII.) 5 Bystanders or persons entering treated areas shortly after spraying are not likely to receive measurable exposure; thus exposure in the general population is extremely unlikely. Literature Cited 1. Environmental Protection Agency. Rebuttable Presumption Against Registration and Continued Registration of Pesti cide Products Containing 2,U,5-T. Federal Register. j*3_, 17116-17157. April 21, 1978. 2. Environmental Protection Agency. 2,U,5-Trichlorophenoxy- acetlc Acid (2,I,5-T) (including all acid, ester, and salt tfroartmiuloantsiotnosr) Decision Certain and Emergency Order Suspending Uses. Federal Register. 1R5e8g7iUs- 15897, announced February 29, 1979 3 Lang, M. L. Realistic Evaluation of Human Exposure from Application of 2,b,5-T Sprays. Unpublished report of The Dov Chemical RPAB, August UC,omp19a7n8y s(uAb6mBi,ttVeodlutmoeEIPIA,iAnppreensdpoinxsVe).to 2.U.5-T U. Leng, M. L. Comparative Mataholism of Phenoxy Herbicides la Animals, in "Fate of Pesticides in Large Animals" Ivle, G. W., Dorough, H. W., Ed. Academic Press, Hew York, I.T. 1977; p. 53-76. 5. PFiapteer,ofV.2 H.; Rose, J. Q.; Leng, M. ,U,5-Trichlorophenoxyacetic L. ; Gehring, P. Acid (2,U,5-T) J. The Follow ing Oral Administration to Rats and Dogs. Toxicol. Appl. Pharmacol. 1973, 26, 339-351. { C ^ _ 7 C c c t C I V VVV * i \j .1 i '.! - "i -1 A -A 11. LENG et al. 2,4,5-T in Hitmans 155 6. Gehring, P. J.; Kramer, C. G.; Schvetz, B. A.; Rose, J. q.; Rove, V. K. The Fate of 2,b,5-Trichlorophenoxyacetic Acid (2,b,5-T) Following Oral Administration to Man. Toxicol. Appl. Pharmacol. 1973, 26, 352-361. 7 Shafik, M. T.; Sullivan, R. C.; Enos, H. F. A Method for Determination of Low Levels of Exposure to 2,b-D and 8. 2,b,5-T. Intern. J. Environ. Anal. Chem. 1971, 23-33. Sauerhoff, M. V.; Braun, W. H.; Blau, G. E; Gehring, P. J. The ing Fate Oral of 2,b-Dichlorophenoxyacetic Acid Administration to Man. Toxicology 1(927,7b,-D8), Follow 3-11. 9- Sauerhoff, M. W.; Chenoveth, M. B.; Karbovaki, R. J., Braun, W. H. ; Ramsey, J. C.; Gehring, P. J.; Blau, G. E. Fate of Silvex Following Oral Administration to Man. J. Toxicol. 10. Environ. Health Matsumura, A. 1977, The F,at9ebl-o9f52.2 ,b,5-Trichlorophenoxyacetic 2Ac0i-2d5 in Man. Japanese J. (in translation). Occupational Medicine 1970, 12(9). 11. Kohli, J. D.-, Khanna, R.N.; Gupta, R. N.; Dhar, M. M.; Tandon, J. S.-; Sircar, K.P. Absorption and Excretion of 2,b-Dichlorophenoxyacetic Acid in Man. Xenobiotlca 197b, b(2), 97-100. 12. Kohli, J. D.; Khanna, R.N.; Gupta, R. H. ; Dhar, M. M.; Tandon, J. S.; Sircar, K.P. Absorption and Excretion of 2,1,5-Trichlorophenoxyacetic Acid in Man. Arch. Intern. Pharmacodyn. Ther. 197b, 210(2). 250-255. 13. Feldmann, R. J.; Malbaeh, H. I. Percutaneous Penetration of Some Pesticides and Herbicides in Man. Toxicol. Appl. Pharmacol. 197*, 20, 126-132. lb. Newton, M.; Norris, L. A. Potential Exposure of Husnms to 2,b,5-T and TCDD in the Oregon Coast Range. Fundamental and Applied Toxicology, in press 1981. 15 Lavy, T. L. Measurement of 2,b,5-T Exposure of Forest Workers, August 30 to October 3, 1978. Project Completion Report to National Forest Products Association, December 22, 197&, submitted to EPA in response to 2,b,5-T RPAR, February lb, 1979* 16. Ramsey, J. C.; Lavy, T. L.; Braun, W. H. Exposure of Forest Workers to 2,b,5-T: Calculated Dose Levels. Unpub lished report of 'Hie Dov Chemical Company submitted to EPA in response to 2,b,5-T RPAR, February lb, 1979* 17 Nony, C. R. -, Bowman, Oiler, W. L. Trace MA.naCl.ys;isHolodfer,2 ,Cb.,5-LT.r;icYholuonrgo,phJe.noxFy.-, acetic Acid, Its Glycineamide and Their Alkaline Hydro 18. JWl.oylzfPaehb,alremH..CSRoc.nij;.uAg1ra9mt7se6ts,ro6ni^gn(,12JM).,ouFsI.8ejIOS-Bt1la8oi1ofd6f,., Urine and Feces. D. C.; Comer, S. W. 1E9x7p2o,sur2e, of Spraymen 29-31. to Pesticides. Arch. Environ. Health 1 n P 1i oU 1i q- u u n L lJ 0 U d / 156 PESTICIDE RESIDUES AND EXPOSURE 19 Lavy, T. L. i Shepard, J. S.; Mattica, J. D. Exposure 626 630Measurements acetic Acid of in Applicators the Forest. SpJr.ayAiunrgic2.,bF,o5o-dTrCihcehnl.orIo9p6h0e.nox2Sy- -. --------------------- 20. Lavy, T. L.; Walstad, J. 0.; Flynn, R. R.; Matties, J. D. 2,b-0 Exposure Received ty Aerial Application Crewe During 21. 1Fo9r6e1s)t. Wolfe, Spray R. R. , Operations. J. Agric. Food Armstrong, J. F. j Staiff, D. Chen. (Submitted C.; Comer, S. W.; Durham, W. F. Exposure of Apple Thlnners to Parathlon Residues. Arch. Environ. Contaa. Toxicol. 1975, 257-267. 22. Lavy, T. L.; Shepard, J.3.; Bouchard, D. C. Field Worker Exposure Environ. CaonndtamH.elTiocxoipctoelr, Sip9r6ay0 , P2a*jt_,te9r0n-96f.or 2,b,5-T. Bull. 23. Kolaodln-Hednan, B.; Erne, K.; Hakansson, M.; Engqvlat, A. Kontroll av yrkesmasaig exponering for fenoxisyror (2,b-D och 2,1,5-T). .(Testing of Professional Exposure to Phenoxy Acids). Arbete och Halsa, Vetenskaplig Skriftserie 1979:17 (in Svedish). 2b. Council of Europe "Standard Safety Phrases for Operators and (p. 6bU)s.ers", Pesticidea bth edition, Strasbourg, 1977, 25. Xoclba, R. J.; Keyes, D. 0.; Liaowe, R. V.; (Cainins, R. P.; Dlttenber, D. D.; Wade, C. E.; Gorrlnaki, S. J.; Mahle, N. H.; Schvetx, B. A. Results of a Two-Year Chronic Toxi city sad Oncogenicity Study of Rata Ingesting Diets Con taining 2,b,5-Trichlorophenoxyacetic Acid (2,b,5-T). Fd. Cosset. Toxicol. 1979, 17, 205-221. 26. Smith, F. A.; Murray, F. J.; John, J. A.; Nitachke, K. D.; Koeiba, R. J.; Schvetx, B. A. Three-Generation Reproduc tion Study of Rata Ingesting 2,b,5-Trichiorophenoxyacetic Acid in the Diet. Fd. Coaaet. Toxicol. 1961, 1_, bl-b5. 27. Leuachner, F.; Leuschner, A.; Huhscher, ; Dontenvill, W.; Rogulja, P. v. Chronic Oral Toxicity of 2,b,5-T, Batch No. 503, Control No. 15357b6 - Called for Short 'a.b.S-T' - in Sprague Davlay Rata - Repeated dosage over 130 weeks - (with special attention for carcinogenic properties). Unpublished report of Laborstorium fur Phanmkologle und Toxikologle, Hamburg, April 9, 1979 Submitted to EPA by The Dow Chemical Company, August 1979 28. Leuschner, F.; Neumann, W.; Neumann, B.; Dontenvill, W.; 2Ro,gbu,l5j-aT, P. v.; Leuachner, A. in a Reproduction Study Chronic Covering Oral Toxicity of Three Generations in Sprague Davlsy Rats. Unpublished report of Laborstorium fur Pharmakologia und Toxikologle, Hamburg, May 2, 1978. Submitted to EPA by The Dow Chemical Company, August b, 1973. 19. Young, J. D.; Ramsay, J. C.; Braun, W. H. Pharmacokinetics of 2,4,5-T PGBE Estsr Environ. Health, 1981, A8.p,p4l0l1a-d40D8e.rmslly to Rscs. J. Toxicol. Received October 28, 1981. Hc ohff-5\tifi 'Uu.L*it>'e.'U.i} '"'rJCi*- .l i sItpei&~ lCmjz.. rxara Bulletin' ofi ntamination a Volume 24 Issue 1 January 1980 ..S TIYdoaekmnytaiogfiucBbaiatiyonby1ofTC. bMloirydaaznaeksi, aKnd. ARkeilyaatemda,CoSmpKoaunnedkso,inS.GoHboyr-iFi,ishanfdroTm. ^'~2r3 TIPnuofplnuelna1ct3ieoonfs,PeNsittirciifdiecsataionnd Saonmd eRoefstphieraOtioxnidiAzecdtiAvintiaelsogiunesSoonil MbyicrCo.b.Mial. Fdilsuhx, oCf. ADr.oMcleotrca1l2fe5,4HB.eMtw.eAeknaEgis,taunadrinDe. WSe.dMimceLnetesseand W20ater b_y D. J. Wil IcnlecaorrpForaracttiioonn ooffCLuablteulreeddPHesutmicaidneCsealnlsdbEynMv.irMonumrakeanmtailaCndheJ.mFiucaklasmiinto TCIaoatixiroincnsas,nhJtirp.EifnfeGc3t1rsasosnSRhreipmropdbuyctAio.nL.anBduikDeimsrau,pJtri.o, nB.oRfv.thN.ei.eEdegng-e-hLneenrg,thandReJ*. THNoaenxuuircmosaEencftefre,ectDito.snPo.ofVftahtidheyeaP,VhaenycdttooRar.lkNSaanlgaoaiilbdh(uICsnhodaolncpahlmaicnionreb3i7osnexOuvsitpuos)sibtiyo. nM.anMd. FIvaitee ofD40iisopropyl Methylphosphonate (DIMF) in a Lactating C..o-wuby G. W. CLihdadrlaec, tLe.riLza. tNioenedohfatmhe, ZC.oJn.tRamoiilnena,tiBon. Ro.fRMoaarrikj,uaannda Dw.itDh.PBaaryasqeuat b4y9J. A. EanffdecAt dorfeDnai-l2S-ettehryollhoegxeynIesPishtIhnalVaitteroinbythFe.FPe.mBaellel Rafcjnhibition of Hepatic Contents contBinEuCeTdA6o2n4I<S1bS)aN1c:-01k7060c7(o1-49vM8e01r) Sprinqer-Verlag 17815 Bull. Environm. Contain. Toxicol. 24, 90-96 (1980) K - y t t e - ' O 'e v ) j Field Worker Exposure and Helicopter Spray T. L Lavy. PJ.aSt.tSehrenpaordf, 2a,n4d,5D-.T<51. Bouchard Department o f Agronomy, University o f Arkansas, Fayetteville, Ar. 72701 <:o io The herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) has proved to be very effective in: the control of broadleaf species in rice fields,! grasslands, and forests. The herbicide breaks down rapidly in the soil (WHITESIDE and ALEXANDER 1960) and leaves little or no residual effects upon the environment.: However, because questions have arisen on the safety of direct exposure to 2,4,5-T, the herbicide has been placed on the Environmental Protection Agency's (EPA) list for Rebuttable Presumption Against Registration, a process designed to allow clear evaluation of the benefits and risks involved with a compound before it is released for future use. Position Document 1 on 2,4,5-T issued by the EPA indicates that data are inadequate on measurement of 2,4,5-T exposure to field workers involved in actual spraying operations. Some earlier research suggests that the herbicide is fetotoxic and possibly teratogenic for mice in doses above 20 mg/kg/ day (ROLL, 1971) and is fetotoxic for rats at 25 to ISO mg/kg/day (SPARSCHU et al. 1971). The objectives of this study were to measure the direct exposure encountered by people in the actual spray area and to determine the distribution range of 2,4,.5-T sprayed from a helicopter. MATERIALS AND METHODS Applicators and other crew members in the follow ing operations were used to gather the human exposure data: helicopter (5-man crew), a tractor driver spraying rice levees, tractor mist blower (4-man crew), and forest backpack spray workers (12-man crew). The spray materials used were low volatile ester formulations of 2,4,5-T. The actual materials included Thompson Hayward's DedWeed LV-6 and Dow Chemical Company's ESTERON 245. These materials were applied ^Published with approval of the Director of the Arkansas Agric. Exp. Stn. 00071-948806S1p/8r0in/0g0e2r4--V0e0r9l0ag50N1e.4w0 York Inc. r Spray viridlla. At. 72701 itic acid 1 the , grasslands, Idly in the ives little However, of direct placed on list for , a process inefits and released ,5-T issued :e on .'kers le earlier rtoxic and i 20 mg/kg/ it 25 to jasure the . actual l range of :he followi exposure iver -man :-man ile ester Is included ical applied the Arkansas a at rates of 2 lb/A (active ingredients) in water. o Applications by helicopter and tractor used 5 gallons of water per acre, and the backpack spray contained 10 gallons per acre. The rice levee was sprayed in the afternoon and other operations were begun in early morning when wind was less than 5 mph. Studies were completed between July and October, 1978, with air temperatures ranging from 18 to 32 C.. Time in the field for.each operation included: helicopter, 11S c_o ; min; tractor rice spraying, 65 min; tractor mist blower : in forest, 2^5 min; and backpack, 180 min. All crew ? members were instructed to work in a manner no differ 4 ent from their normal operations. . An attempt was made to calculate respiratory i exposure. Vapors and air borne particles of 2,^,5-T in : the spray material were collected through a face mask ' respirator. .This triangular shaped device was placed j over the nose and mouth to filter all air breathed by i each worker. A polyurethane filter set in the mask had l been preextracted before use to prevent any interfering ' peaks on the analytic chromatogram. After these filters were exposed to the spraying operation, they were taken from the masks and stored in methanol. In spite of the preextractions, interfering peaks occurred that preven ted effective analyses. External exposure was measured by attaching 100cm2 gauze patches to the outer garments of all crew members. The patches were constructed by modifying a procedure used by WOLFE etal. (1975). Nine layers of cotton gauze, backed with two layers of Whatman No. 1 filter paper, were taped along the borders with masking tape. At spray time in the field the patches were attached in six locations for each worker: upper back, upper chest, bicep-deltoid area of each arm, and upper front of each thigh. Immediately after the spray application, the patches were removed from the cloth ing. To minimize contamination, only project supervis ors were permitted to remove patches. As the patches were removed, the masking tape was cut from the edges to prevent the glue on the tape from interfering with subsequent gas chromatographic determinations and to allow each patch to be disassembled as it was placed in an individual amber-colored jar containing methanol as a storing, extracting solvent. The jars were kept at a controlled room temperature (1 C) until analyzed. For calculation of exposure based upon these patches, each worker was weighed and photographed in his work clothes, his exposed skin area was noted, and a formula derived from WOLFE et al. (1975) was employed. An additional effort was made to calculate exposure to individuals who might inadvertently be in an area 91 being sprayed with 2,1,5-T. For this test one indivi dual with gauze patches attached to clothing on his head, shoulders, arms, chest, and front and back thighs, stood directly under the path of the helicop ter from which crewmen sprayed. Another individual equipped with six patches, arranged as on crew mem bers, walked through the area that had been sprayed with ESTERON 215 two hours before. To measure the width of a helicopter spray pattern and to obtain information on drift (with the helicopter at an 80-ft height applying 2,1,5-T with a microfoil boom), mylar sheets ( 9 X 9 in) were placed on the ground at intervals of 80, 160, 320, 610, and 960 feet on each side of the spray path. A total of three replications were included in the study. The mylar sheets were attached to 9 X 9-in floor tile to keep them from being moved by the wind or helicopter. Immediately after the spraying was completed, the mylar strips were removed from the tile and placed in jars of methanol in a manner similar to that used with the gauze patches. Analyses for 2,1,5-T employed the S3tfx gas chroma tographic analytical procedures of MATTICE et al. (1979). All values in this study are reported as the methyl ester of 2,1,5-T unless otherwise stated. RESULTS AND DISCUSSION Helicopter crews received low levels of 2,1,5-T on their patches (Table 1). In general their patch exposures were relatively uniform, except for the mixer of TABLE 1 Milligrams of 2,4,5-T Detected on Individual 100 cm2 Gauze Patches of Crews Applying the Herbicide. Crew tad Duty Body Left vt Chest Back arm (kg) Righe Left Right Ave./ arm thigh thigh X Helicopter pilot flagman flagman mixer super* visor 72.6 86.3 ND 0.052 ND 0.058 ND 0.046 0.010 0.067 0.034 0.014 00..001904 95.8 86.3 0.024 0.051 0.023 0.039 00..001312 00..001218 0.006 0.007 0.263 0.088 81.7 0.028 0.103 0.058 0.064 0.037 0.018 e indivi- on his ack helicopvidual w memprayed ay pattern helicopter crofoil the 960 feet hree mylar o keep ar. the laced in used with as chromaal. i as the id. patch the mixer of )0 cm^ Right Ave./ i thigh X 00..001904* 0.007 * 0.088 0.018 0.043 f O o Crew Jj}F and Body Left 'Right Left Right Ave./ 9 Duty we Chest Back arm (kg) (mga)rm7 thigh thigh X in 1 * Rice Lave* driver 0.02 0.02 0.03 0.03 0.59* 0.03 i 4 Mist blower driver driver mixer 84.0 0.31 106.7 0.58 79.5 0.74 11..0112 0.08 0.44 01..0526 00..6567 0.17 0.58 1.01 tO.77 4.49 1.08 8.76* Cr~Dn * super- * visor 95.3 0.27 0.38 0.52 0.47 0.64 1.30 i Backpack sprayer * sprayer 4 sprayer ii sprayer sprayer 5 sprayer sprayer sprayer sprayer sprayer sprayer sprayer 0.94 0.07 0.75 5.61 0.79 0.95 2.41 1.31 2.25* 1.57 0.54 1.52 2.26 0.65 b1.86 0.91 17.96 2.46 00..0613 b 0.65 2.57 1.34 0.27 2.33 221...107117 1.23 0.53 02..0400 2.92 08..0918 0.20 2.40 06..1505 1.47 0.18 1.19 2.82 54.85* 1.80 1.19 0.76 240..6188 0.53 0.04 4.01 31.76 2.53 0.30 0.60 1.98 4.32 3.61 0.75 22.47* 68.93* 6.19 1.06 25.65 1.79 0.08 2.73 2.47 11.09* 15.32 ______________________________________________________ 5.43 aThis value exceeds 50Z of the total 2,4,5-T detected on all six patches, thus Indicating that non-uniform deposition occurred. ^Sample was lost. the mist blower crew who received considerably more exposure than did his fellow workers. The average exposures for the operators of backpack sprayers were greater than those for the other studies. The members of this crew who received the highest 2,^,5-T amounts on their patches received more than twice the patch exposure of workers with highest amounts in the other studies. Calculations based upon the formula derived from WOLFE et al. (1975), the photographs revealing exposed skin areas, and the 2,4,5-T analyses from the gauze patches indicated that external exposure values ranged from 0.0036 to 0.0136 mg/kg for helicopter crews. Values for the mist blower crew were from 0.046 to 0.205 mg/kg, while those of the backpack crew ranged from 0.081 to 1.85 mg/kg. The exposure of the tractor driver spraying the rice levees was 0.046 mg/kg. 93 patches or that hands habrtuaiiy were"r ^ b ^ area to clean or dry them off. Thus, extrapolations of values based on any one patch or .on an average patch concencration in relation to dermal exposure would not necessarily result in the correctly calcu lated exposure. The exposure received on different portions of the body of a person directly under the spray path of the helicopter varied from 0.01 on the chest to 6.48 mg on the left front thigh. If we assume that the sprayed individual weighed 76 kg and was wearing shoes, short-sleeves, long trousers and no hat, the calculated potential exposure for this individual is 0.86 mg/kg. There was considerable variation in amounts of 2,4,5-T on the patches worn by this indi vidual; however, the average amount detected per 100cm2 patch was 2.07 milligrams on a acid equivalent basis. Calculations for 2 lb/A. active ingredient (acid) indicate that a helicopter should deliver to the land surface a total of 2.23. milligrams per each 100 cm2. The exposure received by this individual directly under the spray path of the helicopter should represent the maximum 2,4,5-T external exposure that could occur to someone who was inadvertently exposed to the forest operation. Although 2,4,5-T was detected on the gauze patches, it should be pointed out that in the recent human exposure study conducted by LAVY et al. (1979) there was relatively low correlation (0.45) between the amount of 2,4,5-T detected on gauze patches and the 2,4,5-T excreted in the urine of exposed individuals. In that study a value of 0.04 was obtained when the milligrams of 2,4,5-T excreted in the urine of each worker was divided by the milligrams of 2,4,5-T body exposure as estimated from analyzing the gauze patches from each worker. Using this information, if we assume that 4% of the 2,4,5-T which was predicted to come in contact with exposed dermal area was actually absorbed and consequently excreted in urine, the individual directly under a helicopter spray path would have absorbed and excreted 0.034 mg/kg 2,4,5-T. The worker walking through a field which had been sprayed with ESTERON 245 two hours earlier was outfitted with a set of six patches. Analysis of these patches revealed no detectable 2,4,5-T. Sensitivity limits of the technique would have detected 2,4,5-T in excess of 10 micrograms. 94 cd CD CD 178 `u x a u x w U m erage :posure. .y calcu- :ions of .y path of to 6.48 .at the .ring .at, the idual is n in .is indi. per 100.valent dient iver to per each vidual ter should ure that . exposed uze patches, human 9) there n the and the ividuals. hen the of each 5-T body ze patches f we icted to actually the path 2,4,5-T. o had been is outfitted 2 patches limits of excess of 1 -i 2,4,5-T Deposition Pattern When Applied by CD Helicopter using e Microfoil.Boon. CD ~NI i 0 ?I Distance from Spray Path (ft) 80 160 320 640 960 (mg/pad)* Ir 2.78 0.98 1.65 0.30 0.82 0.13 0.06 0.08 0.08 0.03 0.70 0H.0D2 0H.0D1 HD HD HD : 1 t** 5 0H.0D1 HD HD HD HD HD HD 0H.0D2 ND HD 1.80 Values below 00.0.211 mg/pad Averages (X) 0.04 0.13 vers below detection limits HD (ND). HD HD HD HD Although wind speed was nearly negligible at the time of the spraying, some drift is indicated. The first three analyses listed in Table 2 at all distances were all lying to the leeward side of the helicopter. The last 3 analyses were on the windward side. Only two of the twelve samples taken beyond 320 feet of the spray path showed trace levels of 2,4,5-T. All other samples were below the 10-microgram detection level. These data indicate that workers applying 2,4,5-T are receiving much less than the 20 mg/kg levels of 2,4,5-T reported to have caused fetotoxicity in mice (ROLL, 1971). This information in conjunction with the 2,4,5-T excretion studies (GEHRING et al., 1973) and a recent human exposure study conducted by LAVY in November, 1978, indicates that 2,4,5-T quantities received by applicators should be below any known possible health hazard levels. ACKNOWLEDGMENTS Appreciation is expressed to the Southern Region Pesticide Impact Assessment Program and to National Forest Products Association for support of the study and to Martha Davis for her assistance in manuscript preparation. 95 1 o o>; >.. . m o 0 REFERENCES 9 Federal Register 43(78):17116-17157, EPA, RPAR Position Document 1. X^ril 21, 1973. LAVY, T.L., J.S. SHEPARD, and J.D. MATTICE: J. Agric. Fd. Chem.(Manuscript submitted). LAVY, T.L. 1978. Research Report submitted to National Forest Products Association and EPA. (November, 1978). ! MATTICE, J.D., T.L. LAVY, and R.E. LEA: JAOAC (Manuscript in preparation). ROLL, R. : Fd. Cosmet. Toxicol. 671 (1971).' SPARSCHU, G.L., F.L. DUNN, R.W. LISOWE, and V.K. ROWE: Fd. Cosmet Toxicol. , 527 (1971). U.S. DEPARTMENT OF AGRICULTURE (1972). WHITESIDE, J.S. and M. ALEXANDER: Weeds 8, 204 (1960), WOLFE, H.R., J.F. ARMSTRONG, D.C. STAIFF, S.W. COMER, and W.F. DURHAM: Arch, of Environ. Contam. and Toxicol. 3, 257 (1975). 96 ;~io '**r>s .i O L ... OOVlil 715259 ro V*J v*j ro MATE R I A L SAFETY DATA SHEET FAGE: 1 d o u c h e m i c a l u .s .a . m i d l a n d Mi c h i g a n 4864c e m e r g e n c y p h o n e : 517-636-44 00 EFFECTIVE DATE: F4 SE^ 79 PRODUCT CODE: 87120 PRODUCT NAME: TOROON fR> 101 MIXTURE WEED AND BRUSH KILLER MSC: 0381 INGREDIENTS (TYPICAL VALUES-NOT SPECIFICATIONS > : X: 4-AMINQ-3*56--TRICHLORGPICOLINIC ACID* (PICLORAM)-* TRIISOPROP ANOLAMINE SALT 2,4-DICHL0R0PHEN0XYCETIC ACID. TRIISOPRGPANOLAMINE SALT SEQUESTERING AGENTS. WATER* AND ISOPROPANOL :: : 10.2 : :: : 39.6 : : 50.2 : SECTION 1 PHYSICAL DATA BOILING POINT: IBP >180F. 82C : SOL. IN WATER: INFINITE VAP PRESS: APPROX. 32 MMHG S 20C : SP. GRAVITY: 1.143 68/68F* 20C VAP DENSITY <AIR = 1>: NOT APPLIC. .* X VOLATILE GY VOL: 50?; 9 APPRCX. 100C APPEARANCE AND ODOP.: DARK BROUN LIQUID. SECTION ? FIRE AMO EXPLOSION HAZARD DATA FLASH POINT: 114F. 46C* : FLAMMABLE LIMITS (STP IN AIR) METHOD USED: TCC : LFL: NOT DETER. UFL: NOT DETER. EXTINGUISHING MEDIA: WATER FOG, ALCOHOL FOAM, C02, DRY CHEMICAL. SPECIAL FIRE FIGHTING EQUIPMENT AND HAZARDS: SELF-CONTAINED AIR SUPPLY AVOID GETTING WATER FROM CIRE FIGHTING INTO WATER SUPPLIES- KEEF AWAY FROM POSSIBLE SOURCES OF IGNITION. AUTOIGNITION 498F, 37CC. *N0 FLASH POINT BY TOC WHEN TESTED TC 200F, 93C. SECTION 3 REACTIVITY DATA STABILITY: COMBUSTIBLE. KEEP AWAY FROM IGNITION SOURCESINCOMPATIBILITY: CONSULT MANUFACTURER FOR SPECIFIC CASES. HAZARDOUS DECOMPOSITION PRODUCTS: HYDROGEN CHLORIDE AND NITROGEN OXIDES UNDER FIRE CONDITIONS. HAZARDOUS POLYMERIZATION: WILL MOT OCCUR. SECTION 4 SPILL* LEAK. AND DISPOSAL PROCEDURES ACTION TO TAKE FOR SPILLS (USF. APPROPRIATE SAFETY EQUIPMENT): ABSORB SPILLS (CONTINUED ON PAGE 2 ) (R) INDICATES A REGISTERED OR TRADEMARK NAME CF THE COW CHEMICAL COMPANY 1 7 823 DOW 1 715260 m a t e r i a l s af e t y data sheet page: 2 DOU CHEMICAL U.S.A. MIDLAND MICHIGAN 4864Q EMERGENCY PHONE: 517-636-^00 EFFECTIVE DATE: 2* SEP 79 PRODUCT CODE: 8712Q ( PRODUCT IC0NT*D): TCRDON (R) 101 MIXTURE WEED AND BRUSH KILLERHSD: 0331 SECTION * SPILL* LEAK. AND DISPOSAL PROCEDURES (CONTINUED) ACTION TO T**KE FOR SPILLS (USE APPROPRIATE SAFETY EQUIPMENT): (CONTINUED) WITH INERT MATERIAL SUCH AS SAND DP SAWDUST. IN CASE OF LARGE SPILLS. DIKE AREA TO CONTAIN. CONSULT MANUFACTURER FOR CLEAN-UP. DISPOSAL METHOD: BURY WASTE IN NON-CROP LAND AWAY FROM WATER SUFPLIES Zi i Z TONrf SECTION 9 HEALTH HAZARD DATA INGESTION: LOW IN SINGLE DOSE ORAL TOXICITY; LD50 (RAT) APPROXIMATELY 700Q KG/KG OF BCOY WEIGHT. EYE CONTACT: CAUSES MOOERATE IRRITATION. MAY EVEN CAUSE TRANSITORY CORNEAL INJURY. 1 SKIN CONTACT: MAY CAUSE SLIGHT IRRITATION EVEN A MILD BURN UPON PROLONGED REPEATED EXPOSURE. SKIN ABSORPTION: NOT LIKELY TO BE ABSORBED IN TOXIC AMOUNTS. INHALATION: LOW VAPOR TOXICITY? ACGIH. TLV FOR ISOPROPANOL 400 PPM (1978). EFFECTS OF 0VEREXPOSUPE: GASTRIC UPSET. LIVER. KIDNEY DAMAGE AND CENTRAL NERVOUS SYSTEM DEPRESSION SECONDARY TO ISOPROPANOL. SECTION 6 FIRST AID-- NOTE TO PHYSICIAN first aid p r o c e d u r e s : EYES: TPRIGATE WITH FLOWING WATER IMMEDIATELY AND CONTINUOUSLY FOR 15 MINUTES. REFER TO MEDICAL PERSONNEL. SKIN: CONTACT WTLL PROBABLY CAUSE NO MORE THAN IRRITATION. WASH GCF IN FLOWING WATER OR SHOWER. INHALATION: REMOVE TO f r e s h AIR IF EFFECTS OCCUR CONSULT MEDICAL PERSONNEL. INGESTION: IF SWALLOWED. INDUCE VOMITING IMMEDIATELY BY GIVING TWO GLASSES CF WATER AND STICKING FINGER DOWN THROAT. CALL A PHYSICIAN. NOTE TO PHYSICIAN: EYES: MAY CAUSE MODERATE IRRITATION. STAIN FOR EVIDENCE OF CORNEAL INJURY. IF COPNEA IS BURNED. INSTILL ANTIBIOTIC STEROID PREPARATION FREQUENTLY. CONSULT OPHTHALMOLOGIST. SKIN: MAY CAUSE MILD IRRITATION. TREAT AS ANY CONTACT DERMATITIS. IF BURN IS PRESENT. TREAT AS ANY THERMAL BURN. RESPIRATORY: INJURY IS UNLIKELY. o r a l : LOW IN TOXICITY. SYSTEMIC: LIVER AND KIDNEY ARE PROBABLY TARGET ORGANS FOR OVER EXPOSURE. NO SPECIFIC ANTIDOTE. TREATMENT BASED ON THE SCUNO JUDGMENT OF THE FHYSICIAN AND THE INDIVIDUAL REACTIONS GF THE PATIENT. SECTION 7 SPECIAL HANDLING INFORMATION (CONTINUED ON PAGE 7 ) (R) INDICATES A REGISTERED OR TRADEMARK NAME- OF THE OOW CHEMICAL COMPANY DOW 1 715261 M A TERIAL SAFETY DATA SHEET PAG: 3 DOW CHEMICAL U.S.A. MIDLANO MICHIGAN 48640 EMERGENCY PHONE: 517-6 2o-44-0 0 rnu to < u ci FFECTIVE DATE: 24 SrP 79 PROOUCT CODE: 87120 FODUCT (CCMT'D): TGRCON (R) 1G1 MIXTURE WEED AND BRUSH KILLESHSC: 0331 SECTION 7 SPECIAL HANDLING INFORMATION (CONTINUED) MN 0 1 2 3 3 2 ENTILATION: RECOMMEND LOCAL VENTILATION. RECOMMEND CONTROL OF ISCFRGPAHOL TO SUGGESTED GUIDE. ESPIRATQP.Y PROTECTION: NONE NGRMALLY NEEDED? FR ISOPROPANOL USE A NIOSH APPROVED ORGANIC VAcOR RESPIRATOR. ROTECTIVE CLOTHING: CLEAN. BODY-COVER ING CLOTHING. YE PROTECTION: SAFETY GLASSES WITHOUT SIDE SHIELDS. SECTION 8 SPECIAL PRECAUTIONS AND ADDITIONAL.INFORMATION PRECAUTIONS TO EE TAKEN IN HANDLING AND STORAGE: SEE LABEL - KEEP CUT OF REACH OF CHILDREN. DO NOT SWALLOW. AVOID CONTACT UITH SKIN. EYES. AND CLOTHING. WASH WELL AFTER HANDLING. KEEP CONTAINER CLOSED. KEEP AWAY FROM HEAT AND OPEN FLAME. PROVIDE EYE FOUNTAIN AND W4SHING FACILITIES NEAR WORK AREA.' DO NOT STORE NEAR FOOD FEEDSTUFFS r FERTILIZERS SEEDS. INSECTICIDES. FUNGICIDES CR OTHER PESTICIDES. CO NOT CONTAMINATE WATFR TO 3E USED FOR IRRIGATION. ADDITIONAL INFORMATION: REVISIONS 9/24/79 -- CHANGED SPECIFIC GRAVITY, STABILITY, EYE CONTACT, SKIN CONTACT, SKIN ABSORPTION, INHALATION, FIRST AID PROCEDURES, NOTE TO PHYSICIAN. SPFCIAL HANDLING INFO., ADDED CENTIGRADE TEMPERATURES. FLASH POINT AMD METHOD USED. LAST PAGE. (P) INDICATES A REGISTERED OR TRADEMARK NAME OF THE DOW CHEMICAL COMPANY THE INFORMATION HrRSIN IS GIVEN IN 5000 FAITH, BUT NO WARRANTY, EXPRESSED OR IMPLIED, IS MADE. o -2C-f c A L B E R T M. K L IG M A N , M. D., Ph . D. HO SPITAL OP THE U N IV E R S ITY OP PEN NSYLVANIA 3 0 th A N O S P R U C E S T R E E T S P H ILA D E LP H IA , PA. IS IO A August 22, 1967 CD Mr. V. K. Rowe, Biochem ical Research Laboratory, 1803 Building, The Dow Chemical Company Midland, M ichigan 48640 Dear V. K. : I am anxious to report my work with the acnegens. I hope that continued support w ill be possib le. I can com e alm ost any tim e in Septem ber, or early October. I prefer to come on a Tuesday evening and to return to Philadelphia on Wednesday afternoon. How about calling at your convenience to set-up an acceptable tim e? I believe I have much that w ill be of interest to you. With every good w ish, I rem ain Sincerely yours, CD C"O'O ft A M K /a r August 9. 1967 THE DOW CHEMICAL COMPANY 813 M ID LA N D . M1CMIOAM 4 * 4 4 0 66Z /!0N W Albert M. Kligman, M. D. , Ph. D. HD eopspairttaml eonftthoef DUenrimveartsoiltoygyof P ennsylvania P36htihlaadnedlpShpiaru, cPeeSntnrseyeltvsan ia 19104 ^ CO Dear Dr. Kligman: I have your note of a few weeks ago and apologize for not answering irtepsooortn eorn. thWe ew odrokwtahnatt yyoouu thoavcoemdeonteo wMitihdlathned atconpergeesnesn.t aAtp rthoeg ress present time I do not know when w ill be a good tim e. 1 hope we can wfoorrkyoiut oinr eaanrylytimtheis wfhaelln. itIswothueldrebaeniymtpimo sesiwb lheenfoirt wyoouu?ld bIfe yboeust w ill let me know the answ er to these questions, I w ill do my best to fix a date. r-o Ibneeannsfwouenrdtoto yboeurcaqruceinstoiognenIs daondnoIt dkindownotw khnetohwerthaactnceagrecnins ohgaevnes wlikeeretopodtiesnctuasscntehgisenms.attIeramfuvrethreyr inwtiethreysoteud. , Wh oew'reeveloro, kainngd fsohrou ld ward to your v isit. My best personal regards. Sincerely yours, V. K. Rowe Biochem ical Research Laboratory 1803 Building ks cc: Correspondence --.V. K. Rowe (2) 17827 D EPARTM EN T OP DERM ATO LOGY A L B E R T M. K L IG M A N . M. D.. PH. D. H O S PITA L OF THC U N IV E R S ITY O F P EN NSYLVANIA 38TH AND SPRU CE STREETS P H ILA D E LP H IA 4 , PA. QX EVero rsen 2 -4 8 0 0 Extension 4 S I July 8, 1966 MB iro.chVe.mKic.alRRoweese, arch L aboratory, 1701 Building, MThiedlaDnodw, CMhiecmhiigcaanl Company Dear Mr. Rowe: deceived 2JIJL 1 1966 Bioche, cC .c" Supplementing data submitted by Dr. Kligman on the tetra- chlorodibenzo-p-dioxin study, enclosed is additional information on Groups #1 through #6. We trust this information w ill be of help V to you. Yours truly, afa E n closu re AS edcerleetaFr.y AtolleDnr. K ligm an 28 A L B E R T M. K L IG M A N . M. D.. PH. D. H O S PITA L OP TH E U N IV E R S ITY OR PEN N S YLV AN IA 30TH AN D SPR U C E ST R EE TS P H ILA D E LP H IA 4 . PA. 815 DEPARTM ENT O F DERM ATO LOGY RECEIVED JUN 2 1966 EVero reen 2 -48 0 0 E x t e n s io n 491 June 22, 1966 Mr. V. K. Rowe, Biochem ical Research Laboratory T17h0e1 DBouwildCinhge,m ical Company Midland, M ichigan Biociiem, Res. Lab. Dear V. K. : Now that I have collected the detailed data, it is evident that the tetrachlorodibenzo-p-dioxin study was by no m eans a tiny or trivial affair. This study was supervised by one of m y graduate derm atologists; he kept giving me a negative read-out throughout the many months of study. I personally saw the subjects in the last two groups which received the highest doses. oa (ZZ CZ The skeletal report I sent was further reduced from the very bony sum mation he gave m e. I was hopeful that the report might be sized to the signifi cance of the r e su lts. I alm ost sent you a letter saying, "We did the work you ordered and found nothing". (I g u ess th ose happy days are gone). W herever the subject could not be follow ed for six w eeks owing to sudden discharge, or to institutional decisions, detailed data are deleted. I am grieved that so little has been learned, especially since practically the whole grant was spent in laboratory work. This was a discouraging project. With every good w ish, I rem ain Very sincerely yours, EA nMcKl o/sau r e Albert M. Kligman, M. 17829 / CZHPPZrnn 266oniv D EPARTM EN T O F DERM ATO LOGY A L B E R T M . K L 1G M A N , M. D., P h. O. HO S PITA L OP THE U N IV E R S ITY OP PEN NSYLVANIA 3 6 th A N O S P R U C E S T R E E T S P H ILA D E LP H IA , PA. 18104 RECEIVED JUN 1 196G Biochem, Res. Lab. EVCRORCCN 2 - 4 6 0 0 CVCRORCEN 6 * 3 4 5 9 EXTENSIO N 2 43 1 May 31, 1966 Dr. V. K. Rowe, Biochem ical Research Laboratory T17h0e1 DBouwildCinhgem, ical Company Midland, M ichigan Dear Doctor Rowe: w ere aInlsom ydodnieoxoinn trheepvoortl,u nIteoemrsittdeudrminegntthioenlotnhgatpCerBiCod's oavnedr SwGhPicTh's the agent was topically applied. No abnorm alities w ere found. This further strengthens our. resolve to use larger quantities in an attempt to produce acne. Respectfully submitted A M K /a 17830 :X J u ly 9 , 1965 3PDIAi6hoeltbpiohleaparrdiatttmneadMllepn. hoSt Kfipaorlutifgh4cmeeD, aePSUnr m,etnrnaleMnvteose.tlyDrsosl.gvi, cyayPn hpi.Df ia . P ,e n n ' s| y l v a n i a SO\CINJOO4l O O o00 D ear Dr. K ligm an: O maakghwIco2lhroir,hetad3easwahnimmncicjloten7ekh.ssuvyg,eLjs/eg8dkeDlirhes-Tnii,citnb0hdoe[ddatejaoitthuncforergroatkrgpasarayyaecttormhp.oyhtsdneoori,.l.caouonf amoasbrtnoe1uulab6dsayndriccdltnbmwolfbesiieefeergn.igicnuisdeh0srczronaee.eao5dglips^an-ia!a[jipyncoatreo-pdantrahddoneitecidse1io|/staf.,k0uxonfnciiriilheornomremiivjjggdg1.aeghr0hilr/absktlrhoytgdaTaoras.ihheeatstioovm2rsoe0wtIexhadtriihleseadclilaoci.wshyastlfhimaisvneyhIs1o0egpsaaud0mhfrloneeafstavamartentedotteiocdaotfcrreslrieie,osavaa-leytd pbdrtcstrI+ttheoonoaeerAuuos+evebctt*pmdaqtenerbwoewdsr1luiigenonaoetaabdsaesneeanerrAosoedtqrecrasuieseeeariurttpessat.aopqoo0st4iresmoueunar.2WrntsiahereaertIse*rehnebo.epgdcofii,fiisihtnsutnVaathekatondisbllieeda;nmAy0!l,1Phpt'i.rih5waCa4aa1cfevuraplseoeAtstottpplooghe4hfll*orwfyy?ana85aa2poimhb0snsteeeo$mmmmugrnvap4pr..:iiime's'f0cccfalotaahvrrrn.iooosocyetAt1fhjgggiearrxjiprmrermtaaettaaaaoaoblmmmlmtabdtfiboactseoseiyenaottfvlthmnauaneseelfg?t,sllmreaofueto*>h1dwbsinpaoamsno4etie,lsslesnl.st dnhse y as kogaaotaoroplvWeeirlwnueersfsfhoaoqaateidcenyann,uloeuxtlsooatnicttpettcnhheepoomuetedetfrsioopxalutaaatt-rhebroteedeon, e v e . wdwnIttssfhhnyayeeeoeesvrsvutvateleeemdpdihlmeromupootwpmbrhsiricoeeaaceagonfalrchfseefolhaweaslsmytzrnsohast,rshhbkrtiiionedesettwhilswovetmbntiowihenenuaefcoilgontdattetlt,rurreijwmaaitbsarohnbeetiauetbithncwttlilhhoirtahkjjjcneaeet.iehccs,olihsdhrysmaoIii';gpptotphmerttfayoodltniyqpdootgyhceunehieoncstct,hagooenacnsifnssdposostduacneiteonttgsrryumyetsvgpheqktpaeeeeausiostmliieuttovgeonangdendpntcfrhyeraieopmscfrmoiebrsacmoqertanahabrtbupnonibaaloioeecrttubsrueo.niissmetdtlht.fihfafIigcoetathcrtt t DOW 780402 A. M. K lig m a n ,' M.D. - 2! - July 9 , 1965 ^ aebuaotsaiihsassenuspt tecivtpanahcyweclgI.tooirhiimcanmutewahalisrndTeteoiifmhdtmucoeherpluewoundeirctmnqossioitvup.usbhteroaeitissgohror,ceeeenodproduvI;allerrgy.aoebtIhtsoiapu,etowTtetlniiciaihonensaofetuveenleaddmntidirStu,umieGmisncteuIiOtdb,stg1eTowwtitgr'hsh3ceoiehootasuhasernftlthiedv:ipemc!dteweaelaniarroxhsdViesaelaperofk;vfeneauneaaesrt^sitltmoiwadtnoyopeaeehkoysvbndarutestpavostlreooeehrrpdxwvtsoeeopptaishidsrr.eptleoic.rlhmoicrtamnheerAteesmeWtaeliqdsntaohheou,dtenosneniur, eg h pwhwohitbTssneuneaeeeohimdvrsrrttehahvhieiiartovenaeia. ndvsitaitwdniehn.iousaodaoi mnhs-afiwcmaIalandadpenelatsesexeoethakavrpttdaoiheeeonoffulrereeoddbilirwwpdmnosemfseiedtbhistraennhedevnomtsefrauasotiwyi.tlaoniduussanouudp,trnccsoTbgihepctnegheospfoaedi,lusewts!s,aiesrstthriewsefiieoixodsedec-dxhrtu,hwbpbpp,ppaeeorrespbocittlseooiauutmekowulrttrvsmehacesh'eaeeeotp.oinocsrfoltehatosncIssttuhhhtoItrwahseaeoauvoaxrreutruvetaxpsliedmnpaepond,tesogicebtiurnownoaveirtnenmdoheet nhysml.upocewicranpeptodtereiAonmeeeod'wktes.liahnxtssiteeoottehdI,bd hckbftlYsohioeeaooereesnulmvpuqtaedeabumxsatrlihknpiettieheedeon.ddasaembattedtaeIphanabpthaahzoreeasrtiuorsnevotpieeaialruthm,liaaiat ninanfIbtoredtddeoenwsimrcfcsoioaooilaunibtvrrllgedseedhc5yirne0sloitondglu/iuy5ttgrh0bwlgiiwrsiehgnusoaosignsclltrchujtqrkoelbti.uynhdhltiehaota'eapd.l:wsniivnwatsaehnoyrthreedaletuganoslecbcatrnohgrtlthdehhalsloyeuuaorzv.tibloonet.isfnrtoeagccsraniIohmmtcavleeobpedpwerlryoieionsar-usgrtlooedna Io t hh oepr es , I p hl ea av se e a nd sowne or et d h yeos ui tra qt eu e st ct i o n si, cont a b c u t t if me. you have any S incerely yours, ' |1 VB17.i0o1Kc h. Be mRuoiiwlcdeailn gR e s e a r c h L a b o r a,1;t,o r y VKR/jd A ttach. ; 11I cc : Medical Department: Gordon, Holder, Krame] J. E. Peterson L. Eilverstein . H. R. Hoyle V. K. Howe (2) T j 6 . 2 5 -66631-7 M OO A L B E R T M. K L 1G M A N , M. D,, Ph . D. HOSPITAL OP THE UNIVERSITY OP PENNSYLVANIA 3 6 th AN O S P R U C E S T R E E T S P H ILA D E L P H IA , PA. 19104 January 23, 1968 810 Mr. V. K. Rowe Biochem ical Research Laboratory T18h0e3 DBouwildCinhgem ical Company Midland, M ichigan 48640 O vON-NOOJ' Dear V. K. : This note is a follow-up to my report of July 8, 1966. In that study, you w ill recall that 6 groups of healthy adult subjects received sm all and ipnrcorteoacsoilnlgaiddodseoswnofbtyetyroauc.h lUornofdoribtuennazote-lpy-,d inooxtina. sinWgelefoslulobwjeecdt da esvpeelocpifeidc acne nor was there any evidence of toxicity. a newThpiasneenl coofu1r0agseudb jmecetstoanpdroacpepedliemd o0r.e0 5v img ol roofuasly1%. sWoleuttihoenn ianssaelcmobhloeld chloroform to a one inch square on the back. These applications were made every other day for one month. The treated sites were covered with a non toecsctlsu swiveeregdauonzee: sqUurainrea.ly sEisa,chCwBCee,k BfUorN,6 wSGeeOkTs,, Athlekafloinlleowpihnogsplahbaotaraseto, raynd Creatinine clearance. C learly, this exposure was im m ensely greater than the form er one. 8 of 10 su bjects showed acne form lesio n s Usually beginning 3 to 4 w eeks. This began as with a typical developm ent of com edones. In 3 instances, tlahesteledsifoonr s4 ptroo7g rmesosnetdhst,o siinnfclaemnmo aetfoforyrt pwuasstumleasdaendto psappeuedlesh. eaTlinhgesebyleascio n s tTivhee thriesatotmlo genict.anBd ioclpinsiiecsa lwmeraen iofbestataintieodn sinw5erinestinanecveesryatwvaayricooums psataragbelse. to classical chloracne. The lesions were indistinguishable from those obtained by Dow 6X and Halowax. In no instance was there laboratory or clinical evidence of toxicity. The subjects rem ained w ell throughout the study. 1 17833 Mr. V. K. Rowe Page 2 January 23, 1968 i 4o j4 is m uTchhemseorreesduilftfsiciumltptloeminednut cteheaccnoen cinlutshioenhsufmoarnm tehralny idnrathwen,ranbabmit eelya:r . it The process begins m ore slow ly and the doses required are very much greater. H owever, unlike the rabbit ear, the com edones often becom e in ftolamacmn eaitgoernyi.c cIht eism aicacelsrtaanindtyis thanatetxhceelrlaebnbt itsyesatremis feoxrcethpetiodneatelclytiosnenosfitsivuech chem icals. Finally, it may be said that chloracne closely m im ics acne vul garis. The only difference is the paucity of anaerobic organism s in the com gedeno.e siOs noef mchalyorcaocnncelu. de that b acteria are not very sign ifican t in the patho Very sincerely yours, cG AM K/klf ''f / y A lbert M. Kligrpan, M. D. 520380 MASTER COPY THE DOW C H E M IC A L C O M P A N Y MIDLAND, MICHIGAN 4 8 6 4 0 Technical Information In Support of Application for Registration of Revised Labeling for the Use of TORDON 101 Mixture Weed and Brush Killer on Highways, Railroad and Utility Rights-Of-Way and Other Non-Crop Areas 3oO VOLUME I rm 1 6 1970 Registration Section Agricultural Department I7 8 3 S DOW 520382 VI CONTENTS V I FOREWORD C olor S ection Brown I I LABEL COPY G ray I I I PERFORMANCE G reen IV TOXICOLOGY W hite V RESIDUES Y ellow 17837 I b Technical Information In Support ! of Application for Registration of Revised Labeling for the Use of TORDON 101 Mixture Weed and Brush Killer on Highways, Railroad and 'Utility Rights-Of-Way and Other Non-Crop Areas oC7 cn to CoO CO VOLUME I Registration Section Agricultural Department f/ppn^MO(i I FOREWORD TORDON 101 Mixture Weed and Brush Killer has been extensively used since it gained Federal acceptance under,USDA Registration Number 464-306 on June 14, 1963. During the use period from then to now there have been no unusual adverse incidents experi enced by the users. In fact it has been widely accepted as being one of the most satisfactory herbicides available with a broad range of utility against numerous weed and brush pests not readily controlled by other herbicidal products commercially available. Since the initial registration date of June 14, 1963, an uncommon amount of research has resulted in extending the utility of the product with the result that labeling has been revised several times to provide for several uses in addition to those for which the initial application was made. The following tabulation "Chronological Evolution of Registered Uses for TORDON 101 Mixture" gives a summary history of registration activities with this product. This current application contains a proposed revised label along with a two volume compilation of technical informa tion in support of the proposed revisions. In addition, it should be noted there is a proposed name change for the product - from TORDON 101 Mixture Brush Killer to TORDON 101 Mixture Weed and Brush Killer. 17*340 .1 "1 Chronological Evolution of Applications for: Registration of TORDON 101 Mixture-January 5, 1969 Dates and Contents of Applications by Dow Submitted Submission Uses Requested Dates of Actions by USDA Labeling Notification Accepted to Dow March 28, 1963 Sept. 18, 1964 Original application for registration and supporting technical information Proposed label revision and supporting technical information Control of unwanted brush on utility rights-of-way s To provide for above use with NORBAK particulating agent in aerial applica tions June 14, 1963 Oct. 14, 1964 June 17, 1963 Oct. 21, 1964 April 29, 1965 Proposed label revision and supporting technical information To provide for killing unwanted trees by injector and frill treatment June 8, 1965 June 10, 1965 August 4, 1965 Proposed label revision to include additional uses as shown by supporting technical information To provide for extended uses with NORBAK particulating agent in aerial application Oct. 29, 1965 Nov. 12, 1965 Sept. 8, 1965 F e b . 4 , 1966 March 5, 1968 Application for Temporary Permit for investigational purposes with required protocol Application and supporting technical information Application for Temporary Permit for investigational pn ur orrp)ronOsosen i with required To control noxious perennial weeds on roadsides Nov. 10, 1965 Nov. 10, 1965 (USDA Temporarjr Permit No. 464-EXP-l7G) To provide for use with NORBAK parti culating agent on highway rights-of-way March 30, 1966 April 1, 1966 sseoss^c a To provide for March 5, 1968 April 22, 1968 extended use on high (USDA Temporary Permit No, ways and use on rail- 464-EXP-31G) 94G DOW424717 9 /2 2 /7 0 r>/ -- J . E . Jolm auir R. E. Naegele ? F P 9 o to-.-, Unless you have suggestions to the contrary, I propose to answer the Surgeon General in this ^hion. (letter attached) G. J. Williams oo o VIVJ4) lirk*jLzA^ THE DOW CHEMICAL COMPANY BAR STOW BUILDING 2020 DOW CENTER M ID LA N D , M ICH IGAN 48040 Jesse L. Steinfeld, M..D. Surgeon General of the Public Health Service Department of Health, Education, and Welfare Washington, D. C. 20201 Dear Dr. Steinfeld Thank you for your letter of September 15 relative to the use of TORDON 101 by the Department of Defense and other federal agencies. We think that the statement of the Interdepartmental Working! Group of the President's Cabinet Subcommittee on Pesticides is an accurate and reasonable statement and certainly accords with our own judgment on the use hazards of TORDON 101. We also respect and agree with your position concerning any sub sequent information that may become available concerning hazards associated with the use of TORDON 101. The Dow Chemical Company^feels a great responsibility in the production and sale of potontially hazardous materials and' always try to base our decisions on sound scientific data. As indicated in our letter of June 3, 1970 we feel that this is the only ffireper basis for decision-making and we would hope that it would continue to be used by -industr ial, as well as federal, state and local governments. >tv H a . GJW.-llm Sincerely, G. J. Williams Vice President i AG FORMULATIONS INTERIM REPORT NO. 181 AUTHOR: R. L. Van Horn RECEIVED JUN 9 19/5 DOW CONFIDENTIAL 38323 K-NO, 42085 ,, . 9o DATE: June 2, 1975 C-W. SIMON DATA BOOK 1-5480-19 FORMULATION DESCRIPTION,* Water Soluble and Wettable Powder Herbicides -hLJU- Compatibility of Tordon 101 Mixture and Dowco 233 (M-3724) owith Karmex 80 WP and Paraquat CL.__________'____________ ____ O - Ag-0rganic3 Development personnel wanted to know the feasi- bility of tank mixing Tordon 101 Mixture r M-3724 with mL_Ul Paraquat CL plus Karmex 80 WP. cQoc_ CO oC*oo tC\DO FORMULATIONS RES. MGR. K. G. Seymour, 9001 T E O L CENTER FORM. SPEC.C.A. Highhill/E.S. CO LI--U. COOL PLANT SUPT. PMT R&D REP. FORMULATIONS T. Haagsma, 9008 FILE*. Dowco 233 Parsey, 854 Area A B C T 1s Ag Formulations L F. N. Keeney,900] B. Byrd, Chariott Sales Office The compatibility of Tordon 101 Mixture and M-3724 (3.0 lb Dowco 233) was tested in combination with Paraquat CL and Karmex 80 WP as field spray dilutions in water. CO O2 Both Tordon 101 Mixture and M-3724 produced satisfactory C1O3 tank mixes with Paraquat CL and Karmex 80 WP. All spray dilutions settle out upon standing but redisperse easily Oo with mild agitation. No flocculation was observed Q with any of the .spray mixtures after twenty four hour storage. 2< <h<Q-- For commerical use, good continuous agitation will be required during all mixing and field application of these herbicide tank mixes. ^rujsr*. / Jb + 'JL' C L - A4L A received J U N 10 19/0 JUAN A. PAEZ . S 2a 90z/oa ' A L B E R T M. K L I G M A N . M D.. P h . D. h o &p ' tal o r tMi o M v c as i Tv o r Pennsylvania 3 6 r - A N O S P 9 U C C S TftC ETS P N 1L > O C L P H i A , PA*. 1 9 1 0 * January 23, 1968 Mr. V. K. Rowe B18io03chBeumilidcianlgR esearch L aboratory The Dow Chemical Company Midland, M ichigan 48640 Dear V. K .: This note is a follow -up to m y report of July 8, 1966. In that study, yipnorcuortweoacisollilnrlgaeicddaoldsl eotwshnaotfb6ytegtyrrooauuc.hpsloUronoffdohirebtauelnnthazyote-alpyd-,udlintooxstuinab.jseicnWtgselerfoescluleobiwvjeeecddt adsmesvpaelellocpiafenidcd acne nor was there any evidence of toxicity. This encouraged me to proceed m ore vigorously. We then assem bled a new panel of 10 su b jects and applied 0 .0 5 m l of a 1% solution in alcohol chloroform to a one inch square on the back. These applications were made every other day for one month. The treated sites were covered with a non otCecrscetlsautsiwniveinereegadculoenzaeer:asqnUucreai.nrea.ly sEisa,chCwBCee,k BfUorN,6 wSGeeOkTs,, Athlekafloinlleowpihnogsplahbaotaraseto, raynd C learly, this exposure was im m ensely greater than the form er one. 8 of 10 su bjects show ed acne form lesio n s usually beginning 3 to 4 w eek s. This began as with a typical developm ent of com edones. In 3 instances, the lesion s progressed to inflam m atory pustules and papules. These lesion s lasted for 4 to 7 m onths, since no effort was made to speed healing by a c tive treatm ent. B iopsies were obtained in 5 instances at various stages. cTlhaesshicisatlolcohgliocraancdn ec.linTichae l lemsaionnifseswtaetrieonins dwisetrine giunisehvaebrlye wfraoymcotmhopsaeraobblteaitnoed by Dow 6X and Halowax. In no instance was there laboratory or clinical evidence of toxicity. The subjects rem ained w ell throughout the study. 1 XV Mr. V. K. Rowe Page 2 January 23, 1968 These results im plem ent the conclusions form erly drawn, nam ely: it is much m ore difficult to induce acne in the human than in the rabbit ear. gTrheea tperro.ceHssowbeegvienrs, munolrike esltohwe lryabanbdit tehaer,d otshees croemqeudiroendesaroeftevnerbyemcoumche in flam m atory. It is a certainty that the rabbit ear is exceptionally sensitive tcoh eamcnieciaglesn. icFcinhaemllyi,cailts manady bise asnaiedxcthealltencht losyrastcenme cfolorsethlye dmeitmecitcisonaconfesuvcuhl gegdeanor.iess.iOs nToehf emchaolynolrycaodcnnicfelfu.edreentcheatisb athceterpiaaucairtey nofotanveareyrosbiigcn iofricgaanntisimn sthien pthaethcoo-m. Very sincerely yours, A M K /klf  DOW 1136192 MN0 7 7 5 0 6 Evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and 2,3,7,8-tetrachlorodibenzo-o-dioxin (TCDD) toxicity in , C57BL/6 mice: Heproductioo and Fertility in Treated Male Mice and Evaluation of Congenital Malformations in Their Offspring James C. Lamb TV1, John A. Moore1 and Thomas A. Marks2 ,3 National Toxicology Program Research Triangle Park, NC 27709 Research Triangle Institute Research Triangle Park, RC 27709 3Present Address The Upjohn Company Pathology and Toxicology Research Kalamazoo, Michigan 49001 NT?-80-44 I DOW 1136193 TABLE OP CONTENTS 1 S 1 Abstract.............................................. .. . . v Introduction.............................................. 1 Materials and Methods . ..................................... 5 Test Chemicals and Purity. . ........................... 5 Animals and Husbandry.......... . ................... Preparation of Diets ...................... . . . . . S 8 Experimental Design.......................... Toxicopathology............................. Fertility and Reproduction . u Statistical Evaluation ............................... 13 R e s u l t s .......... ; ....................................... 15 Feed Consumption and Body W e i g h t ..................... Organ Weights and Histopathology ..................... 15 15 Fertility.............................................. 26 Teratological Examinations .................... Postnatal Litter Examinations.......................... 36 Discussion.................................................. 46 Bibliography........................ ................. . 52 Acknowledgements............................................ 57 10 10 31 17848 f RT9PTI mn a LIST OF TABLES Ei Table I. Analysis of 2,4-D )Sample for Dioxin. . i. . . . 6 ; Table 2. Analysis of 2,4,5-T Sample for Dioxins . . i . . . . 7 Table 3. 2,4-D, 2,4,5-T and TCDD Concentrations in Stock C o m Oil Solutions and Projected Dosages in1 F e e d ............ . .' . ........... 9 Table 4. Fertility and Mating Efficiency in Treated and Control C57al/6 Mice, 8 Week Total . . . . . . 27 Table 5. Effect of 2,4-D, 2,4,5-T and TCDD on Fetal Develop ment, Group I Control. ............................ 32 Table 6. Effect of 2,4-D, 2,4,5-T and TCDD on Fetal Development, Group II............................ 33 Table 7. Effect of 2,4-D, 2,4,5-T and TCDD on Fetal Develop ment, Group III.................................... 34 Table.8. Effect of 2,4-D, 2,4,5-T and TCDD on Fetal Development, Group 17............................ 35 Table 9. Summary of Most Frequently Occurring Defects in Fetuses Sired by Males Treated with 2,4-D, 2,4,5-T and T C D D ............... 37 Table 10. Percent Malformed Fetuses Sired by Males Treated with 2,4-D, 2,4,5-T and T C D D ...................... 38 Table 11. Effect of 2,4-D, 2,4,5-T and TCDD on Postnatal 4 < Development of Offspring of Treated Males, Group I Control......................................... 39 ii 17849 DOW 113619 LIST OF TABLES (continued) P* age Table 12. Effect of 2,4-D, 2,4,5-T and TCDO orn Postnatal Development of Offspring of Treated Males, Group II . . . ................ . . . . . . . . . . Table 13. Effect of 2,4-D, 2,4,5-T and TCDD on Postnatal 40 Development of Offspring of Treated Males, ; Group III.............................. 4i Table 14. Effect of 2,4-D, 2,4,5-T and TCDD on Postnatal Development of Offspring of Treated Males, Group I V .............. >. ! ............ . 42 C l Table 15. Summary of Malformation Rates (%) in Postnatal Study1 ............................................. 43 Table 16. Summary of Specific Malformations in Postnatal Study............................................ 44 Appendix Table 1. Summary of All Malformations Observed in Fetuses Sired by Males Treated with 2,4-D, 2.4.5- T and TCDD................. 49 Appendix Table 2. Incidence of Fused Sternebrae in Fetuses Sired by Males Treated vitb 2,4-D, 2.4.5- T and TCDD.................... 50 iii OPTQPTI LIST OF FIGURES Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Figure 9. Figure 10. Figure 11. Figure 12. Average Weekly Food Consumption. . . if ,p ' M;ea'n Body Weights for "h" ale Mice. . . Average Weekly Weight Gain . . . .;. 'f ' Average Liver Weight . . .......... Average Thymus Weight............ .. i ! Average Spleen Weight. .......... .. I I: '** Average Testis and Epididymis Weight Average Kidney Weight............ . Average Brain Weight ............ f. Average Sperm Concentration. . . . Average Percent Motile Sperm . . . . Average Percent Abnormal Sperm . . . 17 18 19 20 21 22 23 24 25 28 29 30 iv .i? ' X 3 '*, DOW1136197 <i ABSTRACT This study was undertaken to determine the effects of mixtures (simulated Agent Orange) of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,3,7,8-tetrachlorodibenao--dioxin (TCDD) on reproduction and fertility of treated male mice. Male C57BL/6 mice were given feed containing varying concentrations of 2,4-D, 2,4,5-T and TCDD such that daily doses of approximately 40 mg/kg 2,4-D, 40 mg/kg 2,4,5-T and 2.4 Mg/kg TCDD (Group II) or 40 mg/kg 2,4-D, 40 mg/kg 2,4,5-T and 0.16 Mg/kg TCDD (Group IV) or 20 mg/kg 2,4D, 20 mg/kg 2,4,5-T and 1.2 Mg/kg TCDD (Group III) would be achieved. Controls (Group I) were given a diet with only the corn oil>vehicle added to the feed. In the treated animals, dose-related liver and thymus toxicity were found and body weight gain was significantly reduced. Liver and thymus toxicity showed sigsificant or complete recovery when the mice were returned to a control diet. Sperm concentration, motility and percent 3perm abnormalities were evaluated and no significant effect was noted during or after the dosing period. At the conclusion of an eight week dosing period treated males were mated to untreated virgin females (three per male per week for eight weeks). Mating frequency, average fertility, percent implantation and resorption sites and percent fetal malformations were all measured in relation to the treatment. No significant decrement in fertility or reproduction was noted in the study. There was no evidence of germ cell toxicity. Survival of offspring and neonatal development were apparently unaffected by paternal exposure to the simulated mixtures of Agent Orange. v INTRODUCTION Chlorinated phenoxyacetic acid compounds are,used extensively as herbicides in forestry and agriculture. The Department of Defense : :; !1 ' i : tested and used a number i of i dtiffei rent' Iherbici'des conta\; ining chlorinated phenoxy acids in Vietnam as1 dI efoliants; these i' ncluded' Herbicide Orange, Herbicide White, Herbicide P, urple(, Heribicide Pink and i Herbicide Green (Young et al., 1978). The herbicide most extensively used was Herbicide i* Orange, a 1:1 mixture of the n-butyl esters of 2,4-dichlorophenoxyacetic t i ' acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). It has been estimated that 107 million pounds were sprayed with the majority used in the years 1967 to 1969 (77X of.total herbicide sprayed) (Young et al., 1978). During the synthesis of 2,4,5-trichlorophenol (TCP) and subsequently 2,4,5-T, but not 2,4-D, a highly toxic contaminant is formed. This contaminant, 2,3,7,8-tetrachlorodibengo-p-dioxia (TCDD), has been found in Herbicide Orange at an average concentration of 2 ppm with individual analysis of up to 47 ppm reported (Young et al,., 1978). Occupational or environmental exposure to'humans to TCDD has been associated with a number of clinical disorders (Firestone, 1977; IARC, 1978). The heaviest exposures have involved industrial accidents which occurred in plants ,: 1 ' synthesizing TCP. The most consisteintly documented clinical manifestation has been chloracne, a severe form of1pustular folliculitis which is most frequently observed on the face, neck and upper extremities. ,Other less common clinical findings following TCDD exposure include porphyria cutanea tarda, central and peripheral nervous system disorders, depression and irritability, hepatic dysfunction and altered serum lipid concen trations (Firestone, 1977; IARC 1978; Young et al., 1978). - : r . Q. DOW 1136199 1 A number of Vietnam Ve' ,tei ransVh 'ave expressed concei rn as to health effects that may have resulted from exposure to Herbicide Oraage either through application 1 of the herbicid, e. or through inhabiting 1. defoliated areas (HoIdea, 1979; Rawls, 1979). A particular concern is that Herbicide Orange exposure may be related to reported decreases in both libido and fertility (low sperm counts : aind 'a!bnorm:a' l` ' sperm` f orms) 'and that it may also be responsible for birthi )defects observed in offspring sired by veterans who were exposed to Agent Orange (Bogea, .1979;Holden, 1979). The toxicity of TCDD and the phenoxy acids 2,4-D and 2,4,5-T has been studied in some detail. The.biological effects of these chemicals are well documented in a number of' mammalian test systems (Gehring and Betso, 1978; Moore, 1978). 2,4-D, 2,4,5-T and TCDD have all been investigated for teratogenicity and fetotoxicity when given to pregnant females.. 2,4-D acid and 2,4-D esters show signs of fetotoxicity and embryotoxicity in hamsters and rats at high dose levels, but it is unclear whether the compounds are actually teratogenic (Collins and Williams, 1971; Khera and McKinley, 1971; Schwetz et al., 1971). Exposure of mice to 2,4,5-T during- pregnancy results in congenital malformations (Courtney and Moore, 1971; Neubert and Dillman, 1972; Hood et al., 1979). Studies in rats (Sparschu et al,, 1971) and monkeys (Dougherty et al., 1975), indicate that the teratogenicity of 2,4,5-T may be a species-dependent phenomenon, since gestational exposure to this compound produced fetotoxic but not teratogenic effects (Gehring and Betso, 1978). i -Early studies with 2,4,5-T samples which were contaminated with 30 ppm of TCDD indicated that the herbicide was teratogenic in rats (Courtney et al., 1970). Subsequent studies by Courtney and Moore (1971), using 17854 3 UUW 1136200: purified 2,4,5-T, showed that both 2,4,5-T aad TODD were teratogenic in } t . 1 *' ` " ' j three strains of mice but in rats only TCDD was fetotoxic and possibly , . " 1j teratogenic. TCDD has been shown by other laboratories to be teratogenic and/or embryotoxic in mice at levels above 0.1 pg/kg/day (Smith et al., 1976) and rats at 0.125-2.0 pg/kg/day (Sparschu et al., 1971). i . i Although fetotoxicity and teratogenicity j,. t 'ass.o. c. i. atI1ed with gestational exposures to these compounds have been extensively studied, there is a paucity of data as to the effects of male exposure on'fertility and development of their offspring. Investigations in male rats undertaken to determine whether dominant lethal miu- tations could bte c'aused by TCDD were negative. However, the incidence of fertile matings was decreased but it was not determined whether this was due to the systemic toxicity of TCDD or a direct effect on reproduction (Khera and Ruddick, 1971). Other studies that have considered reproductive competence in males have generally been multigeneration studies of animals treated during their entire lives with one of the compounds of interest. In those studies neither 2,4-D (Hansen et al., 1971) nor 2,4,5-T (Smith et al., 1978) significantly reduced fertility when males and females were given feed i containing the herbicides. Three-generation studies with TCDD demon strated that ingestion of levels greater than 0.1 pg/kg/day decreased fertility and litter survival in the f generation; exposure to 0.01 pg/kg/day decreased fertility in the f^ and f^, generations, but not the fg generation (Murray et al.j 1979). In that case, an increase in the ; I it :! percentage of resorbed implantation sites could be related to female exposure to TCDD, but not to male exposure (Murray et al., 1979). DOW 1136201 The coasequences of chemical toxicity oa male reproductive capa bilities might include loss or decrease in fertility,! abnormal sperm morphology, decreased sperm concentration and/or motility, or lesions in the reproductive tract and accessolry sex glands (Gomes, 1970; Hanson and Simons, 1980). In addition to effects on reproduction or fertility, chemical exposure might cause genetic mutations in the male germ cells which could be expressed in the offspring as an inherited anomaly, or embryo and fetal death (Joffe, 1979; Hanson and Simons, 1980). Another mechanism to explain fetal effects via the male would be that the chemical might actually be transmitted to the female in the seminal plasma which could then result in a direct exposure of the ova. . The dominant lethal (Epstein, 1973; Generoso, 1973) and sperm morphology (Wyrobek, 1979) assays, used routinely in mice to evaluate potential chemical mutagenicity in male germ cells, were employed in this study. Both of these test systems involve chemical exposure followed by fertility testing or sperm evaluation of the animals for the duration of the spermatogenic cycle (approximately 35 days in mice). This approach is necessary since male germ cells are constantly dividing and differ entiating during transit from spermatogonia to spermatozoa with each developmental stage varying in its sensitivity and susceptibility to chemical toxicity or mutagenicity. Experimental .designs which are directed at determining male germ cell toxicity must consider this sperm maturation process to assure that all stages of development are tested. The following investigations were undertaken to determine if compo site exposure to 2,A-D, 2,4,5-T plus TCDD (i.e., Herbicide Orange), could affect reproductive function in male mice. o 6202 ! 2,4-dichlorophenoxyacetic acid (2,4-D) 2,4,5-cricnlorophenoxyacecic acid (2,4,5-T) i 2, 3,7,8-tetrachlorodibenzo-n-dioxin (TCDD) 2,4-dichlorophenoxyacetic acid (2,4-D) (AGR 171114, 98.5% pure) and 2,4,5-trichlorophenoxyacetic acid (2,4,S-T) (AGR 133711, 98.7% pure) were supplied by the Dow Chemical U.S.A., Midland, Michigan. Both samples were analyzed by Dow Chemical for TCDD contamination who reported no TCDD or other dioxin detected in the samples (Tables 1 and 2). The free acid was used to eliminate the volatility problem associated with the butyl ester which would compromise quantification of dose administered and pose an exposure risk to laboratory personnel. The free acid form is readily absorbed from the gastrointestinal tract. 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD) was synthesized by the Environmental Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. The TCDD was reported to be of greater than 98% purity by gas chromatographic analysis 6 TABLE 1 Analysis of 2,4-D Sample for Dioxins 2,3,7,8-Tetrachlorodibenzo-p-dioxin " Hexachlorodibenzo-p-dioxin Hep cachlorodibenzo-o-dioxin Octachlorodibenzo-p-dioxin Concentration Noc detected Hot detected Not detected Not detected Detection Limit 1 ppb 1 ppb 20 ppb 5 ppb DOW1136203 17858 wnn *******'**1*'**1" . . tI' ; 11 ' i" . "; :'.iit TABLE 2 , Analysis of 2.,4,5-T Sample for Dioxins 1 2,3,7,8-Tetrachlorodibenzo-p-dioxin Hexachlorodibenzo-p-dioxins: Occachlorodibenzo-p-dioxin , , Concentracin ( l *: 1 i 1 Noc Decactad Not detected Not detected Detection Limit 0.5 ppb 0.03 ppm 0.3 ppm i * t"^ O 1 i < DOW113G205 8 performed by HIEHS. The principal contaminate was 2,3,7-trichlorodibeazo-dioxin. Animals and Husbandry I Four week old male and 10 week old female C57BL/6N inbred mice (Cesarean-Originated, Barrier Sustained) were purchased from the Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts. Upon arrival the mice were eartagged and housed in plastic cages with stainless tops (males, one per cage; females, ten per cage). Absorb-dri hardwood bedding (Barnes Supply, Durham, HC) was used, and cages were cleaned once each week. The animals were kept in constant temperature (20 + 2C) and humidity (R.H. 5 0 + 10X) on a fixed cycle of 12 hours light-12 hours darkness. The mice were allowed food and water ad libitum. The powdered diet was open formula NIH-31 prepared by Zeigler Bros. Co. of Gardners, Pa. Preparation of Diets Stock solution of the test chemicals were prepared in a corn oil vehicle. The calculated and analytical values are given in Table 3. The test diets were prepared each week for 8 weeks by adding the appro priate stock solution into the feed (2 vol/wt). The concentration of chemicals in the feed was not changed during the 8 week exposure period study. Feed consumption (gm/mouse) was measured once a week. Approximate dose levels were projected using consumption of 5 gm feed/day by a mouse weighing 25 gm. The controls (Group I) were given a diet containing 2% corn oil. Group II consisted of mice that received about 40 mg/kg/day of 2,4-D, 40 mg/kg/day of 2,4,5-T and 2.4 Mg/kg/day of TCDD for a total dose of 2.24 gm/kg of 2,4-D and 2,4,5-T each and 0.13 mg/kg of TCDD over the entire 8 weeks. Group. Ill mice were treated at a rate of 40 mg/kg/day Treatment Group I (Control) II HI IV TABLE 3 2,4-D, 2,4,5-T and TCDD Concentrations in Stock Corn Oil Solutions and Projected Dosages in Feed * 2,4-'d1 ** ppm mg/kg/day 2,4,5--T* . , ** PPm mg/kg/day 2 TCDD ppb* |Jg/kg/day 0(0) 10,000(9380) 10,000(9310) 5,000(4880) 0 40 40 20 0(0) 10,000(9590) 10,000(9480) 5,000(4830) 0 0(0) 40 600(505) 40 I- -- 40( 39 ) 0 2.4 0.16 2 0 ___ 300(271) - 1.2 Calculated prepared concentrations and in ( ) amounts detected by analysis. . Dose levels based on ideal concentrations in feed and an average feed consumption of 5 gm feed/day/25 gra mouse. ^Samples of oil collected for 2,4-D and 2,4,5-T analyses were extracted with ethyl ether, derivatlzed witli diazometliane, extracted with hexane and analyzed on an electron capture gas chromatograph (ECCC) 2 by the Midwest Research Institute. ' Samples of oil collected for TCDD analysis were saponified in ethyl alcohol and potassium hydroxide, then extracted with hexane and. analyzed with an ECCC by the Midwest Research Institute. H,, 4-*r CTJ 9089811 MOO DOW1136207 10 of 2,4-D and 40 mg/kg/day of 2,4,5-T (same as Group II), but received only 0.16 pg/kg/day of TCDD; the total dosages of 2,4-D and of 2,4,5-T were 2.24 gm/kg and 0.009 mg/kg of TCDD. The nice in Group IV received 20 mg/kg/day of 2,4-D, 20 mg/kg/day 2,4,5-T, and 1.2 pg/kg/day of TCDD, resulting in a total 8 week exposure of 1.12 ga/kg of 2,4-D and of 2,4,5-T and 0.067 mg/kg of TCDD. After the 8 week exposure period all mice were fed standard pelleted ITCH 31 diet. Experimental Design Two hundred male mice were weighed and sorted (by weight) into eight groups (25 per group). One half of the male mice (4 groups of 25 each) were used for toxicity! evaluation, while the other half (4 groups of 25 each) were used for;fertility and reproductive studies. All males were then acclimatized on SIH-31 laboratory chow for three weeks before the chemical exposures were begun. Chemical exposure began when the males were eight weeks old. Body weights and food consump tion were recorded on a weekly basis. The males were assigned to experi mental and control groups such,: that weight diff,erences bi etween groups were minimized. The mice'were then treated with one of the three treated or control diets for eight consecutive weeks. Toxiconathology One hundred of the mice were studied during and after the 8 week feeding period. Four animals from each of the four dose groups were killed by decapitation at 1, 4, 5, 8, 12 and 16 weeks after first receiv ing treated feed. Each mouse received a gross autopsy examination; body and organ (brain, liver, spleen, kidney, thymus and testis/epididymis) weights were measured. These organs as well as lung, duodenum, ear, :al ><=?iv o n UUW1136208, 11 prostate, seminal vesicle, coagulating gland and urinary bladder were fixed in 10% neutral buffered formalin, dehydrated and embedded in paraffin blocks. Six pm histologic sections were prepared and stained with hematoxylin and eosin. The tissues were examined for evidence of histopathologic change. { Also at sacrifice, the vas deferens were removed and spermatozoa milked into a 1.0 ml volume of 0.9* saline. The concentration of sperm : .1 ^ 1'' ' i per vas deferens was estimated with a hemocytometer immediately after collection. Additionally, the percent motile (any movement vs. no movement) sperm was enumerated. The sperm sample was then stained with 0.25% eosin T for 30 minutes. ; Thei `lsperm were evenly,distributed within the staining solution using a Pasteur pipette and four slide preparations were prepared from each sample. The smears were allowed to air dry, were cover slipped and were examined at 400 X magnification. Three hundred sperm were studied for each sample and sperm were classified as normal or abnormal using the criteria of Wyrobek and Bruce (1975) and Soares et al (1979). Fertility and Reproduction Fertility and reproduction assessments were conducted on the remaining 100 mice (four groups of 25).. > After the male mice had been treated with the t e s t :chemicals for eight weeks they were returned to control feed. Beginning the next day, each male was housed with three virgin female mice (fourteen weeks of age) for up to 5 days each week for eight weeks. Each female was examined each morning for evidence of mating by detection of a vaginal plug (Day 0 of pregnancy). Each mated female was removed from the cage, weighed and placed in a cage with other mated females in that group. Females which did not appear to have mated during the 5-day cohabitation period 89841 6029ET1 NiOQ 12 were observed for three more weeks to permit detection of possible pregnancies for which vaginal plugs were not observed. Apparent failure of a female to mate or conceive was verified three weeks after cohabi- tation by killing the animal, removing the uterus, and staining it with . I' , * -i t; " ammonium sulfide to better identify the presence .of implantation sites (Kopf et a l ., 1964). !' ; ; Tor each weekly mating trial one female bred to each male was put in a group to be sacrificed on day 18 of pregnancy.-, for teratology examin- ation. A second bred female from each male was placed in a group which I !. 1 '; ' ! was allowed to deliver and rear her offspring. All remaining dams found i i to have plugs were placed in a "tei ratology backup group" to be subjected to teratological evaluation if the dam selected for day 18 sacrifice was found not to have any live fetuses. The above pregnant mice were systematically distributed to the teratology, postnatal or "backup" groups such that no one group was biased with dams which mated first, second or third. However, if less than three dams had mated, priority was generally given to the teratology group. All mated dams were weighed on days 0, 7, 11, 15 and 18 of gestation. On day 18 of gestation, the dams designated for teratology examina- tion were coded to permit identification only by number so that laboratory personnel conducting the teratogenic analysis did not kn1ow the test group. The mice were killed by cervical dislocation and their reproduc tive status was determined. Implantation sites in each.uterine horn were counted and the general condition of each concepta was recorded. The detection of implantation sites in the uteri of apparently nonpregnant .i . females was achieved through use of ammonium sulfide (Kopf et al., 1964). Live fetuses were weighed individually, sexed internally (surgical incision below navel), and examined for external malformations. Live 17864 DOW1136210 fetuses weighing <0.5' g, or weighing less than two-thirds the mean of their larger littermates, were designated as being "stunted". At least one-half of the fetuses of each litter, all "stunted" fetuses and fetuses having external malformat,ions, were examined fl or visceral alterations (Staples, 1974). The bodies of all fetuses were then processed for skeletal examination (Staples and Schnell, 1964). The heads of each fetus subjected to visceral examination (with the exception of any fetuses which had external head malformations) were cut off at the base and examined by the free-hand sectioning technique described by Wilson (1965). The remaining dams (postnatal group) were allowed todeliver their litters. Live and dead offspring as well as birth weightwere recorded (day 0). The pups were reweighed on days 4, 7 and 21 andviability also was recorded. The dams and their offspring were killed on day 21. The above procedures were repeated weekly for eight weeks resulting in a total of eight sets of data. Four weeks after the conclusion of the breeding study, (week 20 of the experiment), the male mice were killed and autopsied in a. manner identical to that described for the males sacrificed for toxicopathologic evaluation. Statistical Evaluation Statistical evaluations of possible pairwise treatment-control differences in food consumption, body weights, organ weights, fertility, mating efficiency, and sperm number, motility and abnormalities were made by Dunnett's test (Miller, 1966). Analysis of variance procedures were employed to assess the significance of differences among groups, week-to-week variability, and week by group interactions. Analyses of abnormalities among the offspring were carried out employing pairwise 17865 f* 14 :i comparison of co,n. trol versus treated groups : with thej Mann Whitney U test. The analysis of malformations considered ;the average percent malformed fetuses per litter. I DOW1136211 / C Or% 15 UUW1136212 :RESULTS Feed Consumption and Body Weight' Tlie projected food consumption of 35 gm/week (5 gm/day) proved to ; : , . \ I-.; .! t- be a conservative estimate !in all!groups throughout the period of chemical exposure (Figure ,1). Lower food consumption for all groups is indicated in week-2 because only a fraction of the week (5 days) was measured. The addition of 2,4-D, 2,4,5-T or TCDD did not significantly decrease feed consumption during the full 'eight week dosing period in any treatment group, as compared to the controls. " Statistically significant changes in feed consumption were only found in sporadic cases and no general trend of decreased feed consumption could be attributed to the addition of either phenoxy acids or TCDD. Body weight and weight gain, however, showed significant reductions in the treated animals when compared to controls (Figures 2 and 3). This reduction in body weight was most pronounced in group II (2.4 |jg TCDD/kg/day and 80 mg phenoxy acid/kg/day) from weeks 3 through 8 of the study. The Group II animals recovered most of their weight deficit when returned to control diet. Generally all of the mice appeared healthy throughout the course of the study. Only two animals died during the twenty weeks, one in group IV at 5 weeks and one in group II at 19 weeks. Their death did not appear to be treatment-related. Organ Weights and Histopathology i The mean organ weights of animals killed on weeks 1, 4, 5, 8, 12, 16, and 20 are shown in Figures 4-9. Statistically significant increases in liver weight (Figure 4) were observed in all treated groups and was positively correlated with the amount of TCDD exposure (i.e., 2.4 > 1.2 DOV1 1136213 > .16 pg/kg TCDD/day, groups II, IV and III respectively). After conclu sion of exposure the liver iweight, returned toward normal, although Groups II and IV continued to show significantly elevated values even at week 20. The livers of treated mice were enlarged, lighter in color than normal and mottled. The thymus was decreased in weight, which also appeared to be a function of the level of TCDD rather than phenory acid exposure (Figure 5). Although the thymus weights were significantly (p<.01) reduced in Groups II and IV.relative to controls throughout the treatment period (-aeks 1-8), thymic recovery appeared complete and weights were not statistically different from the controls by 4 weeks after the last exposure. No significant treatment-related effects were observed in the spleen (Figure 6), testis (Figure 7), kidney (Figure 8), or brain (Figure 9). Histopathological evaluation showed no treatmentrelated changes in any organs, with the exception of the liver. Even the thymus, which.had decreased in sine to as much as one-third that of the control thymus, appeared histologically normal. The mild toxic effects observed in the liver included hepatocellular swelling, scattered single cell necrosis, increased numbers of mitotic figures, excess extramedullary hematopoiesis, and leukocytic infiltration. These changes were most apparent in group II (2.4 pg/kg/day T O D ; 80 mg/kg/day phenoxy acids) and least apparent in Group III (0.16 pg/kg/day TCDD; 80 mg/kg/day phenoxy acid). These signs of toxicity diminished substantially by the end of the twelfth week of the study (four weeks after chemical exposure was concluded). 17868 AVERAGE WEEKLY FOOD 45.0 UJ i3f ) 40.0 O \ CD 35.0 O 30.0 I-- O. 3 CO 25.0 Z o o I 2345 6 WEEK OF TREATMENT Litec c Figure 1. Average weekly food consiini|>lion before and during the treatment C<5fOJ period of study for tbc wales. Values are mean + S.E.H. >129611 MOO ST29ETIMOQ WEEK OF STUDY Figure 2. Mean body weights for naie mice in all four treatment groups. Significant reductions (p<0.05) in weight, as compared to control, for groups II and III were present in weeks 3-8, group IV in weeks 6-8. Values are mean t S.E.H. DOW1136216 WEIGHT GAIN t S .E .M . (gm) 19 ! WE!EK *O' F TR EA TM E N T Figure 3. Average weekly weight gaiii. Weight gain was significantly (p<0.01) .reduced in Group II relative to control during weeks 4, 3 and 3. Rapid recovery was observed such that no significant difference was present by week 12 in'these animals. Values are mean + S.E.M., n 4 per group. 1 '^ 'V ^ -i 20 tf' DOW1136217 Eo 3 .0 2 2.5 zoUJ in +i x 1.5 o LU 1.0 XLU 0 .5 - > r* ha mo iz> --- 1 i t > t t t i t 4 6 8 10 12 14 16 18 2 0 WEEK OF TREATMENT Figure 4. Average liver weight. Liver weight was significantly (p<.05) increased in Group II (weeks 1-20), Group. Ill (weeks 1-5, week 16) and Group IV (weeks 4-20) relative to controls. Values are mein + S.E.M., n = 4 per group, weeks 1-16, a = 25 per group in week 20. 0 17872 THYMUS WEIGHT t S.E.M.(gm) 0 .0 6 0 0 .0 5 0 0 .0 4 0 0.030 j 0.020 co : teOn OC i 0.010 0.0001 J__ I__L_!__!__ !__L J__ !__ ! 4 6 8 10 12 14 16 18 2 0 WEEK OF TREATMENT figure 5. Average thymus weight. Thymus weight was significantly (p<.01) reduced in Groups II and IV relative to controls (weeks 1-8). Complete recovery;was observed in all groups by week 12. Values are mean + S.E.M., jn = 4 p e r group on week 1-16, n = 25 per group in week 20. ; 1 1'*,,5.. - V> *.w' J..: 22 Ccr oDn CO 0.10 o> J - 0.08 X ou<2 0 .0 6 $ X Q04 UJ LlJ -J 0.02 b (CIL) no IZm > L. 1,, I t J__ !__ I 0 1 2 3 4 5 6 7 8 9 1011 12 !3 14 15 16 1718 19 2 0 WEEK OF TREATMENT Figure 6. Average spleen weight was not significantly changed by treatment. Values are mean + S.E.ti., n = 4 per group in weeks 1-16, a = 25 per group in week 20. 17874 DOW1136220 WEIGHT OF TESTIS AND EPIDIDYMIS (gm) 23 WEEK OF TREATMENT Figure 7. Average testis and epididymis weight was not significantly affected by treatment. Values are mean + S.E.M., n = 4 per group in weeks 1-16, n = 25 per group in week 20. 24 CO 05 tt oo 0 I 2 3 4 5 6 7 8 9 1011 E 13 14 15 16 17 18 19 2 0 WEEK OF TREATM ENT Figure 8. Average kidney weight was not significantly changed by treatment. Values are mean + S.E.M., a 4 per group in weeks 1-16, a = 25 per group in week 20. 17878 A BRAIN WEIGHT (gm) 0.30 0.25 I DA mo E2- 0.20 I 1 I .. L - I J O I 2 3 4 5 6 7 8 9 IO II 12 13 141516 17 18 19 20 WEEK OF TREATMENT Figure 9. Average brain weight was not significantly altered by chemical treatment. Values are mean + S.E.M., u = 4 per group in weeks 1-16, n = 25 per group in week 20. ZZZ9SI MOO LNa> DOVI 1136223 Fertility The average percent matings and overall fertility of the males through 8 weeks of the study are given in Table 4. There was a signifi cant reduction in the mating frequency in males from group III (80 mg/kg/day phenoxy acid, 0.16 pg/kg/day TCDD). This effect was not [i significant in Group II whose phenoxy acid exposure was similar and whose TCDD exposure was 15-fold greater. Therefore, ho dose-related effect could be attributed to this decrease. Also., the percent fertile matings and total fertility were not significantly reduced in Group III or in any group when compared to the control.' When fertility was evaluated'-on a week by week basis, no treatmentrelated changes were observed. Fertility was also studied on an indi vidual per male basis and no significant changes were detected within treated males as compared to controls. At the conclusion of the study sperm concentration and motility and percent abnormal sperm were measured (week 20, Figures 10-12). These values were analyzed, on an individual male basis, to determine whether any correlation existed between low fertility performance (plug frequency, percent fertile matings and total fertility) and low values for sperm quality (concentration, motility, percent abnormal). In all groups there was no correlation between the parameters measured. This would indicate that, even though there was considerable variability within these parameters, variations in fertility could not generally be attributed to specific changes in sperm quality. I The values for sperm concentration (figure 10) and sperm motility (Figure 11) fluctuated considerably from week to week. Percent abnormal sperm were less variable (Figure 12). No treatment-related changes were observed in these parameters. The marked reductions in sperm concentra tion (Figure 10) and increase in sperm motility (Figure 11) which were 1 7 871 DOW1136224 li.Si aiaU A W .W i 27 TABLE 4 1 F e r t i l i t y and M acing E ic ie n c y i s T ris c a d ia d C o n tro l C5 73176 H ie * 8 Ueak T o ta l T re a tm e n t Croup^ Macing^ Frequency F a r t ila M atings (p a re a n t)^ T o ta l* F e rtility (parease) I(C o n tro l) 74.6 1.6 56.2 2.2 i | 42.0 1.9 IZ (80;2. 4) 70.3 2.4 58.3 2.9 41.0 2.6 I I 1 (30;0 . 16) 67.8 2. 4* 55.3 2.3 i 37.7 2.2 IV (40; 1. 2) 73.0 2 .0 60.8 2.9 44.2 2.3 C a lc u la te d dai l y sxposura la g iv e s l a paraacfaaaaa as c o c a l ag pbeaaxy a c id s /le g /d a y ; Mg TCDD/lcg/day Z?rcanc p lugs o bservad/t o t a l fem ales housed w ith o a la a . p 1arcane a r t 11 a a e in g s /fe m a le s w it h p lu g s . #Parcanc f e r t i l e a a c ia g s /e o ta l f c o a la s boused v ie b o s la s . P< .0 5 r e l a t i v e co c o n tr o ls V alues a ra mass s ta n d a rd e r r o r o cha a s a s , i 23 p a r g ro u p . 17873 28 CO 05 to to or Figure 10. Average spera concentration. Sperm concentration was quite variable and the only significant reduction relative to controls was in week 16 (p<.05, Group II; p<.01, Group IV). The marked reduction in all groups at 20 weeks may have been related to the mating of those animals. Values are mean + S.E.M., n = 4 per group in weeks 1-16, n * 25 per group in week 20. r`v , 29 IMlbMUI>UUUUl DOW 1136226 Figure 11. Average percent motile sperm. No significant change was observed in the percent motile sperm (p<0.05) when treated and control values were compared. The drop in-motility seen from week 4 to week 16 may have resulted from not breeding'those males; in contrast, the week 20 (mated) values were much higher. Values are mean + S.E.M., n = 4 per group in weeks 1-16, n * 25 per group in week 20. 30 C<ttooOn cc caun. -i 2< cc o zCQ < -L-J_t 1 J l t I I > < i 0 1 2 3 4 5 6 7 8 9 11 0 11 12131415 16 17 18 1920 WEEK OF TREATM ENT Figure 12. Average percent abnormal sperm. Treatment bad no significant influence on tbe percent abnormal sperm (p<0.05). Values are mean + 5.E.M., n = 4 per group in weeks 1-16, u = 25 per group in week 20. i *&1- IiOiV 1136228 ..fcii observed from weeks 16 to 20 of the study might be at', least partly ' I ;j explained by the fact that the males whose sperm were:checked on week 20 had been through an 8-week intensive mating program whereas the males monitored in the earlier weeks were virgins. Teratological Examinations i The results of the teratology examination of the dams mated with treated or control males for each group by week are detailed in Tables 5-8. A comparison of the tables indicates that the average number of implants per litter, average number of resorptions per litter or average number live fetuses per litter (Tables 5-8) were unaffected by the male's chemical exposures. For example, the mean values for control and Group II (most heavily exposed) were 7.1 vs 7.4 implant'sites per litter; also in Groups I and II there were 4.9 vs 5.0 live fetuses per litter and 2.18 vs 2.37 resorptions per litter.' The average fetal weight was significantly (p<0.05) greater in all treatment groups as compared to controls. The total number of dead fetuses (i.e., offspring which weighed more than 0.3 gm; offspring weighing <0.3 gm were listed as a resorptions) was 1 in Group I, 2 in Group II, 1 in GrouIp ; III and 0 in Group IV for the entire 8 week study. The ratio of male I to female fetuses was also determined; no treatment group exhibited any significant change (p<0.10) in this ratio as compared to the control. Congenital malformations were not significantly increased in the offspring of treated versus control males (Tables 5-10). Visceral malformations were observed with less frequency than external and skeletal malformations in all groups. The incidences of the most frequently observed malformations are summarized in Table 9: eye defects (anophthal- i mia and microphthalmia), jaw anomalies (agnathia, micrognathia), were observed in 1.4 to 2.4 percent and 1.2 to 1.6 percent of the fetuses,. 17083 6ZZ9CTI MOQ Nuaber of (canlea eaaaioeil Maternal weight gain Nuaber of laplanti per litter Nuaber of resorptiona per litter Nuaber of live fetuaea per litter Average fetal weigliL per litter Hale/fcaale Visceral Malformations: Nuaber of fetuses examined Nuaber with visceral aalforaatiooa Skeletal and External Halforaations: Nuaber of fetuaea examined Nuaber with aalforaatlona Table 3 Effect of 2,4-D, 2,4,5-T and TCUD on fetal Development Croup I Control Week of Study Total i 2 . 3 4 3 6 7 8 1 weeks 19 13.1 1 1.0 1.1 i 0.5 2.16 2 0.38 3.9 2 0.1 1.06 2 0.03 39/32 22 12.8 2 0.7 7.7 2 0.4 2.41 2 0.32 3.3 1 0.3 1.06 2 0.02 47/68 22 12.7 1 0.7 8.0 2 0.4 2.18 1 0.32 3.9 1 0.3 1.03 1 0.03 63/64 23 12.0 2 0.8 7.4 1 0.6 2.16 2 0.23 3.2 2 0.6 1.00 2 0.02 69/60 23 10.0 2 0.7 3.4 2 0.3 2.39 2 0.23 3.0 2 0.3 1.03 2 0.02 38/32 19 10.1 2 0.7 3.8 2 0.4 2.16 2 0.33 3.7 2 0.4 1.04 2 0.03 32/38 22 11.4 2 0.8 7.2 2 0.3 2.27 2 0.3 4.9 2 0.3 0.99 2 0.03 32/33 19 12.1 2 0.8 6.6 2 0.6 1.68 2 0.30 4.9 2 0.6 11.01 2 0.03 42/32 171 11.8 2 0.3 7.1 2 0.2 2.18 + 0.11 4.9 2 0.2 1.03 2 0.01 404/419 60 62 68 73 39 39 0 0 0 1 1' 0 1 113 2 117 3 ' 129 4 129 4 70 4 70 0 62 52 0 "0 108 94 ' 43 OJ A55 2 830 26 Values are mean + standard error of tbs aean. ry. Ws i-i& Table 6 Effect of 2,4-D, 2,4,5-T and fCUO on Fetal O evelopurnL Group 11 Week of Study Total 1 2 3 4 5 6 7 8 8 weeks Number of feaalea examined Maternal weight gain 19 14.1 t 0.5 IS 12.7 1 0.9 21 12.2 t 0.8 17 11.5 t 1.0 22 ' 10.8 t 0.7 20 10.4 1 0.9 17 12.6 i 0.9 14 12.0 t 1 . 0 148 | 1 1 2 . 0 t 0 .3 ; Number of implants per litter Nusiber of resorptions per litter Nuaber of live fetuses per litter 9.2 t 0.4 2.37 1 0.27 .8 i 0.3 7.4 t 0.6 1.94 t 0.37 5.5 1 0.7 8.2 1 0.4 2.71 t 0.40 5.6 1 0.5 6.2 t 0.6 1.76 t 0.22 4.5 t 0.7 7.1 1 0.4 2.55 i 0.36 4.5 1 0.4 6.2 1 0.5 2.30 0.45 3.9 1 0.6 7.5 1 0.4 1.88 1 0.3 5.6 1 0.6 7.0 1 0.7 3.43 i 0.71 3.6 t 0.7 7.4 1 0.2 i 2.37 +0.14 5.0 1 0.2 [ Average fetal weighl per litter Nile/fensle Visceral Hal formations: 1.00 1 0.02 62/67 1.14 t 0.03 39/60 1.08 t 0.03 61/48 1.09 1 0.02 36/39 1.02 1 0.03 45/54 1.11 1 0.03 43/34 1.02 1 0.02 42/54 1.10 l 0.03 20/20 1.08 1 0.01t 356/316 | li Nuaber of fetuses examined 66 53 61 42 54 42 47 28 393 | Number with visceral malformations 0 0 0 0 0 020 2| Skeletal and External Half oreat ioita: . ]| Number of fetuses examined 129 99 115 78 100 77 96 50 744 Number with malformations 2 6 4 0 5 1 7 1 26 Values ora M a n + standard error of the M a n * Ib CO CCOA 0C29IIMOO T23ETl MOO Halernal weight gala Mustier of iaplanta per litter Nuaber of rcaorptloua per litter Nuaber of live fetuaea per litter Average fetal weight per litter tlale/fcaale Visceral Halforaationa: Niuaber of fetuaea eaaaiioed Nuaiber with viaceral aialforaationa Skeletal and External Halforaationa: Nuaket of fetuses cxiained Nuaber with alfornatiooa Table 7 Effect of 2,6--0, 2,4,5-T and TCDD on Fetal bevelopaent Group 111 Week of Study ' 23 66 6 a Total 7 8 weeks IS 12.9 1 0.9 ta. o.6 2.66 2 0.58 6.7 2 0.7 1.06 2 0.0] 67/60 16 12.9 1 0.9 7-6 2 0.6 2.27 2 0.66 6.6 2 0.6 l.ll 2 0.02 61/39 21 11.9 2 0.7 7.6 2 0.6 2.16 2 0.36 6.3.2 0.6 1.16 2 0.02 60/63 17 12.0 2 0.9 6.6 2 0.6 1.66 2 0.28 6.0 2 0.6 1.09 2 0.03 33/60 19 10.7 2 0.8 (7.2 2 D.6 2.86 2 0.37 6.3 2 10.6 1.09 2 0.02 66/36 22 10.9 2 0.S 6.6 2 0.6 2.16 2 0.36 6.6 2 0.6 ) .06 2 0.03 61/67 21 10.2 2 0.6 6.8 2 0.6 2.06 2 0.30 6.8 2 0.6 1.00 2 0.02 61/69 12 12.2 21. 1 7.0 1 0.6 2.33 2 0.72 6.7 1 0.7 1.09 2 0.03 29/26 165 11.6 2 0.3 7.2 2 0.2 2.'26 2 0.1 +6.9 0.2 1.08 2 0.01 356/369 6] 66 13 , 97 SI 21 60 66 00 112 6 62 67 68 .... . - 0- 0 82 98 60 66 32 396 50 1........ : 100 56 61 711 20 Values are aean + standard arror of the Man. Nual>r o f ie m *lei examined Maternal weighl gain Number o f implanta per litter Number of resorption* per litter Number of live fetuses per litter Average fetal weight per litter Halc/femalc Visceral Malformations; Number of fetuses examined Number with visceral malforiaations Skeletal and External Malformations: Number of fetuses examined Nnadier with malformations Table 0 Effect of 2,4 -U. 2.4. 5-T ml TC0I) on Fetal Development Crou|i IV a i a.9ii.6 i o.a i o.i 2 23 12.9 1 o.a 1 .3 t 0.6 3 20 11.5 1 0.7 7.0 1 0.6 Week of Study 45 24 12.2 i o.a 7.6 1 0.5 21 9.9 2 o.a 6.0 1 0.5 6 21 9.9 i o.a 6.5 1 0.5 7 IB 11.9 2 o.a 7.5 1 0.6 a 19 11.9 1 0.9 5.9 1 0.7 Total it wuck: ! 164 | 11.5 1 Oj 1 7.0 i o.; 4.00 1 0.50 4.9 1 0.6 1.12 1 0.04 33/45 1.77 1 0.29 5.6 1 0.6 1.16 1 0.03 59/69 1.30 1 o.2B 5.7 1 0.5 1.09 1 0.02 50/54 i.aa i o.3o 5.a 1 0.6 1.11 1 0.02 63/75 ' 1.95 1 0.37 2.43 1 0.35 4.1 1 0.5 4.1 t 0.4 1.10 1 0.03 1.07 1 0.03 45/41 "40/46 2.39 1 0.48 5.1 1 0.6 1.05 1 0.03 42/46 1.5B 1 0.30 4.3 1 0.7 1.07 1 0.03 36/44 2.11 l o! 5.0 ^ o.;' 1.10 1 o i. 1 376/42U t 41 01 67 2 62 tl 77 5. 50 .. Vi 50 46 443 1 | ^ ... 0 0 ' 5 It 129 113 139 86 06 92 82 805 2 5 5 3 2 0 4 4 25 Values are mean + standard error of tlia moan. .......... - ------ ---------------- --- .... - : --" r i'l l ' .- r- - 2E29ETIMOO DOVn 136233 36 respectively. Cleft palate and heart or major blood vessel anomalies were observed in all groups in somewhat lower incidences (Table 9). The total percent malformed fetuses (Table 10) ranged from 3.1 to 3.6 percent and the weekly percentage did not show any treatment-related increases in congenital malformations. A comprehensive listing of malformations observed during the study has been included (Appendix Table 1). Postnatal Litter Examinations 1 When females were allowed to carry their litters to term, the survival and development of their' offspring were studied. The number of live pups and their mean body weight were compared in treated and control offspring (Tables 11-14). ..The lack of a toxic effect is graph ically demonstrated by comparing values for control. (Group I) animals to those for the animals exposed to the highest dose of phenoxy acid and TCDD (Group II). There was a marked reduction in the number of litters from day 0 to day 4 in all groups. In group I the number of litters .fell from 80 to 44 and in group II from 90 to 60. This was accounted for in all groups by cannabalism by the mothers. After day 4, the loss of litters was greatly decreased. Other parameters show little difference between Groups I and II; on day 0, the number of live pups per litter were 4.40 and 4.19, number of dead pups per litter was 0.92 in both groups, and the average pup weights were 1.37 and 1.39. At day 21 the number of live pups per litter were 5.IS and 4.59 and the average pup weights were 7.43 and 7.60, respectively, for groups I and II. No effect on postnatal viability or growth could be attributed to the exposure of the adult male mice to phenoxy acids or to TCDD. The pups were examined externally on day 0 for malformations i (Tables 15 and 16). During the entire eight weeks the total malformation DOW 1136234 37 TABU 9 Summary ai Hose Froquaaely Occurring Daface* la Facuaas Slrad by Mala* Traaead vieh 2,4-0, 2n d te a ts i Trapanane Croup I n ni IV Aaopedalala/ nicropcbaiaia Agaachla/mlcrogaachla elafe Pslac Baarc/Vasaala Anomalia* 1.4(12/830) 1.3(11/830) 0.6(5/830) 0.2(1/455) 1.904/741) 1 1.2(9/744) 0.7(3/744) ` 0.3(2/393) 2.004/711) 1.4(10/711) 0.7(3/711) 1.0(4/394)-. 2.409/803) 1.603/803) 0.7(6/805) 0.7(3/443) Valus* ara paresse Incidane* of pacific anomalia; no. apaelfle aalformaelons par no. obaarvad la glvaa la paraacbaaas. , 78 ' ^ DOW U 3 6 2 3 5 ,* * t** s U v ** A i* fr**4* Us li i U i * i f r * 4*4 ,lV*\l*< --U A J.l *.****S J*" ***" **' 38 IASLE 10 Picetat Maliotsad Fatua Sirad by Malas Trsacad vlth 2.4-0, 2,4,5-T aad TOJO Waak I Trsaeaant Group n H2 IV 1 1.8(2/113) 1.6(2/129) 3.1(3/97) . 2.6(2/78) 2 2.6(3/117) 6.1(6/99) 3.7(3/81) 3.4(7/129) 3 3.1(4/129) 3.5(4/115) 3.6(47112) 3.3(6/113) 4 3.1(4/129) 0.0(0/78) 2.4(2/83) 2.2(3/139) 3 3.7(4/70) 5.0(5/100) 6.1(5/82) ; . 3.5(3/86) 6 u.0(0/7C) 1.30/77) 0.0(0/98) 0.0(0/86) 7 3.7(4/108) 8.3(8/96) 5.0(5/100) | 4.3(4/92) 8 5.3(5/94) 2.00/50) 1.80/56) 4.9(4/82) local 3.1(26/830) 3.6(27/744) 3.2(23/7111 3.6(29/805) Falas ars parease aalioraad acusas, nuabar aalaraad par cuabar obsarvad la glvaa ia poraacbaaas. Ko valas ara slgnlleastly dlffaraae roa cuatro1 (p<0.051. t 7QQ Jk. s *j i Table 11 Effect of 2,4-D, 2,4,5-T end TCDD ou postnatal Development of Offipriii{ of Treated Male* Croup I Control 1 2 3 i 5Week of Study F- 1 Total ! i I week Day 0: Number of litters Huntier live pups per litter Niuiber deed pups per litter Average pup weight Day 4: Number of litter* , Number live pup* per litter Average pup weight Day ?: Nu*tcr of 1liters Number live pups per litter Average pup weight Day 21 i Number of litter Number live pupa per litter Average pup weight 17 3.9A 1 0.70 1.A7 X 0. A3 1.39 X 0.03 15 A.67 X 0.80 1.33 X 0.A5 I.3A X 0.02 15 6.00 i 0.62 0.20 i 0.20 1.37 X 0.A8 10 2.60 1 0.85 1.10 t 0.AI I.A1 t 0.02 5 10 A.00 X 1.10 3.70 1 0.91 1.00 1 0.78 0.AA t 0.18 1.36 1 O.OA 1.38 1 0.05 5 5.A0 t 0.51 0.20 1 0.20 1.33 t 0.03 3 5.00 X 2.51 1.33 X 1.33 1.30 1 0.03 80 A.A0 1 0.32 0.92 t 0.16 1,37 X 0.01 8 5.00 t 1.20 1.87 1 0.10 5 6.60 t 0.93 2.22 1 0.19 10 5.30 1 0.75 2.0A t 0.15 A 5.50 t 0.50 2.A3 t 0.10 A A.75 1 0.75 2.71 1 0.24 44 8 A. 29 X 0.99 3.13 X 0.29 5 6.60 X 0.93 3.6A X 0.33 9 5.78 1 0.64 3.60 X 0.19 4 5.50 1 0.50 4.07 1 0.18 A A.75 X 0.75 4.71 X 0.39 A2 8A A.75 1 0.98 6.00 1 0.91 6.A3 X 0.51 7.02 X 0.75 9 5.78 X 0.6A 7.34 t 0.32 A ..... 5.25 1 0.63 8.7A X 0.21 A 3.50 1 I.0A 8.62 X 0.5A 55 A.00 X 0.95 5.40 X 0.51 7.71 1 0.65 8.07 t 0.51 2 Al 7.50 X 0.50 5.15 1 0.32 6.Al X 0.12 7.A8 1 0.21 Value* are aean + standard error of tlie Bean. COOP 9 3 9 e n MOO s  e z 9 T l NlOfl yV-` Tab(e 12 E H e c l of 1,4-D, 2,1,5-T and TCDD on Postnatal Devclo|uaeut of Offspring of Treated Hales Group II 1 Ucch of Study Total 2 3 4 5 6 1 8 8 weeks inL Number of litters Number live pups per litter Number deed pups per litter Avenge pup weight Day 4: ii 4.16 t 0.53 0.88 t 0.40 1.39 0.03 16 4.88 8 0.68 1.06 * 0.30 1.39 t 0.04 14 t5.29 0.14 0.64 t 0.21 1.33 t 0.02 5 2.80 1 1.20 1.00 i 0.18 1.41 X 0.05 16 3.15 1 0.59 0.19 1 0.26 1.42 1 0.03 II l.SS t 0.74 1.25 t 0.45 1.42 t 0.09 : 6 3.61 t 0.92 1.33 t 0.80 1.38 t 0.07 5 4.00 t 1.41 1.00 1 0.45 1.36 1 0.04 90 4.19 t 0.29 0.92 t 0.14 1.39 t .0I Nuatber of litters Huaiber live pups per litter Average pup weight II 4.63 1 0.46 2.21 t 0.11 II 5.25 t 0.56 2.30 t 0.14 II 5.36 1 0.61 t2.11 0.06 3 4.61 X 0.61 2.59 X 0.19 14 4.64 1 0.58 2.41 t 0.10 3 4.50 t 0.50 2.44 i 0.18 34 i3.61 t 0.33 . 4.25 1.44 2.36 t 0.18 2.41 1 0.21 60 4.19 1 0.25 2.33 1 0.05 Day 1; Number of litters Nuaiber live pups per litter Average pup weight 1 II t4.20 0.44 t3.61 0.19 II 4.13 1 0.65 t3.65 0.25 II t5.36 0.61 3.58 t 0.10 3 4.61 1 0.61 4.12 1 0.29 14 t4.64 0.58 4.08 t 0.22 3 3.61 t 0.88 3.03 t 0.90 3 3.33 1 0.68 4.19 1 0.21 4 4.25 1 1.44 4.04 1 0.24 60 4.58 t 0.25 3.19 1 0.09 Day 21: Number of litters Number live pups per litter Average pup weight 10 4.00 i 0.49 1.28 i 0.48 10 5.00 t 0.58 1.11 t 0.24 10 5.10 X 0.64 1.20 X 0.39 3 t4.61 0.61 8.11 X 0.45 13 t4.92 0.55 8.43 t 0.21 3 t3.61 0.88 5.30 t 0.14 3 3.33 1 0.61 8.43 1 0.11 4. 4.25 1 1.44 1.58 1 0.52 56 4.59 1 0.25 7.60 t 0.16 Values are u r n t standard e rro r of the auan. Table U Effect of 2,4-, 2,4,5-T and TCU on Postnatal Development of Offspring of TreaLed Hales Group III Week of Study 12 3 6 56 1 lt : Tula! 8 8 weeks 1: 0Y 0: Number of litters Humber live pup. per litter Number dead pu|>( per litter Average pup weight Number of litters Number live pups per litter Average pup weight Day 7: Number of llltera Number live pups per litter Average pup weight l)ay 2 Q Number of litters Number live pups per litter Average pup weight 16 5.66 1 0.52 0.5 ; 1 0.36 1.32 1 0.02 12 5.30 t 0.61 2.03 t 0.09 12 5.00 t 0.66 3.25 t 0.21 12 5.00 1 0.66 6.83 1 0.22 II 3.91 1 1.01 1.55 t 0.63 1.39 i 0.06 3 6.33 t 0.61 1.16 t 0.89 3 6.33 t 0.61 2.19 t 0 . 1 1 3 6.00 t 0.58 1.63 1 0.66 12 5.61 1 0.85 0.21 1 0.16 1.31 1 0.2? 8 5.25 1 0.10 2.19 1 0.16 8 5.13 1 1.06 3.52 1 0.93 1 5.63 1 0.91 1.12 1 0.31 9 6.11 1 1.03 0.11 1 0.11 1.36 1 0.06 6 5.25 1 0.15 2.25 t 0.16 6 5.25 1 0.15 3.61 i 0.23 6 5.00 t 0.11 8.39 1 0.25 10 3.80 t 0.80 0.60 1 0.36 1.32 t 0.06 8 6.25 t 0.69 2.50 t 0.10 8 6.25 t 0.69 6.16 t 0.13 a 6.25 t 0.69 8.15 t 0.18 II II 3 2.13 1 0.15 3.02 1 0.89 1.61 1 1.61 0.50 1 0.21 0.90 1 0.61 1.00 1 0.58 1.39 1 0.05 1.31 1 0.02 1.38 511 6.60 1 0.60 5.51 1 0.53 5.00 2.19 1 0.08 2.13 1 0.01 ... 2.81 511 6.60 t 0.60 5.51 1 0.53 5.00 6.61 t 0.16 6.56 i 0.13 6.66 '--- - 5. 6.60 1 0.60 1.66 t 0.26 6 5.50 i 0.62 8.59 t 0.28 1 6.00 10.31 | [. 81 6.66 1 0.32 i' 0.61 i 0.13 I'.'- 1.36 1 0.01 68 6.91 i 0.25 2.31 i 0.06 68 6.92 1 0.26 3.82 1 0.12 66 6.81 1 0.23 t \ V \ t7 iErri f & S' l p Z * t. t 1 1.61 i 0.16 Values are mean + standard error of tlic mean. cG.tT>; o oo 8ES9GTIMOO 6G39ET l MOO Table 14 Effect of 2,4-D, 2,4,5-T and TCUD on Poalnatal Devclopaeul of Offspring of Treated Hales Croup IV Weefc of Study S Total : 8 week I- P*y P= Ihuabcr of litters Nusber live pups per Utter Number deed pups per Utter Average pup weight PiZ-ii Number of liners 19 4.84 1 0.64 0.95 2 0.29 1.36 2 0.02 23 5.35 1 0.68 0.74 1 0.20 1.36 1 0.03 14 II 5.29 1 0.83. 3.82 1 1.06 0.79 1 0.38 1.09 1 0.32 1.39 1 0.03 1.44 1 0.05 IS 3.67 1 0.56 0.79 1 0.28 1.39 1 0.03 10 2.60 1 1.19 1.50 1 0.50 1.43 1 0.05 II 4.45 2 0.71 0.27 2 0.14 1.38 1 0.03 5 3.80 1 1.66 0.80 1 0.49 1.43 1 0.06 108 4.41 2 0.29 )i: ]' 0.84 1.39 1 1 0.11 0.0) lK j 10 10 8 4 9 4 8 3 56 Number live pups per 11 tier Average pup weight 5.57 2 0.43 2.24 2 0.16 5.40 1 0.67 2.41 1 0.08 6.00 2 0.66 2.60 1 0.97 6.25 2 1.03 2.30 2 0.13 3.35 1 0.50 2.40 1 0.19 5.75 2 1.49 2.94 2 0.50 4.88 2 0.55 2.54 2 0.16 4.67 2 0.88 2.38 1 0.28 5.13 1 0.27 2.41 1 0.08 "ifJLi Miuaber of Utters Nuaber live pups per Utter Average pup weight llay 21 i Nuaber of litters Nuaiber live pups per Utter Average pup weight 10 5.00 2 0.47 3.28 2 0.31 10 5.40 2 0.67 4.08 2 0.15 8 6.00 2 0.66 4.06 2 0.18 4 6.00 2 1.08 3.88 2 0.24 9 3.33 2 0.50 3.98 2 0.41 4 5.75 2 1.49 3.80 2 0.33 a 4.88 2 0.55 4.24 2 0.25 3 4.67 3.99 56 5.04 2 0.26 3.94 1 0.10 10 5.00 2 0.47 6.99 2 0.34 10 5.30 i 0.63 8.15 2 0.33 6 5.75 2 0.59 7.53 2 0.40 4 6.00 2 1.08 8.20 2 0.09 9 3.33 2 0.50 8.53 2 0.68 4 5.75 2 1.49 6.66 2 0.74 8 4.75 2 0.59 8.34 2 0.37 3 4.67 2 0.88 7.38 2 0.97 56 4.96 2 0.25 7.80 1 0.18 V a lu e s a re aen + sta n d a rd e r r o r o f Che Mean* -3 CCCOi N DOW 11362*0. IV 43 TASL2 IS 1 Suanary of Malformation &ataa (I) la Poacnaeal Study W*k I Traaesanc Group II III 1 5.4(5/92) 2.1(2/96) 1.1(1/87) 2 2.2(2/90) 3.2(3/95) ' 5.0(3/60) 3 1.1(1/93) 6.0(5/83) 6.6(5/76) 4 0.0(0/37) 5.3(1/19) 8.9(5/56) 5 4.0(1/25) 1.1(1/88) 4.5(2/44) & 2.2(1/45) 0.0(0/32) 2.1(1/48) 7 7.1(2/28) 13.3(4/30) ;3.8(2/53) 8 5.3(1/19) 8.0(2/25) 0.0(0/8) ' Total 3.0(13/429) 3.8(18/468) 4.4(19/432) ^AH fecuaas (liva ar daad) warm aaavsaad to ba at risk. 17 1.9(2/105) 0.0(0/140) 2.4(2/85) 13.0(7/54) 2.7(2/73) 2.1(1/47) 3.8(2/52) ' 4.3(1/23) 2.9(17/579) 1'78 S5 44 DOW 1136241 TABLE 16 Simmury of Spclic Malformations in Poacuatal Study I II ! Anopthalala/ nlcropthalaia 1.9(8/429) 2.6(12/468) Agnathia/oierognathla 1.4(6/429) 1.3(6/468) elafe Lip/palata 1 0.2(1/429) 0.4(2/468) All alaa 0.0(0/429) 0.0(0/468) *0oa exancaphaly; ana dubbed right hind limb. in 2.3(11/432) 1.9(8/432) 0.0(0/432) 0.5(2/432)* IV 1.7(10/379) 1.4(8/379) 0.0(0/379) 0.0(0/379) DOW 1136242 45 rate in these mice was between 2.9 and 4.4 percent. iThe only individual values which approach statistical significance are the malformation rates for week four group IV (40 mg/kg/day phenory acid, 1.2 pg/kg/dav TCDD) (Table 15); versus control.' In that case the control animals had no malformations ;and the treated had 13* malformations; all of these , ' i ' were either eye or jaw anomalies'. ,i ;As seen in the prenatal evaluations, eye and jaw malformations accounted for the majority of thedefects noted (Table 16). Anopthalmia' or micropthalmia were sees in 1.7 to 2.6 percent of the pups and agnathia or micrognathia were seen in 1.3 to 1.'9 percent of the pups for all treatment groups. DOW 1136243 4o DISCUSSION la these studies we have evaluated the toxicity!of three mixtures of 2,4-D, 2,4,5-T and TCDD on reproduction in male mice. Mating frequency fertility, germ cell mutagenesis,; and fetal or postnatal development were all considered in the selection of toxicological endpoints. Male mice were continuously exposed to high doses>of 2,4-D plus 2,4,5-T mixed with 2 or 30 ppm TCDD in the phenoxy acid for 8 weeks. These TCDD levels represent average and high contamination levels within Herbicide Orange used in Vietnam (Young et al., 1978). This study employed the free acids of 2,4-D and 2,4,5-T rather than the butyl esters which were components of Herbicide Orange because of the lower volatility of the acids. The esters are rapidly metabolized to the free acid in both plants and animals, and therefore, the systemic toxicity can be attributed to the free acid (Gehring and Betso, 1978) and should be comparable on a molar basis. The dose levels employed exhibited moderate to low direct toxicity in exposed male mice as evidenced by decreased body weight gain, changes in thymus and liver weights and morphologic changes in the liver. The mortality, however, was quite low. The severity of these toxic effects appeared to be primarily related to the TCDD content of the simulated "Herbicide Orange" mixture. Despite the use of continuous, moderately toxic, chemical exposures throughout the complete period of spermatogenesis, no significant increase in reproductive abnormalities in the 2,4-D, 2,4,5-T or TCDD exposed groups were observed. TCDD has previously been demonstrated to alter spermatogenesis in C57BL/6 mice (McConnell et al., 1978), however, that study used a single high (lethal range) dose of TCDD. Additionally, f 7 o p t j f i n n 47 testicular lesions were only found in clinically ill animals, as opposed . i.I i to those which survived exposure to similar doses (McConnell et al.. . ,I. 1978). Altered spermatogenesis has also been reported in rats (Kociba li et al. , 1976), guinea pigs (McConnell et al., 1978), and monkeys and chickens (Norback and Allen, 1973), although these were again toxic exposures. In the present study, morphological changes were not observed in the testis of treated mice, iThroughout this study testis weight was ! :I ' not affected, nor was sperm motility or percent abnormal spermatozoa. "i Mean sperm concentration, however, was slightly reduced after five and eight weeks of dosing, although the effect was not statistically signi ficant (p>0.10). The levels of TCDD chosen for this study were within the range that had already been shown to result in cleft palate and kidney anomalies when given to pregnant C57BL/6 female mice (Moore et al., 1973). Mixtures of phenoxy acids plus specific levels of TCDD were used in order to better mimic human exposures to Herbicide Orange. Additionally, previous investigators (Neubert et al., 1973) showed that adding as little as 0.1 Mg/kg TCDD to 2,4,5-T increased the teratogenicity in mice of 2,4,5-T in offspring of exposed mothers above that expected by a simple additive effect. The dose of TCDD in this study is at or above the 0.1 Mg/kg/day level. Also, it should be emphasized that human exposures involved mixtures of 2,4-D, 2,4,5-T and TCDD (Herbicide Orange). Certain chemicals, when given to adult males, can cause fetal death or alter normal development in offspring sired by those males (Joffe, 1979; Manson and Simons, 1980), however, such effects were not elicited in the experiments we report by exposing male mice to the 2,4-D, 2,4,5T and TCDD mixtures. As evidenced by the numbers of implants and resorp tions, neither embryo toxicity nor dominant lethal mutations could be DOVI 1136245 48 . . j * attributed to exposure to these chemicals. The unaffected values for tpercent abnormal sperm, which is a test for mutagenicity (Wyrobek, 1979) also leads one to the conclusion that the chemicals,!as given, were not | mutagenic towards the male germ cells. This correlates well with previous i multigeneratioa studies (Murray et al., 1979) and dominant lethal assays (Khera and Ruddick, 1971). : ; The values for percent malformed fetuses also indicated that 2,4-D, 2,4,5-T and TCDD had no influence on the offspring of exposed males. The study was designed such that, if the overall percent malformed fetuses (3; see Appendix Table 1) was doubled in one of the experimental groups, there was a 90% chance that it would have been detected. There was a 70-80% chance of detecting a four-fold increase in congenital defects in any one week. For any specific malformation or class of malformations the corresponding powers would be somewhat less. For example, for visceral defects (background rate 0.44%; see Table 5) the experiment had approximately a 90% chance of detecting an overall rate as high as 3% in any particular treatment group. The only variation which we could find elevated in treated versus control offspring, in the entire study, was the incidence of fused sternebrae (Appendix Table 2). In that case, we observed a statistically significant (p<0.05) increase in fused sternebrae in Group III at week 3 and in Group 17 at week 4. The Incidence in the controls at those times, however, was unusually low (0 in both weeks 3 and 4). This type of skeletal variation has been described as occurring as often as 5-15% or more in offspring from untreated pregnancies in mice and although it is frequently observed, the incidence is quite variable and this anomaly is considered a variation and not a malformation (Wilson, 1973). 17900 DOW 1136246 49 APPENDIX TABLE 1 Summary of All Malformations Observed in Peruse* Sired by Males Treated with 2,4-0, 2,4,5-T and TCDD Visceral Malformations^ Heart/Vessels Anomalies Kidney Agenesis Liver-cvo lobes only Lung-lobes 2/3 normal size Sight kidnay-1/2 normal size l' i :' 0.2(1/455) 0.2(1/455) 0.0(0/455) 0.2(1/455) 0.0(0/455) Treatment Group 11 111 -< [ 0.5(2/393) 0.0(0/393) 0.0(0/393) 0.0(0/393) 0.0(0/393) 1.0(4/394) 0.3(1/394) 0.0(0/394) 0.0(0/394) 0.0(0/394) TV 0.7(3/443) 0.0(0/443) 0.2(1/443) ' 0.0(0/443) . 0.2(1/443) : Skeletal and External Malformations2 Anoptbalmia/microptbalsia Agnathia/micrognachia Cleft palate Cleft lip/nose Open eye Exencaphaly/hydrocephaly No tongue 1 Umbilical hernia Sibs fused/miaslag Spinal centra doubled/mlsallgned Spinal archea fused Mandibles fused Skull bonea missing Eye bones missing Facial bones fused Kinked Tail 1.4(12/830) - 1.3(11/830) 0.6(5/830) 0.0(0/830) 0.5(4/830) 0.2(2/830) 0.0(0/830) 0.1(1/830). 0.1(1/830) 0.1(1/830) 0.0(0/830) 0.0(0/830) 0.0(0/830) 0.0(0/830) 0.2(2/830) 0.1(1/830) Total Malformations2 5.2(43/830) Total Malformed Fetuses2 3.1(26/830) ;; 1 1.9(14/74A) .2.0(14/711) 1.2(9/744) ' 1.4(10/711) 0.7(5/744) 0.7(5/711) 0.0(0/744) 0.3(2/711) 0.0(0/744) 0.0(0/711) 0.4(3/744) 0.1(1/711) 0.0(0/744) 0.1(1/711) 0*3(2/744) 0.3(2/711) 0.3(2/744); 0.0(0/711) 0.0(0/744) 0.1(1/711) 0.0(0/744) 0.1(1/711) 0.0(0/744), 0.1(1/711) 0.1(1/744) 0.1(1/711) 0.1(1/744) 0.0(0/711) 0.5(4/744) 0.4(3/711) 0.0(0/744) 0.0(0/711) 5.8(43/744) 6.6(47/711) 3.6(27/744) 3.2(23/711) 2.4(19/805) 1.6(13/805) 0.7(6/805) 0.0(0/805) 0.0(0/805) 0.2(2/805) 0.0(0/805) 0.1(1/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 5.7(46/805) 3.6(29/805) ^Values are percent incidence of specific anomalies; no. specific malformations pr no. -observations is given in parentheses, values are percent incidence of malformations or malformed fetuses; no. malformatlons -or malformed fetuses per no. observations is given in parentheses. 17901 DOW 1136247 O APPENDII TABLE 2 . Incidane o f Fuaad SCara2a,4b-r0i*, l2n,4,5a-cTusaansdSTlrCaDdD by Mnlaa Traacad w. i^th]j ' Baak I 1 0.9(1/113) 2 1.7(2/117) 3 0.0(0/129) 4 0.0(0/129) 3 1.4(1/70) 6 1.4(1/70) 7 3.7(4/108) 8 2. 1(2/94) Total 1.3(11/830) a p<.05 va. conegei. : Traacaanc Group II; oe 1.6(2/129) 3.0(3/99) 0.9(1/113) 2.6(2/78) 2.0(2/100) 5.2(4/77) 2.1(2/96) 2.0(1/30) 2.3(17/744) .0(1/97) 3.7(3/81) 7.1(8/112)* 2.4(2/83) 3.7(3/82) 3.1(3/98) 0.0(0/100) 0.0(0/36) 2.8(20/711) h 17 1.3(1/78) ''' . 1.6(2/129) - 2.7(3/113) 5.0(7/139)* 2:3(2/86) 3.5(3/86) 2:2(2/92) ; 1.2(1/82) 2.6(21/803) i 8 1 0 9 8 11 MOO 51 Certain anomalies are associated with embryotoxicity, not teratogen- ! icity or mutagenicity. However, with chemical exposure only to the males, not pregnant females, embryotoxicity would not be expected in their offspring. If exposure of the embryo directly to the chemicals had occurred, via seminal plasma or sperm, one would expect to observe | increased embryotoxicity in the first weeks of the study, when the chemical levels in the body (or ejaculate) were the highest. One would have also anticipated that during the.first weeks .of the teratology study germ cell toxicity would most likely have been detected, because the spermatozoa that were evaluated in the first week:of mating had been exposed to the chemicals throughout all stages of the spermatogenic process. If the spermatogonia had been affected by the exposure, the effect would have been most apparent in the last weeks of the mating, because at that time, we were evaluating spermatozoa which were sperma togonia during the entire 8 week dosing period and only began to proceed through the spermatogenic cycle near the end of chemical exposure. 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Chlorinated Phenoxy Acids and their Dioxins - Mode of Action, H e a lth Risks and Environmental Effects. NFR, Stockholm. 11. Generoso, V. M. (1973). Evaluation of chromosome aberration effects of chemicals on mouse g e m cells. Environ, Health Perspectives, 6:1.3-22. 12. Gomes, V. R. (1970). Chemical agents affecting.testicular function and male fertility, pp. 483-554. In: A. D. Johnson (ed.) The Testis. Academic Press, New York and London. 13. Hansen, V. H., M. L. Quaife, R. T. Habenoann, and 0. G. Fitzhugh (1971). Chronic toxicity of 2,4-dichlorophenoxyacetic acid in rats and dogs. Tox. Appl. Pharm., 20:122-129. 14. Holden, C. (1979). Agent orange furor continues to build. Science, 205:770-772. 15. Hood, R. D., B. L. Patterson, G. T. Thacker, G. L. Sloan, and G. M. Szczech (1979). Prenatal effects of 2,4,5-T, 2,4,5-trichlorophenol, and phenoxyacetic acid in mice. J. Environ. Sci. Health, C13(3):189204, (Abstr.). 16. I.A.R.C. (1978). Long-term Hazards of Polychloroinated Dibenzodioxins and Polychlorinated Dibenzofurans. J. A. Moore (Chairman), W.H.O., Lyon. 17. Joffe, J. M. (1979). Influence of drug exposure of the father on perinatal outcome. Clinics in Perinatology, :21-37. 1 8 . Khera, K. S., and W. P. McKinley (1972). Pre- and postnatal studies on 2,4,5-trichlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid and their derivatives in rats. Tox. Appl. Pham., 22:14-28. DOW 1136251 . ___ -- _ auu cue dominant lethal test in Wistar rats, pp. 70-84. In: E. H. Blaire (ed.), Chlorodioxins-Origin and Fate. i- : , 'American Cheat. Soc., Washington, D.C. : ' 'I 20. Kociba, R.J., P. A. Keeler, C. N. Park and P. J.Gehring (1976). ... u ': !2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): results of a 13-week \ i ioral toxicitystudy in rats. Tox. Appi.Pharm.,' 35:553-574. 21. Kopf, R . , D. Lorenz, and E. Saleswki (1964).'. Oer Einfluss von Thalidomid auf die Fertilitt von Ratten im Generationsversuch ber zwei Generationen. Haunyn-Schmiedebergs Arch. Exp. Pathol. Phannak., 247:121-135. 22. Manson, J. M. and Simons, R. (1979). Influence of environmental agents on male reproductive failure, Chapter 6, pp. 155-180. In: V. R. Hunt (ed.), Work and the Health of Women. C.R.C. Press, Florida. 23. McConnell, E. E-, J. A. Moore, J. X. Haseman, and M. W. Harris (1978). The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. Tox. Appl. Pharm., 44:335-356. 24. Miller, R. (1966). Simultaneous statistical inference, McGraw Hill, Hew York pp. 76-81. 25. Moore, J. A. (1978). Toxicity of 2,3,7,8-tetrachlorodibenzo-para- dioxin, pp. 133-144. In: C. Ramel (ed.) Chlorinated Phenoxy Acids and their Dioxins - Mode of Action, Health Risks and Environmental Effects. HFR, Stockholm. 26. Murray, F. J., F. A. Smith, K. D. Hitschke, C. G. Humiston, R. J. Kociba, and B. A. Schwetz (1979). Three-generation reproduction study of rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Tox. Appl. Pharm., 50:241-252. i,.sL%. n "; r* DOW 1136252 ,..-.,.nitmuuimi 55 27. Neubert, D., and I. Dillmann (1972). Eabryotoxic effects in mice treated with 2,4,5-trichlorophenoxyacetic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxia. Naunyn-Schmiedeberg's Arch. Pharmacol., 272:243-264. 23. Neubert, 0., P. Zens, A. Rothenwallner, and H. J. Merker (1973). A survey of the eabryotoxic effects'of TCDD in mammalian species. Environ. Health Perspectives, 5:67-79. 29. Norback, D. H. and J. R. Allen (1973). Biological responses of the nonhuman primate, chicken, and rat to chlorinated dibenzo-p-dioxin ingestion, Environ. Health Perspectives, 5:233-240. 30. Rawls, R. L. (1979). Dow finds support, doubt for dioxin ideas. C&EN, Washington, pp. 23-29. 31. Schwetz, B. A., G. L. Sparschu, and P. J. Gehring (1971). The effect of 2,4-dichlorophenoxyacetic acid (2,4-D) and esters of 2,4D on rat embryonal, foetal and neonatal growth and development. Fd. Cosmet. Toxicol., :801-817. 32. Smith, F. A., B. A. Schwetz, and X. D. Nitschke (1976). Teratogen icity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Tox. Appl. Pharm., 38:517-523. 33. Soares, E. R . , W. Sheridan, J. X. Haseman, and M. Segall (1979). Increased frequencies of aberrant sperm as indicators of mutagenic damage in mice. Mutation Res., 4:27-35. 34. Sparschu, G. L . , F. L. Dunn and V. X. Rowe (1971). Study of the teratogenicity of 2,3,7,8-tetracblorodibenzo-p-dioxin in the rat. Fd. Cosmet. Toxicol., 9/.405-412. 35. Staples, R. E. (1974). Detection of visceral alterations in mam malian fetuses. Teratology, :A37-A38 (Abstr.). 17 o*>-rUn* DOW 1136253 56 36. Staples, R. E., and V. L. Schnell (1964). 'Refinements in rapid clearing technic in the KOH-alizarin Red S method for fetal bone. Stain Technol., 39:62-63.- ; i - ' 37. Wilson, J. G. (1965). Methods for administering agents and detecting malformations in experimental animals. In:' 'J.'G. Vilson and J. Warkany (eds.) Teratology Principles and Techniques. The University of Chicago Press, Chicago pp. 262-277. 38. Wilson, J. G. (1973). Environmental and Birth Defects. Academic Press, H.Y. p. 188. i. J ' 39. Vyrobek, A. J. (1979). Changes in mammalian sperm morphology after X-ray and chemical exposures.^ Genetics 92:sl05-sll9, May Suppl. 40. Vyrobek, A. J. and V. R. Bruce (1975). Chemical induction of sperm abnormalities in mice. Proc. Rat. Acad. Sci., USA, 72:4425-4429. 41. Young, A. L., J. A. Caleagni, C. E. Thalken and J. V. Tremblay (1973). The Toxicology, Environmental Pate, and Human Risk of Herbicide Orange and-It's Associated Dioxin, U.S.A.F. O.E.H.L., Aerospace Med. Div. (AJSC), Texas. 17 3 C8 D01V.1136254 / 57 ACKNOWLEDGEMENTS We acknowledge the valuable statistical consultations of Dr. K. Abeywickraoa, Dr. B. Gladen and Dr. J. Haseman, the assistance of Dr. E. E. McConnell in evaluating histopathological specimens and editing the manuscript, the technical assistance of Ms. M. L. Dellinger, Ms. D. Frazier and Ms. M. Ross, and Ms. W. Peterson for preparing the manuscrip We thank Thomas Mangum for his valuable technical support during this study. We also wish to thank Melissa Marr and Patricia Fisher for performing the statistical analyses of the teratological and postnatal data. The technical assistance of Freida Gerling, Betty King, Loretta Langhoff, Bumes Ray, Lynn Smith and Vickie Wilson is gratefully acknow ledged. This study was partially supported by contract number NQ1-ES-2127 from the National Institute of Environmental Health Sciences and the National Toxicology Program. ^^ ^ ii ii^ ri* A..i*l*i*i-* L ^i*l*i--Lii-t**i ox^iAiiwaifciii* Liii i ^ i i^ iA i* 4 a *-i* / January 28, 1965 MIDI-ANS D IV ISIO N MIDLAND, MICHIGAN Herrn Dr. Hans Merz Dlrector of Production C . H. Boehringer Sohn Ingelheim,am,Rhein West Germany, CONFIDENTIAL Vr\N> VrvNj Dear D r . Merz : Vie very much appreciated the opportunity to talk with you yesterday and I have summarized below our understanding of the essential elements of our conversation, as you suggested. Mi t .iJt I j / j / jif t: iJt Ui tl Ji fUi fl Mt f Mi f. 4i f1 I4 1f Jt iLlHt . At the outset I explained to you that there were four Dow people on'three telephones here. I then introduced Mr. Silverstein, Dr. Henry Tolkmith, who would be on hand to handle any necessary translation, and finally, Mr. Dylewski, an engineer concerned with the development of a new process for 2,4,5-Trichlorophenol. We then began with a series of medical questions posed by Mr. Silverstein. Silverstein: 1. We have isolated and identified a symmetrical and an unsymmetrical isomer of tetrachlorodibenzodioxln. The symmetrical isomer is "2,3,6,7" (German notation) and the unsymmetrical is "2,3>6,8". Limited animal experimentation indicates that the unsymmetrical isomer active. Have you any information on the .vity of these two isomers? AlH7 we stopped research - it was too dangerous". ,ny liver biopsy specimens available for ' study? since we have had no new cases for seven w e liver function tests or kidney function tests used on your chloracne cases been published anywhere? Answer: "Do not know". BOW 1568535 I K J *> 5 . *. f i ... I-., > I D r. Hans Merz 2- - 1-28-65 V ^/ 4 . . ADcs uhnidlfsofweyreaorrcu:naeng"Nogpotreaacvtaaianestyeinostnsino, cofrofedratishadebeiddei rt eainnsdcyiiawddbeeirenaetcbi ecfeotuoiccnofsdnd"dwi.iatiibtohent e?csh loi nr a cynoeu r 5. D id you study catechol amines or ketosteroids in your Achnlsowrearc: ne "Dcaosenso?t k n o w ". qDur.e sMtioernzs s wa ihdic ht h wa terehe a nwsowueldre dc h aebc okv ef u ar st h e"Dr oi nn toot kthnooswe". Dylewski (Engineer): He explained that we are considering a distilled grade of 2,4,5-Trichlorophenol (2,4,5-t ) as part of our product requirement. Dnf oorr.tmMtaoteirodznirseotifitleclrhatltoheridasc nmthe aa tti.enBrcioai telihnbrgiencgmaeuars*et es roimfa al tsnh.aegemd aenngt ehr ado f d ethceid e d BDMp rorro..echeMDeryidenleregzdw'essrtk'oscio mwde xeampssecennrrtiiesbe.vneecreht hi swe liept hsr os pthoi nes t e edd rieps srt toielcldeadttuioroenh aenaandr d mt otohreei nrevaubiptoeount The procedure involves acidification of the aqueous phenate with either HC1 or H2SO4 to a pH of 4.5-5.5 followed by separation of the 2,4,5-T oil from the salt brine, washing of the phenolic oil with water, drying by vacuum distillation and finally distilling of the 2,4,5-T without fractionation in a graphite still. Dr. Merz said that they formerly distilled 2,4,5-T in copper equipment operating with a sump temperature in the range of 130-150C. Chloracne inciters.were formed presumably because of residual cations (Na) in the phenol which produced Na trichlorophenate thus leading to the formation of dioxin compounds. Mr. Dylewski asked if Dr. Merz could name a particular concentration of salt below which it would be safe to operate a distillation. Dr. Merz would not name a tolerable level but suggested that a water extraction could be better affected by use of a retainer solvent such as methylene chloride or chlorobenzol for the 2,4,5-T. BOW 1 56853G I{ t 17911 DOW 1 568537 Dr. Hans Merz -3- 1-28-65 Dr. Trapp asked Dr. Merz to describe how Ba(OH)2 functions to produce a better quality product. Dr. Merz replied that Ba(OH)2 traps carbonate which is an impurity in the caustic. Dr. Merz was asked if he knew what the material of con struction of the reactor autoclave was, and he replied, "Iron, or common steel". In closing, Dr. Trapp informed Dr. Merz that we had not yet received the secrecy agreement papers from Boehringer and Dr. Merz said that he would check immediately on this because he was certain that they were completed and had assumed that they had been mailed. -ft.fl 4JJI fi-fi .ff.tf. UM MJi -ff!! ifa ffff 7Ttt ffff f n f W f f u f f u f f 1Ttt Wir danken Ihnen nochmals fr Ihre weiterer Untersttzung, Dr. Merz. mit freundlichen grussen, *' .f Aylsi/S Ji/ kalter B. Trapp Assistant Director Benzene Research Laboratory 474 Building ' be: Hamburg Office (Qrote/Kube) Q. A. Orless S. V. Dylewski L. Silverstein \ 1792 I<-Y' i. 'A r -> C. H. B O E H R I N G E R CHEMISCHE FABRIK Poiiochrift: C. H. B ochringer Soho, (Q lo fflb c ia in Rbeio DOW Chemicals Company Midland / Michigan U.S.A. L Ihre Zeidiea Betrifft Ihre Nadirtchc /o n J Unsere Nadiridic ro n DCrJo.aMere Zzc/icOhcae 12oG SOHN V lofdbdm 7111 bei Selbscwihi 06 132-7 I U BF conchur<iohgredrb nIog4c*l1he7ii7ar7h7cxo ALalioedCcAodceostnilobaGnekbrMauacinha 41/01 CDoeuntrsacdhHBjaarnikdi ADGo,oaFcilriialHe aMmabinuerg | Deutsche Baak AG, FiiU F naiiurt (M.Kxeiupukiuc lagelhcin an Rbeio Nr. i Posiiihcthkofiia: Frankfurt (Main) Nr. 16 @ Ingelheim am Rhel den 1 5 . 1 2 . 1 9 6 4 Sehr geehrte Herren* whrend eines, krzllchen Besuches Ihrer Herren Dr. Trapp, Lueck lind Silveratein erwhnten wir einen wissenschaftlichen Bericht,, in welchem- die Isolierung des chlorakneaktiven Wirk stoffs sowie die Folgerungen fr die betriebliche Arbeitsweise ausfhrlich beschrieben sind. Herr Sllverstein zeigte darauf hin Interesse an der berlassung eines Exemplars dieses Be richtes. Bis heute haben wir den Inhalt dieses Berichtes ausserhalb unseres Hauses niemandem zur Kenntnis gegeben, da wir besonderen Wert darauf legten, die ausserordentliche Gefhrlichkeit des Tetrachlorbenzodioxin nicht allgemein bekannt, werden zu lassen Da Sie aber den gleichen Wirkstoff aus den Nebenprodukten Ihrer Trfchlorpfieril-Produkt!on isolieren konnten/haben wir uns-`.. entschlossen, Ihnen diesen Bericht zu berlassen. Wir mchten Sier aber- bitten, diesen ebenso wie die brigen. Ihnen bereits bergebenen Verfahrensunterlagen streng vertraulich zu behandeln und ausserhalb Ihrer Firma niemandem zur Kenntnis zu bringen. Wir hoffen, dass der beiliegende Bericht (Versuche zur Auffin dung des bei der 2,4,5-T-Sure-Herstellung auftretenden Chlor akne -Erregers) vom 12.9*1956 Ihnen bei der Lsung Ihres Chlorakne problems ntzlich sein wird und verbleiben mit freundlichen Grssen G.BU BOEHRINGER S0H Anlage (Dr. Kudszus; (Dr. Merz) ; '' ( ' O O MDUo.iwSd.lACa n.hde,m iMcailchCigoamnpany Honored G entlem en: wdaaLsseuhkesieccccdhkoDr inubtafcrhoenilenddur g.saSiiosaionMcl vosblrape.rytcirieSosooftninelfcvivenoterihnfsrwiisinsctetgehwmirlnoeoierptpnahsoetchirrnooyatwneo.teieunddargcmaat inpvesraeoicancieseetreudanrb.utesriDefstaistrcn. cai neTrr eesrpat hpafosupirs,ltwl,yaenilndl Javtcypspf;eionihoaorrntdoolumlrucindsa,ceeoetU.cuy~hnhhc~naytotlohtsoowttonioueeflreyor(vehoontsobeuouattueirwovrrl,tnn)wei,szcwitodohtoitDeushedafleodhciitcosTlyaoaaiyvxdonlutoeriuisfenesueoirddcpduelTtcioirohnssotrrhcesmccti celeeonmohmeoosilwxsivttpoeatteamidrrgyrtnoaheteoypoottn,uhhormrerdeeeansrasinsoyeanptcoollevalwoeoulryrence.niysepatt kaelr nodWnottt ootofacteuarwneotcwa'tssgnomhhsi.efodmirueswattlahhdHoeneiosifaonshapgfwfsabteeohekvmyrycverpeoeimenuanro,rlta rt tio n dwup seereoterderWtummoec atihyinionooanput ei oionntfh a2t(hti, ^se o,t5hsl -eaoTtliueoantnicco)il o nd s)oeofdof cf yrheDolopuerorca.rcctn9hel,(oEre1xa9xpc5cen6rieitmwe rpeisrnloltbsi nlbeeomnthoeatfhn e d w ith frien d ly g reeting s C . H. BOEHRINGER SOHN ' ti ' D r. Kudszus D r. Merz A ttached papers "Tran* / /<r/ .' *ir. 17314 S0989S l MOO Zz i oNN SL 151874 mn o 1 2 3 3 TC1H6H0EE3MICBDAUOLILWDPHINYCGSHICESMRIECSEAALRCHC OLAMBOPRAANTOYRY OT problemI a b 13'<j 6 A. J . Erbel 16-15-65 EFFECT OF 1 , 2 , 4 , 5-TETRACHLOROBENZENE PURITY ON FORMATION OF $ HLORACNEGENS IN 2 4 ,5-TRICHL0R0PHEN0L PROCESS aao. Three id e n tic a l experim ents were run using d iffe re n t grades of 1 ,2 ,4 ,5 -tetrach lo ro b en zen e. The products were analyzed and te ste d , on ra b b its to d eterm in e i f th e re wene. any d iffe re n c e s in chloracnegenic a c tiv ity . 00W 1;5 6 9 2 0 3 J W '' ' ar^-v** TYPEOFREPORTi R e s e a rc h . . PAOESi. . STAOE DISTRIBUTION! ' (*C0MFMtTREP0T;; MOLANOCRI (4 C<m) EX.EC''LUTfI.V-'ECRvES>ECARhCHa m b e rla iir- * C hTGNKe m... MiWBK.c a.arHlilgBlehoPsrtssaoh*f.d"y, lseiyc s R e s e a rc h L ab: A nHa.l yHt.i cGa li lLl a b o r a to r y : B loLKc..hSOeimllsvoRener ss et ea irnc h L a b , * * *H:Y. KH^o.Ryolew e- ...... - ..V-.T- **,** '-*: D oEw. icCid. e SStaeechtiloinng: E . TAC.. . RJ B.. rDNi toiteorttnoznl Re er s. L a b .; M iHd.l..a nBda sDseihveisr io n- A d m in is tr a tio n : B eRn z. eCn e. -SP aroude ruscvt-s R e se a rc h .: ri c i g e r P hJe.n oTl . SLe uc tnidoqnu: is t M iKd.la nEd. DC oivuilstieorn R e s e a rc h : O rfNgf..a nHPic.o fCHf ehanebmbee.rrsPgtreroorhd . R e s .: P rRo c. eRs s. WE noglfin e e rin g : 1 7915 nm c~oa* rtirru n (.1.4. if- FOR USE OF DOWEMPLOYEES ONLY 17916 EFFECT OF PURITY OF 1 , 2 , 4 , 5-TETRACHLOROBENZENE ON CHLOROACNIC ACTIVITY IN 2 , 4 , 5-TRICHLOROPHENOL PROCESS PURPOSE: ofpofrrom1c ,aeA2tsis,so4,na-,5t ho-ptrfaeertettroaxoec xhifcpl otehbrreoiymb- ppeerrnnootzgsderuanwcmetesretpoiunrruiidntthyeet.not2i fd,y4e t,e5arn-mtdriincmehinl otihmreoizpeihnetfhnlueoeln c e EXPERIMENTAL: - V--Odf(r7neoe8sm3i'gt-hT7n6i34aer6n-tde3-d)BGp ou7waui8snlad3ds i7--sn7d8g-o3i4fs--27at}n4i1-ld-,lLw2eda,dw4isva, i5dasdn-ietdusedsttetirhldailencentahodsl roetairhnotcdrbre.yceeatsnmhtzeaepe'lonlrfrireeztomimeowadneitnsrhef.irenoogmOpbontlCaaenCinen't1*the'.4tdih.r-i'dr , d ' ` > These th re e grades were th en hydrolyzed under- id e n tic a l ...... **-.conditioxis^toe'2 >4i,5-trichlorophenol. inta onei iter**stirred^v'i-- Parr reactor as follows: ' . 13 mm5oo1ll.0s ( 2m( 11l 63 o8 gf. 5) a ng)h 1 y d, 29r7o,%u4 , s 5F m-lateekttehr aaNcnahoOllHo r o b e n z e n e -? usa ntnditliltlhHweneoa*i2tthep,d4r e5, t5s0os-0ut-r1mrie8cl 0hso%lhCfoo the 2 ,4 ,5-trichloroph wrehfonoeo.dort-al wa3nm0eiasxtogmetarlrgaie.nec-ute,e-tTxedohtsrpe,awecqnmitueteehdetdn'hCacahnwCnedo1id4tlhta.rJwianCpanHCssa1fnof4elf.rair"sc3e.h.eVTde5h-dbe.ataonot.hd.f.af "Tu2m5a0hn7nee4iadfrsopeBCurhsCrlmpede1nedg,^oc.:tlwbb^iyvHe^eifi.nrVltyaghH.,ceP*.t8u..iC8-(^o,S%..rnie,(lsAinlvn)8ot9t.v%ameCcidhaco-nernboddvgyerc8ar8eesm%vpiosap. nprsptoTerAtraeoLttirm-oWa2nci7,h4l-l7tl,ioo65l8ri-o.toterAbirdtcnaihabwinlleeyc,nrtteizhcoea3p-l0ph.a,e-Lndn3aioisb0olo--xwalien-ned,r, e ) - 0 ________ RorSt havaeetemsere,rpaaoalrecbf hpb5oeiLTtfr ialotebhdcaoecrro/aeaaftaosnrr3i/ys71'd0a%dfl oeyafsr,y aswrbu. aeee'boirneubgsi)ts u se otbqemluusiivtttistaoe.lnde sn Tttohi nteoyt hBe2wo0weBraaeinopoacpl hplDeipcPmlMaieitcdiaaotlnt ost h e . ' *- . I xl ep on io.Ht h^cTa sr-oe was nrTK .lkfYoc<lLlf:iJcwauoliiilt pi rsBtKi'onfcoohteee.mdg*hfalnRidrensai.g;tBLfialsbr^.L.tct;otMnhsuaimydsen2rgeTffd^iVTu1(9nL6l i5ek)tetel yr:. ( R e s t r i c t e d : F o r u s e w ith in th e Dow C h e m ic a l Company O nly  e CONCLUSION e1p hf, f2een, c4oTtl,5heop- tnrerotetrchsaeeucshlsctl.so.h lrooshrbooewanczntehengaeet naaicns y ua sci metdipv uai trtyitpi eirnse stiehnnett,h2eh\ a4vp,e5la-nnt roti cmghreal oadseruor-a b le DOW 1 56920B A6 -J1E5:-s6c5b a **.* - ir W .-v ;. rz r.tr' RESTRICTED: F o r u se w ith in th e Dow C h em ical Company O nly / V sii. ; n : ioe CO i iiii. I i \ \ ii O rn cn > -/ -\*sno3ft 1313 B2^0NW .lOMIVDCMm1bDor 1 , 192 Hr. Paul i l "ibty DiopraGucts Ihrarbment Abbott Head r.uiJ-diir; ja--c r*ir t0o5 to GUIPAS!-?, FCn EH-DIJ TA f . G 0 Tvnht o k i c g l g e o a l v;ron:-:-\;i:y*.": <:; a i.- d r. : A G d lC U L V U IA L F O riF J L A T x 0 ;tg turo, 2371 Euford Avon'..3, ;;t. "au ^. )cj i'; the ann " as , at G. a rapt. of Kero is the information that i:r. J unhr.n has asked fc-r in his letter of October 1 9 , I anali ta! 1 up tee materials as he liete them in h io letter. 2 ,4-I>, 2,4,5-T ^'nd HOPA 2.4- 3 (2,4-dicklor sohor.oxy acetic acid), 2,4,5-? (2 ,4,5 -trichIcro- phenexy acetic acid-) and MO? C4-chlcro-o-toio::y acetic acid) and their salts and esters fern: the leads for a wide variety of herbIcidal formulations. The LD.^q values for both the active ingredient and, in several Instances, uno formulations are given in the onclosed reprint crtitlod, n,;u:;m.vy of Toxicological Information on 2.4- 3 and 2,4,5~T Type Herbicides and im Evaluation of the He ear.':; to Livestock Associated with Their Use". The hazards involved in their handling and use are covered in the nap or entitled ''Health Hazards Associated i/ith Handling and Use of Hordcides". G live;: The toxicological information on Gilve:; is summarised in the en closed bulletin entitled, "giV'ex Technical Bulletin Ho. 1 ". One additional statement may to made, Gilvox is not absorbed through the slcln in acutely toxic amounts. Balaoon The information desired on this product and its commercially avail able formulations is given in tiie enclosed reprint entitled "Toxi cology of Dalapon Godlum" and the ACD data sheet KG-10 entitled ''Toxicological Information Relative to Dov/pon or Radapon". Dirltro The dlnitro herbicides that Dev/ sells are formulations containing allcyldinitrcphenolo. The toxicity of these herbicides has been shown to be directly dependent upon the content of the available free alkyl dlnitro phenol and in the case of Dow delectivc Heed Killer, upon the methyl alcohol content. The enclosed reprint 17921 a u l i* -- 'J- N o v . 1, 1 :nt.LilcJ "fjxiaolcjieal Loudies on Laboratory Animals of Certain Alhyldinitrophenols Used in Agriculture" summarises Che toxicclog leal ini'orma tien on h ,3-d Ltro o-scc butyl-phenol used in Dow General 17eed Kill er*f Dor/ Hoed Kil.1 er. The tc;cicol summarized in the Cilose titled ''Hethancl" v--,\ho h herbicicl.as are di OCUG 3D-22 on- Vil' ---- ---- -previously mentioned paper entiClc "Health Haza:ads /seco late 'Handlinn and Use of Herbicides". Erbon M An Please rafor to tihheo eoncc.lo:sed Technical Bulletin entitled "I'rbrn*5, page 3 ^or the sisaaary cr toxicological information on Baron which is the cnuloifiable formulation of Erhon. TCA Podium The toxicological information on this product is given in the enclosed bulletin on Godium TCA. Of interest, is the disucssion of health hazards 0iven on this herbicide in the paper entitled "Health Hasards Ass Use of Herbicides". Garln c c b c C Garlcn la an emulsifiablc* formulation containing Dalapon and Gilvex esters as the active Ingredients. The toxicological infor mation on Garlon may be summarized as follows: Garlon has a low acute oral toxicity; the J\D.-0 for rats being in the range of -< 3 -A s * of body weight, iii may cause only very mild eye irritatic. when in contact with the eye and mild olein irritation if chin contact is prolonged or frequently repeated. It i3 not absorbed through the chin. Uhea diluted with water to recommended use concentrations, Garlon presents no hazard from handling. When handling Garlon reasonable care and cleanliness should be practiced to avoid shin and eye contact. A y tro n The toxicological information on Zyfcron and on Dow Crab Grass Killer are summarised in the enclosed data sheet on "Dow Crab Grass Killer". Paul, one further idea has come to me that may be useful. Hov; about collecting labels from representative formulations and sending them cn to Mr. Dunham? They nay prove helpful to him. They 'an be obtained ssi the Labeling Lection of the Legal Department, phone 6 if3 or 6-^120. - / 7 i irJis' . U ) - \- - BMai crskj : A. W:;.*ol1 fHcr. c a v e h r.rhs*. :! lit1: vro 't f u a i w - n j cc; T23.14-11-20 T23.14-23-20 T 2 .30-193-20 T2.30-62-20 T ? 22 .. 33 00 -- 11 31 31--2200 ^ 'Pn. . y 1 - i o - 2 o 17922  t' ' i U.^. ^O1.*.*! V. nl.n^i( 1 0 3 4 C'. i iu o a J i n ; . i r Pilli.adslpiiia 3 IJarch 19, Dr. V. K* Houo Diojhciicol Feccarch Laboratory Tho Dow Chiclical Ccnoany Midland, MichiGan 1 > M/x a.iLj'^ S Diccfi'^m, f;3. Loi. MN07328C^DO^ 781921 Doar Dr. Rovroi *! I herewith report results of repeated Insult nothod of patch tost -j with Kuron In nocordanco with your lottor of January 2, 1959 As reported In ay lottor of January 16, 1959 the Initial application of Kuron In tho patch tost study was 53 aqueous eolation, subsequent applications wora 13, except for the final or challenging application; 53 solution was used. Fifty nolo subjocto were employed. Tho toated solution saturated a Johnson and Johnson lintlne dice, 1$ inches in diameter. This was applied to tho back of tho subject and allowed to remain for tuonty-four hours. A freshly pre pared disc, or patch, was again applied in tuonty-four hours. This procedure was repeated ovory othor day for tualvo conoccutivo applications. Following tho last application, a final or challenging application was Dado after tiro weeks ties. After each removal of tho patch, I personally examined it3 sito for cutaneous reaction. The result of tho study is shown In Table 1. As eoon in tho Table no cutaneous reaction was observed after tho first application of 53 solution. To dotoimins what concentration of Kuron exerted ^primary cutaneous reaction, patch tests were performed on aubjccts other Mian the fifty studied subjects. This was reported in ny lottors of Fobruary 0, 1959 ^nd Fobruary 16, 1959* As stated In these lottors, none of the aubjccts reacted to 5 10, 20, 5 and 50 per cant concentration. As a final tost Kuron mdiluted was poured on the forearm and allowed to remain for two hours. L'o cutaneous reaction resulted. From this study it could not bo concluded that Huron exerted any cutaneous reaction. As coon in tho. Table, all but ono of tho subjects showed negative reactions to all applications, Including the challenging ono. Tho exception was Cubjact Iluiabor 26, who choved one and two plus reactions5 on tho 10. 11, IP. end challenging application. As reported to you by telcpiiono, to cucludo a fatiguing action, it xras proposed' to re-tost this subject a'ter a rest period of several weeks. Accordingly, (your lottar of aroh 11, 1959),tha first re-test was r.cri'orned with the following concentrations of Kuron,' as well as with four ether maples that jeu coat. First Tret luron a'.'c.'j :.v/no J*1LJ.-O.1.oi`JonLoprerceent,,miin1 195 GoGJ e-r deTiw -. ..w."^:-J:.:z*.s.r.c1e.lT*i~ 12 G ..Ci per ce.L .-il ^ ' * eweo l_x 0twi per ceut 17923 ir |lr Cottar toj Dr. V. K. ibi.o J Tho Dow Cyclical Co. r ^ ^ r - l y.?nt (24 touro lator) Enron 1.0 per cent In water Couco 134 1.0 per cent in socano oil Dowco 135 0.5 per cont in eocene oil Cowco 136 0.1 per cont in water Dovco 137 0.1 par cont in vator Tho result of both those ro-tosts vac negative. This aqftnccs that tho aforementioned reactions on tho last four applications of Subjeot^krabor 36 l in tho patch toot study was a fatiguing one, and cot allergenio. Considering tho | concentration in actual uao of Huron, throe to four parts per nillion, a fatiguing action is inconceivable. - Tho study choued no primary irritant action of Huron, a fatiguing action only in one subject and no evidence of allorgonic action. four3 vory sincerely, DOW 781922 - vK/cadc Encloouro JOSEPH V. KLAUDER, M. D. a. DOW 781923 J- J.-i** w-i.%V. C. a. I . Name: K-vtv.n Common Name: Pag* 2 DOW 781924 DISTRIBUTION The Dow Chemical Company, Midland Director of Research - R. H. Eoundy Central Research Index Legal Department - H. H. McIntyre - E. C. Britton Research Laboratory - R. P. Perkins Technical Service and Development - A. Hart Spectroscopy Laboratory - N. V/right Agricultural Chemical Research - 0. H. Hammer, T. A. Hymas, Physical Research Laboratory - G. D. Jor.33 g . E. Lynn Agricultural "Chemical Development - H. E, Gray, K. Earror.s, L. L. Coulter Midland Division Medical Department - Dr. H. H. Gay Safety Department - 17. L. Tisdale East Main Laboratory - E. N. Luce {West Main Laboratory - L. M. Greene Special Services Laboratory - V. A. Stenger yrescotts Division - L. C. White Texas Division Central Research Index Industrial Health and Medicine - Dr. D. J. Kilian Agricultural Chemical Research Laboratory - R. W. Colby i Wostorn Division Central Research Index Safety Department - D. 1she r e , Pittsburg Agricultural Research I 'oratory - J= R . : bV > Jd :e a l "'V mio l 61 7 1 1343 MIDLAND M a y ,12, 1958 * * : j ; ; y . i ~f r } * 1 T. Hyraaa ............... . Agricultural Chemical Research 47- B-uilding `: * - s.- A J* * 2., TONICITY INFORMATION ON SOME RECENTLY RELEASED DOW AGRICULTURAL CHEMICALS ' t-T j **.-v-\ / l-v * V> X. Rowe has asked ,me ,,to. send you the .toxicity, informa tion on some agricultural I,chemicals recently released to w Sales ... I hope'the followiiig Is of help to you w i t h 'your w paper. 3 Esteron .2^4,5-OS'.,.VA, j Hat, Tin -range .f IVO and 2.0 . :03 n > - A s - vj C.-ViuC - Veon 1 0 Q .,v ,f. .. ( r^. --j . j .?.t,rNo test run. g t . f .re- i":1- r.Ci "t %*... r. + Reddon concentrate Rat, in range of 0.5 to 1.3 g n * A s -i ' * ' . 1 ' rj 2ateroq Brush Killer OS No testa run. DowMCP amine Weed Killer Rat, in range of O .63 to 2.0 g m . A s * OOW: 1430004 *M O \ Garlon Rat, range not determined b u t > 2.0 gm./kg. Erbon Inverton Rat 1.12 gm./1cg. Guinea pig O .85 go./kg. Rabbit 0.71 gm./kg. Chick 3.17 a.As* Rat, range not determined but ? 1 .0 n ./k g . Esteron 99 Dalapon No test run. Rats, mice, guinea pig, rabbit and chick 3*86 to 9.33 ri*As* Novon Baron Brush Killer X Rat, range not determined but > 2.0 a.As* 17827 Rat, in range of 1.0 to 4.0 g m . A s * No test made. .A r -, M & lv. .a., V T- Kymas 2- - May 12, 1958 EYE CONTACT Veon 100, Dow MCP amine Weed Killer,.Inverton, and Dalapon are markedly irritating and damaging to the eye. Eye protection such as face shields,' goggles with side shields or their equivalent should be ;worn. , r * . Esteron 2,4,5 OS Reddon concentrate, Garlon, Erbon; Novon Baron, and Brush Killer X are only very slightly to slightly irritating to the eye. Minimum eye protection should'be worn, ,, SKIN CONTACT Most of these products are moderately irritating to the skin on prolonged or repeated contact. None of them present a problem from skin absorption. Baron, in strong solutions and as the undiluted formulation may cause acme-foiro dermatitis upon repeated skin contact so that special attention should be given to Its handling. -They may all be handled safely if suitable precautions1-'are :taken to avoid prolonged or repeated skin contact. At use concentrations most of these materials do not pre sent a problem from skin or eye contact. The following table on the toxicity of various products to fish may be of some use to you. SOW 1430005 17928 T. Hymas -3- May 12, 1958 DOWJ4 3 0 0 0 G Highest Concentration Lowest Concentration Showing No Effect Causing Complete Kill Material______ ^__ _________ ppm_________ _________ ppm__________ Diluent Oil Diluent Oil Plus Emulsifiers Emulsifiers' Alone Esteron 2,4,5-T Esteron Brush Killer 2,4-D, Dowanol 97B Ester 2,4,5-T, Dowanol 97B Ester 2,4-D, Sodium Salt 2,4,5-T Sodium Salt Dalapon, Sodium Trichloroacetic Acid, Sodium Salt Sllvex, Sodium Salt Silvex, Polypropylene Glycol Butyl Ether Ester Kuron Baron 1 .0 , l -N.*O ^ 10.0 ^ 2 .0 2 .0 7.0 10.0 4,000 1,000 2,500 4,000 20.0 1.0 5.0 6.0 10.0 10.0 ^ 40. 0 ^ 4.0 5.0 20.0 15.0 >4,000 1,500 > 6,000 > 6,000 25.0 5.0 9 .0 15.0 (1) Concentration Is on oil basis. *- (2) Concentration is that which could be contained in this much oil. (Emulsifier to oil ratio 15:85). V. K. Rowe suggested also that you might find the enclosed summaries on Dalapon useful. If there is any further help we may give, let me know. 0 Mark A. Wolf Biochemical Research Laboratory 12-634 Building Phone - 8991 MAW/no <l c : a x ' . & I- 17929 .i :Z.:; . .... iff--V ' ; ; I*---'W--- -i. <* r" , 1349 ^ P-4-jCou-^. -16 - V-*'- '9 J V A program for the evaluation of potential aquatic herbicides as to their toxicity to fish has been initiated. A total of five compounds has been tested. The results of those evaluations are as follows: Compound tested Fish species tested Kuron Sunfish Kuramine II 2,4,5-T ethanol II 2,4,5-T ester II ethynylcyclohexanol II 05 10 e m ' Ejom 2 8 .5 71.4 0 8.3 08.3 10 0 .0 100.0 50 .0 92.0 41.6 58.3 Percent Kill 50 100 200 PPm PPm ppm Control 85.7 100.0 100.0 09.1 16 .6 50.0 00.0 16.6 100.0 100.0 100.0 00.0 100.0 100.0 100.0 00.0 75-0 - - 00.0 Each compound was tested in a minimum of ten fish. The fish were trapped in Lake Jackson, Texas and placed in one-gallon tanks, five fish per tank. The tanks were aerated by a Saxton aerator and the fish were not fed during the course of the trial. The herbicides were introduced into each tank and the fish exposed for a period of twenty-four hours. Kuron exhibited considerable toxicity above 05 ppm. Kuramine exhibited low toxicity at all concentrations whereas the remaining three compounds tested were considerably toxic. Chemical Formulations J. N. Lipscomb Approximately 710 compound were received and filed in the compound room. A. Experimental Veterinary Formulations - One experimental Trolene screwworm smear T F -30 was made. This is a modification of TP-28, made to prevent settling of the thickener. Ten injectlbles were made and are as follows: TF N o . ,Description 31 Pure--ethyl succinate to check for irritation 32. Contains the inactive ingredients of TF-29 to check for irritation 3 3 K-lQ,2j56 in Robane, fatty acid 34 K-1 9 , 2 3 6 in ethyl succinate 3 9 K-26,019 in ethyl succinate DOW 1429984 Cvx i-- O"VJ