204 Cu1mE. Vm.ws ON PESTICIDESCanad. Med. Ass. J.100

R48um. L'article commence par un bref his-torique de Ia l6gislation britannique sur

la propret6 et la puret6 des ailments, puis expliqueIa philosophie et le fonctionnement de l'organisationvolontaire qui contr6le dans ce pays les r6sidus despesticides pr6sents dans les ailments concernant leconsommateur.En principe, aucune loi n'a encore fix6 de taux

admissible des r6sidus de pesticides. Gependant unesurveillance continuelle est exerc6e afin que le tauxdes r6sidus reste en dessous de celui que les normesm6dicales jugent dangereux pour la sant6.

REFERENCES

1. FILBY, F. A.: A history of food adulteration andanalysis, Allen & Unwin Ltd., London, 1934.

2. HAMENCE, J. H.: The 1860 Act and its influence onthe purity of the world's food. In: Pure food and

pure food legislation, edited by A. 3. Amos, Butter-worth & Co. (Publishers) Ltd., London, 1960, p. 5.

3. Great Britain, Research Study Group on Toxic Che-micals in Agriculture and Food Storage: Toxicchemicals in agriculture and food storage: reportto the Minister of Agriculture, Fisheries and Food.-the Minister of Science, the Secretary of State forScotland and the Minister of Health, Her Majesty'sStationery Office, London, 1961.

4. Great Britain, Ministry of Agriculture and Fisheries,Workin Party on Precautionary Measures AgainstToxic .hemicals Used in Agriculture: Toxic che-micals in agriculture: residues in food: report, HerMajesty's Stationery Office, London, 1953.

5. Idem: Toxic chemicals in agriculture: risks to wildlife: report, Her Majesty's Stationery Office, Lon-don, 1955.

6. Great Britain, Ministry of Agriculture, Fisheries andFood: Pesticides safety precautions scheme, HerMajesty's Stationery Office, London, 1966.

7. Great Britain, Advisory Committee on Pesticides andOther Toxic Chemicals: Review of the presentsafety arrangements for the use of toxic chemicalsin agriculture and food storage, Her Majesty'sStationery Office, London, 1967.

Significance of Pesticide Residues in Foods in Relationto Total Environmental Stress

H. F. KRAYBILL, Ph.D.,* Washington, D.C., U.S.A.

THROUGH the utilization of pesticide chemi---cals man has achieved a more abundant sup-ply of food and fibre and enhanced the control ofpest-vectored diseases. Associated with such pestcontrol procedures is the problem of chemicalcontamination of the environment of man, ani-mals and aquatic organisms. An awareness of thisproblem by the general public and environmentalhealth scientists has led to the promulgation ofnew statutes by groups of nations to govern thecontrol of chemical residues in the food supplyand the total environment. This concern for en-vironmental pollution evolved from earlier recog-nition of the hazards of fallout radioactivity, bac-terial toxins and, more recently, by the presenceof fungal metabolites in certain food crops.A balanced account of the overall problem of

environmental pesticide contaminants and resi-dues was portrayed in the President's Science Ad-visory Committee Report on MUse of Pesticides."'Regulatory and legislative procedures advancedfor enforcement of standards of safety or other

Presented at a Symposium on Current Views on Pesti-cides, sponsored by the Food and Drug Directorate,Department of National Health and Welfare, Ottawa,Ontario, June 5 and 6, 1968.*Asslstant Director for Biological Sciences Research,Bureau of Science, Food and Drug Administration,Washington, D.C.Reprint requests to: Dr. H. F. Kraybill, AssistantDirector for Biological Sciences Research, Bureau ofScience, Department of Health. Education, and Welfare,Food and Drug Administration, Washington, D.C. 20204,U.S.A.

standards have not been restricted to nationalscope but indeed have become a matter of inter-national co-operation and agreement.

It is no longer appropriate or desirable to viewthe pesticide contamination problem relevant toman's total exposure and human health in termsof one environmental component, such as food,but rather an overview must prevail encompas-sing the total environment. Reinforcement ofthese considerations necessitates recognition ofthe potentiating role of multiple pesticide che-mical exposure and the interaction of other che-mical stress agents and drugs from which manmay receive a constant challenge. It is, therefore,incumbent upon local, state and federal agenciesthat regulatory programs prevail and legislationbe enacted for control, elimination or minimiza-tion of the presence of pesticides and pesticideresidues in food, water, air and other parts ofman's environment.

ExPosu1.E ASSESSMENT

Man and animals are exposed over their entirelifetime to various atmospheric contaminants,water pollutants and toxic residues in food. Inconsideration of the risk involved and safetymeasures to be implemented, the impact is firstviewed in terms of exposure of the general pop-ulation. In this context the greatest exposure to

Canad. Med. Ass. J.Jan. 25, 1969, vol. 100 Current Views on Pesticides 205

From AirConc = 2xl0" (jg/mIntake = 13xl03m3

From H2OConcr0.03ppblntake-365 litres

TOTAL EXPOSURE35mg

4.96mg.

Absorbants Inhalants

Cosmetics -3.5mg.Aerosols JClothing > 1.46mg.House Dust )

From Food

Cone. .037 mg./kg. of Wet DietIntake 803 kg.

Fig. 1..Sources of pesticide exposure.

pesticides of most consumers in the general pop¬ulation results from residues in food. The authorhas stated2 that for individuals in the generalpopulation 90% of the total persistent pesticideexposure arises from pesticide intake in food.This statement is further corroborated by datapresented by Campbell, Richardson and Scha-fer.3 In Fig. 1 the data presented demonstratethe need for considering environmental factorsother than food. A recalculation of the data fromthe above referenced sources has been madeand the estimated annual environmental expo¬sure to DDT + DDE through ingestion, absorp¬tion and inhalation routes of exposure is reflectedin Fig. 1. For the general population organo¬chlorine insecticide ingestion, represented byDDT + DDE in food, would be approximately85% of the estimated total exposure. It is recog¬nized that precise data are lacking on the com¬

ponent environmental exposure to pesticides fromsources other than food and water. The magni¬tude of the concentration of pesticides contri¬buted by potable water supply can be accuratelymeasured since broad surveillance programs inthe United States have been designed for thatpurpose. Determination of the exact exposurelevels in air has been somewhat more difficultowing to lack of adequate collection instruments.Only recently have some significant advancesbeen made in this area according to Yobs.4The "general population" in those geographical

regions where aerial spraying for crop and forestinsects or mosquito abatement programs takesplace receives, of course, higher atmospheric lev¬els of pesticide exposure. Another example ofatmospheric exposure for the general populationis the excessive and continuous use of aerosolspraying for insect control in homes and institu¬tions and of Vapona (DDVP) strips for fly con¬

trol. In such instances the above figures for pro-portionate levels of total exposure to pesticidesfrom foods would have to be revised downward.

Blood levels of DDE in selected members of thegeneral population have suggested the impor¬tance of considering the environmental insultfrom aerosol spraying and other domestic appli¬cations. Studies in south Florida by Davies etel./' conducted on persons having no recent or

remote history of being occupationally exposedto pesticides, have revealed DDE levels in theblood of a combined population of male and fe¬male whites in the range of 1.8 to 19.4 ppb or a

mean of 8.0 ppb. Similarly, among non-whitemales and females the range in DDE levels inthe blood was 3.6 to 54.2 ppb or a mean of 16ppb. No explanation was given for the ethnicdifferences in blood levels of DDE other thanthat one can assume variant chronic environmen¬tal exposure.5 Further consideration is beinggiven to environmental exposure to pesticidechemicals in various other substrates. For exam¬

ple, residues in clothing, rugs, blankets (formothproofing), in dust from vacuum sweepers,and on contact surfaces such as pesticide-treatedand painted walls, may become absorbed by theskin on contact or inhaled by volatilization or

dispersion into the air. To our knowledge no

measurements have been made on residues indrugs from plant materials treated with pesti¬cides. However, levels of chlorinated insecticidesin cosmetics have been determined by Edmund-son et al.e

Since many of the cosmetics are labelled as

containing lanolin, analyses were made and vari¬ous organochlorine insecticides were determinedin the lanolin cosmetic products. It might be ex¬

pected that organochlorine insecticide chemicalswould be taken up by natural oils and fats, in¬cluding wool fat, especially since sheep are

treated with these pesticides for control of ecto-parasites. Analyses were made for BHC (a, p andy isomers), dieldrin, p,p'-DDT, p,p'-DDD andp,p'-DDE. The products examined were eyeshadow, lipstick, hair spray and dressing, andcreams and lotions. The following levels of DDT-(- DDE were found in (a) hair dressing.3.83ppm total DDT + DDE (DDT-3.5 ppm, DDE-0.33 ppm); (b) lipstick-8.50 ppm DDT; (c)hair lotions and sprays.3.1 ppm DDT -+- DDE(DDT-2.8 ppm, DDE-0.3 ppm); and (d) eyeshadow.0.16 ppm DDE. All products but eyeshadow contained BHC, dieldrin, DDT andDDE. Based on some rough quantitative esti-mates of usage by men and women, the annualDDT + DDE exposure (largely absorption)contributed by these products was approximately3.5 mg. per person (Fig. 1).Thus far no mathematical models have been

constructed to integrate the component contri¬butions of all these sources of exposure. Ultimate-

206 Current Views on Pesticides Canad. Med. Ass. J.Jan. 25, 1969, vol. 100

ly this will be necessary to provide an accuratemeasurement of the stress from pesticides in notonly food but also those other environmentalcomponents which challenge the general popu¬lation. In current epidemiological studies con¬

ducted by the U.S. Public Health Service, a sur¬

veillance of these exposure sources is being madefor evaluation of the relative contribution of pest¬icide exposure from all these environmental con¬

tributors.7Another segment of the population that is con¬

sidered at high risk relevant to pesticide expo¬sure are those who are occupationally exposed,such as formulators, aerial spray pilots, pest con¬

trol operators, agricultural applicators and chem¬ical manufacturing plant employees. These mem¬

bers of the population receive exposure to pesti¬cides by one or all three routes of entry into thebody.inhalation, absorption and ingestion. Itmay seem irrelevant to consider this populationgroup in relation to evaluation of the potentialhazard from the usual environmental exposure ofthe general population to food, water and air.

PESTICIDE EXPOSURE/ \

ABSORPTION INGESTION INHALATIONM 4

1. OCCUPATIONAL fnvironmFNTAI . OCCUPATIONAL2. ENVIRONMENTAL ENVIRONMENTAL 2# ENV|R0NMENTAL

OCCUPATIONAL EXPOSUREPEST CONTROL OPERATIONS

2. AGRICULTURAL APPLICATIONS3. FORMULATION OPERATIONS4. MOSQUITO ABATEMENT

OPERATIONS5. PESTICIDE MANUFACTURING

ENVIRONMENTAL EXPOSUREl.AIR2. WATER3. FOOD4.C0SMETICS-DRUGS5. CONTACT SURFACES6. AEROSOL USES7. PERSISTENCE IN SOILS8. AUTOMATIC DlSPENSING DEVICES9. PESTICIDE STRIPS

Fig. 2..Types of pesticide exposure of various popula¬tion groups.

However, from epidemiological considerationstheir exposure and the magnitude of their ex¬

posure must be recognized in considering what¬ever limitations are imposed for this group sincetheir total exposure reflects a summation of allexposures, including the maximal exposure ex¬

perienced by the general population under allconditions. A diagrammatic representation oftypes of pesticide exposure of various populationgroups is shown in Fig. 2.The aspect of environmental exposure that is

of primary concern to regulatory agencies such as

the Food and Drug Administration is the extentand magnitude of pesticide residues in and on

foods. This concern is motivatcd by traditionssupported by law and policy of many decades toassure the consuming public that the food supplyis reasonably free of contaminants and henccsafe and wholesome. To this end, standards of

safety are established which, within the Foodand Drug Administration, relate to establishmentof tolerances for chemical pesticides on or infood and feedstuffs as provided for in the Pesti¬cides Chemical Amendment of the Food, Drugand Cosmetic Act (Section 408). Obviously, ex¬

tensive treatment of the legislative and regulatoryphases of the tolerance problem is not the pri¬mary objective of this report but rather attentionwill be directed toward the scientific aspects ofthe problem of pesticide residues in and on foods.With respect to previous discussion of total en¬

vironmental impact of pesticide exposure it is ofinterest, however, to note that Section 408b ofthe Food, Drug and Cosmetic Act gives appro¬priate consideration to "other ways in which theconsumer may be affected by the same pesticidechemical". This would certainly imply that thetoxicologist must look beyond the challenge toman from a pesticide residue in food that is in¬gested and must consider the relative contribu¬tions from air, water, cosmetics and drugs, atmos¬

pheric levels from aerosol spraying and others.Evaluation of the integrated environmentalstress, which is the ultimate goal, does introducesome complexities in safety evaluation when de-liberations are under way in the establishment oftolerances. For example, it has been the practiceto require a petitioner for a pesticide toleranceto provide data which will reveal the extent ofpersistence of the pesticide in the soil after agri¬cultural application.The residue problem ultimately focalizes on

the so-called persistent pesticides of which theorganochlorine insecticides, such as DDT (withthe metabolites DDE and TDE), aldrin, dieldrin,gamma BHC, chlordane and heptachlor and itsepoxide are notable examples. None of the cur¬

rent legislation attempts to define persistentpesticides. However, in recent years, because ofconcern over persistent pesticides, repeated billshave been introduced in Congress which, in ef¬fect, would practically eliminate or greatly re-

strict the use of persistent organic chemicals.These pesticides may be present in high con¬

centration as residues on food crops at harvesttime because their chemical nature imparts some

resistance to biodegradability. If not completelyremoved, and in some cases this is impossible,these compounds appear as residues in the som-

atic tissue of man and animals from ingestion offood and feeds in which such residues appear.Because of this situation some of the compoundsmay require a high tolerance. One of the incon-gruities of the persistent pesticide problem is thatthese persistent pesticides, since they are resist¬ant to environmental degradation (air, light andwater) and are therefore efficacious in insect con-

Canad. Med. Ass. J.Jan. 25, 19G9, vol. 100 Current Views on Pesticides 207

trol, do contribute to the appearance of residuesin substrates such as food and human adiposetissue, where they are not desired. It has beensuggested and considered that perhaps applica¬tion of persistent pesticides should be limited toearly phases of crop maturation whereas duringthe later stages of crop development a non-per-sistent or degradable pesticide might be used.Such a procedure, utilizing both types of com¬

pounds, might achieve the goal of reduction or

partial elimination of persistent pesticides, as

recommended in the PSAC Report on Use ofPesticides.1As useful as the persistent pesticides are in

insect control, they have a long residence time inthe soil and are capable of contaminating cropsin successive years after initial application, eitherthrough direct entry into root crops, such as

potatoes, carrots, sugar beets, ete, or by trans-location to the leafy and stem portions of a plantor crop that is later to be consumed by domesticanimals or man. Some illustrations of such occur-

rences follow:(a) soybeans containing endrin.this crop

was grown in soil where cotton had been grownand treated with endrin;

(b) carrots containing endrin.grown in soilwhere a crop had been previously treated withendrin;

(c) alfalfa containing dieldrin and heptachlorepoxide.alfalfa was grown in soil where a previ¬ous crop had been treated with these pesticides;

(d) dried sugar beet pulp from sugar beetscontaminated with dieldrin.this crop was grownin soil which had previously been treated withaldrin for several years.The tolerances in feed crops have been pur-

posely established to minimize or preclude trans¬fer of pesticides as residues into meat, poultry,eggs and dairy products. Remarkable progress isbeing made in this direction under current uses

of persistent pesticides in agricultural practices.The previously mentioned products are the typesof foods that present the highest pesticide resi¬dues, but detailed reference to this matter willbe made later.The quantity of pesticides actually consumed

by man has relevance to health significance. Forthis reason one might consider the setting oftolerances for pesticide residues on the pro-cessed foods or the "ready-to-eat preparedfood" as the ideal practice. However, the ob-jection to such a proposed procedure in estab¬lishment of tolerances is that one could not ade¬quately refer residues above tolerances in thefood at this point in the distribution system to

appropriate corrective action. Hence, this systemis impractical for a control program. The

tolerance establishment makes use of data fromexperimental animals on "no effect" levels, cu-

mulative potential of the pesticide, metabolicfate and maximal contribution to the total dietwhich might be expected if all commodities forwhich tolerances are sought have residues at thetolerance levels.all of which is extrapolated to

potential effects on man. The tolerance level thatis set permits an adequate margin of safety be¬tween that level and the "no effect" level ob¬tained from animal experimental data, keepingin mind the proportion of the total diet con¬

tributed by the food crop which man wouldconsume and from which the particular pesti¬cide residue might be anticipated.Another factor in the consideration of the ap-

plicability of tolerances in terms of safety is thatthe tolerance must be at such a level as to en¬

sure safety for the consumer, if an individualdid consume a particular raw food which con¬

tained residues at the tolerance level. As pre¬viously stated, however, in such deliberationsthe amount of food consumed in the raw stateis compared with the proportion consumed inthe processed state where residue reduction oc¬

curs.8In the United States the Food and Drug Ad¬

ministration examines some 25,000 samples offood annually to ascertain the adequacy of com¬

pliance and the practices used in pesticide ap¬plication to the end that food and feed cropsare within the established tolerances. During a

four-year period about half of the samples ex¬

amined contained residues of one or more pesti¬cide chemicals. Only 3% of these samples ex¬

ceeded legal tolerances or, if no legal toleranceshad been established, were beyond the guidc-lines for excessive residues. Of the samples con¬

taining residues, 75% of the individual pesticideresidues found were below 0.11 ppm and 95%of the residues were below 0.51 ppm.s

In order to acquire definitive data on pesti¬cide residues in foods as actually consumed,various systems have been employed. One ofthese systems is the total diet study or "marketbasket survey" used by the Food and Drug Ad¬ministration. Detailed description of this pro¬cedure has been referred to elsewhere," but, inessence, samples of food obtained bi-monthly atretail stores in five geographical regions are pre¬pared for consumption and composited into 12classes of similar foods for more reliable ana¬

lysis and minimization of the dilution factor.The food intakes are those selected for a 16- to

19-year-old male group reflecting maximal con¬

sumption of about 4 kg. (8.8 lbs.) of food andbeverage daily. This is almost twice the intakein the standard adult diet of an individual at

208 Current Views on Pesticides Canad. Med. Ass. J.Jan. 25, 1969, vol. 100

TABLE I..Averaue Daily DDT and DDE Conteviof Total Diets ou Prepared Meals

(U.S. Public Health Service Studies)

YearsDDT DDEmg. mg.

PHS household meals. 1902-04 0.314 0.173(Wenatchee, Wash.)10

PHS restaurant meals. 1962-04 0.038 0.044(Wenatchee, Wash.)10

PHS restaurant meals. 1953-54 1.178 0.020(Wenatchee, Wash.)11

PHS institution studv*11"11... 1953-00 0.130 0.039

Mean of PHS studies... 0.199 0.122FDA total diet studv**15' 16.. 1903-04 0.020 0.015FDA total diet study8- ,J. 1905-07 0.028 0.021

*Mean of four studies including meals of meat abstainers(0.041 mg. DDT and 0.024 mg. DDE). Meals taken atTacoma and Walla Walla, Wash., Tallahassee, Fla., andAnchorage, Alaska.

**Assuming intake of 3.78 kg. of diet as compared withPHS study wnere intake was 2.1 kg.

moderate activity, which provides approximately2.2 kg. (4.8 lbs.) daily. Hence, the intake ofpesticide associated with this high food con¬

sumption should present the maximal exposurefor a general population group. Other studies on

total diet pesticide content have been con¬

ducted by the U.S. Public Health Service cover-

ing the period 1953-1964. These studies were

based on complete, prepared meals taken inprisons, hospitals, restaurants and a collegewhere meat was not a component of the diet.10"14In the Public Health Service studies the averagedaily intake of food was about 2.1 to 2.2 kg.,which was considerably less than the total dietintake represented in the Food and Drug Ad¬ministration studies for the 18- to 19-ycar-oldmale. Earlier diet studies conducted by FDAhave been reported by Millsir> and Williams.1"

In Table I a summation of the data for allthese studies is presented, reflecting the averagedaily DDT and DDE content of total diets or

prepared meals during the period 1953-1967.The pesticide residues in household meals dur¬ing 1962-1964 were somewhat higher than thosein restaurant meals taken at Wenatchee, Wash¬ington, even though the total weight of foodconsumed was about the same. Home-grownfoods or specialty produce which could havebeen used in the household meals and whichmay have been unprocessed or eaten raw, con¬

taining higher residues, may have accounted forthis difference. In any event, it was assumedthat the restaurant meals more nearly typify theaverage DDT and DDE intake for the generalpopulation in the United States. If one com-

pares the DDT and DDE content of restaurantmeals for the period 1953-54 with that of 1962-64 there is noted a decrease in daily DDT in¬take from 0.178 to 0.038 mg. and for DDE in¬

take a slight increase from 0.026 to 0.044 mg.Studies in the institutions, including prisons andhospitals, during the period 1953-1960, reflectedfrom the mean DDT value of four studies a

slightly higher value for this pesticide than thatin the restaurant study of 1962-64, but were

comparable in DDT value to the restaurantstudy for 1953-1954. The mean value for DDTdaily intake in institutions for the period 1953-1960 was about 0.167 mg., but the value of0.136 mg. given in Table I represents the in¬clusion of values from food samples taken at a

college in Walla Walla, Washington, wherethere were meat abstainers. It is of interest tonote that the diet for meat abstainers con¬

tributed only a daily intake of 0.041 mg. of DDTand 0.024 mg. of DDE.

For comparative purposes data from theFood and Drug Administration total diet studiesare also included in Table I. It is of interest tonote the general agreement in values of thedaily DDT and DDE content of prepared mealsand diets. The FDA total diet values for DDTand DDE content are slightly lower than anyof the total diet values presented in the PublicHealth Service studies.The amount of DDT in the diet (PHS res¬

taurant study 1962-64) at a level of 0.038 mg.per day would represent a mean concentrationof 0.018 ppm in the total wet diet. A level of0.026-0.028 mg. per day (FDA total diet studies)would represent a mean concentration of 0.0065ppm in the total wet diet, which is a consider¬ably lower value than that for the PHS res¬

taurant study. If one assumes a daily DDT in¬take of 0.038 mg., this would be equivalent to a

daily dosage rate of about 0.0005 mg. per kg.for a man weighing 70 kg.

For the period 1965-67 in the U.S.A., residuesof chlorinated organic pesticide chemicals havebeen found in all diet samples and all foodclasses within samples with the possible ex¬

ception of beverages.8 The average daily intakefor this class of compounds, encompassing some

12 food classes in the total diet, was 0.0013 mg.per kg. of body weight in the general popula¬tion. Meat, fish and poultry contribute about 40/xg. or 40% of the total daily dietary intake ofthese pesticide residues (Fig. 3). If one com-

bines this class of foods with dairy products,then over half of the daily intake (55.2%) ofpesticide residues arises from these food items(Fig. 3). These pesticide chemicals are not ap¬plied directly to these food products but are

carried through as metabolites of the parentcompound and are deposited in tissue or ex¬

creted in the milk and thus indirectly becomesources of the pesticides. Garden fruits, fruits

Fig. 3..Tntake of pesticide residues in average totaldaily diet.5'

and grain-cereal products provided approxi¬mately 10% each of the intake of chlorinatedpesticides. The levels of pesticides ingested inthese products are lower than in the animal,marine and dairy products since control is ex-

ercised over the direct application of chemicalsto the raw agricultural commodities. DDT andanalogs (DDE + TDE) plus dieldrin, lindaneand heptachlor epoxide account for approxi¬mately 85% of the total intake of the chlorinatedpesticides;9 DDT alone, one of the major per¬sistent pesticides, accounted for one-third.For the three-year span 1965-67, the daily

dietary intake of organic phosphate pesticidechemicals has been reported at 0.00013 mg. perkg. of body weight. Malathion alone accountsfor about 77% of the daily intake of this groupof "OP" compounds. Other "OP" compounds,such as parathion, diazinon, ethion and ronnel,were reported in such low frequency and quan¬tity that they do not represent any significantcontribution.1'

Herbicide chemicals, such as 2,4-D, PCP,MCP, 2,4,5-TP and others, represented a levelof residue exposure to the general population ofabout the same order as the "OP" compoundsor 0.00013 mg. per kg. of body weight for thedaily dietary intake.1' Of this total, the common

herbicide 2,4-D contributed one-third of theintake and MCP and PCP combined repre¬sented about one-half of the daily intake ofherbicides.1'The carbamate-type pesticides are found in-

frequently in the total diet samples. Carbaryl,one of the primary carbamate insecticides, whendetected in root crops, fruits, sugars and ad-juncts, represented a total daily dietary intakeof 0.0009 mg. per kg. of body weight for thegeneral population.

Current Views on Pesticides 209

It appears that corrective measures imple-mented for minimizing the indirect sources ofpesticides through reduction and/or cancellationof approved uses and patterns of use of some

of the more persistent chlorinated organic pesti¬cides in forage crops, pastures and animal feeds,have brought about a lower average level ofdieldrin and heptachlor epoxide in 1967. Al¬though the persistent and non-persistent pesti¬cide chemicals appear, for example, in raw

vegetables before preparation, peeling, proces¬sing and cooking removed all but 5 to 25% ofthe residue, depending upon the vegetable andthe pesticide that is to be removed.17

Refined analytical procedures have improvedthe surveillance programs and the ability to de¬tect organophosphate pesticides, and thesechanges may account for the increase in de¬tectable levels and reporting of these chemicalsin foods and total diet. However, there may besome increases in the "OP" compound utiliza¬tion due to gradual replacement of the persistent"OC" (organochlorine) pesticides.8The proportion of food containing residues at

or above the tolerance level is indeed quitesmall. In fact, the current legally adopted toler¬ances for raw agricultural commodities are con¬

siderably above the average levels found in a

significant proportion of the food under surveil¬lance for residues in the United States. Somelow-level residues of pesticides in food havebeen reported for which tolerances have not

been established. These chemical residues prob¬ably appear as normal environmental contami-nants rather than as residues accruing in foodsfrom improper uses in agricultural practices.8

Criteria eor Safety Assessment

Establishment of finite levels for environ¬mental contaminants, such as pesticides in thehuman food supply, is predicated on informationand data relevant to safety. This assessment ofsafety eventuates in the setting of permissiblelevels of tolerances for the various pesticides.The tolerances must be established on the basisof toxicological studies in at least two species ofexperimental animals, one of which may be a

non-rodent. Delineation of the toxicological pro¬cedures and requirements for such studies are

beyond the scope of this report and are dis¬cussed elsewhere. However, such studies on ex¬

perimental animals usually provide data on

acute, subacute and chronic toxicity of the che¬mical pesticides examined. Further indicationsand knowledge of safety may be providedthrough information and data on these che¬micals after a tolerance has been set and the

210 Current Views on Pesticides Canad. Med. Ass. J.Jan. 25, 1969, vol. 100

pesticide has been in extensive use. This typeof additional evidence on safety may be fur-nished through more extensive toxicological re¬

search using newer, sophisticated approaches or

from direct or indirect extrapolation of findingsregarding human exposure to these chemicalpesticides. The clinical, biochemical, pharma¬cological and epidemiological data on humanexposure to these pesticide chemicals may begenerated from studies on occupational or in¬dustrial exposure, accidental exposure, controlledclinical and human toxicological investigations,or from comprehensive epidemiological studiesusing retrospective and prospective approacheson various populations. The latter studies mayprovide direct or presumptive evidence on thesechemicals with respect to disease inductionwhich may necessitate a reconsideration of pre¬viously established tolerances.From the preceding discussion it is apparent

that various procedures are required for quanti-fication of the level of intake and the magnitudeof the total exposure. An estimate of the actualingestion in man is provided through the totaldiet studies, previously alluded to, which havebeen carried out in the United States by theFood and Drug Administration and the U.S.Public Health Service. Comparable studies havebeen carried out in Great Britain and othercountries. The international concern about thepotential dangers of pesticide residues in foodis evidenced by the Food and Agricultural Or¬ganization of the United Nations through theirstandards for acceptable daily intake for severalpesticides. Pesticides not currently covered bysuch standards may ultimately be coveredthrough continued toxicological research. Theacceptable daily intake established by the FAOCommittee on Pesticides in Agriculture and theWorld Health Organization (WHO) Committeeon Pesticide Residues reflects a range of pesti¬cide residue levels for some of the more com¬

monly used pesticides.18 For comparative pur¬poses the maximal value of this range may beused in an attempt to arrive at some measure¬

ment of the problem of potential hazard andthe degree to which current levels of pesticideoccurrence reflect a hazard reduction. Thesecriteria for safety assessment may be referencedas MADI or maximal acceptable daily intake.19In utilizing the MADI this assumes that pesti¬cide levels above the maximum would constitutea hazard to the general population. Such an

index is used in the absence of any threshold or

finite value above which the level of ingestionis clearly a hazard and below which it is clearlysafe.

ORGANOCHLORINES

&% DIELDRIN

i^^^ LINDANE >^^^^^3

1 ^ f HEPTACHLOREPOXIDE

ORGANOPHOSPHATES

^>^ DIAZINON >Z^Q1_

MALATHION <^^^^^^^<^<A

|-';"-"I Total Daily Intake (Market Basket Survey)g23 "Maximum" Acceptable Daily IntaUe-FAO Std.

Estimated Tolerance Intake-FDA Std.

0.1 0.5 1.0 5.0 1050 100

Intake in fjg/kg.of Body Wf.

Fig. 4..Actual pesticide intake compared with FAOacceptable intake and FDA standard of estimated toler¬ance intake.

Another criterion that may be employed inprojections on probable intakes of pesticides forwhich toxicological data are available is the so-

called ETI or estimated tolerance intake. In thisindex there is incorporated an estimate of thepercentage of specific foods in a normal dietwhich would contain a specific pesticide residueand then, utilizing the tolerance level for thatspecific pesticide, the total dose of pesticidefrom foods at the tolerance level is calculated.20Unfortunately, losses in residue due to prepara-tive procedures, such as washing, trimming andcooking, are not taken into consideration.From the three criteria described: (a) Actual

Intake "Total Diet".market basket survey, (b)FAO Acceptable Daily Intake.MADI, and (c)FDA Estimated Tolerance Intake, it is possibleto make comparative evaluations of total intakeand to determine how close these actual in-gestions approach the toxicological guidelinesor safety standards established by FAO/WHOand FDA. In Fig. 4 actual pesticide intake(from total diet assay) is compared with theFAO acceptable intake (using maximal value ofMADI) and the FDA standard of ETI or esti¬mated tolerance intake. It is apparent that thevalues for actual intake of pesticides from totaldiet assay are only a small fraction of thestandards or critical levels promulgated by FAOand FDA. There are some exceptions, such as

dieldrin, where the actual total intake ap¬proaches the maximal acceptable daily intake(FAO standard) but is only about 2% of the

Canad. Med. Ass. J.Jan. 25. 19G9. vol. 100 Curhext Views on Pesticides 211

TABLE II..Most Frequently Detected Pesticides

Frequencyof detect ion

Chemical pesticide %**DDT. 26.7DDE***. 25.5Dieldrin. 17.8TDE***. 10.0Heptachlor epoxide. 7.5Lindane. 4.8BHC. 2.8Endrin. 2.5Aldrin. 2.0Toxaphene. 1.5

**Some samples contain more than one residue.***Metabolites of DDT, usually combined as a group.

FDA estimated tolerance intake. Heptachlorplus heptachlor epoxide yield an actual residuevalue in the total diet which is 10% of themaximal allowable daily intake or FAO stand¬ard but exceeds the FDA standard of estimatedtolerance intake (ETI) by 125%. Lindane andDDT levels in total diet samples appear to bewell below any of the standard values. Dia-zinon, an organophosphate insecticide, appearsin total diets at a level of 10% of the FAO-MADI standard.From data of Duggan and Dawson21 and Tay-

lor and Favors19 a ranking, on the basis of fre¬quency of detection, of the first 10 pesticides ispresented in Table II. In this instance the per¬sistent organochlorine insecticides, such as DDTand its analogs and dieldrin, are the most fre¬quently detected. The first 10 pesticides are

ranked relevant to raw food samples containingresidues over FDA tolerances and the percent¬age of food samples with above-tolerance resi¬dues (1966-67) as follows: toxaphene.5.4%;dieldrin-4.0%; diazinon-3.7% ; DDT-2.8%;parathion-2.6%; chlordanc-2.3%; BHC-2.0%;heptachlor epoxide-1.4%; TDE-0.9%, andmalathion-0.6%.

Significant efforts must be made by industryand government to achieve a substantial reduc¬tion in the danger from pesticide residues. Forexample, if intensive education and complianceprograms are instituted, an estimate can bemade of the reduction in dietary intake of a

pesticide residue that would result if all over-

tolerance shipments of agricultural productswere reduced to the tolerance level. Of thosepesticides appearing in foods as residues whichare over tolerance some do not rank close to theFAO or FDA critical levels in terms of actualingestion in total diets appearing as preparedand cooked foods. In essence, from toxicologicalconsiderations the persistent organochlorine

pesticides should receive highest priority in con¬

trol programs since they have the capacity forsustained biological challenge to the somatictissue due to their long residence time whichmay contribute to potential damage. The organo¬phosphate compounds, commonly recognized as

extremely hazardous during occupational ex¬

posure, at the low level exposure encounteredthrough ingestion in foods are not readily storedin organs and tissues and in vivo are readilymetabolized and eliminated.

Measurement of Biological Effects

Body StorageHuman exposure to the environmental stress

of pesticides evokes certain biochemical-pharma-cological responses, one of which is the in-evitable accumulation and storage in the tissues,the major reservoir being the adipose tissue.There is a dynamic equilibrium between thelevel of pesticide ingested, absorbed and inhaledand the level of pesticide that is ultimately de¬posited or metabolized and eliminated. In ad¬dition to the depot fat, pesticides have beenfound in the brain, liver, kidney and gonads.The levels observed are usually in direct re¬

lationship to the fat content of these organs andthe magnitude of exposure. Fiserova-Bergerovaet al.,-'2 for example, noted a twofold increasein the levels of DDT and analogs in liver, brain,kidney, gonads and adipose tissue of 10 personswho died accidentally and who were occupa-tionally exposed to pesticides in the course oftheir work as migrant labourers on vegetablefarms in southern Florida. These investigatorsalso observed that concentrations of these non-

polar pesticides in the liver were approximately10 times the levels found in kidney, brain andgonads, and may, in part, reflect the function ofthe liver as a target organ and organ of meta¬bolism and excretion. The levels found in adi¬pose tissue are approximately 10 times thosein liver and 100 times the levels found in thekidney, gonads and brain. In the developingfetus the levels of DDT and its metabolites anddieldrin were greater than in the 0 to 5 yearage group and more closely resembled concen¬

trations noted in the older age groups. The find¬ing, corroborated by other investigators, focusesattention on the aspect of placental transfer andthe hazards of pesticide insult to neonatal groupsof the general population. Evidence of placentaltransfer was noted as early as the 22nd week ofgestation. Significantly lower levels of DDT andDDE were observed in children under 5 yearsof age but beyond that no correlation of agewith tissue pesticide levels was observed.2-

212 Current Views on Pesticides Canad. Med. Ass. J.Jan. 25, 1969. vol. 100

i2 ,ooi

TABLE III..DDT and DDE Storage Levels inVarious Types of Exposure

DDT Dosage (mg/Man/Day)

Fig. 5..Dosage levels of DDT (mg. per man per day)versus storage levels of DDT in body fat in ppm.i°

As previously indicated, the level of exposurecan be correlated with concentration of storageof persistent organochlorine insecticides, such as

DDT and dieldrin. Durham, Armstrong andQuinby10 have plotted, on a log-log basis, thedosage levels of DDT in milligrams per man

per day versus storage levels of DDT in bodyfat in ppm and obtained a linear relationship(Fig. 5). The lower part of the curve representsvalues for DDT intake from total diet surveys(intake.0.038 mg. per day; storage.3.9 ppm)including values for meat abstainers (0.041 mg.intake; storage.4.9 ppm) and a general popu¬lation sampling in 1954 (0.164 mg. intake; stor¬age.4.9 ppm). The higher values on the curve

represent intake-storage relationships in prisonervolunteers who received known amounts of DDTranging from 3.5 to 35 mg. per man per day.As more information and data accrue on thelevels of organochlorine pesticides in the diet ofthe general population and comparable valuesfor tissue storage, the lower portion of thiscurve can be plotted so as to provide a more

comprehensive curve for computation of pesti¬cide intake-storage relationships. These relation¬ships have been studied by Lehman,23 who de¬termined in rats the storage ratios betweendietary levels of the various pesticides (DDT,methoxychlor, lindane, dieldrin, endrin and iso¬drin) and the levels stored in the body fat. Itwas noted in these studies that as the dietarylevel of DDT decreases a greater proportion ofthe ingested insecticide is stored. For example,there is a ratio of 12 to 1 at a dietary level of50 ppm whereas at 0.12 ppm the ratio is 57 to 1.If one extrapolates these findings to humans, as¬

suming that man stores DDT at a rate com¬

parable to that of the rat, then a total dietaryintake of 0.02 ppm of DDT, with a DDT fatdeposition of 5 to 7 ppm (Table III) would

Exposurestatus

No.ofpersons

DDTstorage

DDEstorage

EnvironmentalOccupationalGeneral

population

11030

61

ppm6.0 ±0.2614.0 ± 1.5

ppm8.6 ± 0.4819.0 ± 2.2

4.9 ± 0.35 6.1 ± 0.42

represent a ratio of approximately 350 to 1.The storage levels of the organochlorine in¬

secticides are dependent upon the exposurelevels which man and animals encounter. Dur¬ham24 has reported the DDT and DDE storagelevels in individuals who were occupationallyexposed, environmentally exposed (receivingpesticide exposure from community foggingoperations, aerial spraying, ete.) and those ofthe general population who received the usualcontinuous exposure. These values, reported inTable III, reflect the effect of exposure on bodystorage of DDT and DDE.

QO+

QQ°6

Q

1945

Years of Observation and DDT ExposureFig. 6..Storage levels of pesticides between 1941 and

1965.27

The introduction of organochlorine insecticidesfor pest-vectored disease control and crop pro¬tection in 1941 resulted in an increase in en¬

vironmental levels of these pesticides. Accord-ingly, this was reflected in the appearance ofthese chemicals in the body tissues and a gradualincrease in the storage levels of these pesticidesas shown in Fig. 6. It has been maintained bysome investigators that peak concentrationswere reached in 1950, after which there was a

steady decline and then a plateau in pesticidelevels. However, others have claimed that themaximal concentration in human adipose tissuewas reached in 1955, followed by a decline andformation of a plateau in pesticide levels, rep-resenting the presence of these environmental

Fig. 7..Average concentration of DDT-derived mate¬rials in adipose tissue of general populations in variouscountries between 1958 and 1965.-"

contaminants continuously during the last 10years. The values represented in Fig. 6 wouldappear to support the validity of the latter con¬

cept.2* -7

During the period 1958 to 1965 various sur¬

veys in Europe, Asia, the Middle East and theUnited States have been made to determine theaverage concentration of DDT-derived materialsin the adipose tissue of the general populationsin various countries (Fig. 7). England appearsto incur the lowest body burden for DDT +DDE, whereas several areas in India revealed25 to 30 ppm of DDT + DDE in the body fatof the general population. In the latter case

these higher body fat levels for DDT + DDEare certainly a reflection of higher environ¬mental contamination enhanced by vigorouspest control programs, such as mosquito abate-ment projects. The lower levels of DDT + DDEin body fat of Europeans are indicative of thestringent controls on the use of persistent or¬

ganochlorine insecticides in those countrieswhich, moreover, are reflected in decreased en¬

vironmental levels and diminution of residues inlocally grown food and forage crops.-7As indicated previously, the persistent pesti¬

cides have been identified in various organs andtissues. The British have found some of theorganochlorine insecticides in gallstones at thefollowing levels for these specific pesticides:yBHC-0.03 ppm; dieldrin-0.005 ppm; pp'-DDE-0.04 ppm and p,p'-DDT-0.007 ppm.28DDA, the urinary metabolite of DDT, has beenidentified in the urine of people occupationallyexposed to high levels of DDT. DDE has beenfrequently identified in the blood of those peopleenvironmentally exposed (aerosol spraying, mos¬

quito abatement, populations living in proximityto high-use areas of agricultural pesticides) and

Current Views on Pesticides 213

during occupational exposure. It is apparentthat such biochemical indicators will provideuseful measurements of pesticide exposure andhence are useful in assessment of the epidemio¬logical impact of pesticides in relation to humanhealth.

Chemical EpidemiologyConsiderable attention has been given in na¬

tional and international health programs to therequirement for detection and measurement ofenvironmental exposure to pesticides, and offood residues. These programs encompass theestablishment of tolerances and regulatory ac¬

tions to eliminate, control, or reduce the level ofthe environmental exposure. Certainly, the levelof stress can be evaluated and decisions on

safety and assessment of response are foundedon extensive toxicity studies on a wide spectrumof experimental animals including the estimateof "no effect" levels for these environmentalchemical contaminants. However, the chroniceffects of low-level pesticide exposure in man

continue to be a problem for resolution, and thesignificance of this environmental challenge, ifany, in terms of human health, necessitates ap¬propriate epidemiological studies on variant

groups of the population in selected geographi-cal locations and of different ethnic origin, whoexperience a wide range in total exposure. Themost difficult problem to investigate epidemio-logically is undoubtedly the low-level exposureencountered by the general population. To meetthe above objectives the U.S. Public HealthService, in 1963, mounted a full-scale epidemio¬logical program called "Community Studies" inan attempt to establish a cause-and-effect re¬

lationship between pesticide exposure and hu¬man disease.2The literature is replete with data on the mag¬

nitude of exposure of occupational workers andresidents adjacent to locations where pesticidesare applied for agricultural and public healthpurposes. Such data provide a measurement ofstress, as has been previously shown, relevant to

the body burden of pesticides in the generalpopulation. There is lacking, however, informa¬tion on the relationship of this measured ex¬

posure to development of clinical signs or symp¬toms of poisoning or of demonstrable abnormali¬ties of physiological function for the generalpopulation which receives chronic microinsults.Such data are available on controlled studieswith human volunteers and those workers oc¬

cupationally exposed who receive doses of pesti¬cides above those of environmental exposure ex¬

perienced by the general population.

214 Current Views on Pesticides Canad. Med. Ass. J.Jan. 25, 1969. vol. 100

It can be stated that poisoning from pesticidescan be expected to appear most quickly, mostfrequently, most diversely and most severely inthose people most extensively exposed. A widearray of biochemical, physiological and patho¬logical aberrations have been observed fromheavy exposure. Some of the interesting physio¬logical effects studied involve kidney dysfunc¬tion, placental transmission of pesticides andelectroencephalographic dysrhythmia.29 The in¬fluence of certain nephrotoxic insecticide agents,such as parathion, resulting in kidney tubulardysfunction with a lowered phosphorus reab¬sorption index and the ultimate developmentof aminoaciduria and aminoacidemia, has beenone of the most intriguing recent biochemicalclinical studies; it was conducted in Florida on

people occupationally exposed.30 Other investi¬gators have shown that workers exposed tochlorinated hydrocarbon and organophosphorusinsecticides show characteristics of prematureageing and certain behavioural responses such as

defects in memory, inability to concentrate andother aberrant neurological functions.81

DuBois82 has studied the impact of prolongedexposure to organophosphorus insecticides. Al¬though the levels of organophosphates permit¬ted in foods may be below the levels whichwould cause inhibition of cholinesterase activity,somewhat higher levels on prolonged exposuremay result in acquired resistance to the actionof acetylcholine. This finding may explain thefact that various investigators failed to detectmarked cholinesterase depression after prolongedfeeding of organophosphates as may have beennoted from a single exposure to the same pesti¬cide at the same level of administration. Hencereliability of cholinesterase depression as an in¬dex for chronic exposure may be questioned.Furthermore, there may be such an adaptationby the body with development of a physiolo¬gical effect on another target organ or systemelsewhere.

Previous reference has been made to thecorrelation of blood DDT-DDE levels in certaingroups of the population environmentally ex¬

posed. The levels of DDT-DDE have beenfound to correlate positively with random serum

triglyceride levels and with left subscapularskinfold thickness. There does not appear to beany correlation with serum cholesterol level or

any selected disease syndromes.88Repeated references have been made to the

effect of environmental exposure to pesticideson persons with respiratory diseases.84 Althoughthis association of pesticide exposure to chronicrespiratory disease has been previously dis-missed, recent studies in Hawaii have shown

that there is a significant difference at the 5%level of confidence in the combined rates ofreported asthma and chronic bronchitis in twopopulation groups where household use of pesti¬cides was frequent. Repeated attacks of sinustrouble were also reported.85The total environmental exposure to pesticides

from various sources, including diet, air, water,cosmetics, clothing, ete, may present to thegeneral population a continuous low-level chal¬lenge which, in the case of the more persistentpesticides, manifests itself by an observed equi¬librium between the environmental exposure andthe resultant retention in human tissues andorgans. Although the levels of pesticides mea¬

sured in tissues and blood and as pesticidemetabolites in urine reflect a response to sucha challenge, the significant implications of thislow-level chronic exposure in terms of well-defined clinical symptomatology or aberrantphysiological function upon the general popu¬lation are not well delineated at this time andmust await findings from retrospective and pros-pective studies now in progress. Special at¬tention is being given to those persistent pesti¬cides which have the potential for chronic cel¬lular insult and the induction of chronic disease.

Persistent organochlorine insecticidesSummary appear t0 present an equilibrium state

between exposure and retention levels. Eighty-fiveper cent of this total exposure to the general popu¬lation comes from food. Other sources of exposureare air, water, aerosols, cosmetics and clothing.Those who are subject to agricultural and occupa¬tional exposure derive more challenge from inhala¬tion and absorption. Environmental exposure causes

retention in adipose tissue of 6.0 ± 0.26 ppm DDTand 8.6 ± 0.48 ppm DDE. Meats, fish, poultry anddairy products are main sources for persistent pesti¬cides. Tissue and blood levels of pesticides and theirmetabolites reflect magnitude of exposure.

Resume Il existe un equilibre entre le degred'exposition et le taux de retention

pour les insecticides organochlores. C'est la nour-

riture qui est la source d'exposition fournissant 85%du total des pesticides a l'ensemble de la popula¬tion. Les autres sources d'exposition sont l'air, l'eau,les aerosols, les cosmetiques et les vetements. Lesagriculteurs et les autres personnes exposees pro-fessionnellement aux pesticides en recoivent une

grande quantite par inhalation et par absorption.L'exposition du milieu peut causer des retentionsde 6.0 ± 0.26 ppm de DDT et 8.6 ± 0.48 ppm deDDE dans le tissu adipeux. La viande, le poisson,la volaille et les produits laitiers sont les principalessources d'apport permanent des pesticides. Les con¬

centrations serique et tissulaire des pesticides et deleurs metabolites refletent le degre de l'exposition.

Canad. Med. Ass. .* CURRENT VIEWS ON PESTICIDES 215Jan. 25, 1969, vol. 100

REFERENCES1. United States President's Science Advisory Com-

mittee: Use of pesticides; a report, Superin-tendent of Documents. U.S. Government PrintingOffice, Washington. 1963.

2. KRAYBILL, H. F.: Pesticides in public health. Paperpresented at the Michigan State Medical SocietyCentennial, Detroit, Michigan, September 24, 1965.

3. CAMPBELL, J. E., RICHARDSON, L. A. AND SCHAFER,M. L.: Arch. Environ. Health (Chicago), 10: 831,1965.

4. YoBs, A.: Report to United States Federal Committeeon Pest Control. Subcommittee on Pesticide Moni-toring, 1967 (unpublished).

5. . J. E. et al.: Amer. J. Public Health, In press.6. EDMUNDSON, XV. F. et al.: Industr. Med. Sury., 36:

806. 1967.7. KRAYBILL, H. F.: The Public Health Service program

on pesticides. Paper presented at the Idaho An-nual Health Conference on Pesticides. People andProblems, Sun Valley, Idaho, May 25-27, 1965.

8. United States, Department of Agriculture and Foodand Drug Administration: Joint report on theregulation of pesticides in the United States; re-port as basis for discussion with the Federal Re-public of Germany and the Benelux Countries,Washington, December 18-21, 1967 (unpublished).

9. DUGGAN. R. E. AND WEATHERWAX, J. R.: Science,157: 1006. 1967.

10. DURHAM, W. F., ARMSTRONG, J. F. AND QuINBY, G. B.:Arch. Environ. Health (Chicago), 11: 641, 1965.

11. WALKER, K. C., GOETTE. M. B. AND BATCHELOR, G. S.:Journal of Agricultural and Food Chemistry, 2:1034, 1954.

12. HAYES, W. J., JR. et al.: A.M.A. Arch. Industr. Health,18: 398, 1958.

13. HAYES, W. J., JR., DURHAM, W. F. AND CUETO, C..JR.: J. A. M. A., 162: 890, 1956.

14. DURHAM, XV. F. et al.: Science, 134: 1880, 1961.15. MILLs, P. A.: Journal of the Association of Official

Agricultural Chemists, 47: 74. 1964.16. WILLIAMS, S.: Ibid., 47: 815. 1964.17. FARROW, R. P. et al.: Journal of Agricultural and

Food Chemistry, 16: 65, 1968.18. Food and Agriculture Organization of the United

Nations, Committee on Pesticides in Agricultureand World Health Organization Expert Committeeon Pesticide Re3idues: Evaluation of the toxicityof pesticide residues in food: report of a joint

meeting, Geneva, September 30-October 7, 1963.Food and Agriculture Organization of the UnitedNations, Rome, 1964.

19. TAYLOR, R. J. AND FAVORS, J.: Food-Bacterial con-tamination model, staff paper, F.D.A., September28, 1967.

20. LEHMAN, A. J.: Summaries of pesticide toxicity, Asso-ciate Commissioner for Planning and Evaluation(unpublished), Association of Food and DrugOfficials of the U.S., Topeka, Kansas, 1965.

21. DUGGAN, R. E. AND DAwsoN, K.: FDA Papers, 1: 4,June 1967.

22. FIsEROVA-BERGEROVA, V. et al.: Industr. Med. Sury.,36: 65, 1967.

23. LEHMAN, A. J.: Quarterly Bulletin of the Associationof Food and Drug Officials of the fJ.S., 20: 95,March 1956.

24. DURHAM, XV. F.: Arch. Environ. Health (Chicago),10: 842. 1965.

25. QUINBY, G. E. et al.: J. A. M. A., 191: 175, 1965.26. DAvIEs. J. B., WELKE. J. 0. AND RADoMsII, .T. L.:

Epidemiological aspects of pesticides in the South.Report to the 22nd annual meeting of the Ameri-can Association of Industrial Nurses, Miami Beach,Fla.. April 6-8, 1965.

27, KRAYBILL, H. F.: Pesticide residues in mammalliantissues; problems, incidence and controls. Paperpresented at the 19th annual Reciprocal Meat Con-ference of the American Meat Science Association,Ithaca, N.Y., 1966.

28. Great Britain, Laboratory of the Government Che-mist: Report of the Government Chemist, 1966.Her Majesty's Stationery Office, London, England,1967, p. 91.

29. UPHOLT, W. M.. KRAYBILL. H. F. AND DAVIS, R. S.:New leads in health pesticides research. Report tothe 5th Interamerican Conference on Toxicologyand Occupational Medicine, Miami, Fla., August1-4, 1966.

30. DAvIEs, J. E., MANN. J. B. AND Tocci, P. M.: Ann.N.Y. Acad. Sci.. In press.

31. HOLMES, J. AND METCALF. D. R.: Ibid., In press.32. Dul3oIs, K. P.: Arch. Environ. Health (Chicago), 10:

837. 1965.33. WEINER. B. P., WORTH. R. M. AND SHIMAT5U, F.

Y.: Personal communication.34. GANELIN, R. S., CUETO, C., JR. AND MAIL, G. A.:

J. A. M. A., 188: 807. 1964.35. KLEMMER, H. W.: Personal communication.

THE CANADIAN JOURNAL OF SURGERYThe January 1969 issue of The Canadian Journal of Surgery (Robert Janes Memorial Issue) contains the followingarticles: history of surgery, original articles, review article and experimental surgery.

History of Surgery: Dr. Robert Meredith Janes (1894-1966): Professor of Surgery, University of Toronto(1947-1957)-R. J. Delaney. The Changing Face of Surgery-C. F. W. Illingworth.

Original Articles: Massive Pulmonary Embolism: Modern Surgical Management-W. J. Keon and R. 0.Heimbecker. Sacrococcygeal Teratoma-S. Kling. Peptic Ulceration of the Postbulbar Portion of the Duoden-um-J. E. Mullens and G. S. Bird. Cleft Palate Repair: Comparison of the Results of Two Surgical Techniques-C. R. Palmer, M. Hamlen, R. B. Ross and W. K. Lindsay. Resection of Cervical Lymph Nodes in Cancer of theLip: Results in 123 Patients-L. J. Mahoney. Avascular Necrosis of the Femoral Head as a Complication ofTreatment for Congenital Dislocation of the Hip in Young Children: A Clinical and Experimental Investigation-R. B. Salter, J. Kostuik and S. Dallas. Thalamotomy for Pain: Lesion Localization by Detailed Thalamic Map-ping-R. R. Tasker. The Diploscope in Intracranial Aneurysm Surgery: Results in 40 Patients-W. M. Lougheedand B. M. Marshall. Surgical Palliation in Complete Transposition of the Great Vessels: Experience With theEdwards Procedure-G. A. Trusler and B. S. L. Kidd. Separation of Conjoined Thoracopagus Twins: With theReport of an Additional Case-J. S. Simpson. Surgically Created Arteriovenous Fistulas in Chronic Hemodialysis-A. H. Irvine, L. Douglas and B. Koch. Primary Hyperparathyroidism-Z. J. Borowy. Prolapse of the Rectum:Treatment by the Moschcowitz-Graham Operation-J. A. Palmer. Survival After Obstruction of the Colon byCarcinoma-N. A. Watters.

Review Article: Canadian Contributions in Microvascular Surgery-W. G. Beattie.Experimental Surgery: Hyperemia, Hypervascularity and Limb Overgrowth-W. R. Harris. Experimental

Homograft Replacement of the Mitral Valve-R. J. Baird, W. G. Williams, E. H. Spratt and W. J. Coboon.The Canadian Journal of Surgery is published quarterly by The Canadian Medical Association (January,

April, July and October). Subscription rates are $10.00 a year ($5.00 a year for recognized postgraduate traineesin surgery) or $2.50 for individual copies. Yearly subscriptions and back issues are available from The CanadianJournal of Surgery, C.M.A. House, 150 St. George Street, Toronto 5, Ontario.