Endrin: Environmental Health Criteria Series No 130 (Environmental Health Criteria,)

This report contains the collective views of an international group of expertsand doesnot necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.

Environmental Health Criteria 130

ENDRIN

First draft prepared by Dr G. T. van Esch, Bilthoven, Netherlands, and Dr E. A. H. van Heemstra-Lequin, Laren. Netherlands

Published under the joint sponsorshipof the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization

World Health Organization Geneva, 1992

The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the IntemationalLabour Organisation,and the World Health Organization. The main objectiveof IPCSis to carryout anddisseminateevaluationsof theeffectsof chemicalsonhumanhealthandthequality of theenvironment. Supporting activities include the development of epidemiological, experimentallaboratory, andrisk-assessmentmethodsthat could produce internationallycomparableresults,andthe developmentof manpowerin the field of toxicology. Other activities carried out by IPCS include the developmentofknow-howforcoping with chemicalaccidents.coordination of laboratory testing and epidemiologicalstudies, and promotion of researchon the mechanismsof the biological actionof chemicals. WHOLibrary Cataloguing in PublicationData Endrin. healthcriteria; 130) @nvironmental l.Endrin-toxicity 2.Environmental exposurel.Series (NLM Classifrcation: ISBN92 4 l57l30 6 WA 240) ISSN0250-863X The World HealthOrganizationwelcomesrequestsfor permissionto reproduceor translateits publications,in part or in full. Applicationsand enquiriesshouldbe addressedto the Office of Publications,World Health Organization,Geneva,Switzerland,which will be glad to provide the latestinformation on any changesmadeto the text, plansfor new editions, and reprints and translationsalready available. @World Health Organization 1992 Publications of the World Health Organization enjoy copyright protectionin accordance with theprovisionsof Protocol2 of theUniversal Copyright Convention.All rights reserved. The designationsemployedandthepresentationof thematerial in this publication do not imply the expressionof any opinion whatsoeveron the part of the Secretariatof the World Health Organizationconcemingthe legal statusof any country,territory, city, or areaor of its authorities,or concemingthe delimitationof its frontiersor boundaries. The mention of specific companiesor of certain manufacturers' products doesnot imply that they are endorsedor recommendedby the World Health Organization in preferenceto othersof a similar nature that arenotmentioned.Errors andomissionsexcepted,thenamesofproprietary productsaredistinguishedby initial capital letters.

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CONTENTS 1.

SI.JMMARYAND EVALUATION; CONCLUSIONS; 13 ..................."'.. RECOMMENDATIONS Summaryandevaluation "'..'..........13 1.1.1 Exposure """""."'.'......."'..13 --.-"'.' 14 1.1.2 Uptake,metabolism,andexcretion 1.1.3 Effectson organismsin theenvironment.'....."'.'..'.""'. 15 animalsandin vitro...'.."...."'. l5 1.1.4 Effectson experimental .'.."".....' 1'1 1.1.5 Effectson humanbeings........... 18 ............. L.2 Conclusions 18 .....'...'. 1.3 Recommendations..............

Ll

IDENTITY, PHYSICAL AND CIMMICAL PROPERTIES, ANALYTICAL METHODS 2.1 2.2 2.3 2.4

3.

ldentity Physicalandchemicalproperties factors............. Conversion Analyticalmethods

...'......'...""".20 .....'.".""""".'.. 2l '.....'.-"-22 ................".....'22

SOURCESOFHUMAN AND ENVIRONMENTAL 30 ..................... EXPOSURE .......,..,.....""'.'.'30 3.1 Naturaloccurrence .........................30 sources 3.2 Man-made 30 uses........................... levelsandprocesses, 3.2.1 Production ...........30 3.2.1.1Worldproductionfigures ....'.."". 3l 3.2.1.2 Manufacturingprocesses ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND ...........,....32 TRANSFORMATION............ 4.1

32 Transportanddistributionbetweenmedia............................'..' . . . . . . . . . . . . . " " '3. '2. 4.1.1 Air................ .............'........32 4.1.2 Water...........

4.2 4.3 4.3.1 Biodegradation

.......36

5.3

Occupationalexposureduringmanufacture,formulation, 84 .............."". and use '.".'..."."."' 84 5.3.1 Manufactureandformulation ....""""'."......" 85 5.3.2 Application .."".. 87 5.3.3 Appraisalof occupationalexposure

KINETICS AND METABOLISM Absorption,distributioq andelimination 6.1.1 Laboratoryanimals 6.1.1.1Oral administration administration 6.1.1.2 Intravenous 6.L.2 Domesticanimals 6.1.3 Humanbeings.................... in vitro 6.1.4 Systems 6.2 Biotransformation............. 6,2.1 Experimentalanimals 6.2.2 Humanbeings.................... 6.2.3 Microorganisrns................ 6.2.4 Plans...........

6.1

7.

......... 88 ........... 88 ............88 88 ..................... ..........90 ..............91 . . . . . . . . . . . . . . . . .9. .3. . . ................. 93 ............93 ........ 93 . . . . . . . . . . . . . . . . .9. .6. . . ..................... 97 . . . . . . . . . . . . . . . . . 9. .8. . .

EFFECTSON ORGANISMS IN TIIE EI.IVIRONMENT................ 99 ......... 99 7.1 Microorganisms................... ........................ 99 7.2 Aquaticorganisms ...................... 99 7.2.1 Invertebrates ...................... 106 7.2.2 Fish.............. .......106 7.2.2.1 Acutetoxicity ........106 7.2.2.2 Short-termtoxicity .............. ...........,....... 114 7.2.2.3Studiesof resistance 115 7.2.2.4 Interactionwith otherchemicals...................... ......116 7.2.2.5 Specialsnrdies .....118 7.2.3 Amphibia .................... 118 7.3 Terrestrialorganisms .........................118 7.3.1 Honeybees 7.3.2 Birds............ ...................... 119 .......119 7.3.2.1 Acutetoxicity ..................... 119 7.3.2.2Short-termtoxicity .............l2O 7.3.2.3 Studiesof reproduction 7.3.2.4 Interactionwith otherchemicals............... .......l2l ......121 7.3.2.5 Specialstudies ................... 122 7.3.2.6Behavioural studies

.....122 7.3.3 Mammals .....................122 7 . 3 . 3 . 1T o x i c i t y. . . . . . . . . . . . . . . . . ...................123 7.3.3.2Studiesof resistance 7.4 Effectsin thefield .........................1U 7.5 Appraisalof effectson organismsin the environment.............126 8.

EFFECTSON EXPERIMENTAL ANIMALS AND IN VITRO .......T27 8.i

8.2

8.3 8.4

8.5

............127 Acute toxicity of technical-gradeendrin 8.1.1 Oral administration............. .................... 127 8.1.2 Dermal administration ...... 127 8.1.3 Parenteral ........................ 127 administration 8.1.4 Toxicity of metabolitesandisomers .......l3l 8.1.4.1 Mammalianmetabolites ................................... l3 I 8.1.4.2Isomers .................132 8.1.5 Acute toxicity of formulatedmaterial .....I33 8.1.5.1Oral anddermaladministration ....................... 133 8.1.5.2Inhalation ............. 133 Short-term exposure ...................... 134 8.2.1 Oral administration............. .................... 134 8 . 2 . 1 . 1M o u s e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1. .3. 4 .. 8 . 2 . 1 . 2R a r . . . . . . . . . . . . . . . . ........134 8 . 2 . 1 . 3R a b b i t . . . . . . . . . . .........135 8 . 2 . 1 . 4D o g . . . . . . . . . . . . . . .........135 8.2.1.5Domesticanimals ....................... 136 8.2.2 Inhalation .... 137 8.2.3 Dermal administration ...... 137 Skin irritation ..........137 Reproduction, embryotoxicity,andteratogenicity ................... 137 8.4.1 Reproduction .....................137 8 . 4 . 1 . 1M o u s e . . . . . . . . . . . . . . . . . . . ......................I37 8 . 4 . 1 . 2R a t . . . . . . . . . . . . . . . . ........138 8.4.2 Embryotoxicityandrerarogenicity ..........138 8.4.2.1Mouse ................... 138 8 . 4 . 2 . 2R a t . . . . . . . . . . . . . . . . ........139 8.4.2.3Hamster................. ..................... 140 8.4.2.4 Perinatalbehavioural development.................. 141 8.4.3 Appraisalof reproductiveeffects ............142 Mutagenicityandrelatedend-points ...................142 8.5.1 Effectson microorganisms .............. ........142 8.5.2 Pointmutationsinmammaliancells ,,.,,.,144

..."."...".'."""IM 8.5.3 Dominantlethalmutations 8.5.4 Chromosomaland cytogeneticeffects ." " ". " " " " "'.'.'... 144 effects........... S.5.5 Host-mediated ".""......"....145 ....."...".....'."'145 8.5.6 Sisterchromatidexchange. .......'145 8.5.7 Effecs rn Drosophila melanogaster ....."'.i+0 8.5.8 Effectson DNA........ 8.5.9 Appraisalof mutagenicityandrelatedend-points...."". 146 8.6 Long+ermexposwe............ """-.-'147 ........'..147 .................. 8.7 Carcinogenicity .."""""'.'....'147 8.7.1 Oraladministration.............. ......................I47 8 . 7 . 1 . 1M o u s e . . . . . . . . . . . . . . . . . . . 8 . 7 . 1 . 2R a t . . . . . . . . . . . . . . . """'.' 148 150 ...'."'."...""". 8.7.1.3 Tumourpromotion 150 ............"'.."'.."""""'......'. of carcinogenicity 8.7.2 Appraisal ...'....151 8.8 Specialstudies '.......""..".151 8.8.1 Nervoussystem studies."'...".........""""'..15I 8.8.1.1 Electrophysiological studies 8.8.1.2 Histopathological """...'.152 systems......."...... 8.8.1.3 Neurotransmitter " " " "....". " " I 52 8.8.1.4 Appraisalof effecs on the nervoussystem...'..155 ..'... 155 system Cardiovascular 8.8.2 .....""..........""..156 8.8.3 Effectson liver enzymes 8.8.3.1Mouse ""..."'.'.."..'156 . . . . . . .1. '5 7 8 . 8 . 3 . 2R a t . . . . . . . . . . . . . . . 158 .......'."..'....... ............. 8.8.3.3Guinea-pig .'."'158 8.8.3.4 In-vitro srudies .'..'."""""'..... 159 8.8.4 Mscellaneoussrudies........ '..'.'.....'....' 159 8.8.5 Factorsthat influencetoxicity 159 ...................... 8.8.5.1Nutrition............... ..........160 8.8.5.2 Potentiation EFFECTSON HI.]MAN BEINGS

.,.......162

."".""."'..'162 Exposureof the generalpopulation.... '."'..'.."'...'.'.162 9.1.1 Acutetoxiciry 9.1.2 Poisoningincidents "'........162 .................. 165 exposure 9.2 Occupational 9.2.1 Factoryworkers......... """" 165 ...............................'.'.... relationships 9.2.2 Dose-response ". 167 ....". 168 9.2.3 Exposuresto mixtures 170 9.2.4 Appraisalof effectsof occupationalexposures.........'...

9.1

IO.

PREVIOUSEVALUATIONS BY INTERNATIONAL BODIES ... I7I

REF8R8NCES...................

......r13

ANNEX I Chemicalnamesof endrinandits metabolites......................21g ANNEX II Medicalrreatmenr of endrinpoisoning...... ......221 ANNEX III Management of major statusepilepticusin adulrs................223 RESUME RESITMEN

............226 .........234

WHO TASK GROUP ON ENVIRONMENTALHEALTH CRITERIA FOR ENDRIN Members Dr L.A. Albert, ConsultoresAmbientalesAsociados,Xalapa,Veracnrz, Mexico Dr V. Benes,Departmentof Toxicology and ReferenceLaboratory, lnstitute of Hygieneand Epidemiology,Prague,Czechoslovakia Dr S. Dobson,Instituteof TerrestrialEcology,Monks Wood ExperimentalStation,Huntingdon,United Kingdom Dr G.J. van Esch,Bilthoven,Netherlands(Rapporteur) Dr E.A.H. van Heemstra-Lequin,Laren,Netherlands(Rapporteur) Dr S.K. Kashyap,National Instituteof OccupationalHealth, Ahmedabad.India Dr Yu.L Kundiev, ResearchInstituteof Labour Hygiene and OccupationalDi seases, Kiev, Ukraine (Vice-Chairnnn) Dr Y. Osman,Ministry of Health, Riyadh,SaudiArabia Dr H. Spencer,United StatesEnvironmentalProtectionAgency, WashingtonDC, USA (Chairman) Dr C. Winder,NationalInstituteof C)ccupational HealthandSafety,Forest Lodge, New SouthWales,Australia Secretariat Dr K.W. Jager,IntemationalProgrammeon ChemicalSafety,World Health Organization,Geneva,Switzerland(Secr etary) Ms B. Labarthe,IntemationalRegisterof PotentiallyToxic Chemicals,United NationsEnvironmentkogramme, Geneva, Switzerland Dr T.K. Ng, Office of OccupationalHealth,World Health Organization,Geneva,Switzerland

NOTE TO READERS OF THE CRITERIA MONOGRAPHS

Every effort has been made to present information in ttre Criteria monographs as accurately as possible without unduly delaying their publication. In the interestof all usersof theEnvironmental Health Criteria monographs,readersarekindly requestedto communicateany errors that may have occurred to the Director of the Intemational programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda.

**t(

A detailed data profile and a legal file can be obtained from the Intemational Registerof Potentially Toxic Chemicals,palais desNarions, 1211Geneva10,Switzerland(Telephoneno. 798%ffi or 7985850).

:***

The proprietary information contained in this monograph cannot replace documentationfor regisftation pu{poses,becausethe latter has to be closely linked to the source, the manufacturing route, and the pwity/impurities of the substanceto beregistered.The datashouldbeused in accordancewith paragraphs82-84 andrecommendationsparagraph90 of the SecondFAO GovernmentCorsultation (1932).

t0

ENVIRONMENTALHEALTH CRITERIAFOR ENDRIN

A WHO Task Group on Environmental Health Criteria for Endrin and Isobenzanr"retat the World Health Organization,Geneva,from23 to27 July I 990.Dr K.W. Jager,IPCS,welcomedtheparticipantson behalfof Dr M. Mercier,Directorof IPCS,andthethreeIPCScooperatingorganizations (UNEP, ILO, WHO). The Group reviewedand revisedthe draft Criteria monographsandHealth andSafetyGuidesandmadean evaluationof the risks to human health and the environment f,rom exposureto endrin and isobenzan. The first drafts of thesemonographswere preparedin cooperation betweenDr E.A.H. van Heemstra-lrquin and Dr G.J. van Esch of the Netherlands.Dr van Esch preparedthe seconddrafts, incorporatingthe cofirmentsreceivedfollowing circulation of the first drafts to the IPCS contactpoints for Envilsrxlsnl4l Health Criteria monographs. Dr K.W. Jager of the IPCS Central Unit was responsiblefor the scientificcontentof the monographs,and Mrs E. Heseltine,St Ifon-surYEzdre,France,for the editing. The fact that ShellOil Co. madeavailableto IPCSandtheTaskGroup proprietary toxicological information on their products is gratefully acknowledged.This allowed the Task Group to basetheir evaluationon morecompletedata. The effort of all who helpedin thepreparationandfinalizationof the monographsis gratefully acknowledged.

Partialfinancialsupportfor thepublicationof thisCriteriamonograph was kindly provided by the United StatesDepartmentof Health and Human Services, through a contract from the National Institute of EnvironmentalHealth Sciences,ResearchTrianglePark,North Carolina, USA, a WHO CollaboratinsCentrefor EnvironmentalHealth Effects.

11

1. SUMMARYANDEVALUATION; CONCLUSIONS; RECOMMENDATIONS 1.1

Summaryand evaluation

1.r.1

Expsure Endrin is an organochlorineirsecticide which hasbeenusedsincethe 1950sagairst a wide rangeof agricultural pests,mostly on cotton but also on rice, sugar-cane,maize,andother crops.It is also usedasa rodenticide. It is availablecommerciallyasdusts,granules,pastes,andanemulsifiable concentrate. Endrin enters the air mainly by volatilization and aerial drift. In general,volatilizationtakesplaceafter applicationto soils andcropsand dependson many factors,suchasthe organic matter andmoisture content of the soil, humidity, air flow, and the surfaceareaof plants. The most important route of contaminationof surfacewater is run-off from soil. Contaminationfrom precipitation in the form of snow or rain is negligible. Local contamination of the environment may occw from industrialeffluentsandcarelessapplicationpractices. The major sourceof endrin in soil is from direct application to soil and crops.Endrin can be retained,transported,or degradedin soil, depending on a number of factors. The greatestretention occurs in soils with a high content of organic matter. The persistenceof endrin is highly dependent uponlocal conditions; its halflife in soil can range up to l2years. Volatilization and photodecomposition are the primary factors in the disappearanceof endrinfrom soil surfaces.Under theinfluence of sunlight (ultraviolet light), the isomer delta-ketoendrin is formed- In intense summersun,about507oof endrin wasisomerizedto this ketoendrinwithin 7 days. Microbial transformation(in fungi and bacteria) takes place, especiallyunder anaerobicconditiors, to give the sameproduct, Aquatic invertebratesand fish take up endrin rapidly from water, but exposed fish trarsfened to wrcontaminated water lose the pesticide rapidly. Bioconcentration factors of 14-18 000 have beenrecordedafter continuous exposure.Soil invertebratesmay also take up endrin readily.

13

Summaryand evaluation; conclusions; recommendations

The occasionalpresenceoflow levels ofendrin in air and in surface and drinking-water in agricultural areasis of little significance from the point of view of public health. The only exposurethat may be relevant is dietary intake. In general,however,thereportedintake levels arefarbelow the acceptabledaily intake of 0.fi)02 mglkg body weight esrablishedin 1970(FAO/WHO, 1971). 1.1.2

Uptake, metabolism, and excretion Unlike dieldrin, its stereoisomer,endrin is metabolizedrapidly by animals,andverylittle is accumulated infat incomparisonwithcompounds of similar chemicalstructure. Both uptakeandexcretionafteroral administrationarerapid in rats, and its biological half-life is 1-6 days, dependingon rhe doselevel. A steady state, at which the excretedamount equalsthe daily intake, is reachedafter 6 days.A sex differenceis observed,in that malesexcrete endrin andmetabolitesvia the bile much fasterthanfemales,resultingin less accumulationin male adiposetissue.Rats excretethis compound mainly in thefaecesasendrin, anti-12-hydroxyendrin,and a hydroxylated endrin derivativewithin the first 24h (70-7sEo);a third metabolite,12ketoendrin,accumulates in tissues.Rabbitsexcrete507oof themetabolites of endrin in urine, whereasinrats only 2Voareexcretedby this route; only unchangedendrin is found in the faecesofrabbits. Cows administeredendrin at0. I mg/kg of diet for 2 1 daysexcretedup to 65Voasmetabolitesinwine,ZoVoin faeces,partly asunchangedendrin, and3%oin milk, alsomainly as endrin.Thesecows had residuelevels of 0.003-0.006mg/litre in milk, 0.001--0.002mglkg in mear, and 0.020.I mg/kg in fat. Laying herx fed endrinshowedresiduelevels (dependingon thedoses given) of up to 0. I mg/kg in mear, I mglkg in fat, 0.1-O.2mg/kg in eggs (yolk), 0.4 mg/kg in kidney, and 0.5 mglkg in liver. Excepr in liver and kidney, theresiduesfound weremainly unchangedendrin.About 50% of the administeredendrin was excretedin faeces,mainly asmetabolites. Inhumanbeings,rats,rabbits,cows,andhens,themajorbiotransformed metabolite of endrin is anti-12-hydroxyendrin, rogether with its sulfare andglucuronideconjugates.Four othermetaboliteswerefound but in only minor quantities.Mainly unchangedendrinis found in body tissuesand 14

EHC 130:Endrin

milk. After this pesticidewas appliedto plants, unchangedendrin and two hydrophilic transformation products were identified.

1.1.3

Etfectson organismsln the environment The effect of endrin on soil bacteriaandfungi is minimal. Dose levels of 1G-l000mglkg of soilhadnoeffectondecompositionoforganicmatter, denitrification, or generation of methane. Endrin is very toxic to fish, aquaticinverteb'rates,andphytoplankton: the 96-h LC, values aremostly below 1.0 pgllitre. The lowest observedadverseeffect level in a life cycle test on the mysid shrimp, My sidopsisbahia,wasestablishedat 30 ng/litre. Thereported testson the acutetoxicity of endrin in aquaticorganisms were conducted in aquaria without sedimenl the presenceof sediment would be expectedto attenuatethe effect of endrin. Heavily contaminated sedimenthad little effect on speciesliving in open water, suggestingthat sediment-bound endrin has low bioavailability. Tests have not been conductedon aquatic animals living in sediment. The LD, for terrestrial mammals and birds is in the order of 1.G10.0mg/kg body weight. Mallard ducks fed up to 3.0 mg/kg body weight for 12 weeksshowedno effect on eggproduction, fertility, or hatchability. Certain species of aquatic invertebrates,fish, and small mammals havebeenreportedto be resistantto the toxicity ofendriq andexposureto several different organochlorine pesticides led to selection of strains resistantto endrin. Fish kills were observedin areasof agricultural run-off and industrial discharge; and declining populations of brown pelicans (in Louisiana, USA) and of sandwich tems (in the Netherlands)have been anribured to exposureto endrin in combination with other halogenatedchemicals.

1.1.4

Ettectson experimentalanlmals and in vitro Endrin is a highly toxic pesticide, the signs of intoxication being neruotoxic. The oral LD, of technical-gradeendrin for laboratory animals is in the rangeof 343 mg/kg body weight; the dermal LDro for rars is 520 mg*lg body weight. No substantialdifference in acuteoral or dermal toxicity was found betweentechnical-gradeandformulated (emulsifiable concentrateand wettable powder) products. 15

Summaryand evaluation; conclusions; recommendations

Short-term experimentsfor oral toxicity have beencarried out using mice, rats, rabbits, dogs, and domestic animals. In mice and rats, the maximumtolerateddosesfor6 weekswere5 and 15 mgAg diet (equivalent to 0.7 mg/kg body weight), respectively.Rarssurvived a 16-weekexposure to i mg/kg diet (equivalent to 0.05 mg/kg body weight); rabbits died after receiving repeateddosesof I mglkg body weight. In dogs, a doseof 1 mg/ kg of diet (approximatelyequivalentto 0.025 mglkg body weight),given over 2 years,was without effect. Thenewologicalbasisof theobservedsignsof intoxicationis inhibition of gamma-aminobut5nicacid (GABA) function at low doses.Like other chlorinated hydrocarbon insecticides, endrin also affects the liver, and stimulation of enzyme systems involved in the metabolism of other chemicals is evident, as shown by, for instance, decreasedhexobarbital sleepingtime in mice. Dosesof 75-150 mglkg applieddermallyasa dry powderfor 2 h daily causedconvulsions anddeathin rabbits but did not result in skin irritation. Productionof systemictoxicity without irritation at the sire of contactis noteworthy. Long-termstudiesof toxicity andcarcinogenicityhavebeenperformed in mice and rats. No carcinogenic effect was found, but thesestudieshad shortcomings, including poor survival of the animals. The no-observedeffect level for toxicity in a two-year study in rats was I mg/kg of diet (equivalent to about 0.05 mg&g body weight). Tumour promoring effecrs were not demorstrated when endrin was tested in combination with subminimal quantitiesof chemicalsknown to be carcinogenicto animals. The Task Group concluded thar the data are insufficient to indicate thar endrin is a carcinogenic hazard to humans. Endrin was found to be nonmutagenicin severalstudies. In most studies,it wasnot teratogenicto mice, rats,or hamsters,even at dosesthat causedmatemalor fetotoxicity. The no-observed-adverseeffect level was 0.5 mg/kg body weight in mice and rarsand 0.75 mg/kg body weight in hamsters.Endrin did not induce reproducriveeffects in rats over three generatiors when given at a dose of 2 mg/kg of diet (about 0.1 mg/kg body weight).

16

EHC 13A:Endrin

A number of the metabolites of endrin have similar or higher acute toxicities than the parent compound, The uansformation product, deltaketoendrin, is lesstoxic thanendrin, but l2-ketoendrin is consideredto be the most toxic metabolite of endrin in mammals,with an oral LDro in rats of 0.8-1.1 mglkg body weight.

1.1.5

Effectson human belngs Severalepisodesof fatal andnon-fatalaccidentalandsuicidalpoisoning haveoccurred.Casesof acutenon-fatalintoxicationdueto accidentaloverexposurewere observedin workers in an endrin manufacturingplant. The oral dosethatcausesdeathhasbeenestimatedto be approximately10 mg/ kg body weight;thesingleoral dosethatcausesconwlsions wasestimated to be 0.25-1.0 mg/kg body weight. The primary site of action of endrin is the central nervoussystem. Exposureof humansto a toxic dosemay lead within a few hours to such signs and symptomsof intoxication as excitability and convulsions,and deathmay follow within 2-I2 h afterexposureif appropriatetreatmentis not administeredimmediately.Recoveryfrom non-fatalpoisoningis rapid and complete. Endrin does not accumulatein the human body to any significant degree.No long-termadverseeffectswerereportedin 232 occupationally exposedworkers(lengthof exposure,4-27 years)wrdermedicalsupervision (observationtime,4-29 years). The only effect observedwas indirect evidenceof a reversiblestimulationof drug metabolizingenzymes. Endrin wasdetectedin virtually noneof a largenumberof samplesof adiposetissue,blood, and breastmilk analysedin many countries.The Task Group attributedthe absenceof endrin in humansamplesto the low exposureof the general population to this pesticide and to its rapid metabolism. Endrin was detectedin blood (at up to 450 Fgfiitre) and in adipose tissue(at 89.5mg/kg) in casesof fatal accidentalpoisoning.No endrinwas found in workers under normal circumstances,The thresholdlevel of endrinin blood, below which no sign or symptomof intoxicationoccurs, hasbeenestimatedto be 50-100 pgllitre. The half-life of endrin in blood may be in the order of 24h.

t7

Summaryand evaluation; conclusions;recommendations

1.2

Conclusions Endrin is an insecticide with high acute toxicity. It may cause severe poisoning in cases of over-exposure caused by carelesshandling during its manufacture and use or by consumption of contaminated food. The general public is exposed to endrinmainly asits residues infood; however, the reported intake of endrin is generally far below the acceptable daily intake established by FAOAVHO. Such exposures should nor consrirure a health hazard to the general population. When good work practices, hygiene measures, and safety pre€autions are enforced, endrin is unlikely to present ahazard to exposed workers. It is clear that rurcontrolled discharges of endrin during its manufacture, formulation, and usecan result in acuteenvironmental problems associated with its high toxicity. The effects on wildlife of its agricultural use are less clear, although fish and fish-eating birds are at risk from surface run-off. Declines in the populations of some avian species have treen associated with the presence of high levels of residues of various organochlorines in the tissuesof adults andineggs. Endrinhas beenmeasured in someof these species; however, it is very difficult ro separarethe effects of the different organochlorines present.

1,3

Becommendations i. Endrin shouldnot be usedunlessit is indispensableandonly whenno lesstoxic alternativeis available. 2. For thehealthandwelfareof workersandthegeneralpopulation,the handlingandapplicationofendrinshouldbeenrrusred only to competently supervised, well-trainedoperatorswhowill follow adequate safetymeasures and apply endrin accordingto good agriculturalpractices. 3. The manufacture,formulation, agricultural use, and disposal of endrin should be managedcarefully to minimize contaminationof the environment,particularlysurfacewater, 4. Peopleexposedregularly to endrin shouldundergoperiodic health evaluations. 5. Epidemiologicalstudiesof exposedworker populationsshould be continued. 18

EHC 130:Endrin

6. In countries where endrin is still used,food should be monitored for endrin residues. 7. If the use of endrin continues,more information should be obtained on the presence,ultimate fate, and toxicity of l2-ketoendrin and deltaketoendrin.

19

2. IDENTITY, PHYSICALANDCHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1

ldentity CAS chemical name:

(l aa,2B,2aB,3 a,6o',6aB,78,7au)3,4,5,6,9.9-hexachloroI a,2,2a,3,6, 6a,1,7a-x,talaydro-2,7:3,6-b]oxirene dimethanonaphth[2,3 (9Cr-CAS)

Former CAS chemical name:

-hexachloro-6,7-epoxy1,2,3,4,10,10 I,4,4a,5,6,7,8,8a-octahydro1,4endo,endo -5,8-dime&anonaphthalene

ruPAC chemical name:

lR,4Sy'aS,5S,6S,7R,8R,8aR)1,2,3,4,10,10-hexachloro1,4,4a,5,6,7,8.8a-octahydro-6,7epoxy-1,4:5,8-dimethanonaphthalene

Chemical structure:

Endrin is the endo,endostereoisomerof dieldrin Empirical formula: crrHsclp Relative molecular mass: 380.93 Commonname: Endrin CAS registry number: 72-20-8 RTECS registry number: I0i575000 Synonyms: Endrex,Experimental Insecticide 269, Hexadrin, Nendrin, NCI-COO 157, ENT17251,OMS 197,and Mendrin Trade name: Endrin 20

EHC 130:Endrln

Not lesstlvt92vo,Impruities include aldrin (0.03%), dieldrin (O.42Vo), isodrin (O.73Vo),endrin half-cage ketone (l.57Vo), endrin aldehyde (O.OSVo), and heptachloronorbomene (O.@Vo)@onosoet al., 1979).

Purity:

2.2

Physlcaland chemicalpropertles Table 1. Physicaland chemical propertiesof endrin

Physicalstate

Crystallinesolid

Colour

White to light-tan

Odour

Mild chemical

Melting-point

226-230'C (decomposesat above 245 "C)

Flash-point

None (dry powder is non-flammable,but commercial solutionscontraininflammable liquids wifr flash-poinlsas low as 27'C)

limits Explosion

Non-explosive

Specificgravity(density)

1.64g/ml at 20 "C

Vapourpressure

2.7 x 10-7mmHg at 25 'C (36 pPa at 25 "C)

Solubility in water

Practicallyinsoluble (0.23 mg/litre at 25'C)

Solubilityin organic solvents

Sparingly soluble in alcohol and petroleum hydrocarbons;moderately soluble in aliphatic hydrocarbons;and quite soluble in solvents such as acetone, benzene, carbon tehacfiloride, and xylene

Log P octanolAvater partitioncoefficient

5.34

Stability:

Technical-gradeendrin is stable in storageat ambient temperatwes. Endrin is stable in formulatiors with basic reagents,alkalineoxidizing agents,emulsifiers,

21

Identity,physical and chemicalproperties,analytical methods

wetting agents,and solvents. It isomerizesunder the influenceof ultravioletlight. It reactswithconcentrated mineral acids,acid catalysts,acidoxidizing agentsand active metals. When mixed with certain catalytically active carriers, endrin tends to decompose;however, most active dust carriers can be deactivated by the addition of hexamethylenetetramineand form stable mixtures with endrin. When heatedto above 20OoC, endrin undergoesmolecular reaurangementsto form delta-ketoendrin,a compoundthat is lessactiveas an insectide (IARC, 1974;Donosoet al., 1979).

2.3

Gonverslon factors I ppm = 16 mg/m3at 20 "C i mg/m3= 0.063 ppm at 20 oC

2.4

Analyticalmethods Most of the analyticalproceduresusedsincetheearly 1960shavebeen basedon the following steps: (D extractionusing a suitablesolvent; (ii) clean-upby liquidfliquid partition followed by column chromatography; (iii) further separationfrom co-extractivesby gaschromatography (GC); and (i") quantificationwing an electron-capture, coulometric,or Hall electrolyticdetector General proceduresbasedon thesesteps are not specific for endrin; therefore, its identity must be confirmed in environmental samples.This can be achievedby chemical derivatization and massspectrometry(Chau & Cochrane, 1969, l97l; Belisle et al., 1972: Chau, 1974; Safe & Hutzinger, 1979). Roos et al. (1987) used size exclusionchromatographyto clean-up pesticidesafter extraction with ethyl acetatefrom fish oils, animal fat, cereals,vegetables, fruit, andliver. Therecoveriesof endrinwereg}-957o, at a limit of detectionof 0.02 mg/kg.This methodwasfound to be adequate for screeningand requires only 157oof the amount of solvents normally used. 22

EHC 130:Endrin

Giibeli & Clerc (1988) describeda relatively simple gas-liquid chromatographymethodfor the detectionand approximatequantification ofchlorinatedpesticidesinethanolicextractsofmedicinalplants(tinctures)' The methodwasbasedon extractionwith hexaneand capillary GCFNielectron-capturedetection.Thelimit ofdetectionforendrin was0.005 mglkg with a recoveryof 7'l .SVo. manypesticidesfrom extractsof crops Suzukiet al. (19'14)separated and soil into different groupsby column chromatographyprior to thintoobtainsystematicidentificationanddetermination. layerchromatography Silica gel wasusedfor the columnchromatographyandfor thethin-layer plates;glasscolumnspackedwith different absorbentswereusedfor GC detectionwith separation.Determinationwasdoneusingelectron-capture a 6Ni source. To improvetheseparationby heatof28 organochlorineinsecticides, including endrin,using gas-liquid chromatographywiithelectroncapture detection,Suzuki & Morimoto (1986) testedthree chemically bonded, fusedsilicacapillarycolumns.Thecolumnpreparedwith OV- 17performed best.The methodwasusedwith minimal clean-upand gavegoodresults samples,avoidingthedisadvantages intheanalysisofextractsofseveralsoil oflow resolutionofpeaksin packedcolumns,handlingofglasscapillary columnsand the high cost of GC-massspectrometrysystems. Kiang & Grob (1986) developed a screeningprocedure for the determinationof 49 pollutantsof high priority, includingendrin,in soil or sludge.Methylenechloride at two pH valueswas usedin the extraction procedure,which was followed by capillary GC. No clean-upprocedure wascarriedout. Separationandidentificationwereperformedwith a GCmassspectrometrysysteminvolving a 30-m fused silica column; a 60-m column was usedfor quantification.Recoveryof endrin from soil in the base-neutralextract was 92+ 14Vofrom 2.O4mglkg but only 70+ 87o from 20.4 mgftg. Japengaet al. (1987) describeda rapid clean-upprocedurefor the simultaneousdeterminationof groupsof micropollutantsin sediment.The sampleswerepretreatedwith acid,mixed with silica, and extractedon a Soxtrletcolumn with a mixture of benzeneandhexane.Humic substances and elementalsulfur were removed by passing the extract through a chromatographiccolumn containing basic alumina on which sodium sulfite andsodiumhydroxidewereabsorbed.After silicafractionation,the

23

Identity,physical and chemicalpropert'rcs,analytical methods

concentrations of polycyclic aromatic hydrocarbons, polychlorinated biphenyls,andctrlorinatedpesticidesweredeterminedby GC. Therecovery of endrin was reported to fluctuate between 93 and l03Vo. The efficiency of clean-up with sulfuric acid and confirmation with potassiumhydroxide-ethanolhydrolysis wasstudiedfor 22 organochlorine pesticidesandpolychlorinatedbiphenylsin watersamples(Hemandezet al., 1987);analysiswasbyGC/electron-capturedetection, andthepesticides were extractedby partition with lSVodiethyl ether in hexane.After cleanup with sulfuric acid, only 4.9Voof the endrin was recovered; however, with thepotassiumhydroxide-ethanoltreatment,9T-lOO7ow asrecovered, dependingon the endrin concentrationand the length of treatment, Method 8080 of the US Environmental Protection Agency (EPA) (Manual, SW-M6) was evaluatedin a single laboratorystudy by LopezAvila et al. (1988). Since the Florisil clean-upprocedurerecommended doesnotseparateorganochlorinepesticidesfrompolyctrlorinatedbiphenyls, GC analysis on a packed column may result in false identifications; therefore,silica gel was substitutedfor Florisil, a capillary glasscolumn was used instead of the packed column, and a procedure to remove elementalsulfur incorporated.Detectionlimits for liquid manicesranged from 0.02 to 0.09 pgAitre for organocNorinepesricides;for solid matrices, arangeof l-6 Fg/kgwasfound Therecoveryofendrininliquid wastewas up to I027o at a spikedconcentrationof 1.0 pg, but for a sandyloam soil it varied from47 to74%o. Donahue et al. (1988) compared rwo rechniquesfor quantifying environmental contaminants in human serum: peak area matching and linear regression.No statistically signifi,cant difference was seen in the resultsobtainedby thesetwo methodswhen theconcentrationof ctrlorinated pesticideswas> 0.5 pgllire. The sampling and determination of endrin in air were described in detailby NIOSH (1989). A methodfor determiningresiduesof themetaboliteanri-l2-hydroxyendrin,presentastheB-glucuronide,in urine wasdescribedby Baldwin & Hutson (1980). Following oxidation with sodium metaperiodateand hydrolysis with a mild base,the metaboliteis determinedby gas-liquid chromatographywith electron-capture detection.

24

EHC'130:Endrin

Polychlorinated biphenyls and 21 chlorinated pesticides, including endrin, were analysed in samples of water, soil, and sediment in six laboratoriesusing uniform calibration solutions, analytical methods, and specialsoftwareoperatingon minicomputersto control theoperationof the mass spectrometer. The results obtained for solid samples with four cornbinations of methods for extraction and clean-up were compared; althoughnocombinationwasoptimalfor all samples,shakerandsonicator extraction,bothwithFlorisil clean-up,gavethebestresults. Severalfactors that affected the quality of the results were identified, including errors in computation and transcription and inadequatereview of data (AlfordStevenset al., 1988). Seventeenlaboratoriesparticipated in an international comparisonof analysesfor organochlorine compounds (Holden, 1970). The results for endrin, summarized in Table 2, were more variable than those for other insecticides. In an inter-laboratory collaborative study reported by a Committee of the Ministry of Agriculture, Fisheries, and Food of the United Kingdom (Anon., I 979) for the dererminationof endrin in pork fat (fortified to 0.019 mg/kg), themeanrecoveryin 11 laboraroriesw as84Vo, but the rangewas 5-l3lVo. Table2. Besultsfor endrinof an interJaboratory studyof the analysisof organochlorine compounds (Holden,1970) Type of sample

No. of laborator-Mean @ncen- Standard Coefficient Ranoe ies withresults tration (mg/litre deviation of variation for endrin or mg/kg)(%l

Solution 17 in hexanea

5.929b

Cod liver 14 oil

0.02

Chicken 16 egg

0.136

0.073

54

0.07-o.3"

Sprat

0.132

0.039

29

0.09f-0.21

14

1. 0 1

17.1

4.9-8.2 ND.-0.2G

"Containingendrinand five other organochlorineinsecticides olrue (nominal,fortified value.7.0$mo/litre cTwelvelaboratoriesre6orted no deteciable residue dValuereported to be si.rspect one.laboratorythat reported suspected presence of endrin "Excluding 'tsxcrudrng one taboratorythat reporteda ,trace'ofendrin

25

Identity, physicaland chemicalproperties,analytical methods

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Thier & Stijve (1986) reported a comparative study among 53 laboratoriesin Switzerlandon the analysisof avegetablefat spikedwith 13 organochlorine and five organophosphoruscompounds. Endrin was presentat a concentrationof 0.08 mg&g andwas identifiedby 77Voof the laboratories. Some of the methods that are used for the analysis of endrin are summarized in Table 3; the estimates given of the accuracy of the proceduresand the limits of detection refer to the specific investigations and are not absolutevalues. The percentagerecoveriesare an indication of the accuracyof the methods; the precision of individual method is of interestparticularly in regard to inter-laboratory comparisons, The many publications on specific procedures are reviewed in the Codex Alimentarius Commission public ation Recotnmendations fo r Metlnds of Annlysisof PesticideResidues,CAC/PR8-1986 (FAOflVHO, 1986a). That review lists 14 individual publications; ir also liss the following compendiaof methods,which may be consulted.

- Official M ethodsof Analysisof theAssociatbn of Official Analytical Chemists,14thEdition, 1984 PesticideAnalytical Manual, WashingtonDC, Food and Drug Administration -Manual on Analytical Methods for Pesticide Residues in Foods, Ottawa,Health ProtectionBranch,Health andWelfare Canada,1985 -Mbthodensammlung zur Riickstandsanalytikvon Pflanzenschutzmineln (Methods for Analysing Residuesof Plant ProrecrionAgents), Weinheim, Verlag ChemieGmbH, 1984 - Chemistry laboratory Guidebook,W ashingtonDC,US Deparrmenr of Agriculture Whatever procedure is adoptedshould be carried out following the requirementsof the Codex Alimentarius Commission publicatton Codex Guidelines on Good Laboratory Practice in Pesticide Residuc Analysis, CAC/PR7-1984(FAO VHO, 1984).

29

3. SOURCES OF HUMANAND ENVIRONMENTAL EXPOSURE 3.1

Naturaloccurrence Endrin doesnot occur naturally.

3.2

Man-made sources

3.2.1

Production levels and processes, uses Endrin is a foliar insecticidewhich acts againsta wide rangeof agricultural pestsat dosesof the active material of 0.2{).5 kg/ha. It has a broadspectrumof control andis particularly effective againstLepidoptera. It is usedmainly oncotton but also againstpestsof rice, sugarcane,maize, and other crops. It is also used as a rodenticide (IARC, 1974). An endrin emulsionof,2Voklled4Mo of Achatinafulica snails,an agriculturalpest, in India (Singtq 1988). A generalindication of thepossibleusesof endrincanbe derivedfrom the maximal residue limits recommended by FAOAMHO (1986b; see section10).

3.2.1.1

World production figures Endrin was developed by J. Hyman & Co. and licensed to be manufacturedby Shell Intemational Chemical Co. and Velsicol Chemical Co. in 1950 (Thompson, 19?6). It was made in the USA by Shell and Velsicol and in the Netherlandsby Shell. Its usehasbeenbannedin many countriesandseverelyrestrictedinothers@onosoet al., 1979;Gips, 1987; Pearce,1987).Shell discontinuedmanufactureof endrin in 1982:it is still manufacturedin Mexico. Whetstone(1964) estimatedthat 2.34.5 million kg of endrin were sold in the USA in 1962. Imports of endrin into Japan in 1970 were 72000 kg. The armual quantiries of endrin that were used in paddy rice production in Bali over the pericd 1963--'12varied from 171 to 10 700 kg (Machbub et al., 1988). After 1972, endrin was no longer used. 3A

EHC 130:Endrln

?.2.1.2 Manufacturingprocess Endrin is produced by condensingvinyl chloride with hexachlorocyclopentadiene,dehydrochlorinatingthe adduct,andsubsequentreaction with cyclopentadieneto form isodrin, which is epoxidized by peraceticor perbenzoic acid (Whetstone, 1964). The intermediate isodrin can be manufacturedvia 1,2,3,4,7,7-hexachloronorbomadiene (US EPA, 1985).

31

4. ENVIRONMENTAL AND TRANSPORT, OISTRIBUTION, TRANSFORMATION 4.1

Transportand distributionbetweenmedia

4.1.1

Air Endrin can enterthe air by volatilization, evaporation,andaerial drift during application, and as a vaporu from manufacturing and formulating plants.Most studiesshowedrapid volatilizationfollowing applicationto soils andcrops,the extent of vaporization dependingupon a large number of factors,including soil organicmatter,moistwe content,airhumidity, air flow, and surfaceareaof plants (Donosoet al., 1979).

4.1.2

Water Endrin can reach surfacewater by severalroutes, including effluents and wastedisposalfrom endrin manufacturingandformulating plants and careless aerial application, but by far the most important route of contamination is surfacerun-off from soil and crops. Run-off is affected by numerous,complex factors,suchasintensity of precipitation, irrigation practices,soil permeability,topographicrelief, organiccontentofthe soil, and the degree of vegetative cover. Soils of low permeability and low organic content allow copious run-off after heavy precipitation @onoso et al., 1979). Contamination of surface water by industrial effluents and careless practices and disposal (such a,swashing of drums and spray equipment in streams)results in regional effects. In 1961, studies were conducted in the Bayou Yokely basin in Louisiana,USA, where3300 acres(1335 ha) ofsugar-canewere treated with nearly 2000 lb (907 kg) of endrin between June and August. Of 18 water samplestaken between April and November, six contained endrin at levels of 0.001-O.36ltgftitre,with an averageof 0.1 pgllitre, In 1964,the areawastreatedwith 1200lb(544 kg) of endrin,andthepattern of residueswas the same.The meanresiduelevels in samplestaken in Septemberwere 0.44 Stgllitrengrab samplesand0.53 pgllitre in carbon adsorptionsamples;after three months, the averagelevels were 0.03 and 0.M pgnitr", respectively.Sedimentsamplescontained165 pgTkg;after threemonths,this level had decreasedto 70 ttgkg (Lauer et al., 1966). 32

EHC 130:Endrin

Another, lessimportant sourceof water contaminationis run-off from endrin-coatedseeds.Marstonet al. ( 1969)foud thatalthoughapproximately llVo of the initial amount was washed off by water under laboratory conditions, in field conditions the loss was smaller. The total amount detectedin the watershed6 daysafter aerial application of endrin-coated seedwas0. 12Voof the applieddose.The highestconcentrationfoundin the water was 0.O71tgllitre. A third possiblesourceof contaminationis fall-out by precipitationin the form of rain and snow, but the measruedlevels are negligible (see section5.I.3.2).

t,,

Soil

The major sowce of endrin in soil is from direct application to soil and crops. The amount of endrin that reachesthe soil dependson the type of crop and the method of application. The fate of endrin in soil determines the degreeto which the rest of the environment (water and afinosphere)is contaminated.hr soil, endrin can be retained, transported,or degraded, dependingon a large number of interrelatedfactors (Donoso et al., 1979). When endrinwas appliedto tall, densecropssuchas tobacco,no residue appearedin thesoil; whenit wasappliedto soil, the amountthatremained dependedon the retentiveability of the soil. Although endrin hasstrong absorptivepropertiesin soilssuchasclay andsandyloam,limited residues were found. Far greaterretention was found in soils with a high organic content,in which it wasadsorbedquickly andwasdifficult to remove.The degreeto which endrin was retained in the soil dependednot only on the soil type but on numerousother factors such as volatilization, leaching, wind erosion,surfacerun-off, and crop uptake (Harris et al., 1966).In general,thepersistence of endrinis highly dependentuponlocalconditions, and residuelevels can rangefrom tracesto milligrams per kilogram. Its half-life in soil canbe as long as 12years(Donosoer a1.,1979). The factors that affect the degreeto which endrin is retainedin soil (Donosoet al., 1979)can be generalizedas follows: (a) (b) (c)

Endrin appearsto be lesspersistentifit is appliedto the soil surfaceor to crops rather than being mixed into the soil. Volatilizationandphotodecompositionaretheprimaryroutes for the disappearanceof endrin from soil strfaces. Microbial degradationof endrin occurs anaerobically and is acceleratedby conditionssuchas flooding and soil deprh.

33

Environmentaltransport,Qistribution,and transformation

(d) (e)

4.'t.4

Soil cultivation andcrop rotation acceleratethe dissipation of endrin. When the percentageof organic matter is high, as in muck soils, the persistenceof eldrin is greater.In sandy soils, volatilization is high and persistence is low.

Soil-plants River and basin sediment was brought on land near Rotterdam, the Netherlands, after dredging. Once the sediment had settled for several years,the land was usedfor agriculture, Someof the sedimentcamefrom a basin near a pesticide manufacturing plant and was contaminatedwith many organochlorine hydrocarbons, including the pesticides hexachlorobenzene,aldrin, dieldrin, and endrin. The meanconcentration of endrin in the sedimentof the basin near the plant (expressedin mg/kg on a dry weight basis) was 0.48 (range, 0.01-2.6) n 1976 and 0.59 (< 0.01-3.6)in 1977.In crops,the concentrationof endrin rangedfrom none detectedto 0.06 mglkg of product; in carrots,however, levels up to 0.73 mg/kg were found (Wegmanet al., 1981).

4.2

Abioticdegradation When endrin was heatedto above200 "C, as can occur during gasliquid chromatographyar 230 oC, the molecule was isomerized to a ketone,delta-ketoendrin(1, Fig. l) andan aldehyde(3). A minor product oI the thermal reirrangement was an isomeric alcohol (4). Endrin is also transformed to delta-ketoendrin(1) under acid-catalysedconditions (Phillips et al., 1962). kradiation with ultravioletlight for 48 h alsoresultsin rearrangement to this ketone (37Vo)and,to a much lesserextent,to the aldehyde(97o) (Rosenet al., 1966;Plimmer, 1972;Mukerjee, 1985).Endrinunderwent a photolytic reaction in hexane and in cyclohexane after irradiation at 253.7and300nm,resultinginahalf-cageketone,pentachlorophotoproduct (2), in80Vo yield. This photolytic product has also been identified in the field and was found to be highly resistant to oxidation and reduction (Plimmer, 19721'Zabiket al., 1971;Mukerjee, 1985).When an acetone solutionof endrinwasirradiatedwith light from amercurylampin a quartz cell for 2Ah, rlueemetaboliteswere formed by the loss of one chlorine atom from the initially produced delta-ketoendrin;one of these was compound2 (Durejaet al., 1987). 34

EHC 130:Endrln

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35

Environmenta I tran sport,d istrlbution,and transformation

Endrin has been reported to isomerize to delta-ketoendrin during 5 years' storagein the dark at room temperature(Plimmer, 1972. kr sunlight, mainly the ketone is formed (Soto & Deichmarur"1967; Roser; 1972); approximately5Mo isomerization to the ketone took place withinT t 2 dayswith exposureto intensesunmer srm(Burton & Pollard,

r974). Thephotochemicalproductsareimponant asterminalresidues:deltaketoendrin was found on cotton plants and on cabbageand apple leaves after applicationof endrin (Plimrner,1971:Mukerjee, 1985).

4.3

Biotransformation The mechanisms by which endrin is removed from the environment include photodecomposition and bacterial degradation. These factors and theii effects on the persistence of endrin have been reviewed by the US Environmental Protection Agency (Donoso et al., 1979).

4.5.1

Biodegradation Microbial degradation of endrin depends on the presence of an appropriatemicrobial speciesandsuitablesoil conditions;it occursunder anaerobicconditions (Donoso et at., 1979). Biodegradation is aided by fungi andbacteriasuch asTric hoderma, Pseudomonas,arrdBacillus. The major ffansformationproductis delra-ketoendrin(Patil et al., 1970). About 150 isolates from various soil samples were screenedto investigatetherole of thesemicroorganismsin degradingendrin; 25 of the 150 isolates were active. At least seven metaboliteswere fowrd, but conversion of endrin into the ketoendrin was common throughout (Matsumuraet al., 1971).

4.3.2

Bioaccumulationandbiomagnitication The bioconcentration factors cited below are simple rarios of the exposure concentration and the concentration in organic tissues. They shouldbe usedwith cautionas indicatorsof bioaccumulationpotential:a high bioconcentration factor can represent little uptake of a low concentration, and a low bioconcentration factor can be found with considerableuptake of a high concentration.The bioconcentrationfactor

36

EHC 130:Endrln

should thereforealwaysbe cited with thepertinent exposweconcentration of endrin. Soil invertebratessuchasslugs andearthwormshad bioconcentration factors of 14 to 103. Bioconcentrdtion factors in a number of aquatic organisms are given in Table 4. These ratios differ extensively between different qpes of aquatic organisms. Bioconcentration factors of 140 to 222 were found for four blue-green algae,(Microcystis aeruginosa, Anabaena cylindrica, Scenedesmusquadricauda, and an Oedogonium species)after 7 days' exposureto endrin at a concentrationof I mg/litre of water( Vance & Drummond, 1969). In a study of the accumulation of endrin in stoneflies (Pteronarcys dorsata) exposed to 0.03, 0.07, and 0.15 pgllitre of water, the bioconcentrationfactor rangedfrom ll30 to 348, decreasingwith increasingwater concentrationsover the 28-day exposure period (Anderson & DeFoe, 1980). h bullheads (lctalurus rnelas),the bioconcentrationfactor was 3700 after exposurefor 4 days to 0.60 pgllitre and6200 after exposurefor 7 daysto 0.26 pglitre (Anderson & DeFoe, 1980).The bioconcentrationfactors for endrin in sub-aduls of leopardfrogs (Ranasplwnocephala) exposedto 0.01,0.012,O.016,0.022, and0.030 mg,/litrewere7 1.4,34.4,5 1.8,59.4,and94.3,respectively.Subadultsexposedto 0.01, 0.012,and 0.016 mg/itre for 96 h and sacrificed 60 h later had bioconcentrationfactorsof 6.1, 4.8, md 1.2, respectively (Hall & Swineford, 1980), indicating a relatively rapid elimination of residues. In daphnids and molluscs, a direct linear relationship was found betweenthe logarithm of the equilibrium bioconcentrationfactor (and the reciprocalclearancerate constant)and the log P octanol/waterpartition coefficient for non-degradable,lipophilic compounds with partition coefficientsrangmgfrom 2 to 6. This relationshippermitscalculationof the times required for equilibrirm and for significant bioconcentrationof lipophilic chemicals,which were found to be shorter for molluscs than for daphnids. The equilibrium biotic concentration for both molluscs and daphnids decreasedwith increasing chemical hydrophobicity. The relationshipbetweenthe bioconcentrationfactor and log P octanol/water partitioncoefficientwaslinearfor compoundsthatdidnot attainequilibrium within a finite exposuretime (Hawker & Connell, 1986). In a study of the bioaccumulationof endrin from food by lobsters (Homarus americanus),endrin dissolved in methanol was added to seawater,andmusseltissuewas soakedin the solutionfor 2 h to provide

37

Environmentaltransport,distribution,and transformation

Table 4. Bioconcentrationfactors for endrin in aquatic species Species

ConcentrationLenqhol Bioconcen- Relerence of endrinin expSsure trationtactor water(pg/litre)

Clam (Mercenaria mercenarial

5 days

Mussel (Hyridella aus|/alis)

24days

Easternoyster 0.05 (Crassostrea virginica)

7 day

2780

Mason& Rowe (1e76)

Waterflea (Daphnia magna)

1.0

'| day

2600

Metcalfet al. (1e73)

Fathead minnow (Pinephales promelasl

0.015

-

38

Duke& Dumas (1e74) Ryan et al.

(1e72)

Spot (Leiostomus xanthurus) Flagfish (Jordanella tloridae)

480

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aconcentrationofendrinof 4.7 mgkgwet weight' Lobsterswerefedthe preparedfood every otherday for 2 weeks,andexcretion wasfollowed for an additional 4 weeks during which time the lobsters were fed uncontaminatedtissue. Liver andmusclewere analysedfrom two or three lobsters sampled after feedings L, 2, 3, 5, and 7, and from one or two lobsters sampled during the excretion phase at 1,2, atf, 4 weeks. The concentrationof endrin reacheda maximum of 1.95 mglkg wet weight in the liver after 2 weeksof feeding; this level declined by abott 65Voaftq 4 weeksof excretion.The time to 907oequilibrium (uptake)was 15 weeks, and the time to SWo cleararrce(excretion) was 4 weeks (Mcleese et al',

r980). Bluegill sunfish (Lepomismacrochirw) exposedto water containing 1aC-labelledendrin at l pgllitre at temperaturesof 2O-22 oC rapidly absorbedtheradioactivity,and,within48 h,914oof theradioactiveendrin had been taken up (6Vo was lost by volatilization from a control tank without fish).Within 8 daysafterthefishhadbeenreplacedincleanwater, lessthan 157oof the absorbedlabel had beeneliminated; for threefish left for a longer period, the half-life of loss was about4 weeks,the loss curve being linear (Sundershan& Khan, 1980)' Endrin accumulatedrapidly in the tissuesof channel catfish (Ictalurus punctatus) exposedto nominal concentrationsof 0.(X, 0.4, or 4.A mgikg of diet for 198days.After ttrat time, all groups were fed an endrin-free diet. Endrin was not detected 28 days later in fish that had received 0.(X or 0.4 mglkg, and the level in to 0'011 mg/kg of tissue the groupthat hadreceived4.0mg/kg decreased in 28 daysandwasbelow the limil of detectionwithin4l days(Argyle et xantlnrus expored al., 1973).SimilarresultswereobtainedforLeiostomas to 0.05 pg/litre of water: at theend of the study at 5 months,a residuelevel of 78 ltgkgtissue was found, and no endrin was detectedin fish after 18 water(lowe, 1965).Endrinthusseemstodisappear daysinuncontaminated rapidly from tissues.h2nTilapiazilli (Alexandriastrain)fry (3'36 cm, 825 mg) exposedto 0.025 pgAine (one+enthof the 96-hLCro)for 28 days, and595'4ltgl the totalcontentof endrinwas327.4,167.4,297.6,446.5, (El-Sebae,1987)' kg after4, 7,14,21, and28 days,respectively Sheepsheadminnow (Cyprinodon variegatus) were exposed for 23 weeks to endrin at levels of O.O274.72 pgllitre of water, from the embryonic stage through hatching until adulthood and spawning (see section7.2.2.2).Four-week-oldjuvenile fish accumulated25fi) timesthe concentrationin the water,adults,6400 times,andtheir eggs,5700times (Hansenet al., 1977).

39

Envlronmentaltransport,dlstrlbutlon,and transformation

The transfer of en&in through the food chain licherrreindeerhumanswas studied in the northern part of Swedenby analysing lichen {Cladonia alpestris), a major food sourcefor reindeer during the winter, together with samples of tissues from reindeer, which are eaten in considerablequantitiesby Lapps.One4-year-oldreindeerwasslaughtered in 1979 and a 3-year-old in 1981, and muscle and liver were taken for analysis.The armualuptakeby reindeerwas 2.0 mg. The averagelevel of endrin in lichen was l.9l (range,1.27-2.78)ltgfug; t.+S a\d 2.41tghg were found in the muscle samplesfrom the two reindeer and 0.55 ard 4.72 ltgkg in liver. The calculated transfer of endrin from lichen ro reindeerwas 0.77o.The estimatedannualconsumptionof reindeermuscle by Lappswas 70 kg for malesand32 kg for womery consumptionof liver was 3 and 1.1 kg, respectively. The armual intake of endrin was thus 30.3 pg for malesand 13.8pg for females(Villeneuveet a1.,1985).

40

5. ENVIRONMENTAL LEVELSANDHUMAN EXPOSURE Many of the datareported in this chapteraremeasurementstaken at a time when endrin was usedmuch more widely than at presentor with little control orrestriction. They arethereforeareflectionofahistorical situation in many corurtries.Thesedataareincluded in thedocumentasan indication of the result of indiscriminate use and disposal of endrin. Data from countries where endrin may still be used are scarceor unavailable.

5.1

Environmentallevels The levelsofresiduesassociatedwith the useofendrin in agriculture or with thedischargeof industrialeffl uentscontainingendrinaresummarized in Tables5-9; thelevels ofresidueslesseasily associatedwith specific uses or dischargesare given in Table 10.

5.1.1

Air A critical summary of studieson the atmosphericlevels of pesticides in the USA, e.g., in community air, was made by Donoso er al. (1979). Someof their conclusionsareworth repeating: "Endrin concentrationsare highestin the atrnosphereover agricultural areasand probably reach their peaklevelsdwing thepesticideuseseason.Of all urbancommunitiesthose surrounded by farmlands run the highest chance of atmospheric contamination. Urban communities far removed from agricultural areas areunlikely to experiencesignificant contamination." llhe maximum level ofendrinin air,58.5 ng/nf , wasfoundin arural townin anagriculturalarea in the southof the USA, but the normal weekly variation was between0.8 and6.5 ng/m3(Stanleyet al., 1971).In a later studyof the samerown, the averageannualatmosphericlevels were3.2nglm3in 19'12,2.3ng/m3in 1973,and5.3 ng/m3in I 974,with thehighestlevelsin August;in I 974,rhis was2'l .2nglm3(Arthur et al., 1976).The resulrsof a nationalmonitoring programmeforpesticides inthe airof variousstatesof theUSA showedthe occasionalpresenceof endrin over agricultural areasat levels of the same order of magnitude:mean of positive samples(8Eo),2.6nglmr, with a maximum value of 19.2ng,/nf (Kutz et al., 1976). Endrinwasnot foundin rain-watercollectedatdifferentlocationin the United Kingdom, using a method wirh a derectionlevel of I nglirre of 41

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water(farant&Tatton, 1968),nor inatrnosphericair(Abbottetal., 1966); however, endrin hasnever beenusedextensively in the United Kingdom. Themeandaily intake of endrin by ffialation in thewestempart of the Netherlandswas calculated on the basis of an air concentrationof 4l pg/ m3(maximum, 300 pg/rrf) to be 0.S pglday or0.3 mgfear, on thebasisof air samplestaken in the period 1975-81 (Guicherit & Schulting, 1985). Table7. Concentrations of endrinin organismscollectedin a cotton-growing areain the Republicof Chadin 1969 Sample

No. of Concenfation (mS/kS) Comments samPles M"." R*s"

Fish,two species

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Birds found dead soon after insecticide application;deaths of some birds atbibuted to endrin

From Everaartset al. (1971); LD, limit of detection

5.1.2

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of 0.27-2.03 pgfl itre andsedimentcontainedlevelsof 4?.4-lO 676 mg/rg dry weight (Barthelet al., 1969). Endrin wasfound in l77o of samplesof bottom sedimentfrom 59 sites on the Detroit River, USA, at levels up to 43 ltgkg (limit of detection, 1.0 pg&g) (Harndy & Post, 1985).No endrin was detectedin sediment samplescollected in 1980-82 from riverine and pothole wetlands at 17 locationsin the north--centralUSA (Martin & Hartman, 1985) or in samplesof sedimentfrom 34 stationson the upper Great Lakes in 1974 (< I ttglkd (Glooschenkoet al., 1976). Noneof 60 samplesof bottomdepositcollectedin 1974from 19 rivers and their estuariesin Japancontainedendrin (< 0.01 mg/kg) (Japanese EnvironmentalAgency, 1975). No endrin was detectedin sedimentand particulatesfrom the River Elbein Germanyin I 983-85(Sturmet al., I 986).Sedimentfrom Rotterdarn Harbourcontaineda total of 3-59 Fglkg aldrin, dieldrin, and endrin.No endrinwasfound at sevensitesin theElbe Estuary(Japengaet al', 1987)' A housing estatein the Netherlands,comprising about 800 housesand public buildings,wasbuilt in 1983directly on a 4-m+hick layerof harbour sludgetransfenedin 1962-64from about20 harbourbasinsin Rotterdam and the industrial areaaroundthe Nieuwe Waterweg.Organic solvents, polycyclic aromatichydrocarbons,heavymetals,and endrin and related pesticides,were detectedin the sludge. One-third of the soil samples contained collectedinthegardens(7I locations),0-40 cmbelowthesurface, endrin andrelatedpesticidesat a meanconcentrationof 1.2 mg4dganda maximal concentrationof 19.5mgftg dry weight (Van Wynen & Stijkel, 1988). In surface sedimentsfrom'five sites in Manukan Harbour. New Zealand,only traces(nonedetectedto < 0.1 pg/kg dry weight) of endrin werefoundfox et al., 1988). Particulatesfrom two sitesin the Shattal Arab River in Iraq contained endrinat 84 and 154 pglkg, anda sitein theTigris River containedZl7 ltgl kg. No endrin wasfound in the EuphratesRiver. The meanconcentration of endrinin surfaceandsubsurfacesedimentfrom the Shattal Arab River rangedfrom 3 to 18 (range,none detectedto 32) pgfkg; no endrin was found in surfaceandsubsurfacesedimentfrom the Tigris River. None was found in surface sediment from the EuphratesRiver, but in subsurface

67

Environmental levels and human exposurc

sedimenta meanconcentrationof 11 (5-25) pgTkgwasdetected@ouAbul et al., 1988). 5.1.2.3

Sewage sludge Endrin was found in only a few of 444 sludge samplesanalysedfrom sewagefteatrnentworks in the united Kingdom. The mean concentration was 0.1I mg/kg of sludge,with a rangeof 0.0l-O.7 I mg/kg (Irdclntyre& Lester, 1984).All samplesof non-disinfectedinfluent at a pilot plant in JeffersonParish,LA, USA, containedendrin, at an averageconcentration of 0.67 (0.25-l.58) ngline (Lykins et al., 1986). Sludgefrom threemain wastewater treatmentplantsin Kuwait was analysedover a 6-monthperiodin 1984-85.Two grabsamplesweretaken fromeachplanteverymonthtogivea totalof 36 samples.Themeanendrin levels for the three plants were 0.A2,0.02, and 0.06 mg/kg (Samhan& Ghobrial, 1987). Sewageplant effluents before and after treatment were analysedin Baghdad(haq) in 1982-83.Endrin wasfound in 8/15 samples takenbeforetreatrnent,at ameanconcentrationof0.2gI (0.08l-2.637) ltgl litre, and in 6/15 samplestaken after treatment,at a meanconcentrationof 0.194(0.072-1.197)pgllitre (Al-Omaret al., 1985a).

5.1.3

Water

5.1.3.1 Surtacewater Data on the concentrationsof endrinin surfacewaterconcemmainly thoseregions in the USA where useof endrin was widespread,such as in Mississippi and Missouri, over the period 1957-65. The highest concentrationswere found in 1963 in the Lower Mississippi, with a maximum level of 0.214 ltglitre. The concentrations and the rate of occurrencedecreasedconsiderably later (Breidenbachet al., 1967),ln a surveyin 19&48, a maximal level of 0. I 33 pg/litre wasreporredro have beenfound in the Missouri basin in 1967.No endrin was detectedin 1968 (Lichtenberg et al., 1970). In 1974, the concenrrationsin the Lower Mississippiwas0.0045pgllitre in Augusr-November(Brodtmann,19?6). In one samplefrom the PotomacRiver, at Quantico, endrin and endrin aldehyde were identified at concentrarionsof 0.fi)5 urd 0.006 pgllitre, respectively (Hall et al., I 987). Endrin wasnot found in the w atersnear the L,os Angeles County ocean ourfalls (< 0.00005 Fgllitrey (Green et al., 68

EI]C 130: Endrin

1986)or in surfacewater in Louisianain 1980(< 1.0ng/litre) (McFall et al., 1985).In a programmeto monitor surfacewaterin the USA in 197680, endrin was found in only O.lVoof samples,at a rnaximumvalue of 0.(X pglitre (Carey& Kutz, 1985). No endrinwasfound in waterfrom 33 sitesin the UpperGreatLakes in Canada(< 0.01 pg/litre) (Glooschenkoet al., 1976)'In Ontario,where endrin wasusedonly sparingly,no residueswerefound in 197I or I 97577 (Miles & Harris, 1973;Franket al., 1981).In watersamplestaken I m endrinwasfound belowthesurfaceat 14 stationsonLakeOntarioin 19811, of 0.000044-0.m0145pg/itre (Biberhofer& Stevens, in concentrations 1987). In a surveyof theaquaticenvironmentin The Netherlands,including drinking-water, 1826sampleswere taken at 99 samplingsites between September1969and 1977;tracesof endrin were reportedoccasionally (Wegman& Greve,1978,1980).Studiesof surfacewaterin otherareasin Europefailed to show the presenceof endrin (Wilson Committee,1969; Engst& Knoll, 1973;Uhnaket al.,1974; Galassi& Provini, I 98 I ;Hrubec, 1988).In 1984-85,waterfrom a numberof rivers in Germanycontained endrinat levelsofnone detectedto0.30 Pglitre (Braun,1985);surface water in Greeceoccasionallycontainedlevelsof 0.0003-0.0004pgllitre (Albaniset al., 1986). No cndrin was found in surfaceor drinking-waterin the stateof Sa6 Paulo(Brazil) (Lara& Bancto, 1972),but it wasfound in waterreseryoirs of basinsin SadPauloat concentrationsof nonedetectedto 1.02Fglitre (Celcstc& Caccrcs,1987;Cacercset al., 1987).En
Environmental levels and human exposure

detectedto 13 pgllirre (Kassabiet al., 1988).Threeof 15 grab samplesof surfacewater sourcesin SouthemAfrica (OrangeFree State)contained endrin, at a concentrationof 2-4 Fgllitre (Hassetter al., 1987). Endrin waspresentin theKalinadi River in India asa resultof runoff, especiallyfromagriculturalareas,araconcentrationof2 pg/itre (Kudesia & Bali, 1985).kr theChaoPhrayaRiver andklongsin Bangkok,Thailand, no endrin (< 0.001 pgnife) was found in 19M (Onodera& Tabucanon, 1986).Analysesin Bali of 16 samplesof river waterin thedry seasonand 15 samplesin therainyseasonshowedthepresenceofendrinat40 pgnitre once,in the rainy season(Machbubet al., 1988). 5.1.3.2

Rainand snow No endrinwasfound (limit of detection,1-2 ng/itre) in atmospheric precipitationin rheform of snow( I 7 samplesin I 976)andrain (8 I samples in 1976 and 1977)on the Canadianside of rheGrearLakes and inland in areasremotefrom anynearbyindustrialor urbancontamination(strachan et al., 1980).Four of 16 samplesof rain-warercollectedar four sitesin Canadahad levels of 0.00013-O.09044Fgllire and anorhersamplehad 0.0048pgllitre; no endrinwasdetecredin theorher11 samples.The mean endrincontentsin samplestakenar anorhersitein 1977,1981,1983,and 1984 were none derecred,0.000ffi5, 0.000085,and 0.0fi)049 Fgflitre, respectively(Strachan,1988).Endrin was nor detecredin snow samples collectedar 12 siresin the NorthwestTerritoriesof canada in 19g5-g6 (Gregor& Gummer, 1989).

5.1.3.3

Drinking-water Data obtainedin 19&-67 from selectedmunicipal drinking-water treatmentplants in Mississippi and Missouri, USA, showed thar the concentrationin approximatelylU%oof the samplesexceeded0. I pgllitre in thefirst yearbut thattheconcentrarions werelower in 196547 (Schafer et al., 1969).The most recenrsrudy on US drinking-waterwas done on finishedwaterinNew Orleans,LA, in 1974,wherethehighestconcenrration measuredwas 4 ng/litre (US EPA, 1974). During 1976,endrin was found at a meanconcenrrarionof 4 ngflitre (range,l-7 ngllitre)in drinking-waterin Ouawa,Canada(Williamser al., 1978).

70

EHC130: Endrtn

The meanconcentrationof endrin in drinking-water at the El-Abbasia station, Egypt, in 1986 was 3.507t 1.45ng/itre in 10 samplestaken before purification and 1.845+ 1.29 nglliue after purification (AbdelRazik et al. 1988). Drinking-water from the North Coast region of New South Wales, Australia,was analysedin 1986-87: 147of 659 samplescontainedtraces of endrin (none detected[< 0.005] to 0.05 FeAitrel (Ang et al., 1989)'

i.l.3.4 Groundwater Water in wells usedasa sourceof water for mixing pesticidesin fruit orchardsinWestVirginia (USA) wasfound tocontain endrin at about I ng/ litre in 1985 and in 1986. The water in these wells was not used for drinking-water. Endrin had not beenused in the areasince 1970, and the authors cite their results as evidencefor the persistenceof endrin and its capacity to conJaminategroundwater many years after cessationof use (Hogmire et al., 1990).

i.l.4

Organisms in the environment

;.1.4.1 Birds Endrin was found in the carcassesof four of 16 turkey vultures (Cathartesaura) in southernCalifomia, USA, in 1981,at levelsof 0.110.23 mglkg wet weight, but in noneof six common ravens(Corvuscorax). It wasalsofound in two offour vulture eggs,at 0.10(range,nonedetecled to 0.52) mg/kg wet weight,but innone of 30 raveneggs(Wiemeyeret al., 1986). Endrin was found in eggs of shag (Phalacrocorax aristotelis) and connorants (Phalacrocorax carbo) at one of five collection sites in the east,south-east,andsouthof keland, at a geometricmeanconcentrationof 0.30 (range,0.06-1.60)Fg/kg (Wilson & Earley, 1986). Eggs from two speciesofpasserinebirds,threespeciesofgull, four speciesoftem, andthe night heronwerecollectedin Italy in 1982-83. Endrin w asfound in 30 eggs ofthe night heron (Nicticorax nycticorax), at an averageconcentrationof 0.I 1 (0.03--0.27)mg/kg, in 50 eggsof the gull-billed tem (Geloclelidon nilotica), at a concentrationof 0.28 (0.05-1.31) mgkg, and in 38 eggsof the tree sparrow (Passer montanus) and 33 eggs of the hooded crow (Corvuscorone), at concentrationsof 0.17 (0.09-0.33) and 0'21 (0.0771

Envlronmentallevelsand human exposure

0.31) mg/kg. It wasnot derectedin eggsof theotherspecies(Fasolaer al., 1987). No endrin was found in 98 eggsor in the Iivers of 112nestlingsof rooks(Conus frugilegrz,s)collectedfromfi verookeriesin northemGermany in 1982-83(Beyerbachet al., 1987)or in 45 eggsandthe liversofeight younglapwings(Vanellus vanellus)collectedin I 984and I 986(Beyerbach er al., 1988). Detectableresiduesof thecomrnonestorganochl'rinepcsticideswcre found in 0.9Voof l12pools (mostly of l0birds) of srarlings(Sturnus vulgaris) collectedin l29sites in the USA in 1979 and in 1.6Voof 129poolsin 19{J2. In mosrsrares, no endrinwasderectec.l, butlevelsof 0.01 and0.17mg/kg wet weightwerefound in two (Buncket al., l9g7). Endrin waspresentat microgramlevelsperkilogramof wet weighrin 272 samplesof liver,muscle,fat,andeggsfromnorrhemfulmars(Fulmarus g lacialis), black-leggedkiuiwakes (Rissa tr idacty la), and thick-billed murres (Uria lomvia) collecredin 1975-77 on prince Leopolcl Island, NorthwestTerritories,Canada(Netrleship& peakall,l9S7).Ir wasfound in 8 of 108carcasses of heronsanalysedin theUSA sinceI 966,ar levels of 0.10-O.86mg/kgwet weighr(Ohlendorfet al., 1981)but wasnorfound in 255 pools of wings from black ducks(Ancsrubripes)andmallards(.21. plaryrhynchos) collectedin theUSA in l98l-82 (proury& Bunck,l9g6). Endrinwasnot derected in six eggsof Forster'sLem(Slernafc,rsteri) collectedon Creen Bay and Lake poygan, Michigan, USA in l9g3 (Kubiaket al., 1989).Nonewasfound in a toralof 107eggscollectedin 1975-80from l0 speciesof colonialvarerbirdsnesringin areasaround Green Bay and Lake Michigan. The specieswere liule gulls (Lares minutes),grenn-backed herons (Butorides striatus),blacktems(ChtMo nias niger),hening gulls (L. argentatus), ring-billedgulls (L. delawarensis), common tems (S. hirundo), Forster's tem (S.forsteri), double_crested cormorants(Phalcrocorax aarllls),black-crowned nighther ons(Nycticorax nycticorax),and cattle egrets(Bubulcu.llbis). The limir of derecr.ionwas 0.1 mg/kg in 1977and0.05mg/kg in 1978(Heinzet al., 1985). Of five eggsfrom peregrinefalcons (Falco peregrlnas)collectedin Arizona,USA, in 1978-82,one collecredin l97ti containedendrin ar 0.20mg/kg dry weighr,one collectedin l98l containedno derecrable amount (< 0.01mg/kg) and rhree collectedin l9g2 contained0.02_ 0.&t mg/kg (Eltis et al., 1989). 72

EHC 130: Endrin

'n T7 eggs from tree sparows (Passer No endrin was detected (Delichon urbica),28 eggsfrom martins from house montanus),4eggs white storks (Ciconia ciconia), or eggsfrom nine other speciesof bird in Germanyin 1984.The livers of 25 nestling,13 young, and 17 adult white storksalsocontainedno detectablelevel of this pesticide(limit of detection, 0.001mg/kg) (Heidmannet al., 1989).

1.4.2

Fish and shellfish The endrin concentrationsin red mullet (M ullet barbatus) collectedat six locationsin the PagassitikosGulf (Greece)in 1985-87were< 0'0050.5 pglkg fresh weight of fillets (Satsmadjiset al., 1988)' The mean concentrationsinliver, brain, kidneys, andmuscleof 22 ttout(Salmo trutta farioL.) takenfrom four rivers in Ledn, Spain,in 1985were0. 1(X, 0' 123, 0.157,and0.157 ngftlgwet weight.The incidencein the four organswas 4.54-22.73Vo(Teran& Siena, 1987).Endrin was found in 29 samplesof fi sh collected in Italy, at a median concentrationof 0'0 19 mglkg (Cantoni et al., 1988).Organochlorinecompoundswere measuredin three samples of liver from cod (Gadusmorhua) colle*telin three areasof the North Sea in 1977-37 ; endrin waspresentat a concentrationof < 5 pg/kg of product (De Boer, 1989). Endrin was not detected (< 0.01 mg/kg) in two or three replicate samples,eachcomprising threeto five bluegill (Lepomismacrochirus) and commoncarp(Cyp rinus carplo), collectedfrom downstreamsitesexposed to irrigated agriculture and from non-i:rigated upstreamsites on the San JoaquinRiver andtributariesin Califomia, USA (Saiki & Schmitt, 1986). Endrin wasalsonot found in waternearLos AngelesCountyoceanoutfalls (< 0.0m05 pcnire) or in mussels(Mytihu californianus) (< 0'1 ttg/kg wet weight) that had beensuspendedat the monitoring sitefor 2 monthsto provide a measure of the bioaccumulation of chlorinated hydrocarbon contaminants(Greenet al., 1986).No endrinwasdetectedin fish samples takenat nine locationsin north--centralUSA (Martin & Hartman, 1985), andendrin wasnot detectable(< 0.00I mg/kg) in 527 samplesof edible fi n andits tributaries(Maryland)overthe fishharvestedfromChesapeakeBay period 1976-80or in 20 samplesof roe and gonadaltissue@isenberg& Topping,1985). No detectablequantity(< I pg/kg) of endrinwasfound in two species of crayfish (Procambarus clarkii andP. acutus) commercially harvested

73

Environmental levels and human exposure

from dual-cropped ponds and from warers of the ^A,tchafalayaRiver Basin and the Mississippi River in southem Louisiana, or in sediment and water collected from several ponds and at the Basin three times during 1986 and 1987 (Madden er al., 1989). Endrin was measured at levels of 0.4 and 66 ltgkgin American ecls (Anguilla rostrala) sampled at various sites between Lakc Ontario and the mouth of the S[ Lawrence river in 1982 (Castonguayet al., l9g9). Endrin was not detectable (< 0.002 mg/kg) in 'mosr' composite samples ( l _ I 5 fish of l0 different species) collecred from 10 sites on the Crear Lakes and tributaries between I 980 and 198 I , although in a few casesconcenrrations up to 0.01 mg/kg were found (Devaulr, 1985). Endrin was nor present (< 0.005 mg/kg) in fillets of Fall Run Coho salmon (Oncorhynchus kisutch) taken from 14 sires on the Grear Lakes in 1984. In mosr cases, three samples per site were analysed, and the fish were 2-3 years old (Devault et al., 1988). Johnson er al. (1988) measured rhe inpur of organochlorine pesticides from precipitation and runoff to five small lakes peripheral [o the canadian Great Lakes and the levcls of rcsiducs in fish caught in the lakes. While cndrin was dctectablein precipitation (at 0.46 and 0.54 nglitrc at the lwo sampling sitcs), nonc was measurcd in runoff watcr and no dctectablc residue was fbund in fish. Thc mcan conccntrarionsof endrin in I 3 commcrcial ly important fish species collcctc'd in thc north-west Arabian Gulf varicd bctween I and 28 ftgkg, and thosoin fivc spociescollecredfrom Hor al-Hammar Lake in Iraq in 1985 were347 pg/kg wer weight of edible rissue.Enclrinrcsiducs wcre dctccrcd in approximar ely 9oo/oof the fish (DouAbul ct al., l9g?a). Sampfcs of Barbus xanlhopetrus collected in thc Shatt al Arab River ancl in Hor al Hammar Lake containc236) (DouAbul cr al., 1987c). Freshwarer mussel (Cbrb iculafluminea) collccted in the Shatral Arab River conraincd 166-540Fg/kg (rangc, t40-583) (DouAbul et al., 1988). Endrin was prcsent at conccntrarionsof 1.9-12.2 Fglkg of muscle rissue(wer weight) in three fish spccies and at 0.t18-7.7 ttskg in three T'ilapia species collectcd ncar Alcxandria, Egypr, in 1985 (El Nabawi cr al., 19g7). 74

EHC 130: Endrin

Endrin was present at 0.003-O.004 mglkg in black pomfret (Parastro mateusniger), mackerel (Rastrelliger kanagurta), and marine vala (Chirocenlrzs sp.) and at 0.08 mglkg in Ex:n (Euthynnus affinis) collected off the Indian coast (Radhalaishnan& Antony, 1989)' It was found in one sampleof fish at 0.019 mg/kg wet weiSht andin one shellfish sampleat 0.034mglkg but in noneof 312 otherspecimersof I I typesof fish, crustaceans,andmolluscs obtainedfrom five sitesin Java,Indonesia (limit of detection,0.01 mglkg) (Koemanet al., 1974). No endrin was forurd (< 0.005 mg/kg) in 60 samples of fish and inJapanin 1974(Japanese shellfishcollectedin l9 riversandtheirestuaries EnvironmentalAgency, 1975). The medianconcentrationof endrin in the eggsof 15 adult chinook salmon(Onchorhynchustshawytscha) collectedin Lake Michigan in I 982 was 23.5 pg/kg wet weight (range,3.9-126.3)(Giesy et al', 1986)' Compositesamplesof wholefishof selectedspecieswerecollectedin 1983 near the shores of 13 tributaries of Lake Michigan and Grand TraverseBay. Two of eachof the following specieswere collectedfrom eachsite:conrmoncarp (Cyprinuscarpio),bowfin(Amia calva),channel catfish (lclalu rus punctatus),pumpkirseed (Lepomisgibbosas),rock bass (Ambloplites rupesfrls),small-mouthbass(M icropterus dolomieu),lat gemouth bass(M. salnnides),lake trout (Salvelinusnamoycush),and pike (Esor lacias);thecompositescomprised3-1 1 fi sh.Endrinwasnot detected (limit, 0.fi)5 mg/kg) (Camanzoet al., 1987). Yellow perch(Percaflavencens)weresampledineightreservoirsand lakesin Ohio andWisconsin,USA, in 1978J9 ' Endrin wasfound in four fish at levelsof 0.008-0.02mg/kg,which weremuch lower thanthelevels found of polychlorinatedbiphenyls,DDT and dieldrin (Carline& Lawal, 1985). 1.4.3 Mixedspecies Herons(Nyctanassaviolacea),water snakes(Natrix spp.)nraccoons (Procyon lotor), charnelcatfish(Ictaluruspunctatus),crappies(Potnoxis spp.),frogs (Rana spp.),andcrawfish(Procambarusclarkil) werecollected from threewatershedsin Louisiana,USA in 1978-79-Endrin was found in a heron at 0.014mg/kg and in a catfish at0'022 mgAg, but inno other case(limit of detection,< 0.05 me/kg) (Dowd et al., 1985)'

75

Environmentallevelsand human exposure

5.1.5

Other food and feed

5.1.5.1

Cereals Endrin hasbeenusedextensively for the control of insectpestsin rice. Typically, oneto four applicatiorn aremade,dependingon local conditions, the last application usually not later than one month before harvest. Data on residuelevelsareavailablefrom India ( I 969-70), Thailand( I 968-70), the Philippines, Indonesia(1965), and Venezuela(1969). The levels in polished rice were 0.01--0.04mg/kg of product (mean, 0.014 mgfkg), exceptin India where higher levels in the order of 0.12 mg/kg were found. Bran, which is used mainly :rs a component of poultry feed, contained a mean level of 0.35 mglkg (range,< 0.01-2.3 mg&g), and low levels of delta-ketoendrinwere found (FAOAMHO,1971) Endrin has been used to only a limited extent on grain crops. The residues in different tlpes of treated grains in the USA were generally below 0.05 mgtkg of producr, exceprin oarsin which levels up to 0.5 mgl kg werefound. LnIndia, up to five applicationson sorghumgaveresidue levels below 0.02 mg/kg; in the USA, the levels in sorghumwerebelow 0.05 mg/kg. Straw of cerealscontainshigher levels:rice strawhad up to 3 mg/kg,, and sorghumstraw up to 0.4 mg/kg (FAOIilHO, l9Z1). Wheat imported into the United Kingdom in 1987-88 did nor contain endrin (< 0.01 me/kg) (Osbomeet al., 1989).

5.1.5.2

Fruit and vegetables Endrin is occasionallyused for control of field mice (voles). No residuewasfound in applesat harvest(derecrionlimir, 0.01--0.002mglkg of whole fruit) when it was sprayedon the ground under treesin orchards in autumn or spring. The levels were sometimes higher in fallen fruit, rangingfrom< 0.fi)2to0.02 mg/kg of product(Horsfallet al., 1970;FAO/ wHo,1971). Only 14 of 15 fiX) samples of fruit and vegetablesimported into Sweden during the period 1981-84 contained endrin, at a maximum concentrationof O.02mgkg (Anderson, 1986). The pesricideanalysis programme of the Swedish National Food Administration on fruit and vegetables,including potatoes,showednoresidueof endrin abovethe 1imit

76

EHC130: Endrin

of detectionof O.O2mgft;gin 13 724 samplesanalysedin 1985-87 (B.G. Ericsson,personalcommunication, 1990).The meanendrin concentration in 137 samplesof grapeproducts(including seeds,skins, marc andlees)in Italy was6.2-16.2 pglkg (Marinelli et al., 1986).Sevenof 306 samplesof apples(fivetypes) collectedin 1980-83fromfiveregions of Italy contained endrin (limit of detection,0.00l mg/kg) (Foschiet al., 1985). InPakistan, in 16samplesof cucumbersprayedat the time of maturity with a 0.057oendrinsolutionat a rateof 100gallons/acte(1123 litres/ha), the endrin concentrationsranged from 3.(X to 6.69 mg&g. The residues persistedin the edible portion of cucumberup to 14 days and diminished thereafter(Illahi et al., 1986).Endrin wasfound in l77o of samplesof peas collectedfrom fields andmarketsin Faisalabad,Pakistan,at a level of L34.3zttglkg. The residuespersistedfor up to 12 days and then decreased (Illahi et al., 1987).No endrinwasfound(< 0.02 mg/kg) in 141 samplesof fruit and vegetablesfrom Pakistanin 1982-83(Masud& Farhat, 1985). In an analysis of soya bean and soya beanstraw in a US monitoring prograrnme,sevenof 177 samplesof soya beanscontained a geometrical meanof < 0.001(maximum, 0.03) mg/kg, andoneof eightsuaw samples contained< 0.01 mgAg (Careyet al., 1978).Endrin wasusedin up to four applications on sugar-canein the USA, with an interval of 45 days or longerbetweenthelastapplicationandharvest.Theresiduesfoundincane were usually < 0.05 mglkg of product(FAOAMHO, l97l). i.l.5.3

Meat, poultry, and chicken eggs Bovine fat (40 samples),pig fat (45 samples),calf fat (45 samples), sheepfat (22 samples),poultry fat (42 samples),and eggs (44 samples) analysedin the Netherlands in 1983had a medianendrin concentrationof < 0.04 mg/kg (DutchAgricultural Advisory CommissiononEnvironmental Pollutants,1983).No endrin was fowrd (detectionlimit,0.005 mg/kg) in samplesof beef,pork, goat,mutton,poulory,or eggsanalaysedin Italy in 1985-87 (Cantoni et al., 1988) or in 'most' samplesof pork, rabbit, or poultry analysedin Rheinland/Pfalz,Germany, in l98l-84 (Kampe, 1985).Dietary surveysin the United Kingdom demonsrratedno endrin in meat (detection limit, 0.02 mg/kg) (United Kingdom Ministry of Agriculture,FisheriesandFood, 1989). Endrin was present in l0.8Vo of 2032 samples of bovine fat from carcassescollectedfrom slaughterhouses in Brazil, at a mean level of

77

Envlronmental levels and human exposure

0.01mglkg;thehighestlevelwas0.09mglkgof ri.ssue (DePaulaCarvalho et al., 1984).Endrin was presenrin hens' cggslrom four of five areasin Mexico, at concentrations of 0.00€. I I mg/kgof wholeegg,andin I I of 16 samplesof chicken meat, at an averageconcentrationof 0. l2 (none detectedto 0.6) mg/kg on a far basis(Albert, 1990). Endrin wasdetectedin 86 of 221samplesof hens'eggs(78 nariveand 143commercial)collecredin1975-:77in Iran, ar a meanconcenrrationof 0.017 (range,0.003-{. 13)mg/kg (Hashemy-Tonkabony & Mossrofian, 1979).No endrinwasfound(limit of detection,0.02mg/kg)in samplesof about 25 eggs of scwc& ducks collectedon 1l lcral marketsin Java, lndonesia,in 1972(Koemanet al.,1914). It was found in 14of 367 hens'eggscollerctcd {rom 6l farms in I I districtsof Kenyain 1984;in rhreeof rheeggs,rhcleveI was> O.Zmg/ kg (Mugambiet al., 1989). Heating, baking, frying, and steamingof tissuesobrainedfrom broilersfed endrinat l0 mgkg of diet for 8 weeksdid not significantly reducethe level of residues:raw, 28.2; baked,20.8; friet,22.1; and steamed,19.4mgkg of dry rissue(Ritcheyet a1.,1972).

5.1.5.4 Milk and milk products Themeanendrinconcentrarion in 20 samplesof freshbuffalomilk in Kalubia,Egypt, was 0.02mg/kg of milk far (range,< 0.01--0.03 mg/kg (Abdouet al., 1983).Cows' milk (39 samples)collecredin lirur areasof Bagdad,Iraq, in 1981-82 containeda mean of 60 (none detectedto 40O)1tg/litre(Al-Omaret al., 1985b). The averageconcenrration of endrin in l0 samplesof evaporarcd cows'milk from threemaincitiesin theagriculrural regionof Mexicowas < 0.007mgllitre of milk far (Albert et a1.,1982). Endrin was found in powderedmilk at anaverageconcentration of 0,06mglkg andin checscat a concentration of 10-27.2mg/kgon a fat basis(Atbert,1990). The levelof endrinin milk in rheUSA was< 0.001mg/itre (on a fat basis)(FAO/IVHO, 1971).No endrin (<0.5pg/lirre) was found in 308 samplesfrom bulk rransporrs of milk collecredin Ontario,Canada,in 1977(Franket al., 1979)or in 359 samplescollectcdin I 983 (Franket al., 1985). 78

EHC130: Endrtn

No residuewas found (detectionlimit, < 0.005 mg/kg) in samplesof milk, cream, butter, and cheesein Italy (Cantoni et al., 1988) or in 12 samplesof cows' milk collectedin 1984-86 from different areasof Spain(< 0.01 mg/kg fat) (Barcelo& Puignou,1987). i.l.5.5

Fat and oils The most important useof endrin is for thecontrol of insectsin cotton, the numberof applicationsbeing l-12; cottonseedoil is usedfor cooking and for the manufactureof margarine,while the extractedcake is used as cattle feed. Endrin is thuspresentboth in the cottonseedand in the edible it wasfound that alkali oil andcakes.In a studyofthe extractionprocesses, washing and bleaching had no marked effect but that deodorization reducedthe endrin levels to below the limit of detection(0.03 mgfkg) (Smithet al., 1968). In field studiescarriedout in theUSA, couonseedcontainedendrinat a maximum of 0.1 mg/kg, althoughthe levels wereusually much lower, delta-Ketoendrinwas not detected.The levels in crude, decolourized,and deodorizedoil in VenezuelaandBrazil wereall < 0.02 mg/kg of product. Spot samplesof refined cottonseedoil from California, USA, contained ( limits of detection) < 0.03 mg of endrinand< 0.02 mg of delta-ketoendrin GAO^VHO,1971). samplesofraw oil and ofoil at various stages One-hundred-and-ten of proccssing,i.e., neutrali zed,hydrogenated,decolourized,deodorized, andshortcnings,wcrc collectedfrom sevenoil processingfactoriesin kan in 1974.Endrin was found only in raw and neutralizedvegetableoils, at concenffationsof 0.fiX--0.fi)5 mflitre. Raw imported and native oils containcd< 0.0 I mgl i tre,cxceptfor nativesunfloweroiI which contained 0.026 mg/litrc (Hashcmy-Tonkabony& Soleimani-Amiri, 1976). Endrinwasfoundin60 samples ofsix varietiesof themajoredibleoils and oil seedsused in India, including groundnut, sesame,mustard, coconut, and hydrogenatcdvcgctableoils, collected from a market in Lucknow. Vegetableoil containcd6 pgflitre, mustardoil, 72 ltgllitre, and scsameoil, 16901rg/kg.Of the different typesof oil seeds,only mustard scedcontaincdcndrin,at22 ttgkg (Dikshithet al., 1989a). Endrinwasfoundata mcanconcentrationof 0.184(0.097-O.288)mg/ kg in samplcsof cod-liveroilanalysed in Germanyin 1985(Ali, 1986).No

79

Environmental levels and human exposure

residue was found in vegetableoils and fats imported into the United Kingdom (detectionlimits,0.02 and0.001mg/kg,respectively)(Abbot et al., 1969). 5.1.5.6

Animal feed . Residuesofendrin in pressedcottonseedcakesariseprimarily from the l-5vo of oil left in thecakeafrerextraction.Theresiduesin cakesfrom Brazil, lndia, the USA, and Venezuelawere mainly < 0.01{).02 mg/kg product,levels up ro 0.08 mg/kg were found occasionally(FAOAVHO, l97l). The meanconcentrarionof endrinin 32 samplesof carrlefeedfrom a local market in India was 0.020 mg/kg (range, 0.0134.027 mgAC) @ikshith et al., 1989b).No endrin wasfound in 79 samplesof cattlefeed in Pakistan(Parveen& Masud, 1987).Endrin wasnor presenrin samples of domesticand imported animal feed analysedin the USA in 1981-86 (Luke et al., 1988). None of 42 samplesof chicken feed collected from 6l farms in 11 districrsof Kenya in 1984conrainedendrin (Mugambi et al., 1989).

5.1.5

Miscellaneousproducts Endrin wasfound in 5 of 25 robaccosamplesimportedinto Germany at concentrations of 25-50 pglkg (Cetinkaya,1988).No endrinwasfound in cigarettesof 14 brands collected in Finland in 1960-84 (MussaloRauhamaaet al., 1986).An averagecontentof 0.006 pglcigarette(range, nonedetectedto 0.O2Stglcigarerre) wasfound in Switzerland(Zimmerli & Marek, 1973). When raw cotton imported into Germany from 15 countries was analysed,endrin was found in samplesfrom the USSR and Mexico at a concentrarionof 3 pgTkg(Cetinkaya& Schenek,1987).

5.2

Exposureof the generalpopulation

5.2.1

Total-diet studies Studiesoncomplete prepared mealsin theUSA,startedin May 196I andcontinuedto thepresent,haveshowntheoccasional presence ofsmall amountsof endrin(Williams,1964;Cummings,1965,1966;Dugganet al., 1966,196'71' Martin & Duggan,1968;Comeliussen,1969, 1970,1972: 80

EHC130: Endrin

Manske & Comeliussen, 1974; Manske & Johrson, 1975; Johnson & Manske, 1976, 1977;Manske & Johnson,1977; Johnsonet al', 1981a, 1984).Thesemeasurementsindicate that the total averagedaily intake of endrin from food decreasedfrom 0'009 pglkg body weight in 1965 to 0.0005pglkg body weight in 1970(Duggan& Lipscomb, 1969;Duggan & Comeliussen, 1972),with a frrther decreasesubsequently'In total-diet studiesof adultsin theUSA, representativefoods werepurchasedin 27 US cities in 1980-82; the daily intake of endrin was found to be < 0'001 ttgl kg body weight in 1978,but nonewasdetectedin 1979,1980,or 1981-82 (Gartrell et al., 1986a). Furthersnrdiesinvolvedretail purchaseof 234 food itemsrepresentative of the total diet of eight US population grouPsin 1982-84 and preparing them for consumption. The daily intake of endrin in the groups, which includedpeople aged6-11 months,2 years, 14-16 years (females)'1416 years(males),25-30 years(females),25-30years(males),6G65years (females),and60-65 years(males),wasO.1-0'2ng/kgbgdyweight(FDA, 1988;Gunderson,1988). Endrin was not presentin the total dies of infants and toddlers in the USAduring 1974-75(Jolnsonetal., 1979).Itwas fowrdin oneinfantfood sampleat 0.011 mg/kg and in one sampleof toddlerfood at 0.009 mg/kg of food in a study in 1975-:76(Johnsonet al', 1981b).Very low residue levels were found occasionally in market-basketsamplesrepresentingthe average2-weekdiets of infants (98 samples)and toddlers(110 samples) collectedin l0cities in four geographicareasof the USA n 1917-:78 (Podrebarac,1984).In total-dietstudiesof infantsandtoddlersin theUSA, representative foods werepurchasedin 13 US cities in 1980-82;the daily intake of endrin by infants was found to be < 0.001 pg/i(g body weight in 1978,andthat by toddlers,< 0.001 pgAg body weight in 1979,but none was detectedin the otheryears(Gartrell et al., 1986b). Fresh food was bought from foru retail grocery stores in Toronto, Canada,in 1985 and combined in five food composites: fresh meat and eggs, root vegetables(including potatoes),fresh fruit, leafy and other surface vegetables,and cows' milk. The concentrationsof endrin in the five compositeswere usedto estimatethe annual dietary intake of endrin from products in Ontario. Endrin was detectedin all compositesexcept eggs and meat; the concentrationswere 0.32 pg/kg in leafy vegetables, 0.27 ltglkginfruit, 0.37 Fglkg in root vegetables,and0'27pg/kg in milk. (Davies,1988). The totalannualintakewasestimatedto be 3 1.8pg,@erson

81

Envlronmental levels and human exposure

In a total-dietstudycarriedour in rheUnitedKingdomin l9g5_gg, 25 samples were obrained in 1984-85 which comprised the 16 food groups consideredmost likely to contain residuesof organochlorine compounds.No endrin was derected(limit of detecrion,0.001--0.02mg/ kg, dependingon thefood group).Endrinw asalsonordetected(< 0.0I mg/ kg) in 176samplesof pulsespurchasedfrom rerail our.lersin 19g6_g7. except in 3 of 2A samplesof mung beansin which a mean value of < 0.01 mg/kg (range,none derected,to0.06 mg^g) was found (Unired Kingdom Ministry of Agriculture,FisheriesandFood, I 9g9). No endrin was detectedin completepreparedmeals during surveysin the United Kingdomin 1965(Robinson&McGilt, 1966;McGill & Robinson,1968). Similarresulrswereobrainedin Switzerlandin 1973(Zimmerli& Marek, 1973),andvery low levels were found in rwo of 73 samplesanalysedin 1985(wiithrich er al., 1985).No endrinresidueswercfoundin roral-dicr studiescaniedour in the Nerherlands in 1976-7g(Dc Vos cr al., l9g4). 5.2.2

Levels ln human tissues Although the concentrationsof many chlorinatedhydrocarbon insecticides,such as DDT, dieldrin, hexachlorocyclohexanes, and hexachlorobenzene, andof their metabolitesin blcxrdor adiposetissueo[ the generalpopulationor ofoccupationaly exposedworkers have been found to be an excellentindex of the level of exposureof rhe gencral population,this is not thecasefor endrin,becauscit is eliminatedrapi<Jlv.

5.2.2.1

Adipose tissue Exceptin a few cases,endrinwasnot demonstrated in adiposerissue samplesfrom the generalpopulationin the USA in 1962-66(Hoffman et al., 1964,1967),1964(Hayeser al., 1965; ZavoneLal., I 965), lg70_74 (Kutz et al.,l979a,b),and1975-79(US EpA, 1983);Canadain 1967_68 (Kadiset al., 1970);Mexico in 1975(Albert et al., 19g0);Argentinain 1968-69;(Wassermann eral.,1969);Belgiumin l963-69 (Wit, 1971);the United Kingdom in 196l (Hunteret al., 1963),1964(Robinsoner al., 1965),and 196547 (Eganet al., 1965;Abbou er at., 1968, l9l-2); the Netherlands in 1969(wit, l97l ); Switzrrlandinlgi2(zimmerli & Marek. 1973); Germany in 1970 (Acker & Schulre, 1974); Francein l97l (Foumierer al., 1972);Spainin 1978(HeneraMarteacheet al., l97g); lndia in 1964 (Dale er al., 1965);or WesremAustralia in 1965_66 (Wassermann er al., 1968).

82

EHC130: Endrtn

No endrin was found in 9l samples of adipose tissue obtained at autopsyinKingston, Ontario,Canada,n1979 and 1981or in 84'samples from Ottawain 1980and 1981(Williams et al', 1984),or in adiposetissue obtainedat autopsyfrom92 malesand49femalesin Ontariomunicipalities in 1984(limit of detection,2.4pgTkg)(Williams et al', 1988). Theseresultsindicate thatendrin is either absentor presentat very low levels in the adipose tissue of the general population. It is therefore surprising that Kaniz & Castello (1966) reported the presenceof endrin in nine adiposetissuesamplesfrom Liguria, Italy, at a meanconcentration was2.49mg/kg. Pavan of0.93 mg/kgof tissue.Thehighestconcentration et al. (1987) found endrin at 0.1 and 0.3 mglkg in 2 of 92 samplesof adiposetissueobtained at surgery from people living in the Province of Turin, Italy. In areaswhere endrin has been used extensively, however, suchas India and the lower Mississippi, it hasnever beenfound in human adiposetissue(Brooks, 1974). One of 62 adiposetissuesamplesobtained at surgery from people in Ciudad Juarez,Mexico, in L977-:78contained endrin at 0.02 mgTkg (Redetzkeet al., 1983). 5.2.2.2

Organs [r samples of liver, kidney, gonad, and brain obtained from the generalpopulationofAlberta (Canada),no residueofendrin wasdetected ffadis et al., 1970).

5.2.2.3

Blood No endrinwasdetected(limit of detection,0.0I mg/kg) in 4m0 blood samplesfrom the generalUS populationin 1976-80(US E P A, 1983),or in areaswhere endrin has been used extensively, such as India and the lower Mississippi (Brooks, 1974), or rn26 blood samplesfrom thegeneral populationin Nigeria (Atuma, 1985).

5.2.2.4

Breast milk Endrin wasnot detectedinbreastmilk in studiesin theUSA in 196678 (Strassman&Kutz,1977;Currieet al.,1979;Kutzetal.,1979a;Bamett et al., 1979), in El Salvadorand Guatemala@e Campos& Olszyna(Kanitz& Castello, Marzys, 1979),in Belgium,Italy, andTheNetherlands

83

Environmental levels and human exposure

1965;Hendrickx & Maes, 1969;Wegman& Greve, 1974),andin Japan (Yakushijiet al., 1979).No endrinwas derected(< 0.01mgflitre)in 50 breastmilk samplesfrom morhers(aged 18-32 years) in Leiden, The Netherlands,in 1969(Tuinstra,l97l). Ir was found in one of l2 samples from mothersageA2l-31 in Pavia,Italy, in 1988,at a concentration of 0.01 pglkg of whole milk, but nor in four samplescollectedin Crotone. southernIraly (Bianchier at., lggg). 5.2.2.5

Appraisal of exposure of the generat poputation The occasionalprescnceof row concentrationsof cndrin in the air of areaswhereendrinis usedin agriculturecannotbeconsi<Jerecl a significant sourceof contaminationfor thegeneralpublic.Thevery low concenlrations that have been found in surface and drinking-water are also of little significancefor public healrh. The source of exposure that may bc relevant is dietary intake. Apart from accidental c.ntamination, however, intake of cndrin by the gcneral population in the countries examined has bcen and is still far bclow the maximum acceptabledaily inrakc of 0.2 pg/kg body wcight csrablishedby the Joint FAOIVHO Mccting in 1970 (FAOAVHO, l97l). This applics equally to the total intakc, when the intakc from dictary sourccs is a
5.3

Occupationalexposureduring manufacture, formulationand use

5.3.1

Manufacture and formulation Endrin hasnot becn detcctedin the blood, plasma, or urine o[ workers exposcd occuparionally ro cndrin (Hayes & Curtey, l96ft; Jager, 1970). Endrin was detcctcd in blood only after accidenral 'vcr-exposure. Jager (1970) estimared rhat the threshold level of endrin in the blcnd, below which signs or symptoms of intoxication do not occur, Iies betwccn 0.05 and 0.10 mg4itre. He estimatedrhe half-life of endrin in thc blo<xlr. bc in ths ordcr <>l'A lt. 84

EHC 130: Endrin

The total exposure of workers in a manufacturing and formulation plant was estimatedon the basis of determinationsof the quantity of the endrinmetaboliteanri I 2-hydroxyendrinin urine.Urineof workersexposed to endrin for sevendayshadconcentrationsof up to 360 pglg of creatinine; no wrchangedendrin was found. Assuming an averagedaily excretion of 1.5 g creatinineper day, thetotal daily excrettonof anti-L2-hydroxyendrin intheurinemay beupto540 pg. This givesaminimal absorptionof0.5mg endrin, indicating that inhalation of duss and absorptionthrough the skin may be significant during occupationalexposuresin manufacture.It is not unreasonableto assumethat, asin other species,approximately half of all the endrin absorbedis excreted in the urine as anti-12-hydroxyendrin, since both endrin and this metabolite arepresentin the faecesof workers (Ottevanger&Van Sittert, 1979;Baldwin & Hutson, 1980). Thus, I mg/ day may be the more accuratefigure for exposurein this manufacturing plant. The concentration of anti-L2-hydroxyendrin in urine decreased more slowly than the concentrationsof endrin in blood, with a half-life of 55-:75h(Van Siuert,1985).

i.3.2

Application Endrin is appliedin agricultureby high-pressurespraying with a hand gun, spraying orchards with a power air blast or boom to control mice, dusting potatoes,sprayrngrow crops, or application from aircraft. These methodsof applicationresult in dermalandrespiratoryexposures. The potential dermal and respiratory exposureof workers applying endrin formulations in the field has been quantified in a few studies. Respiratoryexposrueto endrin during sprayingoforchards, high-pressure sprayingof crops,and piloting of aircraft variedfrom 0.01 to 0.14 mg/h; dermalexposureduring suchactivitieswas 0.01-1.64 mg/h. The activity thatcausedthemostexposurewasdustingpotatoes,which wasassociated with a respiratory exposure of 0.41 mglh and a dermal exposure of 18.7mg/h. Total exposure,calculatedas a percentageof a toxic dose/ [ = {dermal exposure (mgih) + [respiratory exposure (mgl h)x l0l] + [dermallDro(mg/kg)x 70] x l00,was0.2l-1.57o@urham& Wolfe, 1962)(seeTable 11).Thesefigures show that althoughendrin is acutelyhighly toxic it canbe usedsafelywhenreasonableprecautionsare taken(Wolfe et al., 1963;Jegier,1964;Wolfe et al., 1967;Hayes, 1975). Endrin was not found in the blood of 20 pesticide sprayers or in 19 controls in Choluteca,southemHondwas (Steinberget al., 1989).

85

Environmental levels and human exposure

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EHC 13O: Endrln

Appratsalof occupatlonalexposure No residues were found in healthy workers. The range of threshold levels of endrin in blood below which no sign or symptom of intoxication occurshasbeenestimatedto be 50-100 pflitre. The halflife of endrin in blood may be in the order of 21h following occupational exposure' The concentration of anti-L2-hydroxyendrin in the urine decreasedmore slowly than the concentrationof endrin in blood, with a half-life of 5575h.

87

6. KINETICSANDMETABOLISM 6.1

Absorption,distribution,andelimination

6.1.1

Laboratory animals

I

6.1.1.1 Oraladministration Rat: Onemalerat wasfed raC-endrinar a level of 30 mg/kg of diet for 8 days. About 6&-707owas excretedon the first day; after three days, the faecescontainedmore then 807oof the administeredradiolabel; by day 9, 847ohad beenexcreted;andthere appearedto be a level of saturationafter 6-7 days of feeding. Only 0.5Vowas found in the urine. About 75-807o of thelabelin thefaeceswasin at leasttwo differentmetabolites.The adipose tissuestored34 mgkg, giving a sroragerare of about l0 (FAO/WHO,

r97r).

After femaleratsweregivena singleoral doseof raC-endrinat16,64, or 128 pgTkgbody weight,excretionwasrapid.The biological half-life of thedosesof16and64pg/kgwasl-2 days;however,tharof 128pglkgwas approximately6 days, showing thar excrerionof higher dosesis slower (Korte et d., 1970). Six CFEratsof eachsexweretreatedwith a singleoral doseof 0.5 mg laC-endrinin arachisoil (approximatelyequivalent ro 2.5-3.0 mg/kg body weight),andtheradiolabelexcretedin urine andfaeceswasmeasuredover 3 days. The animals were then killed and the radiolabel measuredin tissues.A sexdifferencewasnotedin rherateof eliminationinfaeces:667a of thedosewasexcretedin 3 daysby malesand377oby females;excretion was slower in femalesbut tendedto increasedaily betweendays I and 3. Smallquantitiesofradiolabelwereexcretedin theurine,femalesexcreting three times more than males. No radiolabel was found in exhaled air (Ilutson et al., 1975).The resultsaresummarizedin Tables 12 and 13. Threeratsof eachsexwereeachgiven a singleoral doseof 8 1rgt4Cendrinin peanutoil (by gavage)daily for I 2 days.A sreadysrare(ar which the excretedamountequalledthe daily intake) was reachedafter about 6 days.Femalesstoredabout rwice as nntch(T|Vo)as males(l4Vo).The radiolabelwas excretedmainly in the faeces:afterthe first 24h,70-:75Eo of the radiolabel was found in faeces as hydrophilic metabolites; 88

EHC 130:Endrin

subsequently, only metabolites were present. Four days after the last dose, males retained orliy 5Vo and females l5%oof the administered radiolabel (Klein et al., 1968; Korte et al., 1970). Table 12. Rates of excretionof radiolabelby rats treated with a single oral dose of raO-endrin(percentageof radioactivityadministered)

Male Female

Urine

Faeces

Dtl--DaytTtS

D-ari-"ay 2-D-il

1.3 1.8

0.6 2.5

0.6 2.9

30.6 2.3

14.4 10.7

21.2 24.2

Table 13. Recoveryof radiolabelin rat tissues3 days after a singleoral dose of laC-endrin(percentageof radioactivityadministered) Sex

Urine Faeces Liver Kidneys Fat Skin

Males 2.7 Females 7.5

66.2 37.2

1.2 2.0

0.6 0.4

1.7 2.3 8.0 4.0

Remaining Total carcass

12.2 86.9 28.1 87.2

Rabbit: A Dutch strainmalcrabbit was givcn twooral doscsof 4.7 mg taC-endrinin olivc oil at an interval of 14 days. Between days I and 13, 37o/oof thc lirst dosc was excrcted in the urine and 497o in the faeces: the seconddose was eliminatcd similarly. By day 49,50qo had been excreted in urinc and 47o/o in faeccs. Faccal cxcrction was rapid, being almost complctc within 24 h, and consistcd virtually cntircly of unchanged cndrin. Thc urinc containcd only mctabolites (Bcdford et al., 1975a).The cxcretion ol'mctab<>litcs in rabbits thus appcarsto differconsidcrably from that in rats: approxirnatcly half o[ a dose of r{C-cndrin is cxcrctcd in the urinc ol' rabbits and approximatcly 2o/oin rats; endrin mctabolites are cxcrctcd in ral facccs ovcr scvcral days (aftcr a singlc oral dose), whcreas in rabbits faccal cxcrcl.ionis rapid, bcing almosr complcte within 24 h, and consistsvirtually cntircly of unchangcdcndrin. The probable cxplanation is that thc rmrlccular wcight thrcshold for biliary secretion of anions is 325+ 50 in rars and 475+50 in rabbits (Hirom et al., 1972). The glucuronidc and sulfatcconjugates of monohydroxyendrin have molccular wcights of 572 and 410, rcspcctivcly. Thercfore, conjugates of thc cndrin mctabolitcs arc climinatcd in thc bilc and faeccsof rats and in the urinc in rabbits.

89

Kin et'rcsan d metaboIi srtt

Dog: Threebeagleswerefed a dietcontaining endrin at aconcentration equivalentto 0. I mg/kg body weightfor 128days;rwo otheranimalswere usedas controls. The concentrationof endrin in blood was determinedat weekly intervals.The time to reachaplateauin blood waslessthan 1 week, and no significant increasein the concentration of endrin in blood was found during this period. The averageconcentration between day 9 and day 128 was 4 pgllitre. The concentrationofendrin in eight organsand tissuesof dogskilled 7 daysafter terminationof exposurewas < 0.2 mg/ kg of tissue;exceptthat the spleenof one dog contained2.6 mgkg, and adiposetissuecontained0.2-0.8mg/kg (Richardsoner al.,1967).

6 . 1 . 1 . 2 Intrave no us ad m in istration Mouse:Theconcentrations of endrinweredeterminedin tissuesfrom groupsof five adultmaleCFI mice givenendrinintravenouslyat 5 mgAg body weight (-D) in dimethyl sulfoxide. The concenrrarionsprior to convulsions(about 10 min afterinjection) wereapproximately60 mg/kg in liver, 20mgkg in brain andomentalfat, andapproximately5 mg/itre in blood. The concentrationin whole brain 15 min after an intravenous dose of 1.5mglkg body weight (the dose thar causedaraxiain 90Voof animals; TDp was 9.4mgkg. No endrin was derectedin rhe bile of animalswith a bile fistula dosedintravenouslywith the TDroin samples collectedafter 0.5, l, or 2 h (Walsh & Fink, 1972). Ral: Male Holtzmanrats with or without a bile fistula were given a singleintravenousdoseofraC-endrinat0.25 m/kg body weight.More than 90Voof theexcretedradiolabelwas found in the faecesof intact animals overthe7-dayperiodafterdosingorinthebileof animalswithfistulasover 4 days.The meantotal percentagerecoveryof administeredradiolabetin faeces,urine, and carcasseswas 97Vofrom intact animals 7 days after dosing,and94Vofrom animalswith a bile fistula4 daysafterdosing(Cole et al., 1970).No unchangedendrinwasfound in bile; themaiormerabolite w asanti - 12-hydroxyendrin(seesection6.2.I ). Rapidexcretionwasobservedinrats giventwo intravenousinjections of laC-endrinat 0.1 mg/kg body weight at an intervalof 4 days.Excretion of the radiolabelwas exponentialand occurredmainly with faeces;only hydrophilic metaboliteswere presenr.With a dose of 200 pglkg body weight, male rats retained5.2Voarrdfemales l2.l7o of rhe administered dose20 daysafter the secondinjection.The biologicalhalf-life ofendrin after a singleintravenousdoseof 200 pglkg body weight was 2.5-3 days 90

EHC 130:Endrin

in male rats and4 daysin females(Klein et al., 1968;Korte et al.,1970; Brooks, 1974). Rabbit: When rabbits were given raC-endrinintravenously, the radiolabel was excretedmainly in the urine and only as metabolites.A probableexplanationfor the differencein excretionpatternafteroral and intravenousadministrationis thatmuchlowerdoses(microgramscompared with milligrams) were given intravenously(Korte et al., 197O).

11.2

Domestic animals Twelve cows werefed hayfrom endrin-sprayedalfalfa containingan averageof 1.9, 2.8, or 3.7 mgkg endrin; the averagedaily intake of individual animals ranged from 0.M to 0.11mg/kg body weight. The averageconcentrationsof endrin in the milk were < 0.05, 0.14, and 0.15 mg/litre, respectively.When endrindissolvedin soyabeanoil was fed to 11 dairy cows, levels > I mg/kg body weight were requiredin order for significantquantitiesof endrin to be detectedin milk (Ely et al., 1957). Dairy cows(eightJerseysandsix Guerrseys)werefeddietscontaining endrinat 0,0.I ,O.25,0.75,or 2.Omgkg of dietfor l2 weeks.No residues were found (limit of detection,0.01 mg/litre) in the milk of animalsthat received0.1 mg/kg, but up to 0.02 mg/litre wasfound in milk of animals fed0.25 mg/kg andupto0.(X mglitre with0.75 mg/kg of diet; thehighest doseresultedin residuesin milk of 0.1 mg/line. The endrin contentof brain, heart,liver, kidneys, body fat, and muscleswas < 0.1 mg/kg, but renal fat containedup to 0.8 mgAg (Kiigemagi et al., 1958). The concentrationsof endrin in milk of cows given feed containing endrin at approximately0.05, 0.14, and 0.30 mg/kg of whole feed for 5 weekswere0.004,0.01,and0.018mgflitre,respectively(Williams et al., I 964). A steady(plateau)levelin milk wasreachedafteraboutI 5 days. The concentrationof endrin in the milk of dairy cows given feed contaminatedwith relativelylow levelsof endrinroserapidly within a few hours to days and levelled off at a plateau characteristicfor each concentrationin the feed.The averagemilkdietratio for endrinwas 0.07 for feed levels of 0.05-O.3mgftg of diet (Biehl & Buck, 1987). Two lactating cows were fed raC-endrinfor 2l days at an overall dietary concentrationof 0.1 mgTkgof diet, which was consideredto be

91

Kineticsand metabolism

comparableto thehighestdosethatcowsarelikely toreceiveincottonseed cake.Excretionof radiolabelin milk, urine, andfaecesreacheda plateau 4-9 daysafterstartof treatment.Approximately37oof theradiolabelwas. excretedin milk, 657oin urine, and?-UVo in faeces.Unchangedendrinwas not found in urine, but about 307oof the radiolabel in faecesand all of the 0.003--0,006mg/litre found in milk was endrin. The concentrationof endrin equivalentresidueswas 0.001-0.002mglkg in meat and 0.020. 10 mg/kg in fat; mostof theradiolabelin fat consistedof endrin(B atdwin eraL.,1976). Steers,hogs,and lambsfed dietscontainingendrin at 0, 0.1, 0.25,or 0.75 mg/kg of diet for 12 weekshad residuesof < 0. 1 mg/kg in red meat, liver, and kidneys and of 0.02-0.2mgkg in body fat. Feedingendrin at 2 mgkg of diet to steersfor 12 weeksresultedin residuesof 0.9 mg/kg in fat and0.2{.3 mg/kg in redmear,liver andkidneys(Terriereet al., I 958). Thebiotrarsferfactors for endrinin beefandmilk weredirectly proportional to the octanol-water partition coefficients,while the bioconcentration factorforendrin invegetationwasinverselyproportionalto thesquareroot of the octanol-waterpartition coefficient (Travis & Arms, 1988). Six weeksafterthestartof feedingsevenDelawareX New Hampshire malechicksandeightweeksafterthestartoffeedingsevenWhiteLeghorn pulletsa diet containingendrinat0. I mg/kg, theresiduesin eggsandmeat were< 0.I mg/kg andthat in fat, 0.6 mgAg. At a dietarylevel of 0.25 mg/ kg, the residuelevels were 0.24.3 mgftg in eggs,0.1mg/kg in breast meat, and about I mg/kg in fat. With 0.75 mg/kg of diet, the levels were O.4mglkg in eggs, 0.24mgkg in breastmeat, and 3.1mg/kg in fat (Terriereet al., 1959). raC-Endrinwasadministereddaily in com oil ingelatin capsulesro six Iaying hers at a concentrationequivalentto 0.13 mg/kg of total diet for 2l weeks. Ingestion and elimination in eggs and excreta were almost balancedafter about 16weeks. The residue levels in eggs were 0.110. I 8 mgTkgandwerefound in theyolk; noneof theknownmetaboliteswas detected.The levelsof endrinequivalentwere about0.01 mgTkgin breast meat and 0.1mg/kg in leg meat; higher levels were found in the liver (0.a7 mglkg),kidneys(0. 17 mC/kg),andfat ( I mg/kg).Theresidueswere accountedfor by unchangedendrin,exceptin theliver andkidneys,where partprobablyconsistedof polarmetabolites. About5(9oof theadministered radiolabel was excretedin the faeces,lo9o of which was in unchangcd endrin(Baldwinet al., 1976), 92

EHC 130:Endrln

.1.3

t I

Human beings The concentrationsof endrin in the blood of workmen exposedto endrin weregenerallybelow the level of detection:endrin was not found in plasma(< 3 ltgtitre) or f at (< 0.03 mglkg) of workers exposedro endrin for an averageof 88 days(Hayes& Curley, 1968).No endrin was found in the blood of healthypeopleworking in an endrin marrufacruringplant between1964and 1970,at an initial limit of derectionof l0 pg/itre, improvedafter 1965to 5 pgllitre (Jager,1970). Residuesof endrinhavebeenfound in blood only in individualswith signsofrecent intoxicationor who haverecentlyhad excessiveexposure (see section9.2.2). Endrin appearsto be eliminated rapidly from rhe humanbody.

1.4

Sysfems in vitro Isolatedliver preparationsfrom Holtzmanrats were perfusedwith a solutioncontaininglaC-endrinat 0.003mg/ml. Within I h, 50Voof the radiolabelappeared in thebile; andin 6 h, morethan907oofthc torallabel wasfound(Coleet al., 1970).With rhcsamedose,radiolirbclappeareA2l2 timesfasterin thebileof liversisolatedfrommaleratsasin thatof livers from females,which may accountfor thelower toxicity andlower storage of endrinin adiposetissuein malerars(Klevay,197I ). After perfusionof albino rat liver with a physiologicalsolutionconraining40 pg of taCendrin,both endrin andhydrophilic metaboliteswere found (Altmeier & Korte, 1969).

.2

Biotransformation lnformation on the metabolism of endrin up to 1967 was reviewecl (Soto & Deichmann, 1967; Brooks, 1969).

I

,,2.1

Experimental animals A number of investigationshive been carried out since 1970 to elucidatethe identity of severalmetabolitesof endrin in rats (Baldwin et al., 1970;Richardsonet al.,1970 Hutsoner al., 1975:Bedford& Hutson, 1976),rabbits(Bedfordet al., 1975a;Hurson,l98l), cows andchickens (Baldwin et al., 1976).The l2-hydroxy derivativewas reporredro be

93

Klneticsand metabolism

present in the faeces ofrats (Baldwin et al., 1970), and the hydroxyl group was assigned tentatively as.ryn to the epoxide ring. The stereochemical configuration was subsequently shown to be anti to the epoxide group (Baldwin et al., 1973), and this configuration was confirmed by the synthesis of anti-l2-hydroxyendrin (also called 9 -ant i-hy droxyendrin) (Bedford & H arrod, 1973; Bedford et al., I 986a). The chemical structures of these compounds are shown in Figure 2; the chemical names are given in Annex I. Formation of anti-l2-hydroxyendrin (/fl, togcther with its sulfate and glucuronide conjugates, is considcred to bc the major route of metabolism of endrin. Fourothermetabolites have bccn reported,but thcir concentrations are generally smallcr than that of anti-I2-hydroxyendrin and its conjugates. These four metabolites are syn-t2-hydroxyendrin (//; tentative identification), 3-hydroxyen drin (lV; synthesized and structure confirmed by Bedford et al., t 986b), I 2-ketoendrin (l|, and the product of formal hydroxylation of endrin, the 4,5-trans-dihydroisodrindiol (V1; tentative structure). The trans-diol (V1) is a minor metabolite in both rats andrabbis; itmay beformedvia anoxidation-reductionpathwayinvolving intermediatcs of the corresponding ketol (Vfl. Each of the hydroxy compounds is also excretedpartly as its sulfate or glucuronide in the urine of animals (Bedford et al., l975a,b; Hutson et al., I 975). The threc monohydroxylatcd derivativcs of cndrin,.tyn- and anti-|2hydroxyendrin (ll and IID md 3-hydroxycndrin (/V), are the products of the action of liver microsomal monooxygenascs on endrin (Bcdford & Hutson, 1976). These alcohols are also conjugatcd to glucuronides and sulfatesto some extent in the liver. Comparativemctabolic studieswith rat liver microsome preparatiolts have shown th atlrreesyn-12-hydroxyendrin, but not its free anri-isomer, is the precursor of l2-kctoendrin (l/) (Hutson & Hoadley, 1974). Rats cxhibit a scx difference in thc rate o[ mctabolism. The major mctabolite in animals of cach scx is anli-12-hydroxycndrin, which is excrctcd via thc bilo as thc glucuronidc; this undcrgocs enterohepatic circulation and is eliminated as the aglyconc in thc facccs, togethcr with twominormetabolites,3-hydroxyendrinand4,5-trans-clihydroisodrindiol. Male rats produce the metabolite at a higher rate than do fcmalcs. The major urinary mctabolite in male CFE rats was l2-kctoendrin, while females excreted mainly anti-12-hydroxycndrin O-sulfate. Endrin and the lipophilic metabolite 12-ketoendrin were the major compouncls found in the organs and tissuesof male and female CFE rats 3 days aftcr a single oral

94

EHC 130:Endrin

-

x o

o d

o o

c o .o o o

E

'xo

.9 c o o

= N

iI

95

Kinetics and metabolism

doseof endrin,but theratioof endrin:l2-ketoendrinwas2/l infemalesand l/8 in males.Thus. I 2-ketoendrincorstituted most of the radiolabel in the liver and kidneys of males and endrin that in the kidneys of females (Hutsonet al., 1975;Hutson, 1981). The metabolismof endrin in rabbits is superficially different from that in rats. The major metabolite is still anti-l2,hydroxyendrin, but it is conjugated with sulfate and eliminated in the urine. Some syn-12hydroxyendrin was also detected as its sulfate in urine, and perhaps conjugationandeliminationpreventedfurtheroxidationto 12-ketoendrin. The respectiveglucuronideconjugateswere alsoeliminatedin the urine, as were the glucuronidesof 3-hydroxyendrinand the 4,5-trans-diol(Vl (Bedford et al., 1975b;Hutson, 1981). Studieswith raC-endrinin lactatingcows showedthar rheresiduesin milk and body fat consistedofunchangedendrin, althoughtracesof 12ketoendrinwereconsistentlyfound in fat. As itrats, anti-t2-hydroxyendrin was the major metabolitein urine and faeces,the urine being the major excretoryroute, as in rabbits. l2-Ketoendrin and syn-12-hydroxyendrin wereminormetabolitesincowurine(Baldwinet al., 1976).Thus,although themetabolicpathwaysof endrinin cowsarequalitativelysimilar to those in rats and rabbits,quantitativedifferencesareseenin faecalandurinary excretion. ln hens,only endrin was found as a residuein meat, fat, and eggs. Unchangedendrin accountedfor about l1vo oftheradiolabel in excreta, and the major metabolite was anti-Iz-hydroxyendrin and its sulfate conjugate.No 12-ketoendrinwasdetectedin tissues,eggs,or excreta.The metabolismof endrin in hens is fundamentallysimilar to that in rats, rabbits,andcows,exceptthat theyproduceneither syn-L2-hydroxyendrin northerelated12-ketoendrin.Therateofmetabolism,however, wasmuch lower thanin cows (Baldwin et al., 1976).The absenceof l2-ketoendrin in birds wasconfirmedin a studyof four specieskilled by endrin(Stickel etal.,1979).Hutsonetal.(1975)suggested rhattheacutetoxicityof endrin in birds is not associatedwith the formation of l2-ketoendrin. 6.2.2

Human beings No endrinwasfound(limit of detecrion,0.(X)I 6 mg/itre) in 14 samples ofurine from workersexposedto aldrin,dieldrin, andendrin,eventhough workerswith a completework history had beenexposedto endrinfor an 96

EHC 130:Endrin

averageof 2160h (Hayes& Curley, 1968).Endrin was not detectedin urine from five men and five women (Cueto & Ha54es,1962; Cueto & Biros, 1967). No unchanged endrin was found in the urine of Dutch workers.exposed to endrin, but it occurred in the faeces (Jager, 1970; Baldwin & Hutson, 1980). Neither 3-hydroxyendrin nor the diol was detectedin urine or faeces (Hutson, l98I). anti-L2-Hydroxyendrinwaspresentin theurine of workers exposed to endrin, and the glucuronide was found in the faeces. Concentrationsof up to 0.36 mg,/gof creatininewere found in urine after 7 days,accompaniedbyasharpriseinthelevelof o-glutaric acid(excreted in the urine of mammals as a metabolite of D-glucuronolactone[Marsh, 19631),indicating that liver enzymeinduction may have occurred'The levels tended to decreaseover the weekend (Ottevanger & Van Siltert, 1979). Endrin, anti-12-hydroxyendrin, l2-ketoendrin, and the betaglucuronide of anti-|2-hydroxyendrin were not found in the blood of workersat a Dutchplant for themanufactureof endrin (limit of detection, Z1tgllitre). Both endrin and anti-72-hydroxyendrin we,refound in the faeces,and all urine samplescontainedthe beta-glucuronideof anti-|2hydroxyendrin up to a concentrationof 0.14 mg/litre as anti-|Z' hydroxyendrin(Baldwin & Hutson, 1980). Hydroxylation at anti-C-|Z is relatively rapid and accountsfor the rapid metabolismof endrin. Evensyn-12-hydroxyendrinis hydroxylated rapidly at its anti-C-I2 position,affording l2-ketoendrin(Hutson,1981). As neither endrin nor its metabolites were found in the blood of exposed,healthy workers, exposurecanbe measuredby determining dztil2-hydroxyendrinin urine. A quantitativerelationshipbetweenexposure to endrin and the concentrationof this metabolitecannotbe established. however,owing to lack of data.

2.3

Microorganisms In mixed anaerobicmicrobial populationsdevelopedusing inocula from soil, freshwatermud, sheeprumen, and chicken litter, endrin (like other cyclodiene compounds) was monodechlorinated at the methylene bridge carbon atom. Neither endrin nor any other compound was further metabolized.The 10 obligateanaerobicbacteriathat madeup the mixed population were subsequentlyisolated in pure culture. Of these,only Clostridium bifermentans,C. glycolium, and other Clostridium species

97

Kinetlcsand metabolism

were capableof dehalogenation, but at arate that was much slower than thatof themixedpopulation(Mauleer al., 1987).

6.2.4

Plants Three experimentswere carried out on tobaccoplants. In the first experiment,2.08 mg of raC-endrinwere applied to the leaveswith free aerationduring theexperimentalperio
98

INTHE 7. EFFECTS ONORGANISMS ENVIRONMENT :.1

Microorganlsms The interactionsof halogenatedpesticidesand microorganismshave been reviewed extensively (Pfi ster, 1972). In tlrree Willamette valley soils (USA) treatedwith endrin at 0, I or 10 mglkg, no effect was found 30 days after application on the function and activity of the microbial population, the decomposition of native organic matter, the transformationof native soil niuogen, ammonification of peptone,or nitrification of ammoniumsulphate(Bollen & Tu, l97l). Even at an annual application rate of 5 lb/acre (5.6 kg/ha) for 5 years,no effect was seen on the numbers or kinds of soil frurgi, the numbers of bacteria, the decomposition rate of organic matter (measuredby CQ producrion),or theoxidationof ammoniumto nitrate(lvlirtinet al., 1959). Endrin at a concentration of 100 mg/kg of soil had no effect on denitrification in soil under anaerobicincubation for 5 days at 30 oCor in an isolated denitrifying bacterium (Bollag & Henninger, 1976), A concentration of 1000mglkg had no effect on methanogenesis,sulfate reduction, or carbon dioxide evolution in anaerobicsalt-marshsediments (Kiene & Capone,1984). The growth ratesof two strainsof blue-greenalgaewere decreasedin the presenceof endrin at a concentrationof 0.29 pgnitre (Batterton et al., 1971), and the productivity of many forms of natural phytoplankton in estuarinewaterswas decreasedby 464owhen they were exposedto I mg/ litre (Butler, 1963).

1.2

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'.2.1

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presentat a temperatureof 9-10 oCfor 12 days.None of the worms in sea water died after exposureto endrin at 0. 1I mg/lite f or 12 days,but two of five worms exposedto 28 mg/kg in sedimentdied in this period (Mckese et al., 1982). The mean96-h LC, for the oligochaetesSrylodrilus heringianus and Limnodrilus hoffmeisteri exposed to sediment from Lake Michigan contaminatedwith taC-endrinwas 2588 t1974 mg/kg dry weight of sedimentinfour assaysand2725 + 955 mglkg in two assays.The toxicity to L. hoffnwisteri appearedto bereducedin thepresenceof S.heringianus. The 96-h EC, burrowing avoidancevalues were 15.3-19 mg/kg for S. heringianus and 59 mg/kg of sedimenr for L. hoffmeisteri (Keilty et al., 1988a). Sedimentreworkingby I,. hofftneisterialoneandwith.S. heringianus wasmeasuredbymonitoringtheburialof a 13?Csmarkerlayer in sediments dosedwith tT- and raC-endrinar concenrrarions of 5.5-81 400 pgTkgof dry sediment.With low endrin concentrations,themarker layer burial rate did not suggeststimulation of reworking by either L. hoffnuisteri or S. heringianus. At higher concentrations,the reworking rates were equal to or slower than control rates at the beginning of the experiment but decreasedthereafter.The presenceofS. heringianus appearedto enhance the reworking response of L. hoffnuisteri. A reduction in the postexperimentalmortality and an increasein the dry w eightof L. hoffneisteri in testswith the two speciesimplies thatL. hofftttcisrerj benefits from the presenceof S. heringianzs, although the reversewas not observed.High concenffationsof endrin in the upper 3 cm of the final sediment showed that the worms had transported the contaminant upward. The bioaccumulationfactorfor S. her ingianw rangedfrom 9.7 ro 43.8andwas consistentlythreeto four times greaterthan thatfor L. hoffmeisteri(1.713.6)(Keilty et al., 1988b). The reworking rates of S. heringianzs in microcosmscontaining sedimentsdosedwith raC-endrinat3.l42 000 pg/kg of dry matterwere measuredat l0 oCbymonitoringa r3tsmarkerlayerburiedincontaminated and uncontaminated microcosms. Alterations in reworking rates were observedat endrin concentrations5.5 ordersof magnitudebelow the LC* of 1650mgkg. At thelower concenrrarions, a possiblestimulatoryeffeci on the marker layer burial rare in the first 300-600 h was followed by a significantdecreaserelative to thecontrols.At thehigherconcentrations, the rates were equal or slower during the first 600 h and decreased 104

EHC 130:Endrin

dramaticallyin the last 600h. Mortality was 9.3-28Voat 11500 and 42CfJ0pg/kg and0-6.7Voat all the otherconcentrationstested,including controls.The dry weightsof the wormsat the endof the experimentwere The bioaccumulationfactors inverselyrelatedto thehigh concentrations. rangedfrom34to 67 on thebasisof gramsofdry organismtogramsof dry sediment(Keilty et al., 1988c). The effect of additionof endrinat 50 mg/kg dry weight of sediment onprotein utilizationby S.heringianuswasexaminedon days4, 8,20, 28, 39, and69. A slight increasein the relativepercentageofprotein to total body weight was observed,but the authorsconcludedthat estimationof total protein is not a useful measureof sublethalresponses(Keilty & Stehly,1989). The totalorganiccarboncontentof sedimenthadlittle apparenteffect on the toxicity of endrinin thefreshwateramphipodHyalella azteca.Tbe l0-day LCrofor endrinin sediment(dry-weightbasis)was4.4 pg/itre at et al., carbonand6.0 pgllitre at77.2Vocarbon(Neb6ker 3.OVototalorganic 1989). The ECrusin thcgreenseaurchin (Sto ngylocentrolus droebachiensis), thepurplc scavchin (S. purpuralus),thered seaurchin(S.y'anciscanus), and the sanddollar (Dendrasterexcentricus)were 103-441 pg/itre for spcrmin astaticsystemand221-> 362 pglitre foremb'ryosin acontinuous oC;salinity,30.0partsperthousand; fl ow of seawater(tempcrature,8.2-8.4 pH 7.8-8.I for thescaurchinsandI 2.5-13.0"C, 30.0partsper thousand, and pH 8.0-8.1 for sanddollar embryos),both with an bxposuretime of 120h. In a larval test of static exposureof Dungenesscrab (Cancer magister),theECrowas2.0 pgllitre (Dinnelet al., 1989). Endrinwastestedat 0, 0.025,0.05,0.1,0.25,0.5, 1.0,2.5,5.0,and l0 mgflitre for its effectson emb'ryosof theAmericanoyster(Crassostrea virginica) and their larvae.Fertilizedeggs were studiedafter 48 h, and survival andgrowth of veligerlarvaewerestudicdin 2-dayold larvaeand in Iarvaekcpt f 10.0mg/litre(Davis& Hidu, 1969).

105

Etfects on organlsms in the envlronment

In the mysid shrimp Mysidopsis bahia, expsel,for the complete life cycle, acutelethality (over 96 h) wasobservedwith endrin at l2O ngflive; increasedoxygen consumption was measurablewithin 24 h of exposure. The lowest-observed-effectlevel for chronic lethality was60 ngllitre; sublethal effects on growth (reduced by day4 of exposure) and oxygen consumption (increasedby day 10 of exposure) were observed before death(over20days).Reducedreproductivecapacity (assessedasproduction of young) was observed at 30 ng/line over 20 days-the time to full maturity (McKenney, 1986). Behaviouralchangeswereobservedin stoneflies(Pterorwrcysdorsata) within 4 days of exposureto 96.17oendrin ar 0.07 1tgllitreand in caddis flies(Brachycentntsamericanzs)at 0.15pgllitre. The 28-dayLCrowas < 0.03 pg/litre for caddisflies and0.07 pgAitrefor sroneflies(Anderson& DeFoe, 1980). 7.2.2

Fish

7.2.2.1

Acute toxicity Endrin is highly roxic for both freshwarerand marine fish. The availabledataare summarizedin Tables 16 and 17.

7.2.2.2

Short-term toxicity Channelcatfish(lctaluruspunctatus)wereexposedcontinuouslyto renewedsolutionsof endrin in water at 15 and 22 "C. Measuredendrin concentrationsof 0.25--0.30Fgllire were found to be acutely toxic to rhe fish within l0 daysor less.Noneof thefish survivedblood concenrrations exceeding0.28 mg/litre, a well-definedthresholdconcentrationof endrin in blood, and none died at lessthan 0.23 mglitre. The concentrationof endrin in the blood of fish exposedto lethal concentrationsin water for periodsinsufficient ro causedeathweremarkedlylower than that in fish that died from exposureto the samewater (Mount et al., 1966). The 28-day L C* for 96.l%oeldrin in bullheads (l ctalur us melas) was 0.10 ttg/litre (Anderson& DeFoe, 1980). In larval fathead mirmows (
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reductionin growth, andsurvivalwasreduced at |.21 pgllitre; with a72h exposure,growth was reduced at 0.63 pgnirre, and all fish died at l. 15 pgaine. conrinuousexposureto0.38 pg/itrefor30 dayssignificantly reducedgrowth, and all fish died at 0.73 ltg[itre (Jarvinenet al., lggg). Sheephead minnows (Cyprinodon variegatus) were exposed continuously for 23 weeks to endrin from the embryonic stage through hatching, until adulthood and spawning. The average exposure concenrrarions were0 (control),0.02i,0.077,0.12, 0.31, urd0.72 1tg/ litre, The resultant progeny were monitored to determineeffects on their survival, growth, and reproduction.Embryosexposedto 0.31 and 0.72 pgllitre hatchedearly; all fry exposedto O.'l2pglitre died by day 9 of exposure.At 0.31 lrg/itre, fry were initially stunred and some died. Survivors seemedturaffecteduntil maturity, when some females died duringspawning;fewereggswerefertile,andsurvivalof exposedprogeny was decreased.No significant effect was observedthroughoutthe life cycle at an exposweconcenrrarionof 0.12 pgllirre (Hansenetal.,1977). Endrin was resredin flagfish (,/oidanellafloridae) at0.21,0.29, and 0.39 pg/litrefor30 days.only thehighestconcentrariondecreased survival, and the two highest dose levels affected the mean number of eggs produced(Hermanurzet al., 1985). 7.2.2.3

Studies of resistance Populationsof mosquito fish (Gambusiaaffinis) developedhigh levelsof resistanceto endrin andothercyclodieneinsecticides . t"rult "r (male) of inadvertentexposureto agricultural sprays.Susceptiblefish showeda LCro of 8.3 mg/litre and resistantfish, 16l mg/titre. Genetic crossing studies show that endrin resistanceis inherited as a single, autosomal,intermediategene(Yarbroughet al., 19g6). and -resistantmosquitofish were exposedto ,. Pesticide-susceptible raC-endrin at 20 or 1000pgflitre, and liver and brain were assayedto determine any difference in distribution, uptake, and nerve binding pattems@abacher& Chambers,1976).The resulrsare summarizedin Table 18' Endrin was takenup fasterby b'rainand liver from susceptible fishthanresistantfish. Inresistantfish,atleastatahighlethalconcentration (1000 trg/litre), endrin enteredthe brain slowly and accumulatedin the Iiver, suggesringa more efficient blood-brain barrier in resistantthan in susceptiblefish. Extraction srudiesprovided someevidencethat endrin 114

EHC 130:Endrln

binds more readily to nonessentialprotein complexesin thenervoustissue of resistantfish, consequentlydecreasingthe amount ofrendrin available to produce a toxic effect. Table18.Meanquantitiesof endrin(in mg/kgtissue)in brainand liverof andresistantmosquitofish susceptible At 20 pg/litre

At 1000pg/litre

Brain Liver Brainliver

Brain

16.98 33.28 0.51

149.31 160.27 0.93

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8.83 16.84 0.52

57.52 353.42 0.16

Susceptible: resistant

1.90 1.90

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1.00

2.60

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0.45

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Cell membrane fractions from resistant mosquito fish bound more endrin thanthosefrom susceptiblefish, andmitochondria from the liver of the resistantgenotypebound less endrin than thosefrom susceptiblefish. Differences in endrin uptake,retention of endrin by brain cell membranes, a blood-brainbarrier,anda structuraldifferenceinmyelinmayaccountfor of somemosquitofish toendrin (Wells &Yarbrough' l9?2)' theresistance In resistant and non-resistantPopulations of golden shiner (No temigonuscryso leucas),bluegill srurfish (Lepomis nwcrochir us),and greensrurfish(Lepomiscyanellas),themediantoleratedlimit at 36 h was 3.0, 1.5,md 3.4 pg/itrc for non-resistantstrainsand3 I 0, 3fi), and I 60 pgl litre for resistantfish, respectively(Fergusonet al., 1964)'

.2.2.4 lnteraction with other chemicals The joint action of endrin with malathion on mortality in flagfish (Jordanetlafloridac) corsistedof enhancedeffects at concentrationsthat weretestedindividually. Theeffectsof hadno effectwhenthe substances thcmixtureon growthfolloweda simpleadditivemodel.Malathiondid not modify thceffectof cndrinon eggproduction.In a separatetest,malathion did not affccttheuptakeor eliminationof endrin(Hermanutzet al', 1985). ln a studyof theinteractionbetweentheaccumulatidnandelimination of taC-cntlrinandtaC-DDTin mosquitofi sh(Garnbusia affi nis),fi sh about

115

Etfects on organisms in the environment

4 cm long were exposedto a nominar concentrationof 3.94 nM endrin or DDT, or to a mixture of the compounds.prior exposureto DDT for 4 h generally reduced the accumulationof endrin in serun1gall-bladder, and whole bodies, whereasprior exposureto endrin for 4 h had little effect on DDT accumulation.Simultaneousexposureto DDT and endrin reduced the accumulationof DDT in the gall-bladder over the 4 h of exposureand in the wholebodiesduring thefirst hours,andit reducedthe acCumulation of endrin in gall-bladderand in the whole body. Endrin revels in fish exposedsubsequentlyonly to DDT or DDE were significanrlyhigher in gall-bladder andwerereducedin the whole body over 4 h. The interactiors observed may be the result of competition for and/or displacement of insecticidesfrom mutual binding sites(Denisoner al., lggj). Ia a study of the relative binding and competition berween organochlorinepesticidesfor serumbinding sites,incubationwith serum from mosquitofish led to theii associationprimarilywith thevitellogeninl lipoprotein and albumin fractions. preincubationof serum with endrin significantlyreducedthequantityof 3H-DDTrhatwasboturdsubsequently, wtrile the reversewas not observed.Although the reasonfor the apparenr quantitativedecreasein binding is unknown,this phenomenonmay be of toxicological importance(Denison& yarb,rough,l9S5). 7.2.2.5

Special studies (Cyprinus carpio) exposedto endrin at the LCro _^ -Fingerlings of carp (0.0065mgAg) for 24hshowed clearinhibirion of cr-amylaseactivity i'ri the liver @aua & Ghose,1985). A group of A0 rainbow trout (Salmogairdneri) were exposedto endrin at 0.12-0.15 pgllirre for 30 days; one unrrearedand one solvenr control group were used. On day 30, l0 fish from each group were sacrificed and examined for the ability of peritoneal macrophagesto phagocytizelatex beads.The remainingfish were immunizedwrttr-tOpg of Yersiniarrckeri o-antigenandexposureto endrincontinued.Assaysioi migrationinhibition facror,plaqueforming cells,andserumagglutination titre were performed2, 14,and 30 daysafter inoculation,and ,"rum *u, collectedfrom all fish to determinethecortisolconcentration.Exposureto endrin hadno effect on thephagocyticability ofperitonealmacrophages, but theresponses in thethreeassaysweresignificantly reducedincomparison with the control values.Serumcortisol concentrationswere significantly elevatedin the endrin-treatedfish. The study did not, however,elucidate 116

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the mechanismof immune suppression,other than showing that a stress responsehad occurred (Benneu & Wolke, 1987a).In another study, tlerefore, control fish were fed cortisol at 20 mgkg and metyrapone at 35 mg/kg body weight, and endrin-exposedfish receivedmeryraponeat 35 mgkg body weight per day in the diet. The fish tharreceivedcorrisol had significantly reducedresponsesin all threeassays;but in the endrinexposedfish that receivedmetyrapone,the migration inhibition factor responsewas completelyrestored,the plaqueforming cell responsewas restoredto 6lvo, and serum agglutinationtitres to 692o.Theseresults indicatethat elevatedsenrmcortisol concentrationplays a centralrole in repressingthe immuneresponse(Bennett& Wotke, 1982b). The concentrationsof serum glucose,liver and muscle glycogen, cortisol, protein, and cholesterol were determinedin carp (Cyprinus carpio) exposed ro endrin at 2 tlg[itre for 6, A, and 72 h. Only the concentrationof cortisol in serumwasclearlydecreased (Cluth & Hanke, 1985). 7.2.3

Amphibla The acutetoxicity of endrinto amphibiarsis summarizedin Table 19.

7.3

Terrestrialorganlsms The acuteoral toxicity of endrin for terrestrialanimalsis high. The availableLDrovaluesare summarizedin Table 20.

7.3.1

Honey bees The 48-h LDroof endrin in workerhoneybees(Apis mcllifera) using a dustingtechniquewas 2.O2+tghee(Arkins et al., 19?3).The LDro for beesafter contactwas 0.65 tlg/bee,and the acuteoral LDro was 0.46 pgl bee(Oomen,1986).

118

EHC 130:Endrln

Table20.AcuteoralLDrosof endrinfor terrestrialspecies Reference LD* Species (mflkg bodyweight) Blrds Mdlard (Anas platyhynchos)

5.6(2.7-11.7)

Pioeon (dolumbia livial

2.0-5.0

Pheasant (Phasianus colchicus)

1 . 8( 1 . 1 - 2 . 8 )

Sharo-tailedsrouse (Pedoecetei phasia nellusl

1.06(0.552-2.04)

Califomia quail

.65) 1.19(0.857-1

Redrvinqedblackbird (Agelaiis phoeniceus)

2.37

Starlinq (Sturnis vulgaris\

2.37J.16

Quail (Coturnix coturnixl

4.22

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Birds

.3.2.1 Acute toxicity TheLDrosof endrinfor somebird speciesaregivenin Table20. .3.2.2 Short-termtoxicity quailwerefedendrinatdietarylevelsof 0, Groupsof40 one-day-old affected in all 0.5,1,5,10,20,or 50mg/kgof diet.Survivalwasadversely testgroups,andtherewereno survivorsbeyondtwo weeksamongbirds was abnormallylow, and fed l0 mg&g or more.Food consumption symptosrs involved lack of muscular coordination, tremors, and occasional

119

Eftectson organismsln theenvlronment

convulsivemovements.Similar resultswere obtainedin 40 one_day_old pheasantsfed endrin at dietary levels of 5 or 20 mg/kg, none of which survivedbeyond8 days@ewiu, 1965). Groupsof 20seven-day-old chickswereunaffectedby dietscontaining endrinat 0, L5, or 3 mg/kg. Whentheconcentrationwasincreasedto 6 or 12mgkg, the birds becamehighly excitableandfailed ro gain weight in comparisonwith controls.The survivalratesover a l2-week periodwere 85 and5%, respectively,comparedwith 1007oin thecontrols(Sherman& Rosenberg,1954). The LCro values for 2-3-week-old hobwhite quail (Colinus virginianus),Japanesequall (Coturnix coturnit japonica), ring-necked pheasants(Phasianuscolchicus),andmallards(Anasplatyrhyrchos) (g_ 13 birds per group)fed endrin in their diet for 5 daysfollowed by 3 days of untreateddier.,were l4-22mg\g diet (Hill et al., 1975; Hill & Camardese, 1986). 7.3.2.3 Sludies of reproduction In a study of reproductionin pheasants,a diet containingendrin at l0 mg/kg reducedeggproductionandchick survival;dietscontainingup to 2mgkg did not affect egg production,fertility, hatchability,or chick survival(Dewiu, 1965). Groups of five female and two male mallard ducks (Anas platyrhyncho.r)were administereddiers containingendrin at 0, 0.5, or 3.0mg/kg for a l2-week ovipositionperiod.Egg productionwas nor affected.The eggswere incubated,and infertile eggs,embryo survival, and hatchabilitywere measured.Fertility and hatchabilitywere not aff'ectcd,althougha 9.6Vodrop in embryo survival was observedin the groupthathadreceivedthe highestdose.Endrinresiduesin body fat were 3.4mgkC of tissuein the group rharreceived0.5 mg/kg and 19.3mg/kg in the group tharreceived3.0 mg/kg. The concenrrationswere higher in females than in males. The endrin residue levels in eggs were none detectedin the conrols, 0.43 mg/kg in thc groupfed 0.5 mg/kg, arf,2.75 mg/kg in the groupfed 3.0 mgAg (Roylanceet al., 1985). Threegroupsof 27 pairsof mallardswerefed endrinat 0, l, or 3 mg/ kg of dry duck mash from Decemberto the summerto investigatethe influenceon reproductionand health.Birds fed I mg/kg reproducedas 120

EHC 130:Endrin

well as the controls; they had significantly greater successin hatching fertile eggs than did those fed 0 or 3 mg/kg and their clutches hatched earlier (not significantly) than those of birds fed 3 mgkg. Endrin accumulatedin eggsto ameanlevel of 1.I mg/kg (wet weight) in thegroup fed I mgltg and2.9 mglkg in the groupfed 3 mg/kg. The concentrationof endrin in adiposetissue was four to seventimes higher than that in eggs (Spannet al., 1986).

9.2.4 lnteractionwith otherchemicals The toxicity of combinatiors of cNordane and endrin was studied in l4-week-oldmaleandfemalebobwhitequail.Eight birdsreceivedI 0 mg/ kg chlordanein the diet for l0 weeks;20 quail were treatedwith l0 mgl kg chlordanefor l0 weeks followed immediately by l0 mg/kg endrin (987d in ttrediet; a fourth group of 20 birds receivedonly 10 mg/kg endrin in the diet. The pesticideswere dissolvedin propyleneglycol. After 9l0 days on a control diet, survivors were sacrificed and their brains dissected.No deaths occurred among the birds fed the control diet or l0mg/kg chlordane.With endrin alone, 15 birds died, and with the combination14birds died.ln birds thatreceivedendrinalone,theresidue levels in thebrain were 0.34-1.84mg/kg in those that died and 0.28O.62mg/r;g in the survivors. ln the birds fed chlordane and endrin, the residuelevels wereO.IT-1.25mg/kg in birds thatdied and0.144.56 mg/ kg in survivors.Birds treatedwith thecombinationhadconsiderablymore chlordaneresiduesin their brains than did thosefed chlordanealone. The maln conclusionof this study was that the additive toxicity of closely related chemicalsshould be taken into accountin diagnosingcauseof death(Ludke, 1976).

7.2.5 Specialstudies The influence of endrin at 5 and l0 mg/kg of feed on the activity of various enzymesin the serum of juvenile cockerelswas studied. The greatestincreasesin activity were measuredfor glutamateoxalacetate transaminase, cholinesterase, andalkalinephosphatase. Smallerincreases were observed for creatine kinase, glutamate dehydrogenase,c,hydroxybutyratedehydrogenase, andphosphohexose isomerase(Hom et al., 1987).

121

Effects on organisms in the environment

7.3.2.6 Behaviouralstudies The effect of a sub-lethal doseof endrin (2 mgft;g diet) on avoidance responseswas studied in eight pens of 25 seven-day-oldCotumix quail chicks for 14 days. The stimulus usedto elicit avoidancewas a moving silhouette,andtheresponsewasmeasureddaily. Group avoidanceresponse was significantly suppressedby exposure to endrin, but the behaviour retumed to normal after2 dayson untreateddiet (Kreit zer&Heinz, 1974) . Adult male bobwhite quall (Colinus virginianus) were fed a diet containingendrinat 0.1 or 1.0mg/kg for 138days(beginningar 3 daysof age),andthentheir performancein five non-spatialdiscrimination reversal taskswasstudied.Treatedbirdsmade36-1397omoreefiorsthanconffols. and birds fed the lower dose made significantly more errors than those given the higher doseafter reversal3 or 4 in thefirst three tests.The effects of endrin were reversed after 50 days on untreated feed. The principal effect of endrin was to impair the birds' ability to solve a novel problem. The mean levels of endrin residues in the brain were 0.075 mg/kg wet weightin thosegiventhelower doseand0.35 mg&g for thoseon rhehigher dose(Kreitzer, 1980). 7.3.3

Mammals

7.3.3.1 Toxicity The LCro values for short-tailedmale and female shrews(Btarina brevicauda)aged180,105-150,and30-75 dayswereS'l-I74 mg/kg dier for 14 days(Blus, 1978). Five groups each of 13-14 pairs of Saskatchewandeer mice (Peromyscusmanbulatus) of various ageswere fed endrin at 0, l, 2, 4, or 7 mgkg of diet for intermittent periods, betweenwhich the animals were either fed a normal diet or were subjectedto 48-h starvation. The animals were sacrificed by exposing them to cold stressat -16 oC and the time of deathrecorded.No influence wasfound on litter production, frequency, or meanlitter size.At thehigherlevelsof feeding,postnatalmortality before weaningwasincreased.Significantparentalmortality occurredat4 mg&g andhigher and appearedto be dose-dependent (Morris, 1968). (Remark: Since the animals in this study were capturedin the field and the periods of feeding altematedwith shortperiodsof starvationin an effort to simulate possibleconditionsin the field, this srudyis of only limited value). 122

EHC 130:Endrln

I

The effects of endrin at 8.0 azlacre (0'56 kglha) on unenclosedfield populations of meadow voles (Microtus penrcylvanicas) and deer mice (Peromyscusmaniculatw) were investigatedin 1966{8. Animals were trapped live on adacent 7-acre (2.8 ha) plots each summer at regular intervals, before and after a single application of endrin. Immediate, significant declinesin the numberof voles were seenon the experimental plot, but no long-termtoxicologicaleffectswereobserved.The population rapidly recovered,exceedingthe initial ard control numbersin all three years.The experimentalvole populationthus appearsto haveresponded to endrin as it would to a local depopulationby trapping.The mouse populationdecreasedsignificantly after the applicationof endrin in 1966 anddid not recover,andthe highly unstable,transitorypopulationon the experimentalplot indicated a long-term toxicological effect (Morris, 1970,1972).

3.3.2 Studies of resistane ; I

taC-Endrinin com oil wasadministeredto a resistantanda susceptible strainof pinemice (M icro tusp itymusp inctorurn)orally at 0.5 mg/lcgbody weight,as follows: days l-5, unlabelledendrin; days6-14,'aC-endrin; andday 15unlabelledendrin.Totalrecoveryof raCin bothfaecesandurine wwT6Vofor theresistantstrainard53Voforthesusceptiblestrain.The two strains produced the same major faecal and urine metabolite,but the resistantstrainproducedabouttwice thequantityasthesusceptiblestrain. The quantitative differences in the excretion of more polar endrin metabolitesmay indicatemetabolicdifferencesbetweenthe two strains and, consequently,the greatertoleranceof the resistantstrain to toxic effects(Peuellaet al., 1975).The major metabolitewasidentifiedascnJiI 2-hydroxyendrin;oneof theothermorepolarmetabolites,found in minor quantities,was suggestedto be a tertiary alcoholof endrin(Petrellaet al., 1977). The degree of toxicity of endrin in first-generationprogeny of susceptibleandresistantstrainsanda crossof the two strainsof pinemice was studied by Webb et al. (1973). The LDro for offspring of susceptiblex susceptibleparentagewas 5.0 mgikg body weight; that for resistantx resistant,2 l. l mg&g; andthatfor suscep tible x resistant,8.6 mgl kg. Theseresultsoffer preliminarysupportfor a geneticmechanismwith intermediatedominance.An increasein resistanceagainstthetoxic effects of endrin was demonstratedin wild pine mice trappedin orchardswhere endrin had been usedfor years.The oral LD, in susceptiblemice was

12s

Ettectson organismsin theenvlronment

about3 mglkg bodyweightandthatin resistantmice,anaverageof 36 mg/ kg body weight. The increasedresisranceappearedto be heritable in the first generation(Webb & Horsfall, 1967;Webb et al., 1973).Although differences in the rate of metabolism of endrin could be demonsuated, especiallyin the activity of mixed-functionoxidase,thesedid not appear to be sufficiently large to explain the resistance(Hartgroveet al., 197?).

7.4

Effectsin the field Episodeshavebeenreportedin which endrinwasconcludedto be the causeof deathin fish and birds. Numerousfish kills were reportedfrom the sugar-canegrowing areasof Louisiana in 1960-63. No association with variablessuchas dissolvedoxygen,pH, or temperaturewas found, but following the developmenrof sensitiveanalyticaltechniquesit was concludedthat the fish had been killed by endrin (Mount & t\tnicki, 1966).Surfacerunofffromfieldswasreportedtobe themain sourceofthe endrinthat contaminatedtherivers (Laueret al., 1966),althougheffluent from an insecticideplant may have contributedsince the fish contained two chemicalsinvolvedin endrinmanufacture(Mounr & Putnicki, 1966). Levels of endrin found in studiesof fish in the wild are siven in section 5.1.4.2. Declines in the population of brown pelicans in l-ouisiana were attributedto endrin,althoughat leastsix other organochlorinepesticides andpolychlorinatedbiphenylswerefoundin rheanimals(Blus et al., 1975; King et al., 1977).The eggsof b'rownpelicans(PeIecanusoccidental i s) in Texas,USA, wereexaminedforendrinresiduesin19?5*81.Thecompound wasrecoveredonly in 1975,in 15of 18 eggs,ar levelsof 0. l-O.3 mg/kg. In the sameyear, rhehighesrlevels ofendrin were found in pelicaneggs in Louisiana,and this maximum coincidedwith the dearhsof large numbersof brown and white pelicans(P. erhyrorhyncos)(King et al., 1985). Endrin was found in one of ten eggsof the Americanwhite pelican (Pelecanuserythrorhynchos)collecredin 1969,ar0.20 mglkg, andin rwo of 35 samplescollectedin 1981,atup to 0.18mg/kgwerweight.Brainsof pelicarsfounddeadin theperiod 1975-81hadlevelsup to 0.80 mg/kg.No endrinwasfoundineggsof thewesremgrebe(Aechmophorusaccidentalis) collectedin 1981.It was concludedthat endrinhad causedsomeof the deathsamongpelicansin California(Boellstorffer al., 1985).

124

EHC130:Endrln

The deathof sandwichtems in The Netherlandswas attributedto the dischargeof a combinationof endrinandrelatedpesticidesinto an estuary from a manufacturingplant (Koemanet al., 1967,1969;Koeman, 1971). On severaloccasionsin Victoria, Australia, large numbersof wild birds,in particularpigeons(Columba liv ia),sparrows(Passer dornesticus) andIndian lnynahs(Graculareligiosa),wereobservedto be paralysedor in convulsions(Reeceet al., 1985).The cropsandlivers containedendrin at levels of up to 1.2 mg/r.g. Fulvous whistling ducks(Dendrocygnabicolor), which nest in rice fields along the south-eastemcoast of Texas, USA, suffered a major declinein populationin the late 1960s,which was attributedto exposure to dieldrin or aldrin. Organochlorinepesticidesweredeterminedin 1983 of 15 adultducksimmediatelyafter their arrival in Texas in the carcasses from Mexico in the spring and before departurefrom Mexico in the auturrrr.Four of the duckswith high levels of dieldrin residuesalso had residuesof endrin;and four otherducks,collectcdin 1967 and 1969,had endrin residues.The geometricmean levels in the diffcrent years werc 0.03-0.08mgkgwct weight;in juvenilesin 19ffi-69,thegeometricmean levcl was0.l6 mg/kg (Flickingcret al., 1986). The cffects of endrin on wildlife were studiedin l98l-83 in fruit orchardsin Washington,USA. A singleapplicationof endrinafterharvest resultedin acuteand chronic toxicity to a variety of avian species;most deathsoccurredsoonafterthe application,but scvcralraptorsdied during the spring andsummcr.The brainsof 73 of 125birds containedendrin at <0.10--0.80mg/kg;detectablelevcls occurredmost irequentlyin the brainsof galliformsand falconiforms.The spccicsin which the greatest numbcrso[ dcathsat"tributedto endrin occurrcdinclude California quail (Callipepta california), chukars (Alectoris chukar), and common barn owls ('l'ytoalbd). Of thc 97 eggsanalysed,68 containeddetectableendrin residues:51had levclsof <0.10mg/kg, and the eggsof l0species containcd0.01-0.17mg/kgwetweight(range,nonedetected to 1.67).The authorsconcludcdthatcndrin wastoxic to wildlife, althoughtherewasno evidencethat it affectcdreproductivesuccessor populationlevel (Blus et al., 1989). Levelsfoundin birdsin the wild arealsogivenin section5.1.4.1.

125

Effects on organisms in fhe envlronment

7.5

Appraisalof effectson organismsin the environment Use of endrin in agriculture is the major sourceof its presencein the environment, but discharge of waste material from manufacturing and formulating plants has contributed to local contamination. World-wide monitoring surveys have shown that the concentrationsof endrin in the biospherearegenerallyverylow (Table l0),bothabsolutelyandrelatively: The levels of residues of other organochlorine compounds,particularly DDE and polychlorinated biphenyls, are generally 100 times or higher rhan those of endrin. Toxicologically significantlevelsof endrinresidueshavebeenfowrd locally in fish andother organisms,particularlyin casesin which endrin wasappliednearriversandlakesandwhenrunoffoccurredinto waterways. Residuesmay alsooccur whenendrinis usedas a seeddressingor in bait to control rodents. The most seriousadverseecologicaleffectsthat have beenreported were the fish kills (and associatedadverseeffects on brown pelican populations)in the MississippiRiver systemin the USA. Although the initial evidencefor ascribingtheseeffectstoendrinwascircumstantial,the results of analysesof dead fish were consideredto confirm a causal relationship;thereis little doubtthat endrinwas a contributoryfactor in at leastsomeof thesefish kills. The evidencethat endrin was rhe primary causeof the declinein the brown pelicanpopulationis lessconvincing, sincethe harmful effectson reproductivesuccesshavebeenattributedto DDE and other factors(Blus et al., 1974, 1979). In summary,agriculnual applicationof endrin shouldbe such as to avoid or minimize contaminationof waterways,eitherby oversprayingor runoff or by leachingfrom dressedseedin rice-growing areas.The effects of the use of baits containing endrin for rodent control on non-target organismsshouldbe assessed in the light of local circumstances. Finally, effluents from manufacturing and formulating plants must be treated adequatelybeforebeing dischargedinro warerways.

126

8. EFFECTS ON EXPERIMENTAL ANIMALS AND VITRO "V The toxicology andrisk assessmentof endrin havebeenreviewed (US EPA, l987a,b;Anon., 1988a,b).

Acute toxicity of technical{rade endrin

l.t

Oral admlnlstration Endrin ishigtrly toxic whengivenby the oral route andismore acutely toxic to mammals than its stereoisomerdieldrin (WHO, 1989), with an acuteoralLDroof7.5-17.8 mg/kgbodyweight (Iable 21),comparedwith 50-60 mg/kg for dieldrin. There appearsto be a sex-dependentsensitivity to the acute effects of endrin, female animals being more sensitive than males. A species-dependentsensitivity has also beenreported, monkeys and catsbeing more susceptiblethan mice andrats. Signs of intoxication may include increasedinitability and tremor, followed by tonic-clonic convulsions,ataxia, dyspnoea,gasping, and cyanosis. Convulsions usually occur 3Od) min after an oral dose, and deathmay occur within 24 h after the administrationof a lethal dose(Speck & Maaske,1958).Animals thatsurvivepoisoningrecovercompletelywith no delayed or persistenteffect.

.2

Dermal administratlon The acutedermalLD*s for technicalendrinin variousanimalspecies aregiven in Table Z2.Endrin is highly toxic when apptiedasa solutionin hydrocarbonsolventsbut moderately toxic when applied asa dry powder. The signs of poisoning are similar to thoseseenafter oral administration.

.3

Pa renteral adm i nl stration The acuteLDrosfor technical-gradeen&in given by parenteralroutes of administration are shown inTable 23.

127

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Table 23. Parental LDrs for technical-grade endrin Species

Vehicle LD* (m9/k9 bodyweight)

Route

Intraperitoneal Com oil

5.6

Intravenous Dimethyl 2.3 sulfoxide Dog

l.e

Graves& Bradley (1e65) Walsh& Fink (1970,1972) et al. Hinshaw (1e66)

Ethanol

lntravenous

Reference

Toxieity of metabolites and lsomers

v.4.1Mammalian metabolites

i

In a comparativestudy, the acuteoral LD,os of endrin and three of its metaboliteswere determinedin ras (Table Z). When the brairs of some of the rats were analysedfor the presenceof endrin and its metabolites,the concentrationof l2-ketoendrin in malerats given endrin at 60 mg/kg body weight was found to be higher (mean, 0.3 mglkg) than that of endrin (0.07mglkg) 22h atter dosrng.In male rats intoxicated with syn-IZhydroxyendrin or l2-ketoendrin (at 16 mglkg body weight each), the concentrations of l2-ketoendrin in the brain 30 min after dosing were much higher (meanvalues,I .9 and 1.4 mgkg, respectively)than thosein thebrainsofrats givena similar butnon{oxic doseof antj- I 2-hydroxyendrin (mean,0.09mg/(d andkilled at the sametime. The sigrs of intoxication were similar to thoseof endrin (Bedfordet al., 1975b). 'Table 24.Acuteoraltoxicityof mammalian rnetabolites of endrinin rats Compound

OralLD* (mg/kgbodyweight) Female 95% Cl

95% Cl

Endrin a nti-12-Aydroxyendrin sy*1Z-Hydroxyendrin 12-Ketoendrin

5.6 2.4 1.2 1.1

3.0-7.9 2.0-3.0 0.6-1.7 0.7-1.5

5.3 5.5 2.8 0.8

3.6-7.4 4.2-7.2 0.8-4.0 0.5-1.2

€5% Cl. 95% confidenceinterval

131

Effects on experlmental animals and in vltro

Theseresults suggestthat l2-ketoendrin may be the acutetoxicant in rats. The production of l2-ketoendrin varies greatly from one mammalian speciesto another,however,andnonehasbeendetectedin birdsofvarious speeiesthar werekilled by endrin (Stickel et al., 1979). 8.1.4.2

Isomers As describedin section4.2, endrin is changedunderthe influenceof sunlight into delta-ketoendrin.The acuretoxicity of this isomer is given in Table 25. It is less toxic than endrin, and, like endrin, ir is more roxic ro female than to male rats. The sigru of intoxication aresimilar to those seen with endrin The acutetocixity of ttreendrin aldehydehasbeenreporredto be > 5@ mgTkgbody weight in male mice (Phillips et al., 1962). Table 25. Acute toxicity of delta-ketoendrin

LDso(mg/kg bodyweight)

Reference

Male rats Oral Female rats Oral

120-180 10-36

Soto& Deichmann(1967)

Male rats

62.1(53.3-72.2) Stanlord Research

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Route

Oral

Institute(1954)

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Intravenous

Malerats

Intraperitoneal 82

Stanford Research Institute(1953)

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Oral

23.6.(19.9-28.0)

Stanford Research Institute(1954)

Male mice

Intraperitoneal

16.7

Stanford Research Institute(1953)

132

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EHC 130:Endrln

1.5

Acutetoxlcity ol formulatedmaterlal

1.5.1 Oral and dermal administration Oral anddermalLDrovaluesfor formulated endrin in rats (Muir, 1970) arepresentedin Table 26.Dry formulationswere administeredorally as l-27o aqtte{)ns suspensionsand dermally in both dry form and asz-SVo aqueoussusperuions. In general,thetypeofformulationdid notsignificantly alter the acute oral toxicity of endrin. The dermal toxicity of tbe 507o wettablepowderwas similar to that of the 207oemulsifiableconcentrate; the27o field strengthdwt was the leasttoxic. in rats Table26.Oraland dermalLD*s for endrinlormulations Formulation

LDro (mgd(gbody weight)

Oral

Dermal

Formulation Active material 20% Emulsifiable concentrate 50o/oWettable powder

2hField streng$ dust

20

7.6

275

Formulation

Active material

4,N

52.20 (undiluted)10.90

3.80

10.90 21.80(dry) 14.40(aqueousl 7.2O

5.50

114.40 5720(dry) 1140(aqueous) 2230

FromMuir(1970)

Tenrabbits(bodyweight,2.44.1 kg) weretreatedwith anemulsifiable concentratecontaining19.47oendrinon clippedskin at a doseof 200 mg/ kg body weight,andthematerialwasallowedto remainin contactwith the skin for 24 h. Four of the l0 animalsdied within 48 h (Andersonet al., 1953).Two of 10 rabbits(body weight, 2.0-2.5 kg) neatedsimilarly with a25Vo dustconcentratedied within 48 h (Hine et al., 1954). 1.5.2

lnhalation Ten adult rats were exposedfor I h to a mist of of an emulsifiable concentratecontaining l9.4qo by weight of endrin in xylene, at a

133

Eflects on experlmental anlmels and ln vltro

concentrationof endrin slightly exceeding2000 mg/m3of air, and were observedfor48h. Theparticlesizeof themist andotherdetailsof exposure were not reported. Three of the animals died l-14 h afier exposure (Andersonet al., 1953). Groupsof l0 Long Evansratswereexposedfor I h to 25Voand3lVo endrin dust concentratesat a concentrationof 2000 mg./m3of air. Particle sizeandotherdetailsof exposurewerenot provided,Five ratsexposedto the 307oandthreeexposedto the25%odustdiedwithin43 h afrerexposure (Iline et al.,1954).

8.2

Short-termexposure

8.2.1

Oral administration

8 . 2 . 1 . 1 Mouse Feedingstudieswereconductedto estimatethemaximumtolerated dosesof endrinin B6C3FImice.Groupsof five malesandfive females weregivena normaldietor onecontainingendrinat 2.5-20mglkgfor 6 weeks,followed by observationfor another2 weeks.Threemalesand four femalesgiven l0 mg/kg died,but no mortality occurredat 5 mgl 5 mgftg of diet. Mean body weight gains were comparablewith thoseof controls.The maximum tolerated dosewas calculatedby exrrapolarionro be 5 mg/kg of diet (NCI, 1978, 1979).

8.2.1.2 Rat Groupsof threemale and two to threefemale Carworthrats, either 29 daysor 6 monthsold, receiveddaily dosesof endrinat l, 2, or 5 mgkg body weightinpeanutoilby gavage,on fivedaysperweekfor 6T-72 days. All ratsgiven I mg/kgsurvived;theincreasedmortility in rheorhergroups was dose-related:2/5 femalesat 2 mgkg and 313males ar 5 mgTkgday died. Pathological findings ar auro?sy included diffuse degenerarive changesin the liver, kidneys,andb'riin, while survivorsshowedno such changes.All treatedanimalslost weightanddevelopedhypersensitiviryto stimuli (Treonet al., 1955).

134

EHC 130:Endrin

Groupsof five male andfive femaleadultSprague-Dawleyrats were endrinat 0, 1,5, 25,50, or lfi) mg/ givendietscontainingtechnical-grade kg diet over a maximal period of 16 weeks and were observed for behaviour,weight gain,feedconsumption,mortality rate,and symptoms levels,determinedonce a week, were of toxicity. Alkaline phosphatase group,andthetotal averagefeed control in the endrin than in rats fed higher consumptionof treatedratswaslessthanthatof thecontrolgroup.All rats fed 10Omg/kgof diet diedduring thefirst two weeksof thestudy,andonly twofemaleratsfed 50 mg/kgof diet survivedtheexperiment.All malerats given 1 mg/kg and all femalerats given 1 and 5 mg/kg of dier survived. Malesappearedto be moresusceptiblethanfemalesto endrinin this study' The symptoms of intoxication were hypersensitivity to stimuli and convulsions: hypersensitivitywas noted in all rats, and convulsions occurredamongratsreceiving25,50,and100mglkg diet.Weightlosswas andsignificantin all ratstreatedwith endrin(Nelsonet al., dose-dependent 1956). To estimatethe maximum tolerateddosesof endrin in OsbomeMendel rats,groupsof five malesandfive femaleswere given diets with or without endrin for 6 weeks, followed by observation for another 2 weels. Endrinwasaddedto thedietin two-fold increasingconcentrations of 2.5-80 mg/kg.Mortality wasnotincreasedat l0 mg&g, andmeanbody At 20 mg/kgof diet,one wcightgainwasnodifferentfromthatincontrols. animal of cachsexdied. The maximum tolerateddosewascalculatedby to bc 15mg/kgdiet (NCI, 1978,1979). extrapolation

2.1.3 Rabbit

I ,

Four of five female rabbits givcn an oral dose of endrin at I mg/kg body weight on five days per week died following the administration of 2, 30, 35, and 50 doscs, respectively. Thc fifth rabbit survivcd 50 doses over a period of l0 weeks. Diffuse degencrative changcs wcrc obscrved in the liver and kidneys but not in the brain (Treon ct al., 1955).

2.1.4 Dog Dogs (mainly two per group) fed endrin at 5-50 mg/kg of diet died within 50 days.They regurgitatedtheir food, becamelethargic,salivated, andlaterrelusedto eat;theybecameemaciatedanddevelopedrespiratory distressand sigrs of stimulationof the central nervou.ssystem.Diffuse degenerativelesionsin the brain, heart,liver, andkidneys,togetherwith

135

Effects on experimental animals and ln vitro

pulmonary hyperaemiaand oedemawere observed.Three dogs fed diets containing 4mgkg of diet for 6months survived, but they showed reducedbody weight gain and a slight increasein liver:body weight ratio; no histopathologicalchangewas observed.Ar 3 mg/kg of diet or less, growth was normal (Treonet al., 1955). Beagles (one male and one female/group; control group, only one dog) were fed diets containing endrin at 0, l, or 3 mg/kg for 80 weeks.No sign of intoxication was observed,and the weight gain of treatedanimals was comparableto that of controls. The ratios of kidney andheart to body weight were increasedar 3 mg but nor ar I mg (about0.(X5 mgikg body weight). No histopathologicalchangewas found in the viscera(Treon et al., 1955). Groups of three male and three female pure-bred beagle dogs (4-6 monthsold) werefed endrinin thedier at 0,0.1,0.5, l, 2, or 4 mg/kg for two years.Additional groupsof four male andfour femaledogs were fed endrin at 0, 1, or 4 mg/kg of diet. Two malesandtwo femalesof each group werekilled after 6 and I 2 monthsof feeding;no other deathoccurred during the study. Convulsions were observedin threedogs at 4 mg and in one female at 2 mg; no other sign of intoxicationor illnesswas apparenr during thestudy.No adverseeffectwasnotedon growth,foodconsumption, haematology,orurinalysis,andno compound-related changewasfound in serumalkaline phosphatase,prorhrombin time, or any of the other clinical chetnicalparametersmeasuredat regular intervals. All organ weights, relative as well as absolute,were normal, except for occasional,slight increasesin liver weight in someof the femalesat 2 and4 mg in the diet. The only histopathologicalchange found was a slight ro moderate vacuolationof livercells in dogsfed 2 and4 mg in thediet.Norenal change was observedin any of the dogs(Jolley er al., 1969). 8.2.1.5

Domesticanimals Sheep and cattle fed diets containing endrin ar 2.5 or 5 mgkg for 112days showedno indicarion of harmful effects (details not given) (Radeleff,1956).Theconwlsions andmusculartremorsthatwereinduced in six I 0- I 8-month-oldmalebuffalo calvesadministereda 207oemulsion ofendrin led to a significantrise in lactic acid concentrarionin the blood of the animals,possiblydue to excessiveproductionof the acid insidethe fasciculatingmuscles(Vermaet al., 1970).

136

EHC 130: Endrin

,2.2

Inhalatlan 'Three mice, threerats, two guinea-pigs,two hamsters,four rabbits, and one cat were exposed to sublimed endrin vapour at an actual concentrationof 5.44 mg/m3for7 Wdayon5 days/weekforupto26weeks' Two rabbits died after 26 and 90 exposures,respectively, and one mouse died after 22 exposures.No convulsions were observed, and all other animals survived. Surviving rabbits showed a granulomatous type of pneumonitis; no histological charrge was found in the other surviving animals(Treon et a1.,1955).

.2.3

Dermal administratlon Three female rabbits with intact skin died after 19, 19, and 25 applications,respectively,of endrin as a dry powder at 150rn/kg body weight for 2hlday on 5 days/week.Applicationsof 75 mg/kg resultedin the death of one of threerabbits after 8 weeks; the other two survived for 13-14 weeks-the end of exposwe.Convulsions,tremors,and twitching of the facial muscleswere the main signs of intoxication. Two of five rabbits (dosenot specified) showedseverefatty degenerationof the liver (Treonet al., 1955).

.3

Skin irritation Dry powdered endrin was applied repeatedlyat a dose of 75 or 150mgTkgbody weight for 2Vday,5 days/weekfor up to 14 weekson intact or abradedskin of female rabbits (see section8'2.3). No skin irritation was observed.Single applicationsof endrin as dry powder at dosesup to 250 mg/kg body weightfor 24 h on rabbit skin causednogross or microscopicdamageto the skin of the animals(Treon et al., 1955).

l.+ I

1.4.1

Reproduction,embryotoxicity,andteratogenicity Reproduction

t.4.1.1 Mouse CFW mice(20malesand20females)werefeddietscontainingendrin (96Vo)at 0 and 5 mg/kg for 120 days, beginning 30 days before mating'

t37

Etfects on experimentalanlmals and ln vltro

Significantparentalmortality (32vo)andreduced litter sizewereobserved, butfertility, fecundity,andthenumberof littersproducedperpair werenot affected(Good & Ware, 1969). 8.4.1.2 Rat Forty male and 80 female Long-Evans rats were fed endrin in the diet at 0, 0.1, l, or 3 mg/kg over threegenerations,eachgenerationbreeding once.No difference in appearance,behaviour, body weight, or number or size of litters was seen.The weightsof the liver, kidneys, andbrain were normal,andno histopathologicalabnormalitywasseenin third-generation weanlings.The only significanreffect was increasedmortality of pups in rhe secondand third generarionsof rarsfed 3 mg/kg (Hine, 1965). Ten male and20 femaleLong-Evansrats were rreatedsimilarly, but eachgenerationbredtwice, weanling ratswerematedafter79 dayson the diets (when they were 100daysold). All pupsfrom the firsr lirrerswere discardedat weaning,and the parentrats were mated again.Randomly selectedpups from the secondlitters were maintainedon the diets and matedwhen 100daysold; this wasdonefor threegenerations. Thenumber of pupsin eachlirter was counredon the day of birth andon the fifth day; on the twenty-first day, the weanlingswere countedand weighed and either sacrificed or savedfor continuation.parent rats were weighed, sacrificed,and examinedgrossly when no longer needed.Ten male and l0 femaleF* weanlingseachfrom the controlsandthehighesrdose-level groupandfive malesandfive femalesfrom the0. I and I .0 mg groupswere autopsied.Body, liver, kidney, and brain weights were recorded,and sectionsof theseorgans and from heart, lung, spleen,and testis were studiedhistologically.Appearance,behaviour,body weight, numberand size of litters, organ weights, and histopathologicalappearanceof F* weanlingswere comparablewfth thosein control animals.No effect on reproductionwas observedin ratsfed diets containingendrin at 2 mgkg over rhreegenerarions(Hine, 1968). 8.4.2

Embryotoxlcityandteratogeniclty

8.4.2.1

Mouse Groupsof l0CD-l miceweregivena singleoraldoseofendrin(99V") at 2.5 mg/kgbody weight(statedro behalf theLDr) in cornoil by gavage on day 9 ofgestation; an untreatedand a vehiclecontrol group were also 138

EHC 130:Endrln

used.Fetuseswereexaminedonday18.No significanteffectwasobserved on intrauterine death or fetal weight, but the incidence of total anomalies was increasedover that in controls:2/1l7 fetuseshad cleft palates,three had open eye, and two had other anomalies.No data on matemal toxicity were reported (Ottolenghi etal., 1974). Theseresultscould not be repeatedby Kavlock et al. FemaleCD-l mice were given endrin (99Vo)at 0 (vehicle), 0.5, or 1.0 (groups of 40 mice), or 1.5or 2.0 mg/kg body weight (groupsof 20 mice) in com oil by gavageon days7-17 of gestation.The animalswerekilled on day 18. Maternal deathsoccurredin the 1.5 and2 mglkg groups,reducedmatemal weight gain wasobservedat andabove I mg/kg, andmatemal liver weight was increasedat 0.5 mgfkg and higher. Fetal weight and skeletal, and visceral maturity were adverselyaffected at dosesof I mglkg and above. No teratogeniceffect or embryonic lethality was observed,even at doses that causedmatemaldeath(Kavlock et al., 1981, 1987)' In a study of the effecs of acute alterationsin maternal health status upon fetal developmentin the mouse,groups of 2l or 40 pregnantCD-l at0 (vehicle), mice weregivena singleoral doseof technical-gradeendrin gestation. The animals day 8 of weight in com oil on 7 or 9 mg/kg body were killed on day 18 of gestation.Three of 2l animalsgiven 7 mg/kg (147o) and 19/40mice gievn 9 mgkg (47Vo)died. Matemal weight gain was decreasedin both test groups; the total number of implantation sites and number of viable litters were not affected, but fetal weight was reduced.Delays in ossification ofthe skeletonand an increasedincidence of supemumarylumbar ribs were observed.Although three fetusesfrom one litter in the 9 mg/kg group hadfusedribs, no significant increasein the incidenceof malformationswasfound. A statisticallysignificant,linear, inverserelationshipbetweenmatemal weight gain and the presenceof supemumaryribs in their offspring was found (Kavlock et al., 1985)'

(.2.2

Rat Five groups of 25 female CD rats were administeredendrin (977o)in methocelin oral dosesof 0,0.1, 0.5, or 2 mg/kg body weight per day on days6-15 of gestation,or vitamin A, used as a positive control. The animalswere killed on day 20. The largestdoseof endrin causedmatemal toxicity, as evidencedby weight loss and mortality (two animals).The fetusesshowedsome slight growth retardation(not significant) but no increasein intrauterinedeathrate.No effectattributableto endrinwasseen

139

Effectson experlmentalanimalsand in vitro

on the mean number of viable fetuses, post-implantationlosses, implantations,corporalutea,fetal sexratio,or fetal extemal,soft-tissue,or skeletalabnormalities.Bent ribs were observedin61522 fetusestreated with endrin,but not in relationto dose.An increasein delayedossification in slemebraeand skull of fetuseswas seen in the treated groups in comparisonwith theuntreatedcontrolgroup.Animalsgivenvitamin A had a significantlyincreased numberof post-implantation lossesandmalformed fetuses(Goldentahl,1978a). Groupsof 32, 15, 28,30, and 15femaleCD ratsweregiven oral doses of endrin(997o)in com oil ar 0, 0.075,0.15,0.30,or 0.45mg/kg body weight on days7-2O of gesrarion.Rarswere killed on day 21. Maternal weight gain wasreducedat doselevelsabove0. 15 mg/kg, bur no increase in maternalliver weight was found. Fetal mortality,weight,degreeof skeletalarrdvisceralmaturation,and incidencesof skeletaland visceral anomaliesshowedno dose-relared effecr(Kavlocket al., l98l). 8.4.2.3

Hamster Three groups of golden Syrian hamsters (7,24, and 8 animals/group) received a single oral dose of endrin (99Vo) in corn oil at 5 mgfkg body weight (stated ro be half the LD*) on day 7, 8, and 9 of gestation, respectively. Two control groups wereused, consisting of57 untreated and 41 vehicle controls. The animals were killed on day 14. The number of resorptions and ofdead fetuses was increased after treatment on days 7 or 8 and to a lesser extent in the vehicle controls. The live fetuses in all three treated groups showed significant growth retardation when compared with controls. The incidencc o[ anomalics was high only after rreatmcnt on day 8: congenital abnormalitieswerc secnin2\o/oof fetuses,withopen eye in22a/o,webbed footin l6%o,clefrpalare in5Vo, andfuscd ribs inSVo.The anomalies that appearcd to be increased significurtly but ro almost the same extent at all three srageswere fused ribs and cleft palate (ottolenghi er al., 1974). These results could not bc repeate
140

EHC 130: Endrln

Thenumberof malformationsin fetuseswasnot increased,but ossification of the stemeb'rae and certainribs was delayed(Goldentahl,1978b).

' , i i

Groups of 18-87 golden Syrian hamsters(LVG strain) were given endrin (987d asa solutionin com oil by gavageeither as a singledoseof 0.5, 1.5,5,7.5, or l0mglkg body weight on day 8 of pregnancyor as multiple daily dosesof 0.75, l. 5, 2.5, or 3.5 mglkg bodyweighton days514of pregnancy.All animalswerekilled on day 15.With singledoses,no effect was found on maternalsurvival,pregnancyrate, weight changeor liver:body weight ratio, The only sign of matemal toxicity was the occurrenceof transientconvulsions2 h afterdosingin onehamstergiven l0 mg, No compound-relateddifference was noted in the number of implantationsites,fetal deathrate, or fetal weight; indicatorsof skeletal matwity were not affected.A dose-relatedincreasein the incidenceof fused ribs was forurd in the groups given 7.5 and l0 mg/kg; increased incidences of meningo-encephaloceleswere observed at 5 mg/kg and above,with no dose-responserelatiorship. No other compound-related skeletalor visceral anomaly was noted. In the study of multiple doses, matemaltoxicity (reducedweight gain andincreasedmortality) andfetal toxicity (increasedmortality, reducedweight,reducedskeletal ossification, andan increasedpercentageofirregular supra-occipitalis)wereobserved at dosesof 1.5mg/kg and higher.No treatrnent-related matemalor fetal effect occurredat 0.75 mg/kg per day (Chemoff et al.,1979).

1.2.4 Perinatal behavioural development Ratsexposedperinatallyto endrinat0, 0.075,0. I 5, or 0.3 mg/kgbody weight from gestation day 7 through day 15 of lactation showed no mortality andnoinfluenceon survivalor growth.Pupsof mothersexposed to 0.15 or 0.3 mg were more active than those of mothers exposedto 0.075 mg or thosein the control group.No cleardifferencein ambulation wasnoted,andat90 daysof agetherewasno difference(Grayet al., 1981; Kavlock et al., 1987). Golden Syrian hamsters(LVG strain) given endrin (98Vo)ar 0 or 1.5mg/kg body weight per day by gastric intubation on days 5-14 of gestationhad a persistentincreasein locomotor activity. Offspring of treatedhamstersambulatedmore than the controls in the open field at 15 days, and long-term observationof activity in the figure-8 maze indicatedthat a significantincreasein this behaviourwas still presentat 125days of age.Other behaviourpattems,including sexual,rearing and

141

Effects on experlmental animals and in vitro

rururing, andwheel behaviour,wereunaffected.Damsrepeatedlyexposed to endrin at 0.75 and 1.5 mg/kg body weight were markedly hypoactive under the sametestingconditions in which thepups werehyperactive.The doseof l.5 mg/kg body weight killed more than half of the dams (Gray et al., 1981;Kavlock et al., 1987).

8.4.3

Appraisal ol reproductive effects Endrin had no reproductiveeffecrsin threegenerationsofrats at a level of 2 mg/kg of diet, equivalent to 0.1 mg/kg body weight. It had no teratogeniceffect in mice, rats, or hamstersafter oral exposureduring the period of organogenesis.The significance of the anomaliesobserved in mice and hamstersby Ottolenghi et al. (1974) is uncertain. Studiesin the samestrain of the samespeciesusing more rigorous protocols and larger numbersof animalscould not confirm their findings, The lowest-observed-adverse-effect level for maternaltoxicity was l.0mg/kg body weight in mice,0.3mg&g body weight in rars, and 1.5mg/kg body weight in hamsters.Embryotoxiciry was observedar dosesof I mg/kg body weight in mice and 1.5mg/kg body weight in hamsters.The overall no-observed-adverse-effectlevels in mice, rats, and hamsters were 0.5, 0.15, and O.7lmgkg body weight, respecrively (Table 27).

8.5

Mutagenicityand relatedend-points

8.5.1

Effects on microorganisms Endrin was not mutagenic in numerousstudies using Salmonella typhimurium(TA98, TA100, TA1535, TA1537, TAl538, TA1950, TA1978, SL4525,51,4700),Escherichiacoli (WP2 uvrA,WPZ uvr , Gal Rs,WP2,hcr,p3478,W3100),K-12 (pol A,*/po\), wp67, cM6l l, and CM57LBacillus subtilis{M45),Saccharomyces cerevisiae(D3, D7), and Serratiamarcescens (a21,a742),with or without metabolicactivationby rat or mouseliver 59 (Fahrig, 1974-Yan Dijck & van de Voorde, 1976; Ercegovich& Rashid,1977;Simmonet al., 1977;Nishimuraer al., 1982; Waters et al.,19821'Glan et al., 1983; Moriya et al., 1983; Rashid & Mumma,1986).

142

EHC 130:Endrin

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Effectson experlmentalanlmalsand ln vltro

No mutageniceffect was observedin S. typhirutrizrn strainsTA98, TAl00, TA1535,orTA1537,with andwithoutmetabolicactivarionwith 59 from livers of Aroclor 1254-inducedrats andhamstersin thepresence of five concentrationsof endrin (0-1 0 000 pg/plare)(7niger, 1987;Tniger et al., 1987).No mutageniceffect wasobservedin S. ryphimurianrstrains TA97, TA98, TA100, or TA102 with and without metabolic activarion with Aroclor 1254-induced rat liver microsomefractionin thepresenceof sevenconcentrationsof endrin(99.AVo), from I nglplateup to I mglplate (Mersch-Sundennann et al., 1988).

8.5.2

Point mutations in mammalian cells Endrinwasweaklymutagenicin 6-thioguanine-resistant mouseFM3A cells(Morita & Umeda,1984;abstractonly).

8.5.3

Domlnant lethal mutatlons Endrin did not show detectabledominant lethality when given as a single intraperitonealdose(0.76 or 3.8 mg/kg body weight) or daily oral doses(0.I or O.25mglkg body weight) for 5 days to sevenor nine male ICR/Ha Swissmice,respectively.This studyinvolved a sequenrialmaring procedure,in which onemalewashousedwith threefemalesfor oneweek, repeatedfor 8 weeks(Epsteinet al., 1972).

8.5.4

Chrom osomal and cytogenetic

effects

Endrin at l0'5 and 10'4M, but not at l06'produceda dose-related increasein the percentageof Ml metaphases and a dose-relateddecrease in thatof M3 metaphases at 48 h in treatedLAZ-fi)7 humanlympoid cells. This effectis closelyrelatedto thereducedrateofcellproliferationinduced by endrin(Sobtiet al., 1983). Intratesticularinjectionof 0.25 mg endrinin salineto threealbinorars doubledthe percentageof chromosomalchangesin comparisonwith that in the single control when rhe tesreswere studiedhistologically l0 days aftertheinjection.Changeswerescoredin 70-75 cells/animal@ikshith& Datta, 1973).The useof a singledosedoesnot aid interpretation,and the increasein chromosomalabnormalitiesmay be related to cytotoxicity rather than to a genetic effect. The relevanceof rhis type of study in mutagenicity testingis unknown.

144

EHC'130:Endrin

Chromosomalstudieswerecarriedoutonlymphocytesfromeight male workers exposedto endrin andfrom six unexposedworkers from the samework area.No increasein thefrequencyof chromosomalabnormalities was found, whethertakenindividually or collectively @ean, 1977)'

,

,5.5

chromosomalaberrationswere fourd in meiotic cells of barley and somariccells of barley and vicia faba grown from endrin-treatedseeds (Wuu & Grant, 1966' l967a,b). After treatmentof root tips with 0'l7o endrin(EC20solution)forl'5_2hatl0oC,thefunctionofthespindlewas destroyedand did not interferewith the spreadingof the chromosomes duringsquashpreparation.Thecentromericregionbecamedistinctand chromosomes.At higher concentrations visible in prophase-metaphase coirtraction,stickiness,and fragmentationof chromosomeswere seen (Bhowmik, 1978). Host-mediated effects In two studies,malecFl mice weregiven singleoral dosesof endrin in dimerhylsulfoxidear3.75or7.5 mgkgbody weight.control mice were dosedwith thesolvent,andpositivecontrolgroupsweregiven a singleoral at400 mg&g bodyweight. saccharonryces doseofethylmethanesulfonate weretheninjectedintraperitoneallyinto each cerevisiaeJDI suspensions of s. cerevisiaewereharvestedand analysed mouse,and the suspensions after 5 h. No increasein mitotic geneconversionwas detected(Brooks,

r976). t.5.6

Sister chromatid exchange

I

of 10'6-10{mollitre in dimethylsulfoxide Endrinarconccntrations failed to increasethe (rt" latterdosewas a cyrotoxicconccntration)

' 1 I

l.S.l

frequency of sisterchromatid exchangc significantly over the control value inratlivermicrosomal S9-activated and unactivatedincubationexperiments using human lymphoid cells of the LAZ4W cell line (Sobti et al'' 1983)'

Etfectsin Drosophilamelanogaster Endrinwasnot mutagcnicto Drosophilamelanogasterafterinjection at0.2 plitre of a0.001o/oaqueoussolurion,in theMuller-5 testfor recessive lcthal mutationson the X-chromosome(Benes& Sram, 1969).

145

Effectson experimentatanimatsand in vitro

8.5.8

Effeets on DNA Endrin at l0-3or 3 x l0-3mol/itre did not inducemutarionin theadult ratliverepithelialculture/hypoxanthineguaninephosphoribosyltransferase assay(Williams, 1979). DNA repair was not elicited in primary cultures of hepatocytesfrom cD- I mice,Fischer344rats,or Syrianhamstersexposedto endrinfor l g h together with tritium-labelled thymine deoxyribonucleotide for incorporation during repair syrthesis. DNA repair was measured autoradiographically. In rat andhamsterliver cell cultures,aconcentration of 10-3mol/itre andin mouseliver cell cultures,l0{ mol/itre endrinwas tested(Maslansky& Williams, l98l). Endrin did not induce unscheduledDNA synthesisin human hmg fibroblastcellswith or withoutmetabolicactivationby rat livermicrosomel (five concentrationswere tested,but they were not given in the paper) (Waterser al., 1982). Endrin at eight concentrationsranging from 0.5 up to 1000nmol/ml did not induce'nscheduledDNA synthesisin primaryrat heparocyres or in a modified Ames test utilizing concentrationgradienf plates and l0 bacterialresrerstrains(eight s. typhimuriwn andtwo E. colli lprobst et al., 1981)

8.5.9

Appraisal of mutagenlcity and related end-points Garrettet al. (r986) evaruatedtheactivity of endrinin a seriesof tests: for reverse mutation (point/gene mutations in prokaryotes),forward mutation(point/genem,rarionsineukaryotes),differential loxicity (primary DNA damage in prokaryotes), enhanced mitotic recombinaiion, gene conversionandcrossing-over,urscheduledDNA synthesis(primary DNA damagein eukaryotes),sisterchromatidexchange,chromosomalbreakage, and dominant lethality (chromosomal effects). Endrin gave negative resultsin all thesetests. The vast majority of the data indicate that endrin is not genotoxic; , however, many of the studies would not reach current standards,or thev give insufficient datato allow an independentassessment.

146

EHC 130:Endrin

Long-termexposure Groups of 20 male and 20 female Carworth rats (28 days old) were givendieti containingendrinat0, 1,5, 25,50,or I 00 mg/kg' With I 00 mg' iwomales andonefemalesurvivedfor 2 years;with 50 mg, four malesbut no female swvived; and with 25 mg, 1l males and 5 femalessurvived. Survival at the lower concentrationswas comparableto that of the control group. Males appearedto be less susceptiblethan females to the toxic actionofendrin.Signsofintoxication,hypersersitivitytoextemalstimuli, andoccasionalconvulsionswereobservedonly at the two highestlevels. The weight gain of femalesfed l, 5, ot 25 mgkgof diet was equal to or greaterthan that of the controls after 40 weeks of feeding. In males fed 5 mg, growth retardation occurred during the first 20 weeks only, while males that received 25 mg showed significant reduction in body weight gain.The body weight gain of malesfed 1 mg was comparableto that of controls.The liver:bodyweightratioswereincreasedin malesfed 5 mg or more and in femalesfed diets with 25 mg or more' Histopathological examination of animals that died during exposure to the three higher dietary levels revealeddiffuse degenerationof the liver, kidneys, brain, andadrenalglands.Thefewsurvivorsat50and100mg showeddegenerative changesin the liver only. No histopathologicalchange was fotmd in surviving rats fed 1, 5, or 25 mgkg diet. There was no increasein the incidenceof neoplasiain the treatedgroupscomparedto the control group Clreonet al., 1955). This study indicates a no-effect level for endrin of I mg/kg of diet (about0.05 mg/kgbody weight)but is inadequatein severalrespects,e'g', andclinicalchemical. andhaematological survivalrate,detailsofpathology,

t, l"

data are not reported.

Carcinogenicity Oraladministration Mouse

of lfi) maleandfemaleC57B1/6Jmice, an inbredstrainwith l?11alowGroups incidenceoftumours,andC3D2F1/Jmice,ahybrid strainwith ahigh incidence of hepatomasin males and a high incidence of mammary tumoursin females,werefed endrin(997o)at dietaryconcentrationsof 0'3

147

Effeets on experlmmtal anlmals and In vltro

or 3 mg/kg from the age of five weeks throughout life. A conrrol group consistedof 2(x) mice of eachsex of each strain. Except for all groups o1 female animals of the C3D2FI/J strain, this part of the experiment was terminated at the 78th week becauseof the early occ'rr€nce of high numbers of mammary fibroadenomas in 7o-9ovo of control and treated mice. Survival, growtlr, food intake, and haematologywere not impaired. Mice of both strainsfed 3 mg/kg diet occasionally developedconvulsions in the early stagesoffeeding but recoveredand survived without signs of illness. They generally showedthe tlpical histological changesin the liver characteristicof high dosesof chlorinated hydrocarbon insecticides. No effectwasobservedon mice fed 0.3 mg/kg diet.The tumourincidenceand type of tumourswere not influenced by the feeding of endrin, andit had no influenceon the incidenceof fib,roadenomas in female C3D2FI/J mice ('tilitherupet al., 1970). Groups of 50 B6c3Fl mice of eachsex were given endrin in the diet for 80 weeks and were then observedfor a further l0 or I I weeks. The initial doses of endrin (97Eo) (z.s and 5 mglkg of diet) were poorly tolerated by males and were thereforereduced after 2s weeks to 1.2 and 2.5 mgkg dietfor males;bur femalesreceived 2.5 and5 mglkg diet during the whole experiment,The time-weightedaveragedoseswere 1.6 and 3.2 mgkgdier for malesand2.5 and5.0 mglkg diet for females,Matched controlsconsistedofgroups of l0 mice ofeach sex;pooledcontrols,used for statisticalevaluation,consistedof thematchedcontrolgroupscombined with 50 untreatedmaleand50 untreatedfemale micefromsimiiarbioassays of otherchemicals.All survivingmicewerekilled at90 or 9l weeks.Mean body weightwasnot affected,but thesurvivalofmalesat thehighdosewas lower thanthat of the controls.The survival of the low-dosemalescould notbeevaluateddueto accidentaladministrationofexcessivequantities of endrin to this group during week 66. The tumour (neoplasticlesionsin the liver) incidences in the high-dose males were higher than those of the pooledor matchedcontrols,but not significantlyso, andthe increasewas not consideredto be relatedto the administrationof endrin (Fredrickson, 1978;NCI,1978). 8.7.1.2 Rat A studyof groupsof 20 maleand20femalecarworth ratsadministered endrin ar 0, l, 5, 25, 50, ahO tOOmg/kg of dier was reviewed in section 8.6.1.1.Bearingin mind rhelimitationsof thisstudy,suchassmall group sizesand low survival at the high doses,no evidenceof an increase 148

EHC 130:Endrln

in the incidence of neoplasiawas found in any of the groups (Treon et al',

l9s5). eachsexwerefeddiets Groupsof 50 weanlingOsbome-Mendelratsof containingendrin (987d at2,6,or 12mgkg for 29 months.The control groups consistedof I fi) malesand 100 females.During the fi rst I 0 weeks of the study, only half the nominal dietary concentrationsof endrin were fed. Sigrs of toxicity occurredin a few animalsin all treatmentgroups, mainly in females,andincludedepisodesof tremorandclonic convulsions with 'outcries', the incidenceof thesesigns being dose-related.Weight gain wasunaffected,andthe survivalratesin control andtreatedrats were similar. The liver:body weight ratios were unaffected.A moderate(not dose-related)increasein the incidenceofcentrilobular cloudy swelling in the liver and of cloudy swelling of the renal tubular epithelium was observed. The lungs of the animals fed endrin exhibited a moderate increase in the incidence of congestion and focal haemorrhages.The tumour incidencein the treatmentgroups was comparablewith that in control rats,andnodifference in thetype of tumourswasfound (Deichmann et al., l970a,b;Deichmann& MacDonald,l97l). In a life+ime study,groupsof 24maleand?AfemaleOsbome-Mendel rats(22daysold) werefed dietscontainingendrinat 0,0.1, 1,5, 10, or 25 mgAg. Because507oof therats at?s mgkg died within thefirst week, this groupwasrestartedwith 32-day-oldrats.Survivaldid not appearto be affectedby treatrnent.The highestincidenceof malignant tumours in male andfemaleratsoccurredat 0.1 mglkg, but themalignancieswerenot doserelated. Treated male rats had a higher incidence of renal diseasethan controls,but this alsowasnot dose-related(detailsnot available)(Reuber, 1978). Groupsof 50Osbome-Mendelratsof eachsexwerefeden&in(97Vo) in their diet for 80 weeks and then observedfor 3l or 34 weeks.Males receiveddosesof 2.5 or 5 mglkg diet; in females,the initial dosesof 5 and 10 mg/kg of diet werepoorly toleratedand werereducedafter 9 weeksto 2.5 and 5 mg&g.The time-weightedaveragedoseswere 2.5 and5.0 mg/ kg for malesand3 and6 mglkg for females.Matchedcontrolsconsistedof groupsof 10 ratsofeachsex;pooledcontrolsusedfor statisticalevaluation consistedof thematchedcontrol groupscombinedwith 40 untreatedmale and4.0untreatedfemaleratsfrom similarbioassaysof otherchemicals.All surviving rats were killed at 100-114 weeks.Body weightsand survival were not affectedby administrationof endrin. A slight increasein the

149

Etfects on experimental anlmals and in vltro

incidencesof pituitaryandthyroidtumourswasobserved,butno consistent statistical significance or dose-responserelationship was found (Fredrickson,1978;NCI, 1978).

8.7.1.3 Tumourpromotion No significant increase in the development ofpreneoplastic changes (hyperplastic nodules) was observed in rat liver after partial hepatectomy and initiation with N-nitrosodimethylamine or N-2-fl uorenylaceramide in combination with the administrarionof endrin (Ito et al., 1980). In vitro, endrin at levels of above 2.5 pglml appeared to inhibit metabolic cooperation in the hypoxanthineguanine phosphoribosyl trarisferasesystem using wild-type 6-thioguanine-sensitiveV79 cells and variant 6-thioguanine-resistant cells. Such inhibition is reported to be an index ofpotential tumourpromoting activiry, although rhe testhasnotbeen validated (Kurata et al., 1982). Endrin stimulated protein kinase C acrivity in vitro only slightly, whereas a reprcsental.iveendogenous ligand of protein kinase C, syn-|,2didecanoylglycerol, srimulated protein kinase C ro a maximal velociry (Moser & Smarr, 1989).

8.7.2

Appraisalofcarcinogenlcity One of several studies in mice suggests an increased incidence of nonmalignanttumours in animalsof onc scx, butthis study was considered inadequate for assessingcarcinogenicity bccause an increascd number of tumours was secn in controls. A second study using a diflcrcnt mouse strain did not corroboratc the increase in tumour incidencc. Scveral longterm feeding studies in rats provide no evidence o[ a carcinogenic effect of endrin. Its tumour promoting activity was Lestedin vitro using protein kinase C stimulation and ATPase inhibition; the resulrsdo not suggestany overwhelming cffect in these systems. After a careful review of this evidence, and taking into consideration the fact that most of the data indicate that cndrin is not genotoxic, the Task Group concluded that rhe data are insufficient to indicate that endrin is a carcinogcnic hazard to humans.

150

EHC 130:Endrln

B

Specialstudies

9.1

Nervoussystem

studies 9.1.1 Electrophysiological The effectsof endrinon bioelectrogenesiswasstudiedin anaesthetized pigeons and squirrel monkeys with chronically implanted electrodes' Endrin was administeredintravenouslytopigeons at dosesof 0.5-4 mg/kg body weight. Doses of 24mgkg and higher caused seizure activity throughout the telencephalon;the lower dose levels causedactivity only in the ectostriatum,a telecephalicvisual projection area' At dosesof 0.5-2 mg/kgbodyweight,endrincausedaspecificincreasein theevocation of potentialsin the ectostriatumby stimulationof the nucleusrotundus,a diencephalicvisual projection area.Reticularformation functions were notorlittle affected.Administrationofendrinto squirrelmonkeysatdoses of 0.2-3 mgikg body weight on 5 days/weekintramuscularlyin com oil and saline emulsion induced characteristic changes in the electroencephalogram(EEG), culminating in electrographicseizures;thesewere transientanddisappearedwhenendrinadministrationwasstopped.Seizures reappearedunder stressconditions, however, severalmonths after endrin treatrnent(Revzin, 1966,1980). Groups of 20-60 Sprague-Dawleyrats with previously implanted weregivenendrinin peanutoil orally at 0.8, 1'7,or 3.5 mg/kg electrodes body weight per day on 5 days/weekfor 28 weeks. Dose-dependent mortality occurredduring the first weekand againat theendof the study. Most changesin the EEG were seenafter one week of exposure:these included severe bursts of multiple spikes accompanied by clonic conwlsions; other animals had runs of spikes without full-fledged convulsions. The convulsions were usually preceded by a period of hyperventilation After a further week of exposure,therats showednormal EEG naces.Someirregularslow-waveactivity was seenin animalsthat were moribund in the lastmonth of feeding(Speck& Maaske,1958). The convulsivepropertiesof endrinat l-2 mgkg body weight were paralyzedmale studiedby intravenousinjection in locally anaesthetized, structures of the placed subcortical were in the which electrodes cats,in brain. Endrin was dissolvedin ethanol(which itself stimulatesor inhibits the centralnervoussystem,dependingon dose).Changesin the EEG and evoked responseswere studied. Hypersynchrony,rhythmic bursts of

151

Effects on experlmental animals and in vitro

spikes and waves, and isolated spikes characteized the preictal state. Seizureswere always bilateral and symmetricaland of a generaltonicilonic type. Responsesin sensory and motor cortexes to sensory nerve stimulation were enhancedthree to five fold. The authorsconcluded that endrin is directly toxic to the mammalian nervous systern, is a potent rapidly actingconwlsant, anddoesnot requiremetabolicactivationto an activemetabolite(Joy, 1976). 8.8.1.2

Histopathological studies Male CDl Swissmice were administeredendrin or sesameoil daily by intraperitonealinjection in gradually increasingdosesof l 5-4.0 mglkg for 4-2Odays.Electron microscopicexaminationof sciatic nerve tissue revealedno morphologicalchangein myelinatednervefibres,myelin, or associatedSchwanncells,but morphologicalalterationswereobservedin unmyelinatednerve fibres and associatedSchwarurcells: axons were swollen,microtubulesandneurofilamentsshoweddissolution,axoplasm was replaced by large clear vesicles, vacuolization was present, and Schwanncells and adaxonalspacesalso containedvesicles(Walker & Phillips, 1987;abstractonly).

8.8.1.3

Neurotransmitter systems gamma-Aminobutyricacid systez?,r: The role of the inhibitory neurotransmitter of the central nervous system, gamma-aminobutyricacid (GABA),in theproductionof convulsionsis well established.Polychlorocycloalkaneinsecticidessuchasendrinhaveapotentexcitatoryactionon the nervous system,and the interactionbetween GABA function and endrin has been studied. Endrin srrongly inhibited GABA-dependent 3€l uptake by mouse brain vesicles, with an ICro (the concentration required to cause 507o inhibition) of 2.8 pmoffiitre. Inhibition was confined to that portion of 5Cl uptake that is GABAdependent. The result demonstratesdisruption of GABA ionophorefunction in mammalianbrain, possibly providing the principal mechanismof toxiciry (Bloomquist & Soderlund,1985).In a comparison of the inhibitory potential of several polychlorocycloalkane insecticideson GABA-dependent36Cluptake,the most potent inhibiror was l2-ketoendrin, followed by isobenzan,endrin, and then dieldrin, heptachlorepoxide, aldrin, heptaclrlorand lindane. This order closely parallelstheir acuteroxiciries(Bloomquistet al., 1986). 152

EHC 130:Endrln

The effect of thesechemicalswas alsostudiedin the tert butylcyclophosphorothioate(TBPS) system, which has been shown to bind convulsantswith varying affinities. The IC* for endrin on 3sS-TBPS binding wasO,22pmofiitre and thatfor l2-ketoendrin,0.036pmol/itre. Thesewere the most potentinhibitors of TBPS binding, and therewas a significant linear correlation between 36Clflux and TBPS binding (Bloomquistet al., 1986). In vitro, endrininhibited3sS-TBPS bindingin tissuefrom male SwissWebstermice with an ICroof 18 nmolfiitre (range,4-90).In vdvo,doses representing25,50, and lOMo of the LDro (8 mgftg intraperitoneally) inhibited 35S-TBPSbinding with ICrs of 77 + 7 nmollitre (LDro) and 39 + 6 nmol/lite(LD/2);noinhibition wasobsewedatLDJ4, indicating a possible no-observed-adverse-effect level. Brain P2 membranesof treatedmice containedendrin and l2-ketoendrin. The linding that the brains of treatedmice containedsufficient endrin or its biotrarsformed productsto achieveTBPS binding and that this was correlatedwith the severity of the poisoning indicatesrhat the acute toxicity of endrin to mammalsis regulatedby GABA (Cole & Casida,1986). GABA-induced36Clflux into membranemicrosacswasinhibitedby endrin at 3.9 + 0.2 nmol/mg protein, which also suggeststhat endrin inhibits the function of this receptor(Abalis et al., 1985,1986).The ICro for 5Cl influx was 0.1910.06 pM and that for 35S-TBPS binding was 0.ffi3 pM (Ganret al., 1987). Endrin inhibitedbothinsectandrat GABA receprorsin a dose-related, non-competitivemanner. It acts in a similar manner on the GABA receptorsin the centralnervoussystemof the two species.The blocking actionmay involvenon-competitivebindingto anallostericsiteassociated with the receptor'schloridechannel(Wafford er al., 1989a). Endrin potentiallyinhibits 35S-TBPS binding to rat brain membranes and alsopotentiatesthe protectiveeffecr of NaCl (200 mM) againstheat inactivationof 3H-flunitrazepambinding siteson the samemembranes. The time coursesof heatinactivationof thesebinding siresin thepresence of NaCl and saturatingconcentrationsof endrin revealedmonophasic componentsconstituting about 887o of the binding sites (Squires & Saederup, 1989).

t53

Effects on experlmental anlmals and in vltro

Endrin has also been shown to inhibit GABA-ergic function in Torpedofish (Matsumotoet al., 1988),chickenembryros(Seifert, 1988, 1989),themosquitofish (Gaarbusiaffinis) (Bonner& Yarbrough,1989), and the cockroach(Periplanetaamericana)(Wafford et al., 1989b). Othcr amine system"s: Studies on the effects of orally administered endrin on the content of biogenic amines in the brain of rats did not contribute to an understandingof the convulsive action of endrin Oliller & Fink, 1973;Hrdina et al., 1974). Cyclic AMP rnetabolism: Endrin did not affect adenylare cyclase activity or inhibit the activity levels of synaprosomalphosphodiesterase, enzymes involved in cyclic AMP metabolisrn, in rat brain. The authors interpreted their results to support their postulation that organochlorine insecticidesexerttheirneurotoxic actionbyselectiveinhibitionofATPases (Kodavantiet al., 1988). in synaptosomes ATPase systems: Inhibition of ratbrainNa*-K'ATPaseby chlorinated insecticidesvaried considerably:endrin and dieldrin were the least active in inhibiting both this enzyme and K*-srimulated para-nitrophenyl phosphatase ataconcentrationof2 x 10-5mollitre. Resultsofexperiments on ATPJ? exchange suggest that DDT is a powerful inhibitor of oxidative phosphorylatiorl which may lead to depletionof ATP. This effect was much lessevidentwith endrin (Folmar, 1978). Endrin causedaboutl5% inhibition of theacrivityof Na'-K-ATPase in rat brainsynaptosomes at thehighestconcentrationtested,120 pM, and oligomycin-sensitive Mg2*-ATPase in rat brain synaptosomeswas significantlyinhibitedin a concentration-dependent manner,to a maximal inhibition of 33Voatthehighesrdose.Endrin did not inhibit oligornycininsensitive Mgi*-ATPase, and it did not affect K*-stimulatd paranitrophenyl phosphatase from rat brain synaptosomes; this enzyme represents the dephosphorylation step of the overall reaction to the Na*-K'ATPase. Oligomycin-sensitiveMg2*-ATPasein beef heart mitochondriawassignificantlyinhibited.The resultsof this studysuggest that the ATPase systemin rat heart and central nervous systemis not selectivelyinhibited by endrin (Mehrorraet al., 1989). Sodium channel: It has been demonstratedusing voltage clamp techniquesin single cells that applicationof DDT prolongs the sodium crurent,which in tum decreases thedepolarizingafter-potentialto initiate 154

EHC 130:Endrin

repetitive afterdischargesin the cell. The repetitive after-discharges facilitate synaptic transmission and result in nervous system hyperexcitability,which atthefunctionallevel is registeredastremorsand eventuallyconvulsiorsanddeath(Narahasi,1987).Even if lessthan l7o of the sodium charurelsrespond in this manner to insecticides,it is sufficient to causetoxicity in the animal.Narahasi(1987)reportedthese effectswith pyrethroidsanda seriesof DDT analogues;suchstudieshave not beencarriedout with endrin.Lund & Narahasi(1983)suggestedthat becauseof the similarity in the symptomatologyof intoxication by the family of organochlorineinsecticides,the targetsiteof endrinmay alsobe the sodiumchannels.

?.r.n

Appraisalof effectson thenervoussystem The effect of endrin on the nervoussystemhas received attention becauseit hasthe well establishedability to causeconvulsionsfollowing acute exposures.Endrin causesconsiderablechangesin EEG activity, which are associatedwith convulsions,at intramusculardoses in experimentalanimalsas low as0.2mgkg body weight. The probableunderlying mechanismsare associatedwith a doserelated,non-competitiveinhibition of the GABA-ergic neurotransmitter system.This is an inhibitory system,and removal of its action leads to increasedexcitationin the nervoussystem. While inhibition of GABAergicfunctionis commonto anumberofpolychlorocycloalkane insecticides, endrin,andparticularlyits metabolitel2-ketoendrin,havebeenshownto be extremclypotentinhibitorsof this function.It appearsthereforethat the acutetoxicityof cndrinisdueto disruptiono[GABA-relatedmechanisms.

8.2

Cardiovascular

system

Studieshavebccnconductedon thephysiologicaleffectsofendrin on theperipheralvascularsystem,renal function,renalhaemodynamics, and thecardiovascularsystemof the dog (Emersonet al., 1963,1964;Reinset al., 1964;Emerson,1965;Emerson& Hinshaw, 1965;Reinset al., 1966; Hinshawet al., 1966;Reddyet al., 1967).After a lethaldoseof endrinwas administeredintravenously,mostof theeffectsappearedto be thedirector indirect result of the stimulatingaction of endrin on the centralnervous system.Bradycardia,hypertension,salivation,hyperexcitability,tonicclonic convulsions, increasedbody temperature,leukocytosis, haemoconcentration, and decreasedblood pH werc scen.Elevation of

155

Etfects on experimental anlmals and in vitro

cerebral venous pressure and cerebrospinal fluid pressure were also prominent features. Increasedlevels of adrenalineand noradrenaline in blood plasma cause increased venous retum and cardiac output and increased arterial blood pressurein the absenceof a rise in total peripheral resistance.Therewasa largeincreasein total limb vascularresistanceand also a decreasein renal blood flow due to arteriolar vasoconstriction.In studieson intact dogs and isolated heart-lung preparations,high dosesof endrin appearedto have a toxic action on the left ventricle of the heart, causing suddenleft heart failure. Aldrin, dieldrin, and endrin inhibited rat brain synaptosomaland heartsarcoplasmicreticulum in vitro in a concentration-dependentmarmer. Calmodulin-depletedCa2'pump activity was insensitivero the action of these compounds.Oral administration of endrin at 0.5-10 mglkg to rars similarly decreased Ca2*pumpactiviry,in additionto decreasingthelevels of calmodulinin both brain andheart,indicatingdisruptionof membrane Ca2*transportmechanisms.Exogenousadditionof calmodulin(l-20 pg) effectively reversedthe endrin-induced inhibition. Ca2npump activity in brain is more sensitiveto endrinthanthatin heart.The resultsindicatethat endrin may produceneurotoxiceffectsby alteringcalmodulin-regulated calcium-dependent eventsin neurons(Mehrotraet al., 1989). 9.8.3

Effects on liver enzymes It is well known that chlorinatedhydrocarboninsecticidessuch as DDT and dieldrin srimulare hepatic microsomal drug metabolism, stimulating the activity of enzymesfor the metabolism of drugs and endogenouscompoundssuchas hormones(Kinoshita& Kempf, 1970).

8.8.3.1 Mouse A single oral, convulsive dose of endrin (20 mg/kg body weight) dissolvedin cornoil wasadministeredto 9-week-oldmaleSwiss-Webster mice. Control groupsconsistedof a group of untreatedmice and a group receivingcom oil. When convulsionsbegan,blood serumwas examined for serum glutamic oxaloacetictransaminase,serum glutamic pyruvic transaminase, and serumlactic dehydrogenase. The activitiesof the three elzymes were significantly increasedabovethoseseenin the two control groups(Luckens& Phelps,1969).

156

EHC 130:Endrin

i I8.3,2

After intraperitoneal injection of a single dose of endrin at 6.25 mgl starting kg body weightto mice,hexobarbitalsleepingtime wasdecreased, 3 h after ttre idection and lasting for 3 days (Hart & Fouts, 1963). Stimulating effectson the hepaticmixed-functionoxidasesystemwere reportedinICRmice aftersingleoraldosesof4and l0 mglkg body weight (Hartgrove a al., 1977). Rat FeedingSprague-Dawleyrats on dietscontainingendrin at l, 5, ?5, 50, or lfi) mg/kg for 16 weeks causedhigh mortality in all groups, especiallyamongmalerats.Theserumalkalinephosphatase concentration was reportedto be dose-relatedlyincreasedin all groupsas comparedto control animals.The effect wasclearestin the groupsfed 25 mg/kg of diet or more (Nelsonet al., 1956). In strain FW 49 rats, a single oral dose of endrin at 5 mg/kg body weight had no effect on pentobarbitalsleepingtime; l0 mg/kg causeda significantreduction,which,however,disappeared after10 days(Schwabe & Wendling, 1967). Endrin causeda significantshorteningofthe durationoftheparalysis inducedby zoxazolaminein male Sprague-Dawleyrats aged5-6 weeks. Endrin was injected intraperitoneallyat 2 mgtkg body weight daily for 3 days, andzoxazolarrine was injected intraperitoneally on thefourth day (Truhaut et al.1974). Male rats given single oral dosesof 2.5, 3.15, or 5.0 mg/kg body weight showedno effect on the variousparameters(detailsnot given) of mixed-functionoxidaseactivity after 12 h, but the level of microsomal protein and electron transport componentsper gram of liver were significantly increasedafter 108 h, in a dose-dependentfashion. Thiopentoneand pentobarbitalsleepingtimes were reducedby a 24-h prior intraperitonealinjectionof endrinat 5 mgikg body weight (Kachole &Pawar,1977). A single oral doseof endrin at 10 mg/kg body weight to male albino rats increasedserum glutamic oxaloacetic transaminaseand glutamic p5mrvictransaminaseactivities, anddecreasedATPase,acid- and alkaline phosphatase, succinicdehydrogenase, andglucose-Gphosphataseactivities significantly 248h after trea&nent(Meena et al., 1978). After three

157

Effectson experimentalanlmalsand ln vltro

successivedaily oral dosesof endrin at 15 mg&g body weight ro SpragueDawley rats,significant increasesin total lipids and triglyceridesin liver andin serumglutamicpyruvic transaminase activity wereseen(Boradyet al., 1983). When two groups of six adult female rars were fed 0 or 28.7 ttgkg body weight, endrin accumulatedin the liver 647 mglkg),and its concentrationin blood increasedprogressivelyup to 28 days.Growth was depressed,The activitiesof the enzymesaspartateamino transferaseand alanine amino transferasewere slightly increased(Illahi ct al., 1986). Similar resultswere obtainedin a study in which rats were fcd 20 pg/kg body weight for 28 days (Illahi et al., 1987). 8.8.3.3

Guinea-pig Groupsof six femaleguinea-pigswereadministeredthreesuccessive intraperitonealinjections of endrin in sunflower oil at 3 mg/kg body weight, and liver and kidneys were studiedVl h after the last injecrion. Treatmentcauseda significantincreasein liver weighranda derreasein hepaticmicrosomalprotein content;renal weight and renal microsomal proteincontentwerenotaffected.Hepaticcytochromeb5 andcytochromec reductaseactivities were increased,while cytochromeP450 and total haem levels were significantly decreased.Related to lhe decreasein cytochrome P450 was a decreasein TPNH-linked aminopyrine-Ndemethylatiorqbut anincreasein DPNHlinked demethylationwasrelated to the increase in cytochrome b5 and cytochrome-c reductase. Lipid peroxidationwas increasedin both liver and kidneys(Pawar& Kachole, 1978).

8.8.3.4

ln-vitrostudies To testthe possibility that phenobarbitalinducescyrochromeP450p indirectlyby increasingtheavailabilityof endogenous glucocorticoids in theliver, phenobarbitalandphenobarbitallikeinducers,includingendrin, were addedto primary monolayerculturesof adult Sprague-Dawleyrat hepatocytesincubatedin serum-freemediumwithout glucocorticoids.Denovo synthesisofcytochromeP450p,measuredasincreasedincorporation of 3Hleucine into immunoprecipitableP45Opprorein, was increased. Endrin at a conce,lrtration of lxl0s M was half aspotentasphenobarbital at2x l&tM (Schuetzet al., 1986).

158

EHC 130:Endrln

I

Miscellaneous

studies

Endrin inhibited rabbit muscle lactate dehydrogenasein vitro (Hendrickson & Bowden, 1976). Exposure of isolated rat enterocytesto endrin reduced the efficiency of the neuropeptide vasoactive intestinal p€ptide after stimulation of cyclic AMP accumulation, as was observed with lindane(Carreroet al., 1989). Endrin at singleoral dosesof 25 mg/kg body weight d'r daily doses of I mg/kg body weight daily for 8 days inducedvarious shifis in the mobilization of theionsofbiologically importantmetalssuchasmagnesium, iron, zinc, andcopperfrom liver, kidneys,brain, heart,spleen,and blood (Colemanet al., I 968; Lawrenceet al., I 968).Ratsreceivingintaperitoneal injectionsof I mg/kg body weightin peanutoil over periodsup to 19 days showed no alteration in the concentrationsof serum proteins or senrm lipoproteins,separatedby paperelectrophoresis, or of albumin, alpha l, alpha 2, beta, or gamma globulins. Protein-bound sialic acid and methylpentosewere increasedonly temporarily; thelevet of Lroundhexose increasedwith time and that of boundhexosaminedecreased(Coleman, 1968). Rats receiving a single oral dose of 50 mglkg body weight, daily intraperitonealdosesof 2 mglkg body weight, or daily intramuscular injectionsof 0.5 or 2.0 mgAg body weight for 45 daysshowedincreased activity of a numberof the enzymesthat areinvolved in gluconeogenesis inlivercells andcellsof therenalcortex.A significantdecrease wasnoted in hepaticglycogen,an increasein blood glucoseand urea, as well as a significant rise in hepaticand renal pyruvatecarboxylase,phosphoenol pynrvate carboxykinase,fructose-1,6-diphosphatase, and glucose-6phosphatase. Furthermore,endogenouslevelsof cyclic AMP wereincreased (Kacewetal.,1973:Singhal& Kacew, 1976).

.5

Factors that influence toxlclty Nutrition Thenuritional stateof Wistarratswasfoundto altertheirsusceptibility to the acutetoxic actionof endrin.Threegroupsof approximatelyl(X) rats were fed a normal diet, a diet containingcaseinas the onty sourceof protein,or a low protein diet for 28 days,and the acutetoxicity ofendrin was determinedafter a single intragasrricadministration.The following

159

Eftectson experimentalanlmelsand in vitro

LD, values were calculated:27 mg, 17 mg, and 7 mgkg body weight, respectively(Boyd & Stefec,1969).

8.8.5.2 Potentiation The acute oral LDrs of equitoxic dosesof combinationsof 10 pesticides,includingendrin,werestudiedin Swissmice. No evidenceof potentiationwasseenwith combinationswith dieldrin,diazinon,malarhion, toxaphene,parathion,DDT, or dioxathion,bul morethanadditiveeffects, i.e., possiblepotentiation,were found with chlordaneand possibly with aldrin (Keplinger& Deichmann,1967). Five groupsof 20 male and20 femaleSprague-Dawley rarswerefed for9l dayson a dietcontaininga combination of 15'pcrsistent'chemicals addedat concentrations of 0, l, 10,100,and 1000rimesthewaterquality objective applicd in Canada.For endrin, thesecorrespondcdto 0.fi)2, 0.O2,O.2,and2.0 Fglkgof diet.No effecron food inrake,growth,clinical chemistry,bonemarrow,or histopathology wereobserved.It wasconcluded that the presenceof these chemicals at 1000times the water quality objectivehadno toxicologicaleffecr(Coteet al., 1985). Six maleandsix femaleSprague-Dawley rats werefed a control diet or dietscontainingendrinat 5 or l0 mglkg, endrin aldehydeat l0 mg/kg, orendrin ketoneat5 m&/kgfor l5 days,at which time threeto six ratsfrom eachtreatmentgroup were given a single intraperitonealdoseof carbon tetrachlorideat 100 plitre/kg body weighrin com oil (l mg/kg).Levelsof senrm enzymcs,bile flow, and biliary excretion of an anionic modcl compound,phcnolphthalcin gluctuonide,weremeasured onday 16.Dicrary treatmcntwith cndrin at cither dosc level did not elevatcscrumenzyme levels.Trcatmcntwith 5 mg/kg significanrlyreducedbile flow and a corresponding rcductionin phenolphthalein glucuronidcexcrction,w hereas the l0 mg/kgdosereducedonly phenolphrhalein glucuronidceicrerionin malerats. Fcmalerats treatedwith either doseshowcda dose-dependent choleretic effect with a commensuratcincreascin phenotphthalein glucuronide excretion. Treatment of rats with endrin and carbon teuachloridedid not resultin potentiationof hepatobiliaryfunctions.The levels of somc scrurn enzymeswere elevated(two-fold) in rats given endrinplus carbontctrachlorideover thosein ratsgiven cndrin or carbon tetrachloridcalone,indicatingan additiveinteraction.Dictarytrcatment with endrin aldchydcslightly increascdthe lcvcls of scrum glutamic oxaloacctictransaminasc andglutamicpyruvictransaminasc; andendrin 160

EHC fiA: Endrin

ketoneinduceda smallelevationin glutarnicpyruvic transaminase levels. Neithercompoundalteredbilefl ow or biliary phenolphthaleinglucuronide excretion.Combinationwith carbontetrachlorideincreasedthe levels of someserumenzymes(two-fold) over thoseseenwith the aldehydeor the ketoneor carbontetrachloridealone(Young & Mehendale,1986).

9. EFFECTS ON HUMANBEINGS 9.1

Exposureof the generalpopulation

9.1.1

Acute toxicity In mildcasesof poisoning,dizziness,weaknessof thelegs,abdominal discomfort, nausea,and vomiting have beenreported.Somepatientshave complained of temporary deafnessor were slightly disorientatedor aggressive. Theonsetofpoisoningisvariableandmayoccw 0.5-10 h after consumptionof contaminatedfood or contaminationof the skin; the interval is usually 1-4 h, dependingon the quantity ingested.Severe poisoningis manifestedby suddenepileptiform fits, with frothing at the mouth,facial congestion,andviolent convulsivemovementsof the limbs, sometimesleadingto dislocationof a shoulderor otherinjury. Thefits may lasl for several minutes and may be followed by a period of semiconsciousness for 15-30 min or wrtil the next fit. In general,these convulsionsoccur suddenly,with no prodromal sign or symptom. An uncommon but very serious symptom observed in two children was hyperthermia(4 I oCorhigher);thehighfeverwasfollowedby decerebrate rigidity. In fatal cases,deathoccurswithin z-lzh.ln survivors,recovery is rapid, within Z h, and uneventful, although some patients have complainedof headache,dizziness,weakness,and anorexiafor several weeks(Davis & Lewis, 1956;Jacobziner& Raybin, 1959;Hoogendamet al.,1962;Hayes,I 963; Weeks,1967;Hayes,I 982).After clinicalrecovery, EEG changesconsistingofbilateral synchronoustheta-waveactivity and occasionalbilateral synchronousspike and wave complexes,believedto be associatedwith brain steminitation, may still be found andmay persist for up to severalweeks(Hoogendamet al., 1962, 1965;Weeks, 1967).

9.1.2

Polsoning Incldents Hayes(1982)reviewedpoisoningcasescausedby endrin.Outb'reaks of acuteintoxicationdueto endrinhaveoccurredby contaminationof flour during trarsport in railway cars.A first episode,which was well studied, occurredin 1956in Wales,United Kingdom (Davis & Lewis, 1956):At least59 peoplewere ill enoughto requiremedicaltreatmenr,and at least 100more had somesymptoms,which were not severeenoughto require medicaladvice.No one died. On the basisof the concentrationof endrin in breadpreparedfrom thefl ow ( I 50 mg/kg),Hayes( I 963)esrimaredthat 162

EHC 130:Endrln

O.2C-n.25mg/kg body weightmay causea singleconvulsionandthat the dose necessaryto produce repeatedconwlsions is about I mg/kg body doseinmantobeapproximately weight.Karplus(1971)estimatedthelethal 10 mglkg body weight. A few conflicting dataareavailableon theconcentrationofendrin in the tissuesof victims of fatal intoxication.Hayes( 1982)quotedlevelsof 7-10 mg/kg in the liver and0.74.4 mg/kg in the brain; however,lO-fold lower levels were reported in the tissuesof autopsiedvictims of an outbreak of poisoning caused by ingestion of bread prepared from contaminatedflour in the Middle East (Curley et al., 197O).ln another incident,two sacksof contaminatedflour containedendrin at 184.5and 234.5mgkg, andthebreadandrollspreparedfrom thecontaminatedflour contained125.67-176.ll mg/kg.The levelsof endrinin serum,collected 30 min, 20 h, and30 h afterconvulsionsin onepersonwere0.053,0'038, and 0.021 mg/litre, respectively;threeother caseshad 0.003-O.0(Xmg/ litreof bloodserum9-19h afterconvulsions.Oneof thesethreepeoplehad no symptoms(Coble et al., 1967).The reportedserumor blood levels of endrin associatedwith convulsionsmust be interpretedin the contextof therapid removalof endrin from blood and the often significanttime lag in taking blood samples after convulsions. When the time between convulsionandbloodsamplingislong, theendrinlevelsreportedarelikely to be much lower than thoseat the time of the convulsion. Four outbreaksof endrin intoxicationoccurredin Doha (Qatar) and Hofuf (SaudiArabia)in 1967,during which 874 peoplewerehospitalized peopleshowedsymptomsof intoxication of whom 26die4 another5(X)--750 weredueto contamination butrequirednohospitalization. Theseoutbreaks of flour by endrin leaking from drums during shipment, The endrin concentrations foundin breadwere48-1807 mg/kg,andthosein theblood of patientswere0.007-O.032 mg/litre(Weeks,1967;Curleyet al., 1970). BetweenJuly and September1984,an epidemicof endrinpoisoning occurredin Pakistan,resultingin acuteconvulsions.In I 8 of 21 affected villages surveyed,70Eo(1061152)ofthe casesfor which agewas known were in children aged l-9 years;9.8Vo(l9ll94) of the affectedpeople died. A compositesugar sampletaken from the housesof three cases containedendrinat0.04 mg/kg.Endrin wasddtectedin thebloodof 12118 patients,at levelsof 0.3-254.0 pgllitre of serum. It was alsodetermined inbrain,kidneys,adiposetissue,andliverofonepersonandfound atlevels of 1680,1760,4010, 1430ytgtLgrespectively(Anon., 1984;Hill et al., 1986;Rowleyet al., 1987).

163

Effectson human bings

In mid-March 1988,threemembersof a family in OrangeCounty, Califomia, USA, becameill within I h of eatingtaquitos(bakedcorn shell filled with spicy meatandsalad).Two of the threehadmultiple giand mal seizures.Subsequently,two other people were reported to have had seizureslessthan 12 h aftereatingtaquitos.All fivepatientshad obtained thetaquitosfrom thesameshopwithin 5 days.The food wasanalysed,and thepresenceof endrinwasconfirmedbut not quantified.The origin of the endrin could not be identified (Anon., 1989). An episodeof acuteendrin poisoning was reportedin 33 Mexican children, who had suddenseizureswithout sensoryalterations(Singh & West, 1985). Several other caseshave been published of single accidental or intentionalintoxications,in children and in adults(Jacobziner& Raybin, 1959;Karplus, I 97I ). Reddyet al. ( I 966)described60 casesoffatal endrin poisoningout of95 encounteredin India aftertheintroductionofendrin in agriculturalwork asan insecticidein 1959.The majority of thecaseswere suicidal.Froth;petechialhaemorrhages, a kerosene-likesmellandmassive pulmonaryoedemawere the characteristicautopsyfindings. Respiratory failure was the most commoncauseof death.The authorsconcludedthat thetoxic doseof endrinis 5-50 mgTkgbody weightor about I g; thelethal doseis about6 g. In a poisoningcasein a l9-year-oldmale who ingested an trnknown amountof endrin, conwlsions and grosspulmonary oedema werefound (Jedeikiner al.,1979). No histologicalchangeswerefound in the liver. At leastsomeof the pulmonarychangesseenin suchcasesmay be due to aspirationof thepetroleumhydrocarbonsolventin formulations of endrin. A caseof polyneuropathyof theGuillain-Barr6typewas attributedto exposureto a mixture of DDT and endrin. Since convulsionswere not recorded, the causal relationship remains doubtful (Jenkins & Toole, '954). In afatal caseof endrinpoisoning,ingestionof I 2 g of endrinby a 49year-oldman causedconvulsions(persistingfor 4 days),hypersalivation, hyperthermia, renal insufficiency, thrombocytopenia, and recurrent hypotension.Deathfollowed afterI I daysduetopulmonarycomplications (infection and haemorrhage)and hypoxaemiacausingbradycardiaand cardiacarrest.The endrin concentrationsin blood 4 h and 6 and 1I days afteringestionwere450,86 and7 1 pgllitre. Endrinlevelsin adiposetissue, 164

EHC 130:Endrin

heart,brain, kidneys,and liver, ll days after ingestion were 89.5, 0.87, 0.89,0.55, and1.32mg/kg,respectively(Runhaaret al., 1985). The medicaltreatmentof endrinpoisoningis describedin Annex II.

2

Occupationalexposure

?.1

Factory workers No fatal casc has becn reportcd due to occupationalexposurein manufacturingand formulatingplants(Van Raalte,1965;Jager,1970), but is alsocertainlydueto the whichmay beduein partto underreporting fact that occupationalexposureinvolving the absorptionof lethal doses occurs rarely under practical circumstances.Furthcrmore, the rapid metabolismof endrinminimizesbuild-up of toxic levelsin tissuesduring normal working days. occurredin amanufacturing Severalcascsofacute,non-fatalpoisoning plant in The Nethsrlandsdueto accidentalover-exposureto endrin(Jager, in thisplantsince1957.Duringthe 1970).Endrinhadbccnmanufactured first 9 ycarsof pr<xluctionof aldrin,dicldrin, and cndrin in the plant, fivc of which involved l7 casesol'poisoningwith convulsionscrccurrcd, more than one convulsion.Threc 0[ thc cascswere due to acuteovercxposureto cndrin amongworkerswho werc handlingthcsematerialsat cvcry day. Thcre wasno fatalityduring 1300manhigh concentrations yearsof exposurc.No evidencewasftrundof skin sensitization,andthere was no caseof permanent,partial,or completeincapacity.No difference wasseenin absenteeism dueto illncssamongtheseworkersin comparison with those in othcr plants, and the results of liver function tests and completeblood cell counts were within normal limits. In the casesof poisoning,recoveryfrom clinical andncurologicalsigns,including EEG et al., 1962,1965;Jager, tracings,wasrapid andcomplete(Hoogendam 1970;Vcrstceg& Jager,1973). A scricsof studicshasbcenpublishedon thc rcsultsof continuing mcdicalsupcrvision follow-up o[ workersin thisplant. A complementary ol' I 89 workcrsandof 52 workerswho hadleft employmentat theplantfor variousreasonswaspublishedin 1973(Versteeg& Jager,1973).These workers had becn exposedto endrin for up to 14.5years in 1973. In

165

Effects on human beings

agre€mentwith data published from a study of 7l workers in an endrin manufacturingplant in the USA (Hayes& Curley, 1968),endrin was not found in the blood of theseworkers, except in casesof accidental, acute over-exposure. Medical supervision of workers employed in the manufactureandformulationof endrinandotherpesticidesfor l-19 years (average,l2years), data on absenteeism,the results of tests for liver function and blood chemistry, blood morphology, urine analysis,the occurrenceof sensitization,thepatternandcowseof EEG changesin cases of poisoning,othermedicalstudies(includingelectrocardiography, chest x rays, blood pressure,body weight), and the incidenceand pattem of diseases,including the occurrenceof malignant growths, showed no difference between workers exposedto endrin and other chemical plant operators.Residuesof endrinwerenot found in plasma(< 3 pgllitre) or in adiposetissue(< 0.03 mg/kg). A significantdifferencewasfoundbetweenworkersexposedtoaldrin and dieldrin only, workers not exposed to insecticides,and workers exposedto endrinonly: endrinworkershadlower blood levelsof theDDT metabolitepcra,para'-DDE than the other workers,and the levels were lower than those in the general population of the surrounding area, althoughDDT andrelatedcompoundshadneverbeenmanufacturedin the plant. A secondparameterthat was comparedwas excretionof 6-betahydrocortisolin the urine. (Increasedactivity of the drug-metabolizing enzymesystemincreasesthe activity of the oxidativepathwayby which 6-beta-hydroxylase convertsendogenouscortisol to 6-beta-hydrocortisol andthus,relatively,diminishesthecontributionof thereductivepathway, leadingto excretionof 17-hydroxycorticosteroids.) Theratioof theurinary excretion of 6-beta-hydroxycortisolto that of l7-hydroxysteroidswas significantly higher in the endrin workersthanin workersnot exposedto endrin (Jager,1970). A third parameterof this enzymesystemthatwasstudiedwasurinary excretion of D-glucaric acid (an end-productof the glucuronic acid pathway in the liver), which hasbeenshown to increaseafter exposureto microsomalenzyme-stimulatingcompounds,like endrin (Hunter et al., I 97 I ; Notten & Henderson,I 975). In theendrin workers,urinary excretion of D-glucaric acid after a week ofexposure increasedsignificantly over pre-exposurelevels and those in a control g,roupof workers. Excretion diminished again after 3 days without exposure(Hunter et al., 1972; Ottevanger&Van Sittert, 1979;Vrij-Standhardtet al., 1979;Van Siuerr,

r985). 166

EHC 130:Endrin

Since anti-L}-hydroxyendrin is the only metabolite found in the urine of endrin-exposedworkers, a study was initiated to find whether there is a conelationbetweenthequantityof thismetaboliteandthatof D-glucaric acid excretedin the urine. A positive relationshipwas found between excretion of the endrin metabolite and of D-glucaric acid after 7 days' After exposure w as discontinued, excretion of anti - l2-hydroxyendrin decreased fasterthanthatofD-glucaric acid.The fact thatendrin-exposed workershadD-glucaricacid levelswithin thenormalrangeafter6 weeks indicates that enzyme induction in endrin workers is reversible. The authors concluded that a urinary level of anti-|z-hydtoxyendrin of 0.130 pglg of creatinineis the thresholdexposurelevel, below which enzymeinductionis not produced(Ottevanger& Van Sittert, 1979;Van Sittert, i985). Endrin did not increasetotal urinary porphyrin excretion over that in a control group of employees(Strik, 1979;Nagelsmit et al', 1979;Vrij-Standhardt et al., 1979). In a follow-up mortality study of the samegroup of workers, vital statusand causeof deathwere assessedfor 232 of a group of more than 1000workers.This groupwasselectedbecausetheyhadexperiencedhigh exposuresin the initial yearsof manufactureandformulation andbecause of the long periods of exposure (mean, 11 years; rmge, 4-21) and observation(meaq M years;range,4-29). Total observedmortality was 25,whereas38 deathswereexpectedon thebasisof mortality statisticsfor the male Dutch population.Of the nine cancerdeaths,threewere due to lung cancer;the remainingsix weredue to cancersof stomach,pancreas, bladder, and kidney, multiple myeloma, and cerebral glioma. It was concludedthat the pesticidesmanufacturedhad no specificcarcinogenic activity(Ribbens,1985).

,2.2

Dose-respo nse relatio nshi ps It has not been possibleto establisha dose-responserelationship between single or repeatedoral exposwes and endrin concentrations in blood, adiposetissue,or organsand severityof intoxication,becausethe actualoral intakein the accidentalcaseswasnot knowq and the onsetof symptoms of intoxication and the time of measuring concentrations of endrin in blood, organs,or tissueswerenot comparable(Davis & Lewis, 1956;Hayes, 1963;Cobleet al., 1967;Weeks,1967;Curley et al., L970; Karplus,1971;Hayes,1982;Anon., 1984).

167

Effectson human beings

Blood sampleshave been analysedin ttuee casesof acute overexposure(Table 28): A formulator and an operator were accidentally splashedwith a 207oendrinemulsifiableconqentrare, which was washed off within 10 min. Neither developedsignsor symptomsof intoxication. The third case was in a formulator who handled technical-gradeendrin powderwithout wearingadust-mask.He hadconvulsions4 h afterstarting work, but aftertreatrnentrecoveredfully thenextday. Blood samplesfrom four colleaguesworking next to him, but wearingdust-masks,were also examined.The authorestimatedthat the thresholdlevel of endrin in the blood below which no sign or symprom of intoxication occurs is 50-100 Fgtitre and that the halflife of endrin in blood is in the order of Ah(Jager,1970).

9.2.3

Exposuresto mixtures A retrospectivemortality studywascarriedout on workersemployed in the manufactureof heptachlorand endrin in a plant in Tennessee,USA, between1952and 1976.The study comprised835 men who had worked for more than 3 months up to 20 years at the plant. No overall excessof deathsfrom cancerwas found; however,there was an excessof deaths from cerebrovasculardisease(7 obsirved, 2.3 expected)(Wang & MacMahon, 1979). A further retrospectivecohort study was conducledto examinethe mortality of workersemployedin themanufactureof chlordane,heptachlor, DDT, aldrin/dieldrin, and endrin in a plant in Colorado, USA, where endrin was manufactured from 1953 until 1965. Approximarely 2100 workerswho had beenemployedfor at leasr6 monrhsin the plants wereinvolved.No excessof cereb'rovasculardisease wasobserved@iuaglia et al., l98l). Neitherstudyprovesconclusivelythatexposweto theseorganochlorine insecticidesis associated with increasedprevalenceofmalignancyorother causeof death,but rhey are limited in design and in the desciptionof ' exposure. A field studywas carriedour in 1983in the Ivory Coasrro assessrhe healthhazardsassociatedwith the handlingand applicationby hand-held sprayersof an ultra-low volume formulation consistingof endrin at 85 g litre, DDT at 333 gllitre, and merhylpararhionat 85 g/litre in petroleum solvent. Groupsof five or six farmerssprayed3 litreThaof the formularion 168

EHC 130: Endrln

workers Table28.Concentrations of endrinin bloodfromacutelyover-exposed Case

Timeof first sampling

(pg/litre) Endrinconcentration First 12h 24h sample later later

Formulator

t h after accident

90

Operator

40 min after accident

27

Directlyafter Formulator withoutdusl-mask conwlsion

80

Fourcolleagues withdust-masks

3 6 h 5 days later later ND ND

25

20

ND

Sametime ND-l0 time as above

ND,notdetectable(< 5 pg/litre)

4-6 weeks after sowing cotton and again l5 or 30 days after the first application.The sprayapparatuswasfilled andcleanedby the samemen. The recommendedprotective clothing was wom only rarely, and the handlingandapplicationtechniqueswerecareless, resultingin manycases in appreciableskin contamination.No adversehealtheffect wasobserved. Absorptionof endrin was monitoredby measuringthe concentrationof anti-|2-hydroxyendrinin spotsamplesof urinecollectcdabout20 h after spraying. The mean concentrationsafter the first, second, and third applicationswere0.34 (range,0.04-0.59),0.52 (range, 0.09-1.4),and 0.45 mglg of creatinine (range,0.(H).92). One personwho hadhandled and sprayedthe formulationcarefully still had anti-|2-hydroxyendrinin the urine after the third application,but at a very low level (0.03 mg/g of creatinine).Measurementsof para-nitrophenol,a metaboliteof methylparathion,inurine indicatedthattherateof metabolismof methylparathion was increasedas a result of enzyme induction by endrin in the liver (Kummer & Van Siuert, 1984, 1986).It was concludedthat endrin accumulatedin most of thefarmersafterthreeapplicationswithin a short period. An increaseto toxiq levels might result if spraying were more frequentandat shorterintervalsandif therecommendedclothing wasnot wom.

169

Effectson human tuings

9.2.4

Appraisal of effects of occupational

exposures

Endrin is a very toxic compound.Severalepisodesoffatal andnonfatal poisoninghave occurred,mostly from accidentalcontaminationof food and alsofrom intentional(suicidal)ingestion.The lethaloral doseis estimatedto be l0 mg/kgbodyweight.In non-fatalcases,recoveryis rapid and complete within a few days. The oral dose that causesa single convulsion is esrimatedto be 0.25 mg/kg body weight, and that which inducesrepeatedconvulsions,1.0mg/kg body weight. Exposureofworkers to endrinfor longperiodsdid not induceadverse effectsthatwereattributedto this compound,althoughoccasionalcasesof acute,non-fatalintoxicationdueto accidentalover-exposurehave occurred. Endrin was not detectedin the blood of workers exposedto endrin at < 3.0 pgflitre. The threshold level of endrin in blood rhat resulrs in intoxicationis esrimatedro be 50-100 tlElli:re. Absorptionof a roxic dose is thereforeunlikelyduringcrccupational cxposureif recommendcd controls andprecautionsareuscd.In fatal cases,endrinconccntral.ions in blood as high as 450 pgllitre havebeenreporred;however,it is not possibleto establisha dosc-response relationship.Sinceendrinis not normally found in air, warer,or food, exceptunderconditionsof contamination,exposure of thegeneralpopulationis not significant.

170

BY INTERNATIONAL EVALUATIONS 10. PREVIOUS BODIES Endrin was evaluatedby the Joint FAO/TVHO Expert Committee on PesticideResiduesin 1963, 1965, and 1970 (FAO VHO,196/',1965, 1971). h 1970, the Committeeestablishedan acceptabledaily intake (ADI) for humansof 0-O.CX[2mg/kg body weight, which was basedon thelevelthatcausesnotoxicologicaleffectinratsanddogs,1 mg/kgofdiet (equivalent to 0.05 mg/kg body weight per day in rats and 0'025 mgikg body weight per day in dogs). TheJoint FAO/$/HO CodexAlimentarius Commissionhaspublished maximum residue limits for endrin (table}9; (FAOAilHO' 1986b). Table29.Codexmaximumlimitsfor the sumof residuesof rdrinanddelta-ketoendrin Commodity

Maximumresiduelimit (mg/kg product)

Apples Barley Cottonseed Cottonseedoil (crude) Cottonseedoil (edible) Eggs (withoutshells) Meat (carcass fat)

o.o2a o.o2a 0.1 0.1 0.024 0.2 o.1b o.ooo8b 1 0.024 o.o2a o.o2' o.o2a

Mirk tat) Poultry(carcass Rice (huskedor polished) Sorghum Sweet maize Wheat

lAt or nearthe limitof detection txtraneous residuelimit The International Agency for Researchon Cancer(IARC) concluded in 1974and 1987that therewasinadequateevidencefor thecarcinogenicity of endrin in experimental animals and that the evidencefrom studies in humanswas inadequate.Endrin was thereforeclassified in Group 3: not classifiableas to its carcinogenicityto humans(IARC, 1974, 1987).

171

Prevlousevaluatlonsby lnternationalbodles

kr 1988, the Pesticide Developmenrand Safe Use Unit, Division of Vector Biology and Control, WHO, classified technical-gradeendrin as highly hazardousin normal use (WHO, 1992).A datasheeton endrin was issuedin 1978(WHO/FAO, 1975).

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174

EHC 130:Endrln

MorbMortal associatedwith endrinpoisoning-Pakistan. Anon.(1984)Acuteconvulsions WklyRep,s3(49):687-695. Protection AgencyOfficeof Drinking Environmental Anon.(1988a)Introduction-US Waterhealthadvisories.RevEnvironContamToxicol,104:1-€. ContamToxico,l104:103-114. Anon.(1988b)Endrin.RevEnvir6n MorbMortal withtaquitoingestion,California. Anon.(1989)Endrinpoisoningassociated WklyRep,38(19):345-347. ArgyleRJ,WilliamsGC,& DupreeHK (1973)Endrinuptakeand releaseby fingerling J FishResBoardCanada,30(11): 1743-'1744. channelcallish(lctaluruspunctatusl. in the BF (1976)Atmospheric levelsof pesticides ArthurRD, CainJD, & Barrentine Delta.BullEnvironContamToxicol,15(2):129-134. Mississippi and other RL (1973)Toxicityof pesticides AtkinsEL, GreywoodEA, & MacDonald California, Riverside, Universityof studies. agriculturalchemicals tohoneybees: Laboratory (Rev.9/73(M-16)). Department of Entomology insecticides in thebloodof thegeneral of organochlorine AtumaSS (1985)Accumulation population of Nigeria. ToxicolEnvironChem,l0:77-€2. of endrinby BaldwinMK& HutsonDH(1980)Analysisof humanurinefor a metabolite to endrin. as an indicator of exposure chromatography andgas-liquid chemical oxidation Analyst,105:60-€5. ofendrinintherat.J AgricFood J, & ParkeDV(1970)Metabolism MK,Robinson Baldwin Chem,18(6):'l117-1123. BaldwinMK, Davis RA, & Burns DT (1973)Structuralstudiesand photochemical of dieldrin. Pestic rearrangement of an animalmetabolite of HEOD,theactivecomponent *|4:227-237. andresidues BaldwinMK,Crayford JV,HutsonDH,& StreetDL(1976)Themetabolism of la0-endrin in lactating cowsandlayinghens.PesticSci,7(6):575-594. by in SpanishU.H.T.milksdetermined residue BarceloD & PuignouLG(1987)[Pesticide gaschromatography.l TecnolAliment,27(4):583-589(in RevAgroquim highresolution Spanish). pesticide residues BarnettRW,D'Ercole AJ,CainJD,& ArthurRD(1979)Organochlorine northeastMississippi,1973-75. fromwomenlivinginnorthwestand inhumanrnilksamples PesticMonitJ, 13(2):47-51. ol Louisiana, Division toxicityin primates. Tulane,University BarthRAJ(1967)Pesticide (Thesis). of HygieneandTropicalMedicine

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176

EHC 130:Endrin

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EHC 130:Endrin

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EHC130:Endrin

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1A

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212

EHC 130:Endrin

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214

EHC 190:Endrln

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216

EHC 130:Endrin

WolmanM & WilsonAJ Jr(1970)Occunenceof pesticidesin whales.PesticMonitJ,4(1): 8-10. WrjthrichC, MUllerF, BlaserO,& MarekB (1985)[Pesticidesandotherchemiealresidues in Swiss diet samples.l Mitt Geb LebensmittelHyg, 76: 260-276 (in German with English

summary). aberrationsinduced Wuu KD & GrantWF(1966)Morphologicalandsomaticchromosomal by pesticidesin barley(Hor&um vulgarel.Can J Genet Cytol,8:481-501. Wuu KD & Grant WF (1967a) Chromosomalaberrationsinduced by pesticidesin meiotic cells of barley.Cytologia,32: 31-41. Wuu KD & Grant WF (1967b) Chromosomalaberrationsinduced in somatic cells of Vrbrb fababy pesticides.Nucleus,10(1):37-46. Yakushiii T, Watanabe l, Kuwabara K, Yoshida S, Hori S, Fukushima S, Kashimpto T, Koyama K, & Kunita N (1979) Levels of organochlorinepesticides and polychlorinated biphenyls(PCBs) in mothersmilk collectedin Osaka prefecturefrom 1969-1976.Arch Environ Contam Toxicol, S: 59-66. Yarbrough JD, Roush RT, Bonner JC, & Wise DA (1986) Monogenicinheritanceof cycfodieneinsecticideresistancein mosquitofish,Gambusia affinis. Experientia(Basel), 42:851-€53. YoungRA& MehendaleHM ( 1986)Effectofendrinandendrinderivativesonhepatobiliary function and carbontetrachloride-inducedhepatotoxicityin male and female rats. Food Chem Toxicol, 24(8): 853-868. Zabik MJ, Schuetz RD, Burton WL, & Pape BE (1971) Photochemistryof bioactive compounds,Studiesof a major photolyticproductof endrin.J Agric Food Chem, 19(2): 308-313. Zavon MR, HineCH, & ParkerKD (1965)Chlorinatedhydrocarboninsecticidesin human body fat in the UnitedStates.J Am Med Assoc,193(10):181-183. Zeiger E (1987) Carcinogenicityof mutagens: predictive capability ot tte Salmonella mutagenesisassay for rodent carcinogenicity.Cancer Res, 47: 1287-1296. Zeiger E, Anderson B, HaworthS, LawlorT, MortelmansK, & Speck W (19871Salmonella mutagenicity tests: lll. Results from the testing of 255 chemicals. Environ Mutagen, 9 (suppl9):1-110. Zimmerli B & Marek B (1973) [The pesticide load ol the Swiss population.l Mitt Geb LebensmittelHyg,,64(4):459479 (in @rman with Englishsummary).

217

ANNEXI CHEMICALNAMESOF ENDRINANDITS METABOLITES Two main systems are crurently used for the nomenclature of cyclodieneinsecticides:'polyhydroaromatic'names,usedby Chemical Abstracts (American Chemical Society) and the Intemational Union for PureandApplied Chemistry (IUPAC), andthe von Baeyer[UPAC system for polycyclic aliphaticcompounds.Benson(1969) and Bedford (1974) proposedthat the latter systembe usedfor the cyclodiene insecticides. The'polyaromatic'systemhas, unfortunately,beensubjecttohistorical variation, and there are differences between the IUPAC, British and American conventionsfor defining the three-dimensionalstereochemistry in this system.As a consequenceof differencesin thenumbering of carbon atomsin the two systemsand the modification of the Chemical Abstracts 'polyaromatic' namefor dieldrin since 1971,considerableconfusioncan arisein the nomenclatureof metabolites.The possiblemisunderstandings that may occur,particularly amongpeoplewho arenot familiar with the various conventions of chemical nomenclature, are illustrated by the different namesthat are given to the major metabolite of endrin; this one compoundmay be designatedas: antl9 -hydroxyendrin (former Chemical Abstracrssystem) anti-8-hydroxyendrin (current Chemical Abstracts system) anti-|2-hy &oxyendrin (von Baeyer/[UPACsystem). A useful discussionof nomenclaturewas given by Brooks (1974). The chemical namesfor endrin and its metabolitesaresummarizedin Table 30.

218

EHC 130:Endrln

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ANNEXII : OF ENDRINPOISONING MEDICALTREATMENT Symptomsof polsoning Endrin is readily absorbedand is toxic when taken by mouth, by skin contact(especiallyliquid formulations),and by inhalation.It stimulates the central nervous systern,and an oral dose of0.25 mglkg body weight san causeconvulsionsin humans.Following accidentalingestion or gross over-exposure,symptoms appear between 20min and l2h and may includeheadache,dizziness,nausea,vomiting, weaknessin the legs, and convulsions, sometimesleading to death. Organochlorine compounds c:ur cause respiratory depression, and they may sensitize the heart to endogenouscatecholamines,leading to ventricular fib'rillation and cardiac arest in severe cases. Respiratory depressionmay lead to metabolic acidosis, and if necessaryblood gases shouldbechecked.Useof anelecrocardiographicmonitor is recommended if symptoms are severe. Endrin is eliminated very quickly from the blood and can be detected for only I or 2days even after massive over-exposures. Signs and symptoms of poisoning occur only at levels in whole blood of above 0.05 pglml.

Medicaltreatment Medical treatrnent is largely symptomatic and supportive and is directed against convulsions and hypoxia. If endrin is swallowed, the stomach should be emptied as soon as possible by careful gastric lavage (with a cuffedendotracheal tubealreadyinplace),avoidingaspirationinto the lungs. In a rural situation wherethis is not feasible,vomiting shouldbe induced immediately. This should be followed by (intragastric) administration of 50 g of activated charcoal and 30 g of magnesium or sodium sulfate in a 3AVo aqueous solution. Oily purgatives are contraindicated, and no fats,.oils, or milk should be given.

221

Annex ll

If conwlsions occur, anticonvulsantsshould be given immediately but slowly, and repeatedas necessary.Diazepam can be given at 10 mg (children, I -5 mg) intrave,rously;thiopentalsodiumor hexobarbitalsodium can be give,nintravenously at a dose of 10 mg/kg, with a maximum total doseof up to 750 mg for an adult; or paraldehydecan be given at 5 ml by intramuscularinjection. Theseshort-actinganticonvulsantsshouldalways be followed by phenobarbitalgiven orally at 3 mg&g (up to 200 mg for an adult), or phenobarbital sodium given intramuscularly at 3 mg/kg (up to 2A0mg for an adult). Morphine and its derlvatives, adrenaline and noradrenaline, should neverbe given. The airway must be kept unobstructed. Respiratory inadequacy, which may be accen&ated by barbinrrate anticonvulsants, should be corrected, and oxygen and/or artificial ventilation may be needed. A guidelinefor the managementof major statusepilepticusis added as Annex III.

222

ANNEXIII MANAGEMENT OF MAJORSTATUSEPILEPTICUS IN'ADULTS" Inltlalmanagement 1. Assessthepatient,verify the diagrrosis,removefalseteeth,placethe patientin a lateralsemi-proneposition,and establishan airway. 2.

Give diazepamintravenously(seeNote l, below),usuallyat l0 mg in 2 ml (0.154.25 mgk$, followed immediatelyby a further l0 mg (2 ml) over l-2 min. This may be repeatedaccordingto response.

3.

Take blood to me$ure levels of anticonvulsantdrug, ethanol,and blood sugar (5 ml of blood in a sugar tube); a sample to measure calcium (5 ml in a plain tube); anda drop of blood ro determineblood glucose.

4.

If the latter measurementshowslow blood glucoselevel, 25 ml of 507oglucoseshould be given intravenously,preferablyby catheter andnot into a small distalvein. If ethanolis likely to be present,give thiamineintravenouslyat 100mg.

5.

Give phenytoinintravenouslyar 250 mg in 5 ml (10-15 mg/kg) no fasterthan50 mg (l ml)/min by infusion pump or slow inrravenous injection (seeNote 2, below).

lf fits continue,transferpatientto the intensivecare unit and consultan anaesthetist 6.

Givechlormethiazoleintravenirusly at 8 mg/ml: a loadingdoseof up to 800mg (lffiml) over l0min at lOml/min, maintainedwith 0.5-1 ml/min (4-8 mg).

%,ff,GE-

guidelines issuedat Guy'sHospital, London

223

Annexlll

7. Give thiopentone intravenously at 5 mglkg as a loading dose, then 1-3 mglkg per h to a maximumblood level of 100mg,/litre. 8. If this fails, consult a neurologist.

3.

Notes l

Diazepam:A bolusinjectionof l0 mg maycauserespiratorydepression andhypotension,which may bepronouncedif thereis concurrentuse of other central nervous system depressantdrugs, especially phenobarbital. Diazepammust no, be given intramuscularly: -added to an intravenousinfusion -with phenobarbital,unlessartificial ventilation is available. Rectaladministrationof diazepam(usinga rectaladministrationset), at 5 or l0 mg in 2.5 ml, may be usedfor the immediatetreatmentof epilepsyinsteadof intravenousdiazepam.

2.

Phenytoinmust no, be given: -intramuscularly -by centralline -into a dextroseinfusion -with any other drug. Intravenously administered phenytoin should be monitored by continuouselectrocardiographic recording.If this is not available,it may be saferto usea diluted solutionof 250 mg (5 ml) in 250 ml of normal saline,no fasterthan50 mg/min. The diluted solutionshould be usedimmediatelyprovided thereis no evidenceof precipitation (this useof phenytoinis not licensed).

4.

Options , The following drugsmay alsobe used: l.

224

Paraldehyde:2 x5 nrl by separatedeep intramuscularinjection or l0 ml diluted in lfi) nrl of normal salinegiven inrravenouslyover 10-15 min. Note: Paraldehydeshould be administeredonly with glasssyringes.

EHC 130:Endrin

2. Phenobarbital:200 mg/rnl, should not be given intravenously except when artificial ventilation is available,and not at all if the patient Themaximalrateof infusionis l0O mg/ normallytakesphenobarbital. min to a maximum doseof 15 mg/kg.

3. Lignocaine: 100mg by slow intravenousinjection, followed by 50-100mg in 250m1 of 57o dextroseat l-2mglmin. Note: This treatmentmust be monitored by electrocardigram. 4.

Diazepam:l0 mg in 2 ml intravenously,or 40 mg in 5fi) ml of 57o dextroseat a maximal infusion rate of 100 mg/h.

5.

Sodiumvalproate:4O0 mg in4 ml, or400-8(X)mg intravenouslyover 3-5 min (up to l0 mg/kg), followed by intravenous. infusion to a maximum of 2.5 glday(unlicensed).

Paediatricdoses For children, dosing should be adapted as follows:

Diazepam: Phenytoin: Chlormethiazole:

0.24.3 mg/kg intravenously I G-20 mg/kg intravenously 5-10 mg/kg per h, equivalentto 0.6-1.25 ml/kg per h

225

RESUMEET EVALUATION; CONCLUSIONS; RECOMMANDATIONS R6sum6et 6valuatlon Expositlon L'endrine est un insecticide onganochlor6utilis6 depuis les anndes 1950contre toute sorte de ravageurs,qui s'attaquentnotatnment au coton mais 6galementauriz, i la canned sucre,au mar'set ir d'autrescultures, On l'utilise 6galementcommerodenticideet avicide.Il estdisponibledansle cornmercesousforme de poudres,de granul6s,de pites et de concentr6s 6mulsionnables. par volatilisation L'en&ine pdndtreprincipalementdansl'atmosphEre et dispersion.En g6n6ral,la volatilisation seproduit aprdsdpandagesur le sol et sur les r6coltes et elle est tributaire de nombreux facteurs comme la teneur en matidres organiqueset en eau du sol, l'humidit6, les courants adrienset I'aire foliaire des v6gdtaux. C'est principalement par lessivage i partir du sol que se produit la contaminationdeseauxsuperficielles.Les pr6cipitations,qu'il s'agissede neige ou de pluie, n'ont qu'une partn{gligeable danscette contamination. Localement, une contaminationpeut 6galementse produire par suite du d6versementd'effluentsindustrielsou den6gligencesdars lestechniques d'6pandage. C'est principalementpar suite d'un dpandagedirect sur les terrainset les recoltesque I'endrinep6nbtredansle sol. Elle peut y €tre retenue, transport6e ou d6grad6e,en fonction d'un certain nombre de facteurs.C'estdansles solsrichesen matidresorganiquesque la rdtention est la plus importante. La persistancede I'endrine d6penddans une large meslue desconditionslocales;sa demi-vie dansle sol peut aller jusqu'i 12 ans. La disparition de I'endrine pr6sente en surface s'effectue principalementpar volatilisationet photoddcomposition. SousI'influence delalumidresolaire(rayonnementultra-violet),I'endrineestisomdris6een delta-c6toendrine.En pr6sencede lumidre solaireintense,on a observdune isom6risationde507ode I'endrineen l'espacedeseptjours.L'isomdrisation peut 6galement s'effectuer par action microbierure (champignonset bact6ries),notanunent en ana6robiose. 226

EHC130:Endrin

Les invert6br6s aquatiques et les poissons absorbent rapidement l'endrinepr6sentedansl'eaumais,transvas6sdansuneeaunon contamin6e, lespoissonsexpos6s6liminentsansd6lai le pesticide.En casd'exposition continue,le facteurde bioconcentrationpeut atteindrel4-18 000' Il est possible que les invert6br6s terricoles absorbent facilement I'endrine.La pr6senceoccasionnellede faibles quantit6sd'endrinedans I'air ainsi que dans les eaux de surface, notarnment destin6esd la enzoneagricole,n'a gudred importanceaupointdevuede consornmation, la sant6 publique. La seule voie d'exposition importante est la voie alimentaire.En g6n6ral,toutefois,les quantit6singdrdesse situent trds de la dosejournalidreadmissiblequi a 6t6 fix6e d largementen-dessous 0,0002mg&g de poids corporelen 1970(FAO/OMS, l97l).

Absorption, m6tabolisme et excr6tion I'endrineestrapidement Contrairementi la dieldrine,sonst6r6oisomdre, m6tabolis6eparI'organismeanimalet,comparativementi d'autrescomposds de structurechimiquesemblable,elle s'accumuletrds peu dansles tissus adipeux. L'absorptionet I'excretionsont rapidesaprdsadministrationorale i des rats et la demi-vie biologique se situe entre I et 6 jours selon 1es quantit6sing6rees.Un r6gime stationnaire,c'estd dire un 6tat d'6quilibre entrela quantit6excr6t6eetla doseing6ree,s'dtablitau boutde 6 jours. On constate rure diff6rence entre les deux sexes en ce sens que les mdles excrdtentl'endrineet sesm6tabolitespar la voie biliaire plus rapidement que les femelles,d'oi une moindre accumulationde pesticidesdans les tissusadipeuxdes mdles.Les rats excrdtentce compos6principalement dansleursmatidresf6calessousforme d'endrine,d'anti-t2-hydroxyendrine ainsi que sousla forme d'un ddriv6hydroxyl6 de I'endrine,en I'espacede Z heures(70-757o);un troisibmem6tabolite,lal2-c4toendrine,s'accumule dansles tissus.Les lapinsexcrdtent5OVodesm6tabolitesde I'endrinepar la voie urinaire,l'excr6tionurinairen'6tantqre de 2V"chezle rat; dansles matidresfecalesdeslapins,on ne retrouveque de l'endrinenon modifi6e. Desvachesi qui l'on avaitadministr6de I'endrinei raisonde 0,1 mg/ kg de nourriturependant2l jours en ont excr6t6jusqu'ir657osousforme de mdtabolites urinaires, 2OVosous forme de m6tabolites f6caux ou d'endrinenon modifrf,eet3Vodansleur lait, cettefois, principalementsous

227

B6sumd

forme d'endrine non modifide. Chez ces vaches, les rdsidus atteignaient 0,003-0,006mgflitre dansle lait, 0,001-O,002mglkg dansla viande,et 0,02-0,1 mg/kg dans la graisse. Chez despoulespondeusesayantregu tule alimentationadditionn6e d'endrine,on a observ6desr€sidus(selonla doseing6rde)qui atteignaient 0,1 mg/kg dansla chair, I mg/kg dansla graisse,0,24,3 mg/kg dansles eufs Qawre),0,Zmgkgdans lesreinset 0,5 mg/kg dansle foie.Saufdans le cas du foie et des reins, les r6sidusprdsents6taient essentiellement formds dendrine non modifi6e. Environ 507ode la quantit6 d'endrine adrninisrCe a 6td excrdtdedans les maderesf6cales,principalement sous la forme de mdtabolites. Clrez l'homme, le rat, le lapin, la vache et la poule, le principal metabolite de I'endrineest I'anti-12-hy&oxyendrine, accompagn6ede ses Sulfo- et glucuro-conjugu6s. On trouve 6galement4 autres m6tabolites, mais en quantites minimes. Dans les tissus et le lait on retrouve essentiellementdeI'endrinenonmodifiee.Aprds6pandagestr desv6g6taux, on a retrouvd de I'endrinesousforme non modifiee ainsi que deuxproduits de transformation hydrophiles.

1.3

Effetssur les 6tresvavantsdans leur milieunaturel L'endrine n'exerce que des effets minimes sur les bact6ries et les champignonste.rricoles.Aux dosesde I 0- I 000 mg/kg de terre,le composd n'a aucun effet sur la d6compositiondes matidres organiques,sur la d6nitrification ou sur la production de m6thane.L'endrine est trds toxique pour les poissons,les invert6br6saquatiqueset le phytoplancton;la CLro ir 96 h, estdansla plupart descasinf6rieured 1,0pgflitre. La dosenocive ld plus faible observdeau coursd'un testportantsur le cycle 6volutif d'un crevette,Mysidopsisbahia,6tait de 30 ng/litre. Les 6preuvesdetoxicitd aigudeffectudessurdesorganismesaquatiques ont 6t6pratiqudesdansdesaquariumsne comportantpasde s6diments;on peut penser que la pr6sence de sddiments attdnue I'effet de I'endrine. D'ailleurs la pr6sencede s6dimentsfortement contamin6s n'a gudre eu d'effet sur les espdcesde pleine eau, ce qui incite I penser que I'endrine fix6e aux sddiments pr6sente une faible biodisponibilit6. On n'a pas pratique d'6preuvessur desanimaux aquatiquesvivant dansles s6diments.

228

EHC130:Endrln

Pour les mammiferest€NTestres et les oiseaux,la DLro estde l'ordre de 1,0-10,0 mglkg de poids corporel. Des canards de I'espdceAnas platyrlrynchos qui avaientregupendant 12semainesde I'endrinedansleur nourriture i des doses allant jusqu'i 3,0 mg/kg de poids corporel, n'ont pr6sent6 aucun effet d6l6tlre que ce soit sur la ponte, la f6condit6 ou l'6closion des ceufs. Il sembleraitquecertaines especesd'invert6br6saquatiques,depoissons et de petitsmammifdresr€sistente I'actiontoxiquede I'endrine;d'ailleurs I'exposition ir diven pesticidesorganochlordsa pu entrainerla sdlectionde souchesr6sistantesi I'endrine. Dansdeszonesoi existentdesdechargesindustrielleset of I'endrine peut ere entrain6epar ruissellementi partir des champstrait6s, on a observ6 une mortalit6 parmi les poissons;par ailleurs, le ddclin des populatiorsde p€licansbruns(enLouisiane)et decaugeks(auxPays-Bas) a 6t6attribueeir une expositioni l'endrineet i d'autresd6riv6shalog6n6s.

Effetssurlesanlmauxd'exp6rience et surlessystemesin vitro L'endrine est un pesticide fortement toxique dont les signes d'intoxicationsontdetypeneurologiques. Chezlesanimauxdelaboratoire, la DLro par voie orale de l'endrinede qualit6 techniquese situe dansles imitesde 3-43 mgikg depoidscorporel;la DLrodermiqueva de 5-20 mg/ kg depoids corporelpour le rat. Il n'y apasde diffdrencenotableconcemant la toxicit6 aigudpar voie oraleet percutandeentrele produit techniqueet les diverses formulations (concentr6sdmulsionnablesou poudres mouillables). Des 6preuvesde courtedurdeportantsur la toxicit6 par voie oralede l'endrineont 6tdeffectu6essur dessouris,desrats,deslapins,deschiens et autres animaux domestiques.Chez les souris et les rats, les doses maximalestoldrdesont 6t6respectivement de 5 et l5 mg/kg de nourriture pendant6 semaines(soit l'6quivalentde 0,7 mg/kg de poidscorporel).Les ratsont survecusi unedosede I mg^cgdenourriturependant16 semaines (soit I'equivalentde 0,05 mg/kg de poids corporel);les lapinssont morts aprdsavoir regud plusieursreprisesunedosede I mg/kgdepoidscorporel. chezle chien,unedosede 1 mg/kg de nourriture(soit approximativemenr 0,025 mg/kg de poids corporel)administreesur une pdriodede 2 ans,n'a produit aucuneffet.

229

R6sumd

Du point de vue neurologique,les signesd'intoxicationobserv6ssont (GABA) dusd I'inhibition dela fonctiondeI'acidegamma-aminobutyrique i faible dose. Comme les autres hydrocarbures chlor6s insecticides, I'endrineagit 6galementau niveaudu foie et la stimulationdes systBmes enzymatiques intervenant dans le metabolisme des autres substances chimiques se manifeste,notanrmentchez la souris, par une diminution de la dur6e du sommeil induit par l'hexobarbital. Desdosesde 75-150 mg&g appliqu6essur1'6piderme deslapinssous forme de poudre slche, tous lesjours pendantdeux heuresont entrain€des convulsionset lamortchez cesanimauxsars toutefoisprovoquerd'irritation cutan6e.Cette intoxication par voie g€n6ralesarx irritation locale m6rite d'6tresignalee. Des 6tudes de toxicit6 et de canc6rog6nicit€ d long terme ont 6t6 effectudes sur des souris et des rats. Aucun effet canc6rogdne n'a 6t6 observ6 mais ces 6tudes pr6sentaienttrrr certain nombre d'insuffisances notamment la faible survie des animaux.Lors d'une 6tudede deux anssur desrats traitespar de l'endrine administreedansleurnourriture, on a estim6 n I mg/kg de nourriture,soit l'dquivalentd'environ0,05 mgtkg de poids corporel, la dose sanseffets toxiques observables.Aprbs administration d'endrine avec des quantit6 infinit6simales de substanceschimiques canc€rogdnes pour I'animal,il na pas6t6 possiblede mettre en 6vidence d'effet tumoro-promoteur. Le Groupe de travail en a conclu que les donn6essont insuffisantespour permettre de consid6rerl'endrine corune canc6rogdnepour I'homme. Plusieurs 6tudes ont 6galement r6vdl6 que l'endrine n'6tait pas g6notoxique. Dans la plupart des6tudes,I'endrine s'estr6v6l6enon t6ratogdnepour la souris, le rat ou le hamster,m€me i des dosestoxiques pour la mdre ou le fetus. La dosesanseffet nocif observablea 6t6 fvalule iL0,5 mglkg de poidscorporelchezla sourisetlerater e0,75mgTkgdepoidscorporelchez leshamsters.L'endrinen'apaseu d'effetssurla reproductiondesratssuivis pendanttrois gdn6rationsqui enrecevaientdansletu nourriture i raison de Zmg44g(soit environ 0,1 mgikg de poids corporel). Un certain nombrrede mdtabolitesde I'endrinesont plus ou moins toxiques que le compos€initial. Ainsi la delta-cdtoendrineest moins toxique de l'endrine, en revanchela l2-c6toendrine est consid6r6ecomme 230

EHC130:Endrin

le m6tabolite le plus toxique de l'endrine pour les mammifbres, avec une DLro par voie orale de 0,8-1,1 mg/kg de poids corporelchezle rat.

Effets sur I'homme Plusieurs cas d'intoxication mortels ou non mortels consecutifs i un accidentou irunetentativedesuicideont6tdobservds. Lescasd'intoxication aigudnonmortelsresultantd'unesurexpositionaccidentelleont6t6observ6s chez les ouwiers d'wre usine de production d'endrine. On estime que par voie orale,la dosemortelleestd'environl0 mg/kg de poids corporel,une doseuniqueprisepar voie oralede 0,25-1,0 mgtkg de poidscorporelpeut provoquer des convulsions. C'est au niveau du systBmenerveux central que l'endrine exerce principalementson action. Aprds exposition i dose toxique, des signes d'intoxication peuventfaire leur apparition et semanifestentsousla forme d'un hyperexcitabilitd et de conwlsions, la mort pouvant survenir dansles 2-12 heures suivant I'exposition si wr traitement appropri6 n'est pas institu6immediatement.En revanche,aprdsuneintoxicationnonmortelle, la recupdrationest rapide et compldte. L'endrine ne s'accumulepas dans le corps humain de manidre importante.Chez232travailleursexpos6sdeparlewprofession,on n'apas constat6d'effes inddsirablesi long terme (duree d'exposition 4-27 ans) lors desexamensm6dicauxpratiquds(durdede I'observation2-29 ans).Le seul effet observ6,indirectementd'ailleurs,consistaiten une stimulation rdversibledesenzyrnespharmacomdtabolisantes. Des analysesont 6t6pratiqu6esdansde nombreuxpayssur un grand nombred'6chantillonsde tissusadipeux,de sanget de lait matemelsans qu'il soit possiblede mettreen 6videncela prdsenced'endrine.Le Groupe de travail attribue I'absencedendrine dans ces echantillonsi la faible expositionde la populationg6ndrald ce pesticideet e sa mdtabolisation rapide. En revanche la pr6senced'endrine a 6tE&cel6e dans le sang (i des concentrationsatteignant450 pg/litre) et dansles tissusadipeux(i la dose de 89,5mg/kg) chezlespersonnesdecddeesd'uneintoxication accidentelle. Dans les conditions normales,on n'a pas retrouv6 d'endrine chez les travailleursexpos6s.Le seuil d'apparitiondes sympt6mesd'intoxication

231

R6sum6

estestim6i 50-1fi) pgllitre de sang.On persequela demi-viede I'endrine dansle sangest de l'ordre de 24 heures,

2.

Conclusions L'endrineestun irsecticidequi pr6senteune tGs forte toxicit6 aigu€. Il peutentrainerdesintoxicatiorngravesen casd'expositionexcessivedue d une manipulationn6gligentelors de saproduction,de sonutilisationou par suite de Ia consommationdaliments contaminds.L'expositionde la populationg6n6raleest principalementdue i la pr6sencede r6sidusdans les denr6esalimentaires;toutefois on estime que la quantitd d'endrine ing6r6eesten g6n6raltrdsinf6rieured la dosejoumalidreadmissiblefix6e par le Comit6FAO/OMS d'expertsdesr6sidusdepesticides.Il n'y a pasde dangerpour la populationgdndralequi rdsulteraitd'uneexpositionde ce genred I'endrine.Moyennantde bonnesm6thodesde travail et le respect desmesured'hygiEneet de s6curit6,l'endrinene devraitpasconstituerwr dangerpour les ouwiers expos6s. Il estdvidentquedesrejetsincontr6l6sd'endrinelors de la production, de la formulation et de l'utilisation de ce pesticidepeuvent cr6er des probldmesecologiquesdus i sa forte toxicit6. Il n'estpas possibled'6tre aussicategoriqueencequiconcemeleseffetsquepeutavoirsonutilisation en agriculture sur la faune et la flore, encore que I'entrainement par ruissellementdu pesticidepuisseconstituerunemenacepour lespoissons et les oiseauxpiscivores.Le d6clin despopulationsde certainesespbces d'oiseauxa 6t6attribu6ilaprdsencederdsidus 6lev6sdedivers organochlor6s dans les tissusdes adulteset dansles eufs. On a proc6d6au dosagede I'endrinechezcertainesde cesespdces;toutefoisil estdifficile de faire la part desdiff6rentsorganochlor6squi sont en cause.

3.

Recommandations t . L'endrine ne doit €re utilisee qu'en cas de n6cessit6et seulement lorsqu'il n'existepas d'autreproduit moins toxique.

2.

Afin de pr6serverla sant6et le bien-€tredes travailleurset de la populationg6n6rale,on ne doit confier la manipulationet l'6pandage qu'i des personnesbien encadr6eset bien formdesqui appligueront

232

EHC 13A: Endrin

des mesures de securitd convenables et dpandront le produit conform6ment aux rbgles de bonne pratique en la matidre. lors de la 3. Il convientde s'entourerde toutelespr6cautionsn€cessaires production,de la formulation,de l'utilisationen agricultureet du rejet de I'endrine afin de contaminer le moins possible l'environnement et en particulier les eaux de surface.

4.

Irs persoruresqui sont habituellement exposdesi l'endrine doivent subir des examensm6dicaux p6riodiques.

5.

Il faut poursuiwe l'6tude6piddmiologiquedes travailleursexpos6s'

6.

Dans les pays oi I'on utilise encorede l'endrine, on devra contrdler la pr6sencede r6sidus dendrine dars les denr6esalimentaires.

7. Au casoi l'on continueraiti utiliser de l'endrine,il faudrait obtenir davantagede donndessurla prdsence,la destin6eultime et la toxicite de la l2-c6toendrineet de la delta-cdtoendrine.

233

RESUMEN Y EVALUACION; CONCLUSIONES; RECOMENDACIONES 1.

Resumeny evaluacl6n

1.1

Exposici6n La endrina es un irsecticida organocloradoque se utiliza desdelos afloscincuentaparacombatir muy divenas plagasagricolas,sob'retodo en el algod6n armquenmbi6n en el uroz,la cafia de azricar,el maiz y otros cultivos.Seutiliza asimismocomorodenticida.Enel comercioseencuentra en forma de polvos, gntnulos, pastasy concentradoemulsionable. La endrina se incorpora al aire principalmente por volatilizaci6n y anastrea6reo.En general,lavolatilizaci6ntienelugardespu6sde aplicarla a suelosy cultivos y dependede muchos factores, como el contenido de materia org6nica y agua del suelo, la humedad, el flujo de aire y la superficie cultivada. La via m6s importante de contaminaci6nde las aguasde superficie es la escorrent(adesdeel suelo.La contaminaci6nporprecipitaci6n en forma de nieve o lluvia es insignificante.Puedeproducirsecontaminaci6nlocal del medio debidaa efluentesindustrialesy pr6cticasde aplicaci6npoco meticulosas. Laprincipal fuentedeendrinaenelsueloesla aplicaci6ndirectaa 6ste y a los cultivos. Puedequedarretenida,sertransportadao degradarseen el suelo, atendiendoa diversosfactores.La retenci6nm6s intensaseproduce en sueloscon contenidoelevadode materiaorgrinica.La persistenciade la endrinadependeengranmedidadelascondicioneslocales;susemividaen el suelopuedellegaralos I 2 afios.La volatilizaci6ny la fotodescomposici6n son los principales factores de la desaparici6nde la endrina de las superficiesdel suelo.La luz del sol (luz ultravioleta)inducela formaci6n del is6mero delta-cetoendrina.En verano, bajo insolaci6n intensa,se observ6 que alrededor del 50Vo de la endrina se isomerizaba a esta cetoendrinaenwrplazo de sietedias.Seproducetransformaci6nmicrobiana (en hongos y bacterias), especialmenteen condiciones anaerobias, originr,{ndose la misma sustancia.

234

EHC130:Endrln

Los invertebrados acudticos y los peces abaorbeqrdpidamente la endrinaa partir del agua,si bien los pecesexpuestostransferidosa aguano contaminadapierdenel plaguicidardpidamente.Sehanregistradofactores de bioconcentraci6n de 14-18 000 tras una exposici6n continua. Los invertebradosdel suelo tambi6n absorbenfdcilmente el compuesto. La presenciaocasionalde niveles reducidosde endrinaen el aire y en las aguasde superficie y de bebida en zonas agricolasreviste escasa importanciadesdeel puntodevistadela saludptiblica.La fnica exposici6n que merececonsideraci6nes la ingestaen la dieta.En general,no obstante, los niveles comunicadosde ingesta se encuentranmuy por debajo de la ingestadiaria admisiblede 0,0002mg/kg de pesocorporal,establecidaen 1970(FAO/OMS, 1971).

Absorci6n, metabollsmo y sxcrecl6n A diferenciadela dieldrina,suestereois6mero,la endrinasemetaboliza r6pidamenteen los animales,y seacumulaen muy pequeflacantidaden las grasasen comparaci6ncon compuestosde estructuraquimica andloga. En la rata,tantola absorci6ncomo Ia excreci6ntrasla administraci6n oral seproducenrdpidamente;susemividabiol6gicaesde l-6 dias,segin la dosis adminisrada. Al cabode 6 dfas se alcanzaun estadode equilibrio en el que la cantidadexcretadaes igual a la ingestadiaria. Se observan diferencias de un sexo a otro: los machosexcretanendrina y metabolitos con la bilis mucho m6s deprisaque las hembras,lo que produce una acumulaci6nmenoreneltejidoadiposodeaqu6llos.Lasratasexcretaneste compuestoprincipalmenteen las hecesen forma de endrina,anti-12hidroxiendrina, y un derivado hidroxilado durantelas primerashoras (70?57o);un tercermetabolito,la 12-cetoendrina, seacumulaenlostejidos.El conejo excreta eI 50Vode los metabolitosdel compuestoenla orina, mientrasque en la rata s6lo elZVoseexcretapor estavia; en lashecesdel conejos6lo se detectaendrinasin alterar. Las vacasa las que se administr6endrinaaraz6nde 0,1 mg/kg de la dietadurante2I diasexcretaronhastael65Voen forma de metabolitosen laorina,elZ0voen lasheces,parcialmenteenforma de endrinanoalterada, y el 34oen la leche,tambi6nprincipalmenteen forma de endrina.Estas vacaspresentaronnivelesresidualesde 0,003-0,006mg/itro en la leche, 0,001--0,002mg/kg en la came,y 0,02-O,l mg/kg en la grasa.

235

Resumen

En gallinas ponedorasa las que se administr6 endrina por via oral seobservaronniveles residuales(dependientesde la dosisadministrada)de hasta0,1 mg/kg en la carne, I mg/kg en la grasa,0,24,3 mg/kg en los huevos(yema),O,2mgkg en el rii6n y 0,5 mgftg en el higado.Salvo en el hfgado y el rif,6n, los residuos encontrados estaban formados principalmentepor endrinano alterada.Alrededordel50Vode la endrina administrada se excret6 en las heces, principalmente en forma de metabolitos. En el serhumano,la rata,el conejo,la vacay la gallina, el principal metabolito biotransformado de la endrina es la anti-12-hidroxiendrina, junto con su sulfatoy su glucur nido conjugados.Se encontraroncuatro metabolitosm{s, si bien en cantidadesmuy reducidas.En los tejidos corporalesyen lalecheseencuentrasobretodoendrinainalterada.Trasla aplicaci6nde esteplaguicidaa plantas,seidentificaronendrinainalterada y dos productos de transformaci6nhidr6filos.

1.3

Efectos en los organismos del medio ambiente El efecto de la endrina en las bacteriasy los hongos del suelo es m(nimo.Con dosisde10-1Ofi)mg/kgdesuelonoseobsery6efectoalguno enladescomposici6ndemateriaorgrinica,ladesnitrificaci6nni lageneraci6n demetano.La en&ina essumamentet6xicaparalospeces,losinvertebrados acu6ticosy el fitoplancr.on:los valores de la CLro a las 96 horas se encuentran ensumayor(apordebajode 1,0pg/litro.El nivel sinobservaci6n de efectos mris bajo en un ensayo de ciclo biol6gico del crustdceo Mysidopsisbahia se fij6 en 30 ng/iuo. L,osensayoscomunicadossobrela toxicidadagudade la endrinapara los organismosacudticosse llevaron a caboen acuariossin sedimentos; cabria esperarque la presenciade sedimentosatenuarael efecto de! insecticida.Los sedimentosmuy contaminados ejercieronescasoefectoen las especiesde aguaslibnes,lo que indica que la endrina ligada a los sedimentostieneuna biodisponibilidadreducida. Arin no sehan llevado a caboersayosen animalesacudticosque viven en los sedimentos. La DLro para mamiferos terrestresy aves oscila entre 1,0 y l0,0mg/kgdepesocorporal. Lospatossilvestres alosqueseadministraron 3,0 mg/kg de peso corporal durante 12 semanasno mostraronefecto algunoen la producci6nde huevos,la fertilidad o la eclosi6n. 236

EHC 130: Endrin

Ciertas especiesde invertebrados acudticos, peces y mamiferos de pequef,otama o son resistentesa la toxicidad de la endrina; la expoSici6n a diversos plaguicidasorganocloradosllev6 a la selecci6nde estirpes resistentesa la endrina. Se observaron muertes masivas de peces en zonas de escorrentfa agricola y descargasindustriales;el declive de laspoblacionesdepelicanos pardos (en Luisiana, EE.UU.) y de golondrinas de mar (Thalasseus en losPafsesBajossehaatribuidoa la exposici6na la endrina sandvicensis) en combinaci6ncon otrassustanciasquimicashalogenadas. Efectos en anlmales de experimentaci6n

in vitro

La endrina es un plaguicida sumamentet6xico; los signos de intoxicaci6n sonde car6cterneurot6xico. La DLro por via oral de la endrina de calidad t6cnica en animalesde laboratorio oscila entre 3 y 43 mg/kgde peso corporal; ta DLro por via cuti{neaen la rata es de 5-20 fnglkg peso corporal. No seha encontradoningunadiferencia en la toxicidad agudapor via oral o cut6neaentre los productos de calidad t6cnica y los formulados (concentradoemulsionabley polvos humectables). Sehanllevadoa caboexperimentosde breveduraci6nparaestudiarla toxicidad por via oral en el rat6n, la rata, el conejo,el perro y animales dom6sticos.En el rat6n y la rata, las dosis m6ximas toleradasdurante 6 semanasfueron 5 y 15 mg/kg de la dieta (equivalentesa 0,7 mg&g de pesocorporal),respectivamente, Lasratassobrevivierontrasunaexposici6n a 1 mg/kg de la dieta (equivalentea 0,05 mglkg de pesocorporal) durante 16 semanas;los conejosmurieron tras recibir dosis repetidasde I mgikg de peso corporal. En el perro, no se observ6 efecto alguno tras la administraci6n de I mg/tg de la dieta (equivalente aproximadamentea 0,025 mg/kg de peso corporal) durantem6s de 2 aflos. La baseneuro6gicade los signosde intoxicaci6n observadoses la inhibici6n de la funci6n del 6cido gamma-aminobutirico (GABA) con dosisreducidas.Al igual que otros insecticidasa basede hidrocarburos clorados, la endrina afecta tambi6n al higado, y se observaclaramenteIa estimulaci6nde sistemasenzimdticosqueparticipanen el metabolismode otras sustanciasquimicas, como lo demuestra,por ejemplo, la menor duraci6n del suerlopor hexobarbital en el rat6n.

237

Besumen

Con dosis de 75-150 mglkg aplicadaspor via curdneaen forma de polvo secodtrante 2 horas al dfa seprodujeron convulsionesy la muerte en el conejo pero sin iritaci6n cut6nea.Esta toxicidad sisr6micasin irritaci6n en el lugar de contacto resulta muy notable. Se han llevado a cabo en ratones y ratas estudios prolongados de toxicidad y carcinogenicidad.No se observ6 efecto carcinog6nico, pero estosestudiostenianciertosdefectos,entreellos Ia reducidasupervivencia delos animales.Elnivel sinobservaci6ndeefectosencuantoa la toxicidad en un estudiode dos aflosde duraci6n en la rata fue de I mg/kg de la dieta (equivalentea unos0,05mg&g de pesocorporal).No sedemostr6ningrin efecto de favorecimiento de tumores cuando se ensay6 la endrina en combinaci6n con cantidadessubminimas de sustanciasquimicas de conocido efecto carcinogdnico en los animales. El Grupo de Trabajo concluy6 que los datos de que se dispone no bastanpara indicar que la endrina suponeun riesgo carcinogdnicopara el ser humano. En varios estudiosse observ6que la endrina no es genot6xica. En la mayorfa de los estudiosno result6 teratog6nicapara el rat6n, la rata o el h6mster,ni siquiera con dosis suficientesparaprovocar toxicidad materna o fetal. El nivel sin observaci6n de efectos adversos fue de 0,5 mg/kg de peso corporal en raronesy ratas y de 0,75 mg/kg de peso corporalenelhi{mster. I-aendrinanoindujoefectoalgwroen lareproducci6n deratasestudiadasdurantetresgeneracionescuandoseadministr6 a raz6n de2mgkg de la dieta (unos0,1 mg&g de pesocorporal). Algunos metabolitos de la endrina tienen toxicidades agudasiguales o mds altasque el compuestooriginario. El productode transformaci6n,la delta-cetoendrina, esmenost6xico que la endrina,perola l2-cetoendrina seconsiderael metabolito miis t6xico en los mamiferos, con una DLro por vfa oral en la rata de 0,8-l,l mg/kg de pesocorporal.

1.5

Efectos en el ser humano Sehanproducidovariosepisodiosde intoxicaci6nmortaly nomortal, tanto accidentalescomo suicidas.Los casosde intoxicaci6n agudano mortal debidaaexposici6nexcesivaaccidentalseobservaronentrabajadores de una planta de fab'ricaci6nde endrina. Se ha calculado que la dosis que por vfa oral provoca la muerte es de aproximadamente10 mg/kg de peso 238

EHC 130: Endrln

corporal; la dosisrinica por vfa oral que provocaconvulsionesse fij6 en 0,25-1,0 mg/kg de pesocorporal. El lugar principal de acci6n de la endrina es el sistemanervioso central.La exposici6ndel serhumanoa unadosist6xicapuedeproduciral cabo de pocas horas signos y sintomas de intoxicaci6n tales como excitabilidady convulsiones;la muertepuedeproducirseen las2-12 horas quesiguena la exposici6nsino seadministrainmediatamente el tratamiento apropiado.La recuperaci6ndespu6sde una intoxicaci6n no mortal es rdpiday completa. La endrinano seacumulaen el cuerpohumanoen gradosignificativo. No se comunicaron efectos adversosa largo plazo en 232 trabajadores expuestos(duraci6nde la exposici6n:4-27 aflos)bajo supervisi6nm6dica (tiempo de observaci6n: 4-29 aios). El rinico efecto observado fueron pruebas indirectas de una estimulaci6n reversible de las enzimas metabolizadoras de f6rmacos, No se detect6endrinaen pr6cticamenteninguna muestrade tejido adiposo,sangrey lechehumanaanalizadasennumerosospafses.El Grupo de Trabajoatribuy6 la ausenciade endrinaen las muestrashumanasa la baja exposici6nde la poblaci6ngenerala esteplaguiciday a su r6pido metabolismo. La endrina se detect6en la sangre(con concentracionesde hasta 450 pgllitro) y en el tejido adiposo(enconcentraciones de 89,5mglkg) en casosde envenenamientoaccidentalmortal. No seencontr6endrina en los trabajadoresen circtmstanciasnormales,El nivel umbral de endrinaen la sangrepor debajo del cual no se produce ningfn signo o sintoma de intoxicaci6nseha fijado en 50-100 pgnitro. La semividade la endrinaen la sangrepuedeser del ordende 24 horas.

Conclusiones La endrina es un insecticidacon elevadatoxicidad aguda.Puede provocarenvenenamiento graveencasosdeexposici6nexcesivaprovocada por lm manejo poco meticuloso durante su fabricaci6n y uso o por el consumode alimentoscontaminados. El priblicoestdexpuestoa la endrina principalmentepor susresiduosen los alimentos;no obstante,los niveles de ingestade endrinaquesehancomunicadoestdnpor lo generalmuy por

239

Resumen

debajode la ingestadiaria admisibleestablecidapor la FAO/OMS. Esas exposicionesen principio no constituyenun riesgo para la salud de la poblaci6ngeneral.Cuandoseaplicanbuenas prdcticasde trabajo,medidas higi6nicasy precaucionesde seguridad,es poco probableque la endrina supongaun riesgopara los trabajadoresexpuestos. Est6 claro que las descargasno controladasde endrina durante su manufactura, formulaci6n y uso pueden originar graves problemas ambientalesasociadosa su elevadatoxicidad.Los efectosdel usoagricola del insecticida en la fauna y la flora estdnmenosclaros, si bien los peces y las aves ictivoras est6n expuestospor la escorrentfaa partir de las superficies.El declivede laspoblacionesde algunasespeciesde aves.seha aribuido a la presencia de niveles elevados de residuos de diversos compuestosorganocloradosen los tejidos de adultosy en los huevos.Se ha medido la endrinapresenteen algunasde estasespecies,pero es muy dificil separarlos efectosde los distintos compuestosorganoclorados presentes.

3.

Recomendaclones L No debe utilizarse la endrina a menos que sea indispensabley s6lo cuandono se dispongade una altemativa menost6xica.

2. Para la salud y el bienestarde los trabajadoresy de la poblaci6n general,el manejo y el uso de Ia endrina seconfiariin s6lo a operarios bien supervisadosy adiestadosqueapliquenlasmedidasdeseguridad adecuadas y utilicen la endrinade acuerdocon lasprdcticasagricolas colTectas. J.

La fabricaci6n,la formulaci6n, el uso agrfcolay la evacuaci6nde endrina se tratar6n cuidadosamentepara reducir al minimo la contaminaci6ndel medio, en particularde las aguasde superficie.

4. Las personasexpuestasregularmentea la endrinadebensometersea revisionesm6dicasperi6dicas.

5 . Proseguir{nlos estudiosepidemiol6gicossobrelas poblacionesde trabajadoresexpuestos.

EHC 130: Endrin

En los pafsesen los que arin se usa la endrina,debenvigilarse sus residuosen los alimentos,

7. Si sigue utilizr{ndose la endrina, debe obtenersemds informaci6n sobrela presencia,el destinoriltimo y la toxicidaddela I 2-cetoendrina y la delta-cetoendrina.