pesticide residues in mammalian tissues, problems

190.

P E S T I C I D E R E S I D U E S I N M A M M A L I A N T I S S U E S , PROBLEMS, I N C I D E N C E , A N D CONTROLS

H . F . K R A Y B I L L

U.S. P U B L I C H E A L T H S E R V I C E W A S H I N G T O N . D. C.

P R E S E N T E D B Y : H O W A R D B O f l D U.S. P U B L I C H E A L T H S E R V I C E _ _ _ _ _ _ _ _ _ _ _ - - - - - _ - - - - - - - - -

I. INTRODUCTION

The p r o l i f e r a t i o n of a g r i c u l t u r a l chemicals i n t o the environment of man and animals has been accelerated by g rea t technological advances of t he pas t two decades. Considerable e f f o r t has been made i n our economy t o assure man a more abundant supply of food and f i b e r through the u t i l i z a t i o n of pes t ic ide chemicals. By cont ro l l ing the environment of domestic animals and man with chemical agents a concomitant problem of environmental po l lu t ion has a r i s en of which man has become acutely aware s ince it r e l a t e s t o the hea l th of human populations, f i s h , w i ld l i f e , and domestic animals. Perhaps public awareness of pes t ic ide environmental contamination was increased through e a r l i e r recognition of hazards of f a l l o u t rad ioac t iv i ty . cen t ly research i n the f i e l d of environmental hea l th sciences has focused a t t e n t i o n on na tu ra l ly occurring contaminants such as fungal metabolites and b a c t e r i a l toxins . With increasing a t t e n t i o n t o problems of environmental po l lu t ion it is not surpr i s ing t h a t Rachel Carson's "Si len t Spring" stimulated a t h r u s t f o r control programs a t l o c a l and Federal l e v e l s . Cer- t a i n l y a more balanced account of the ove ra l l problem of environmental pes t i c ide contaminants and residues w a s portrayed i n the Pres ident ' s Science Advisory Committee Report on "Use of Pesticides" (1).

More re-

Environmental po l lu t ion may involve t o t a l exposure of man o r animals t o a p a r t i c u l a r s t r e s s or a combination of s t r e s s agents. The r e s u l t - a n t exposure and b io logica l challenge can a r i s e from three sources: from inhalat ion, absorption, or ingestion, o r a combination of a l l th ree exposure routes simultaneously.

11. EQUILIBRIUM BETWEEN ENVIRONMENTAL AND BODY LEVELS OF PESTICIDES

There is a balance between the l e v e l of a pes t ic ide i n the environ-

Species ment and the re ten t ion i n the mammalian body, but t h i s i s dependent upon severa l var iab les which may o r may not permit a d i r e c t re la t ionship . d i f fe rence , influence of sex, age, 'and ove ra l l metabolic deviat ions i n cer- t a i n instances y i e ld some discontinuity i n es tab l i sh ing an idea l l i n e a r re - l a t ionsh ip a t l e a s t on the bas i s of animal s tud ie s . In addi t ion, having data on t i s s u e re ten t ion l eve l s , intake l eve l s , and b io logica l responses associated w i t h in take and re ten t ion i n animals (and t h i s ce r t a in ly holds f o r meat animals) it might be possible t o extrapolate these f indings t o t h e i r e f f e c t s on man. These e f f e c t s might be delineated i n terms of acute and chronic tox ic i ty , physiological response or ultimate re ten t ion l e v e l s and t o t a l body burden of pes t i c ides .

191.

The introduction of pest ic ides in to the environment of domestic animals may occur through several procedures : i n buildings and o ther protected she l te rs , (b) mosquito abatement and f o r e s t i n sec t spray programs, (c) d i r e c t paras i te control programs i n animals, and (d) insect control on p lan t crops; t he crops o r forage l a t e r u t i l i z e d as animal feed which may contain a pes t ic ide residue, (e) contaminated water suppl ies . The exposure of domestic animals is not too unlike t h a t of man involving inhalat ion, absorption, o r ingestion, with the exception t h a t accidental exposure and acute poisonings may occur t o man through h i s occu- pat ional use of a wide spectrum of pes t ic ides .

(a) pes t control operations

The low l e v e l prolonged exposure to pes t ic ide chemicals of e i t h e r man o r animal does not e l i c i t a s e a s i l y recognizable o r dramatic response o r symptomology as acute exposure. Environmental control of the long term exposure may a l so be somewhat d i f f i c u l t . Chronic e f f ec t s may usua l ly be ascribed t o those compounds having a "persistence" qua l i t y o r extended residual behavior. The c lass o f i n sec t i c ida l compounds described as organochlorine o r "chlorinated hydrocarbons," because of t h e i r high s o l u b i l i t y and a f f i n i t y f o r body depot fa t , where they are stored and not readi ly metabolized, a r e usua l ly considered f o r t h e i r po ten t ia l chronic e f f ec t s . b r e recently, however, the l e s s pe r s i s t en t , read i ly metabolizable organophosphorus compounds which may present repeated challenges o r poisoning episodes, a r e now being viewed as having capab i l i t i e s f o r sustained adverse heal th e f f ec t s . Because of the po ten t i a l human hea l th hazard posed by pes t ic ide residues i n edible t i s sues of meat animals, game, f i s h o r o ther food products, t h i s area of concern has fos te red comprehensive toxicological research programs.

Chlorinated hydrocarbon and organophosphorus insect ic ides which a r e sprayed on meat animals may be absorbed through the skin and ul t imately s tored i n the adipose t i s sue . Through ingestion o f insec t ic ide contaminated feeds, storage o f pe r s i s t en t pes t ic ide occurs i n the body f a t o r i s excreted i n the mi lk of dairy cows.

The U.S. Department o f Agriculture, cognizant of the need t o help pro tec t the heal th o f man and animals and t o preserve the food and f i b e r supplies from the ravages of pes t s , issued an o f f i c i a l policy on pest ic ides i n 1964 ( 2 ) . In essence, it is the policy of t h a t Department t o promulgate and use pes t control programs which provide the l e a s t po ten t ia l hazard t o man and animals. If res idual pest ic ides must be used t o control o r eliminate pes t s they a re t o be used i n minimal e f fec t ive amounts applied only t o the infested area and a t minimal e f fec t ive frequency. This d i rec t ive f u r t h e r s t a t e s t h a t biological , ecological o r cu l tu ra l methods o r non-persistent and low tox ic i ty pes t ic ides w i l l be used whenever such means a re f eas ib l e and w i l l sa fe ly and e f f ec t ive ly control o r eliminate t a rge t pes t s . of t h i s vigi lance i n pes t control it is a l so emphasized that i n the protec- t i o n of human heal th a l l users of pes t ic ides w i l l avoid unnecessary exposure of crops, l ivestock, f i s h and wi ld l i f e .

As a p a r t

111. METABOLISM AND RETENTION OF INSECTICIDES

There i s a paucity of knowledge and data on the metabolic f a t e o f pes t ic ides . This lack o f understanding of the physiological processes in- volved with various chlorinated hydrocarbon compounds which leave residues i n human and animal t i s sues and the blood and milk of marmnalian species i s

unfortunate. Most of the data accrued was developed i n support of various pes t ic ide reg is t ra t ions where information was required relevant t o U.S. Food and Drug Administration tolerances. insec t ic ides with resu l tan t contamination of feeds i s a grave economic and hea l th problem since t h i s leads t o accumulation of pe r s i s t en t type pest ic ides o r t h e i r metabolites i n the t i s sues of meat animals. The organochlorine insect ic ides such as a ld r in , DDT, d ie ldr in , endrin, and heptachlor repre- sen t the most ser ious problem in terms o f the high retent ion rates of these compounds i n animal adipose t i s sues as they a re received through the food chain s ince meat and meat products a r e consumed by humans and, i n turn, contribute t o the t o t a l body burden of these compounds i n man. According t o Claborn e t a 1 (3) when insec t ic ides a r e fed t o beef c a t t l e and sheep a s a feed contaminant a t dosages l i k e l y t o occur as residues on forage crops, a l l except methoxychlor a r e s tored i n the f a t . The order of t h e i r storage is as follows :

The uncontrolled appl icat ion of

a l d r i n -;z d ie ld r in ===- heptachlor epoxide > BHC DDT ==.

chlordane -1 indane-aendr in >heptachlor>toxaphene

The accumulation of the l i p i d soluble chlorinated hydrocarbons i n adipose t i s s u e of animals can occur from d i r e c t treatment with in sec t i - cides a s well as through ingestion of insect ic ide contaminated forage crops o r pasture. l eve l s f o r pes t ic ides i n the f a t f rom various animals including c a t t l e , goats, hogs, horses, poul t ry (malathion only) and sheep. These tolerance l eve l s a r e l i s t e d i n Table 1. Tolerance leve ls f o r pes t ic ide residues i n forage (alfalfa) a re presented i n Table 2 .

The U.S. Food and Drug Administration has granted tolerance

The Meat Inspection Division of the Consumer and Marketing Service of the U.S. Department of Agriculture i s responsible f o r inspec- t i on , approval, o r re jec t ion of meat and meat food products from animals slaughtered and/or processed a t Federally inspected plants , t o assure t h a t such products w i l l be f r e e of o r within safe tolerances of harmful biologi- c a l agents and pes t ic ide residues. Memorandum No. 316 (Part 311.27 of the Manual of Procedures) was issued by the Meat Inspection Division on Novem- b e r 10, 1964. This memorandum provides f o r instruct ions and standards of compliance f o r the inspectors i n charge of meat inspection, owners and operators of o f f i c i a l establishments, and others t o be able t o car ry out t h e i r respons ib i l i t i es i n assuring tha t meat and meat food products do not exceed safe tolerances of pes t ic ide residues.

The Meat Inspection Division has a b io logica l residue surveil lance program consisting of an objective, a se lec t ive , and an invest igat ive phase. The objective phase i s the random select ion of t i s sues of animals slaughtered a t Federally inspected establishments f o r analysis of chemicals and drugs. This program provides leads on trends and suggests need f o r se lec t ive sampling. The se lec t ive phase i s the analysis of animal t i s sues when a spec i f ic b io logica l residue problem has been ident i f ied through the objec- t i v e phase of the program. w i l l be referred to l a t e r under control and research programs on residues.

Some features of the special invest igat ive work

A s previously indicated, there is l i t t l e information avai lable i n the l i t e r a t u r e on the metabolism of organochlorine compounds with the

193.

TABU 1

Pest ic ide

OFFICIAL FDA TOLERANCES

FOR SOME PESTICIDE LEVELS I N MEAT FAT

A . Organochlorine

DMI

Lindane

Lindane

Methoxychlor

Toxaphene

B . Organophospho rus

Carbophenothion

Dioxathion

Diaz inon

Co-Ral (chlorinated)*

Gu thion*

Linuron

Malathion*

To l e ram e PPm

7

4

7

3

7

0.1

1

0.75

1

0.1

1

4

Specie s

Cat t le , goats, hogs, horses and sheep

Hogs

Cat t le , goats, horses and sheep



Cat t le , goats, hogs and sheep


Cat t le and sheep

Cat t le , goats, hogs, horses, sheep and poul t ry

Cat t le , goats and sheep


Cat t le , goats, hogs, horses, sheep and poul t ry

* Meat o r meat by-products

194.

TABLE 2

OF’FICIAL FDA TOLERANCES FOR SOME PESTICIDE RESIDUES I N ALFALFA*

Pest ic ide

C hlo r ina t ed hydro carbons

Methoxychlor

Organophosphorus

Demeton

Diazinon

Guthion

Malathion

Parathion

Carbamates

Carbaryl (Sevin)

Miscellaneous

Diuron

Tolerance (ppm)

100

5

10

2

135

1

100

2

* Posi t ive l eve l s only given, zero values f o r a ldr in , d ie ldr in , heptachlor (epoxide)

exception of DDT (4). Considering the la rge group and classes of pes t ic ide compounds i n our environment, t h i s suggests the need f o r intensive research. There a r e s i m i l a r i t i e s i n the metabolic f a t e of a few compounds i n a s ingle species but one cannot extrapolate findings on a s ing le compound i n one species t o a wider range of insec t ic ida l compounds. Quite i l l u s t r a t i v e of t h i s point a r e the data of Claborn e t a 1 (5) shown i n Table 3, where a l d r i n and d i e ld r in were fed t o c a t t l e and sheep, including both sexes, f o r four and eight weeks. It is o f i n t e r e s t t o note the var ia t ion i n f a t leve ls of a l d r i n and/or d i e ld r in i n s t ee r s , he i fe rs , wethers, and ewes a f t e r 4 t o 36 weeks following the feeding period. For the c a t t l e the var ia t ion between male and female body retent ion l eve l s was not as marked a s t h a t f o r the sheep, where the wethers appeared t o r e t a in more of the pes t ic ide than the ewes. The sheep appeared t o r e t a i n a higher l e v e l o f pest ic ide f o r a longer period of t i m e .

Further emphasis on the species difference in the metabolism of d i e ld r in i s represented i n the data of Gannon e t a1 (6) shown i n Table 4, where’lambs presented the lowes t residue of d i e ld r in and poul t ry the highest

195.

TABLE 3

PPM OF PESTICIDE RESIDUES I N FAT OF VARIOUS MEAT ANIMALS DURING AM) AFTER FEEDING ALDRIN AND DIELDRIN

A . Aldrin

Steers

Heifers

Wethers

Ewe 6

B. Dieldrin

Steers

He if e rs

Wethers

Ewes

Weeks of Feeding 4 8

70 63

80 86

39 70

48 68

58 79

41 77

60 77

60 79

Weeks a f t e r Feeding 4 8 20 32 36

68

67

58

43

46

56

- 67

55

36

37

45

36

36

46

30

25

15

32

32

1 9

21

25

25

10

9

33 31

10

- 9

7 - 31 33

14 11

Claborn, H. V . , Ebwers, J. W., Wells, R. W., Radeleff, R. D. and Nickerson, W. J., Agr. Chemicals, 37-40, Aug. 1953.

re tent ion of d i e ld r in i n body f a t . Some of the pes t ic ide residue is, of course, found in the mi lk of l ac t a t ing animals as w e l l as i n meat f a t . The data from studies of Gannon e t a1 (7) shown i n Table 5 r e f l e c t the comparative storage l eve l s of d i e ld r in i n milk and body f a t of cows experimentally f ed d i e ld r in i n t h e i r ra t ion.

These feeding experiments provide some assessment of the r e l a t ive r a t io s of the amount of pes t ic ide deposited in body t i ssues , organs, and body f l u i d s re la ted t o l e v e l of pes t ic ide intake. For example, i n Table 6 the f a t storage r a t io s f o r a l d r i n and d i e ld r in f o r various species a r e shown. These data a l so i l l u s t r a t e that there is a var ia t ion in t he metabo- l i s m o r re tent ion o f pest ic ides amng various mammalian and avian species. Chickens apparently have a low turnover rate whereas the bovine, f o r example, have a much higher r a t e of excretion o r less retent ion of pes t ic ide residues. There a r e no experimentally controlled s tudies on man which would permit calculat ion of a f a t storage r a t i o , bu t f r o m calculat ions on d ie ta ry intakes and resu l tan t adipose tissue l eve l s of organochlorine insec t ic ides it is assumed t h a t man's fa t storage r a t i o is similar to t h a t of the r a t and the cow.

196.

TABLE 4

STORAGE OF DIELDRIN I N TISSUES OF DIFFERENT ANIMALS

Dieldrin i n D i e t (PPd

Dieldrin i n Fat (ppm) Hens Steers Hogs Lamb s

0.25 10.2 0.8 0.4 0.4

0.75 35.7 3.5 2.8 0.6

2.25 - 8.7 4.3 1 . 7

Gannon, N., Link, R. P., and Decker, G. C. J. Agr. Food Chem. - 7 826-828 (1959)

TABLE 5

BODY STORAGE I N COWS FED DIELDRIN I N THEXR DIET

Levels i n Milk (ppm) Levels i n Fat (ppm) Levels Fed (ppm) (after 84 days) ( a f t e r 84 days)

0.10 0.02 0.20

0.25

0.75

@.06

0.11

0.90

1.70

2.25 0.28 4.80

Gannon, N. , Link, R. P., and Decker, G. C. Agr. and Food Chem. - 7 824-826 (1959)

TABU 6

FAT STORAGE RATIO FOR INSECTICIDES FED TO MAMMALIAN AND AVIAN SPECIES’

Species

Dog R a t (Male) R a t (Female)

Steers COWS

Steers

cows

Chickens

Wimm Fat Storage Ratio ppm i n Fat

Pest ic ide f ed ppm i n Diet

Dieldrin

Aldrin

Aldrin

Aldrin Aldrin

Dieldrin

Dieldrin

Dieldrin

1 7

3

5

6

5

4

3

40

k a l c u l a t e d frum various reports on feeding s tudies on pes t ic ides .

197.

The a f f i n i t y of unmetabolized pest ic ides f o r ce r t a in t i s sues i s important i n evaluating residue l eve l s encountered i n meat o r meat products consumed by man. Visceral organs such as l i v e r , kidney, and hear t r e t a in l eve l s of pes t ic ides comparable t o the lean t i s sue o r muscle. It i s assumed t h a t pe r s i s t en t pes t ic ides a r e occluded i n the f a t t i s sue of these organs. Kitselman e t a 1 (8) and Ely e t a 1 (9) have shown i n t h e i r data presented i n Table 7 t h a t c a t t l e f ed 1 .5 ppm of d i e ld r in i n hay deposited one ten th t h a t amount i n l i v e r , kidney, and lean meat, but the d i e ld r in was concentrated a t twice t h i s l e v e l i n the adipose t i s sue . Further con- centrat ion, a s might be expected, was re f lec ted i n the b u t t e r made from cream and mi lk from cows fed d i e ld r in .

The organophosphorus and carbamate insect ic ides , since they a r e rapidly metabolized, do not present the residue problem of the organochlorine insec t ic ides which readi ly deposit i n depot f a t a reas .

TABU 7

STORAGE O F DIELDRIN I N CATTLE FED HAY CONTAMINATED WITH 1 .5 ppm OF DIELDRIN

0 rgan Dieldrin Residue ppm

Liver 0.1

Kidney 0.2

Lean Meat (Muscle) 0.1

Adipose Tissue (Fat) 3 .O

Milk -> Cream 4 Butter 5 . 7 - 9.5

Kitselman, C . H . , Dahm, P. A., and Borgmann, A. R . Am. J. of Vet. Res. 11 378 (1950)

-

Ely, R. E., Moore, L. A., Hubanks, P. E., Carter, R. H., and Poos, F. W. J. Dairy Sci . - 37 294 (1954)

Claborn e t a 1 (10) i n some experimental spray programs on c a t t l e , sheep, goats, and hogs, using one percent Sevin (carbaryl) , a carbamate spray solut ion f o r control of t i cks and horn f l i e s , found some absorption o f the pes t ic ide . of swine was qui te low a t 0.04 ppm but goats showed a higher l e v e l of carbaryl i n muscle and bra in t i s sue than c a t t l e , sheep, o r swine. O f significance is the f a c t t h a t i n 7 days the pes t ic ide was metabolized i n a l l t i s sues (adipose, muscle, l i v e r , kidney, and brain) t o very low l eve l s (Table 8 ) . rangelands o r fo re s t s , have an e f f e c t on the residue levels in f ish i n streams contiguous t o the spray area and a l so the game animals. In Table 9

On the f i r s t day a f t e r spraying, the concentration i n t i s sues

Some insec t control spray programs, pa r t i cu la r ly those i n

198.

some data obtained by the Idaho Fish and Game Department, working cooper- a t i v e l y with the U.S. Department of Agriculture, demonstrate t h a t DDT l eve l s in body f a t of deer, goat, and e lk increased manyfold from t h i s exposure (200-2000 fo ld increase) . One beef animal i n the area showed a DDT body f a t l e v e l approaching the tolerance value of 7 ppm f o r t h i s pes t ic ide . There i s now a t rend t o s h i f t away from pers i s ten t pest ic ides i n these areas not only due t o the residue problem i n game but a l so because of the high retent ion by s h e l l f i s h i n estuarine waters.

Surveillance o f market meat and meat product samples has been qui te l imited. Y l s t monitoring of slaughtered animals is carr ied out by the Meat Inspection Division of the U.S. Department of Agriculture,

TABLE 8

CARBARYL

Time After Spraying

1 Day

7 Days

1 Day

7 Days

1 Day

RESIDUES I N SOME TISSUES OF CATTLE, SHEEP, GOATS, AND HOGS AFTER FOUR SPRAYINGS WITH 1.0% CARBARYL

ppm Carbaryl i n Tissues Omen t a1

Fat lhs c l e

CATTLE

0.57 0.13

< 0.04 <0.04

SREEP - 0 . 2 1 0.07

C0.04 (0.04

GOATS

0.38 0.18

7 Days 0.70-0.90 (0.04

SWINE

1 Day <0.04 <0.04

Liver

0.00

<0.04

(0.04

<0.04

(0.04

< 0.04

<O. 04

Kidney

0.10

<0.04

0.04

<0.04

0.06

0.04

<0.04

Brain

0.10

<0.04

0.15

<0.04

23 .O

0.30

(0.04

Claborn, H. V . , Roberts, H. D. , Nmn, H. D. , Bowman, M. C . , Ney, M. C . , Weidenbach, C. P. and Radeleff, R . D. Agr. and Food Chem. - 11 (1963)

74-76

199.

k

rl l-i 0

rl 0

0

ln

0

0

P

cu

rl 0 k

c, cl 0

V

M 0

0

M

0

0

rl 0

0

4

0

0

0

l-i

l-i 0

k

c, cl 0

u

* 0 0

* 0 0

rl 0

0

rl 0

0

N

rl

c, cl 0

V

E)

cu b

ri cu

M

M

P-

rl

d

cu 9 In M

N

3 $:

P

cn E 5 w

200.

bu t l i t t l e of these data has been released i n journal publ icat ions o r re- por t s . from a regulatory standpoint reduce the incidence of unlawful residue l e v e l s . According t o S t r e e t (11) the S ta t e of Cal i fornia made a survey of pes t ic ide residues i n various meat products i n 1963. O f 94 samples t e s t ed none was found wherein DIYT exceeded the tolerance and 22 were found t o be negative. Some beef and pork f a t samples contained from 1 . 7 t o 8 . 8 ppm of DDT + DDD + DDE. A similar survey conducted i n 1964 indicated t h a t 8 7 percent of 1 7 7 samples showed no more than a t r ace (0.1 ppm) of DDT residue. One sample of beef f a t showed DDT over the tolerance and another beef f a t sample had 0.3 ppm heptachlor and 0 .2 ppm heptachlor epoxide.

The high tolerances f o r some chlorinated hydrocarbon insec t ic ides

Samples of beef and pork assayed f o r DDT +DDE by the Milk and Food Research Laboratories of the U.S. Public Health Service a t the Sani tary Engineering Center i n Cincinnati, Ohio, showed values correspond- ing t o the Cal i fornia survey. The range i n values of DM' +DDE i n pork as reported by Campbell e t a1 (12) f o r southeast , northeast , and northwest USA was from 0.26 t o 0.53 ppm with mean values ranging from 0.093 t o 0.114 ppm (Table 1 0 ) . The l eve l s of DDT + DDE reported by same invest igators f o r beef samples where somewhat lower ranging from 0.01 t o 0.25 ppm of DDT + DDE with a mean of 0.14 ppm.

TABLE 10

ORGANOCHLORINE HYDROCARBONS I N BEEF

Location

Southeast

Northeast

No. of Sampl es

DDE 4 DDT (ppm) Min Max Mean

7 De t 0 . 2 5 0.14

2 De t 0.01 -

ORGANOCHLORINE COMPOUNDS I N PORK

No. of Location Samples

DDE + DDT (pprn) Min Ybx Mean

Sou theas t 15 N.D. 0.53 0.109

No rthwe st 10 N.D. 0.22 0.093

Northeast 7 0.05 0.26 0.114

Camphel1,J. E.> Richardson, L. A . , and Schafer, M. L. Arch Environ Health - 10 831-836 (1965)

201.

I V . REDUCTION OF RESIDUES AND DEPLETION OF INSECTICIDE STORAGE

Due t o the increased public hea l th concern relevant t o the body burden of pes t ic ides , p a r t i c u l a r l y the chlorinated cyclodiene insec t ic ides suck as a l d r i n , d i e ld r in , endrin, and heptachlor, recent invest igat ions have been accelerated and provide evidence of important developments i n t h i s a r ea . A reduction of 72 percent i n d i e ld r in storage i n rat t i s s u e was obtained by S t r e e t (13) through administration of DDT. Earlier workers (14, 15) showed t h e influence of DDT i n de toxi f ica t ion of a v a r i e t y of drugs which p a r a l l e l s the effect iveness of DDT on d i e ld r in s torage.

Various drugs were t r i e d by S t r e e t e l a1 (16) t o reduce d i e ld r in s torage and these were qu i t e e f f ec t ive i n some experiments with rats. In Table 11 it i s noted t h a t heptabarbi ta l , aminopyrine, and tolbutamide re- duced t i s s u e d i e l d r i n i n rats f e d 1 ppm of d i e l d r i n i n the d i e t f o r 10 days. Hence su i t ab le drugs might be used not only t o reduce in sec t i c ide residues i n animals, espec ia l ly those providing meat, bu t might a l so be qu i t e effec- t i v e i n reducing the in sec t i c ide body s to re s i n man, p a r t i c u l a r l y i n t r e a t - ment of individuals undergoing heavy occupational exposure to pes t i c ides .

The insec t ic ide a l d r i n and heptachlor a r e transformed i n t o the expoxides d i e l d r i n and heptachlor epoxide, respect ively. Biologically, as a c lass , epoxides a r e of c ~ n c e r n because some epoxides a r e carcinogenic

TABLE 11

DRUG EFFECTS ON DIELDRIN STORAGE I N RATS (Administration of 1 ppm Dieldrin i n d i e t f o r 10 days)

Storage T i s sue Dieldrin Reduction

Treatment u g h 9 SE k Control 7.53 0.89

DDT 4 mg/kg 2.06 0.34 72

Tolbutamide 60 mg/kg 6.54 0.47 13

Tolbutamide 290 mg/kg 3.20 0.72 57

Aminopyrine 75 mg/kg 2.76 0.39 63

Aminopyrine 350 mg/kg 1.40 0.09 81

Heptabarbital 40 rg/kg 4.01 0.67 47

Heptabarbital 225 mg/kg 1.50 0.07 80

S t r e e t , J. C . , Wang, M. and Blau, A . D. B u l l of Env Contam and Tox 1 - 6-15 (1966)

202.

o r mutagenic. cat ion but are considered as s tored i n the depot f a t from which s i t e they a r e u l t imate ly excreted i n the feces ( 1 7 ) . metabolic s tud ies conducted by Terr iere e t a1 (18). shown t h a t a major port ion of d i e ld r in t h a t is fed is excreted by way of the b i l e as an unident i f ied hydrophilic compound.

Toxic epoxides have been viewed as not undergoing de toxi f i -

This has been pointed out i n Korte e l a1 (19) have

A s mentioned e a r l i e r , the U.S. Department of Agriculture is carrying on an ac t ive invest igat ive program re l a t ing t o regulatory control of chemical and/or b io logica l residues i n the edible t i s sues of food producing animals. For example, feeding poul t ry l i t t e r t o l ives tock has been s tudied i n terms of residues l e f t i n meat animals a t time of ante-mortem inspection. In the appl icat ion of pes t ic ides , pa r t i cu la r ly by a e r i a l spraying which may include organochlorine and organophosphorus insec t ic ides , edible t i s sues of animals have been checked t o ascer ta in the e f f ec t s o f appl icat ion prac t ices on l ivestock. The prac t ice of using paradichloroben- zene as a deodorant spray i n garbage f ed t o swine has been invest igated because t h i s chemical leaves a residue and odor i n pork. Some extensive research i s a l so being car r ied out t o ascer ta in the va r i a t ion i n organochlorine compounds such as DMI s tored i n the f a t located a t various anatomi- c a l s i t e s of an an imal ’s body.

From a p r a c t i c a l viewpoint much can be done i n the way of control toward reduction of residues i n edible t i s sues . Such considerations re le - vant t o pes t ic ides involve the appl icat ion of presumed safe dosage l eve l s and s t r i c t observance of whatever time in te rva ls may be necessary between appl icat ion of materials and s laughter t o insure elimination of res iades . With respect t o appl icat ion, t h i s implies e i t h e r chemicals used on l ives tock o r on p lan t mater ia ls which may be l a t e r consumed by l ivestock. c lose survei l lance must be maintained t o guarantee t h a t drinking water f a c i l i t i e s and feed a re not inadvertently contaminated. Although the prac t ice of using so-called “ t r a s h feeds” such as apple o r vegetable pomace has been discouraged because these products have exhibited highly concen- t r a t e d pes t ic ide residues, there must be continuous vigi lance t o prohib i t the use of such contaminated products. Ideal ly , l ives tock producers could maintain low residues by continuous assay of feeds, but t h i s requirement may not be f eas ib l e espec ia l ly f o r average producers.

Certainly

Various attempts have been made t o discover if any treatments a re effect ive i n reduction of residues i n edible t i s sues t o be consumed by man. In some recent unpublished reports gama i r r ad ia t ion processing of f i s h and o the r marine products has been proposed f o r destruct ion of the chlorinated hydrocarbon insec t ic ide residues. Despite any opt imis t ic claims it i s qu i t e un l ike ly from a technical viewpoint tha t ionizing radiat ion could e f fec t ive ly degrade the molecule of DDT, f o r example, s ince the cross sect ion of such a compound does not provide a su i t ab le t a rge t f o r e f fec t ive destruct ion. Heat treatment of meats has been s tudied and Ivey e t a 1 (20) have found t h a t the cooked f a t from beef roas t s contained e s sen t i a l ly the same d ie ld r in concen- t r a t i o n as t h a t determined i n carcass body f a t (Table 1 2 ) .

V . RELATIONSHIP OF ANIMAL TISSUE RESIDUES TO BODY BURDEN O F PESTICIDE RESIDUES I N MAN

The s ignif icance of the residue problem i s evaluated ul t imately i n terms of man’s po ten t i a l source of exposure through ingestion of these

203.

ccmpounds i n the human d i e t . Although the general population receives some exposure t o pes t ic ides i n the environment v i a absorption, inhalat ion, and ingest ion, Kraybill (21) has estimated t h a t 90 percent of the ind iv idua l ' s t o t a l ingested p e r s i s t e n t pes t ic ide arises from pes t ic ide intake i n food. Drinking water i s estimated t o fu rn i sh only 0.02 percent of t o t a l ingested pes t i c i d e s .

O f the major d i e t a ry components such as da i ry products, vege- tab les , cerea l products, meats, seafood, and eggs, a l l o f which may have de tec tab le l eve l s of organochlorine insec t ic ide residues, meats, seafood, and eggs as a c l a s s contr ibute approximately 58 percent of the t o t a l DDT 9 TIDE intake according t o Campbell and co-workers (12). the f a c t t h a t meat and meat products cons t i t u t e about 20 percent of man's t o t a l d a i l y intake, with eggs and seafood representing only a minor f r a c t i o n

Considering

TABLE 12

DE3LDRIN I N FAT FROM BEEF CARCASSES COMPAFBD WITH DIELDRIN LEVELS I N FAT FROM BEEF ROASTS

(Cat t le Fed Varying Levels of Aldrin and Dieldrin)

Dieldrin Renal Fa t Cooked Fat

Sample No. Carcass Body Fat from Roasts PPm

1 0.99 0.88 1 .40

2 3.38 2.90 3 . 2 3

3 8.50 7.84 7.80

4 39.20 44.50 33.30

Ivey, M. C . , Claborn, H. V., Mann, H. D., Radeleff, R. D . and Woodard, G. T. Agr. and Food Chem. 9 374-376 (1961) -

compared t o meats, it i s conceivable t h a t meat and meat products alone may contribute a t l e a s t 50 percent of the t o t a l d a i l y d i e t a ry intake of in- s ec t i c ide residues (Table 13).

Various inves t iga tors have surveyed the t o t a l d i e t s i n se lec ted loca t ions and i n s t i t u t i o n s i n the United S ta tes , including households, res taurants , and ja i ls , t o a sce r t a in the t o t a l d a i l y i n t a k e of DDT and DDE (22 , 23, 24 and 2 5 ) . Although there was some variance i n the t o t a l DDT intake from household and res taurant meals, the household meals i n some ag r i - c u l t u r a l a reas contained a somewhat higher l e v e l of DDT, due perhaps t o spec ia l ty o r unprocessed home grown items of higher res idues. The average t o t a l d a i l y intake of DDT found by these inves t iga tors was 0.184 mg. l a r l y the average d a i l y intake of DMI f o r inmates o f a penal i n s t i t u t i o n was

Simi-

0.202 mg.

204.

The f inding t h a t d i e t , and pa r t i cu la r ly meat o r meat products, has an influence on t o t a l DDT intake and resu l tan t body l eve l s i n man has been f u r t h e r corroborated by invest igat ions o f Hayes e t a 1 (25). O f s ig- nificance i s the f a c t t h a t Hayes and co-irorkers (25) found in eleven meatless meals t h a t were sampled t h a t the mean t o t a l da i ly intake was only 0.041 mg (Table 14). Specimens of retained preserved adipose t i s sue from 10 cadavers col lected a t museums and hospi ta ls during the e ra preceding use of DDT have shown on assay, as expected, zero leve ls of t h i s pes t ic ide . Since the

TABLE 13

ESTIMATED DDT + DDE CONTRIBUTIONS OF MAJOR DIETARY COMPONENTS

Weekly Conc Weekly 9 o f Commodity Consump- DDT + DDE DET + DDE Total

Group t ion (kg) (PPd Intake (mg) DDT +DDE Milk 3.5 0.01 0.035 3.7

Other da i ry products 0.3 0.50 0.15 16.5

Ve g e t ab 1 e s 2.6 0.05 0.13 14.4

Meats, seafood, eggs 2.6 0.20 0.52 57.6

Cereals 0.9 0.03 0.027 2.9

0.05 0.045 4 .9 Others TOTAL 10.8 * 0.907 100.0

- 0.9 -

*Whole d i e t calculated t o contain 0.08 ppm DDT + DDE Campbell, J. E. , Richardson, L. A. , and Schafer, M. L . Arch Environ Health - 10 831-836 (1965)

Source

TABLE 14

PESTICIDE RESIDUES I N TOTAL DIET SURVEYED AT VARIOUS INSTITUTIONS I N USA

Mean No. of Total Daily Intake Meals DDT DDE

( m d ( m d 0.050 1 6 0.202 Penal Ins t i t u t ion

25 0.184 0.092 Restaurant and Ins t i t u t ion (1954) Res taurant (1961-62) 12 0.038 0.044

1

2

Household (1961-62)3

Meatless Meals4

1 7 0.299 0.173

11 0.041

1. Hayes, W . J . , Durham, W. F. and Cueto, C . J. J.A.M.A. - 1 6 2 890 (1956) 2. Walker, K. C., Goette, M. B. and Batchelor, G. S. Ag and Food Chem - 2

3. Curham, W . F., Armstrong, J. F. and Quinby, G. E. Arch Environ Health

4 . Hayes, W. J . , Quinby, G. E., Walker, K. C . E l l i o t t , J. W. and Upholt,

1035 (1954)

- 11 641-647 (1965)

W. M. Arch Ind Health 18 - 398 (1958)

205.

introduction of DDT, however, the general population receiving an environmental exposure of t h i s pes t ic ide has shown i n 61 cases examined on un- r e s t r i c t ed meat d i e t s t ha t the average DDT l e v e l i n adipose t i s sue has been observed t o be consis tent ly a t 4 .9 ppm. However, f o r 16 cases surveyed who had meatless d i e t s the body burden was 2 . 3 ppm o r roughly 50 percent of t h a t shown f o r people on a meat d i e t . the adipose t i s sue l e v e l was approximately the same as f o r those who re- mained on a meatless d i e t . If the intake of meat was increased from twice a month t o twelve times a month there was a s l i g h t rise i n the average bcdy burden of DDT, from 2.3 t o 2 . 8 ppm (Table 15).

If meat was consumed only twice a month

The introduction of organochlorine insect ic ides f o r pes t vectored disease control and crop protect ion i n 1941 revealed an increase i n environmental l eve l s o f these pes t ic ides . Accordingly t h i s was re f lec ted i n the appearance of these chemicals i n the body t i s sues and a gradual increase i n the body burden of these pe r s i s t en t pes t ic ides , as shown i n Figure 1. It has been maintained by some invest igators t h a t peak concentrations were reached i n 1950, a f t e r which there w a s a steady decline and plateauing i n pest ic ide l eve l s . However, others have held t h a t the maximum concentration in human adipose t i s sue was reached i n 1955, followed by a decline and

TABLE 1 5

BODY BURDEN OF ORGANOCHLORINE PESTICIDES I N MAN A S INFLUENCED BY DIET

Average Levels of Pesticides (ppm)

Dietary Exposure No. Cases DDT DDE

P r io r t o DDT Era 10 Zero Zero

Meatless Diet 16 2 .3 3 . 2

Meat l e s s than twice monthly 4 2 . 8 4.5

General Population Unrestricted Meat Diet 6 1 4.9 6 .1

Hayes, W. J . , Quinby, G. E., Walker, K. C . , E l l i o t t , J. W. and Upholt, W. M. Arch Ind Health 18 - 398 (1958)

plateauing i n pes t ic ide l eve l s representing the presence of these environmental contaminants continuously during the last ten years . A p l o t of mean l eve l s of DDT derived materials i n adipose t i s sue of the general population i n USA, a s shown i n Figure 1, would appear to support the v a l i d i t y of the l a t t e r concept (26, 27, 28, 29 and 30).

Curing the period 1958 t o 1965 various surveys i n Europe, Asia, the Middle East, and the United S ta tes have been made t o determine the

206.

average concentration of DDT derived materials i n the adipose t i s sue of the general populations i n various countries. A s i l l u s t r a t e d i n Figure 2, England appears t o present the lowest body burden f o r DDT 9 DDE whereas several areas i n India revealed 25 t o 30 ppm of DDT + DDE i n the body f a t of the general population. In the l a t t e r case these higher body f a t l eve l s f o r DDT +DDE a r e cer ta in ly a re f lec t ion of higher environmental contamina- t i o n enhanced by vigorous pes t control programs such a s mosquito abatement pro jec ts . The lower l eve l s of DDT DDE i n body f a t of Europeans are indi- cat ive of the s t r ingent controls on the use of pe r s i s t en t organochlorine insec t ic ides i n those countries which moreover is re f lec ted i n decreased environmental l eve l s and diminution of residues i n loca l ly grown food and forage crops (30, 31, 32, 33, 34, 35, 36, 3 7 and 38).

The influence of ag r i cu l tu ra l chemicals and spec i f i ca l ly chemical pes t ic ides on the qua l i t y of our environment has been aore f u l l y recognized recent ly due t o public concern regarding environmental po l lu t ion and i ts relat ionship t o the heal th of man, f i s h , wi ld l i fe , and domestic animals. Whether pes t ic ide exposure involving any of these species occurs through inhalat ion, absorption, o r ingestion, there appears t o be an equilibrium between environmental and body l eve l s of pes t ic ides . The organochlorine o r so-called pe r s i s t en t type insect ic ides have been implicated i n the residue problem. The more readi ly metabolizable o r non-persistent organic phosphate insec t ic ides , although highly toxic to man and animals, do not present the va r i e ty of problems encountered i n the u t i l i z a t i o n o f residue producing insec t ic ides . These l a t t e r types of compounds, although afford- ing long-term protect ion i n pes t control do, however, necessi ta te s t r ingent controls i n t h e i r appl icat ion and close surveil lance with respect t o t o l e r - ances. Wherever f eas ib l e , large-scale pest control programs have promul- gated the use o f non-persistent pest ic ides t o obviate the occurrence of residues which have the capabi l i ty f o r sustained adverse heal th e f f e c t s . For the protect ion of human heal th , a l l users o f pest ic ides should be re- peatedly ins t ruc ted t o avoid unnecessary exposure of crops, l ivestock, f i s h , and wi ld l i f e .

Despite extensive research on the tox ic i ty of pest ic ides there is a lack of understanding and information on the physiological processes i n - volved w i t h organochlorine insect ic ides which leave residues i n animal and human t i s sues . The r a t e of metabolism and f a t e of these compounds var ies i n ce r t a in species and is influenced by sex, hormones, cer ta in drugs, and interact ions with o ther pes t ic ides , a l l of which r e l a t e t o the degree of re tent ion i n adipose t i s sues and various organs.

The human d i e t controls t o a la rge degree the body burden of res idual pes t ic ides , a t l e a s t among persons non-occupationally exposed. A major d i e t a ry contributor to pes t ic ide exposure by ingestion is meat, which represents approximately 50 percent of the ingested pes t ic ide . In some l imited surveys of market meats a high percentage of samples had only t race amounts of DDT, with some few samples of pork and beef containing l e v l s ranging from 1 t o 7 ppm of DDT which d id not exceed the tolerance s e t f o r t h i s pes t ic ide .

207.

Various methods f o r reduction o f residues and depletion o f pes t i - cide storage have been t r i e d experimentally, such as the use of DDT t o decrease body l eve l s of d ie ldr in , and the use o f drugs such as aminopyrine, heptabarbi ta l , and tolbutamide, which have proved qu i t e e f fec t ive . There a re many o ther more p rac t i ca l methods than these procedures t h a t can be applied t o reduce residues i n meats, most of which involve control of environmental contamination and s t r i c t adherence t o u t i l i z a t i o n of low residue feed s t u f f s .

The t rend i n u t i l i z a t i o n o r discontinuance of pe r s i s t en t pes t i - cides i s discussed i n terms of the a l t e r a t i o n of the body burden of these pes t ic ides i n man. The decrease i n body f a t l eve l s of DDT over the pas t 25 years can be ascribed t o reported reduction i n volume of use of these res idua l pes t ic ides i n ag r i cu l tu ra l and public heal th control programs. The pa t te rns of the use of the organochlorine insec t ic ides a re re f lec ted i n the body f a t l eve l s o f DDT i n countries throughout the world. Countries having more r e s t r i c t i v e programs on u t i l i z a t i o n and appl icat ion of chlorin- a ted hydrocarbon insec t ic ides appear t o present a lower body f a t residue of DDT and s imi la r organochlorine insect ic ides i n adipose t i s sue sampling of the general population than i n those areas where l e s s r e s t r i c t i v e use occurs.

FIGURE I

Mean Leve ls o f DDT Cer ived M a t e r i a l s i n Adipose T issue (1942-1965) o f t h e General Popula t ion i n U.S .A .

20-

1942 - Hayes e t a l (1958) 1950 1955 - Hayes e t a1 (1956) 1956 - Hayes e t 21 (1958) 1961-62 - Quinby e t a1 (1965) 1965 - - Davies e t al (1965)

- Laug e t a1 (1951)

15

\ \

-@. - - - & - - - - - - -- Y L - - _ -

I I I 1945 1950 1955 1960 1965

I

1940

-20

-15

- 10

-5

-0

CI DDT +DDE o - - DDT a- . - - - - - -A

Years o f O b s e r v a t i o n and DDT Exposure

209.

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37. Wasserman, M. - Private Communication, Sept. 1965.

38. Dale, W. E., Copeland, M. F., and Hayes, W. J., Chlorinated Insect ic ides i n the Body Fat of People i n India, B u l l . of WHO - 33 471-477 (1965)

JAMES F. PRICE: Thank you, D r . Bond. In discussing t h i s , Bob Saf f le d idn ' t mention it but i n put t ing t h i s topic on the program it was t o come under the commercial problem sect ion. The committee d idn ' t intend t o imply that t h i s area of pes t ic ide residues i n meat w a s a commercial problem but we intended t o ask these questions. lance i n the United S ta tes? I think l a t e r on i n the paper, which I regre t he d idn ' t g e t t o , he mentioned some o f the differences between countries i n the l eve l s of some of these residues i n meat products. So, we might ask ourselves the question, if we are going t o be faced with the problem of analysis f o r pes t i - cides a re we going to be faced with something s imi l a r t o the cranberry scare? Certainly, the meat industry wishes t o avoid t h i s . have questions t o be directed t o D r . Bond? D r . Saf f le .

What is the incidence o r the problem of surve i l -

Perhaps we have time f o r one o r two questions, do we

DR. SAFFLE, Univ. of G a . : When you have a zero leve l , do you specify the method of analysis? te res ted from the standpoint of the work o f D r . Lisz, who gave a more precise method i n which he was picking up pa r t s pe r b i l l i o n o r per t r i l l i o n of various pes t ic ides . CO you specify the mthod of analysis f o r zero tolerance?

I am pa r t i cu la r ly in-

DR. BOND: Let me say f i rs t o f a l l , i n the U. S. Public Health Service we do not do any of t h i s s e t t i n g l eve l s . This is a l l done by the Food and Drug Administration, an organ- iza t ion completely d i f f e ren t from the one w i t h which I a m asso- c ia ted. The Food and Drug Administration, of course, has a bear by the t a i l r igh t now because of the recommendation tha t was made t o them a t t h e i r request by the National Research Council on t h i s whole matter of zero tolerances. Some years ago before ana ly t i ca l procedures were accurate t o the degree t h a t they a re now, the allowable l i m i t was usual ly s e t where it could not be detected. But now as methods g e t b e t t e r and be t t e r , you can go down t o parts pe r b i l l i o n and pa r t s p e r t r i l l i o n and even below t h a t i n some cases, then you have t o decide a l eve l t ha t is allowable. The Food and Drug Administration r igh t now i s i n the furrows of s e t - t i n g allowable tolerances on many o f these pest ic ides down i n the p a r t s pe r b i l l i o n l e v e l . Row j u s t t o do the s c i e n t i f i c work t o

213.

determine these p a r t s per b i l l i o n is going t o take, i n many cases, years . guarantee t h a t the t o t a l environment f o r the experimental animals is indeed f r e e of the subject pest ic ide a t that l eve l is a r a the r f r ightening s i tua t ion . Say th i s is a two-year feeding study, any accident along the way can completely knock out your two-year study and you have t o s tar t over. t i o n is well aware of a l l of the problems t h a t now face them i n having t o s e t allowable l eve l s . Furthermore, they are qu i t e aware of t he f a c t that new ana ly t i ca l procedures w i l l constantly be developed which w i l l make it possible t o even go t o lower l eve l s , and the problem is going t o g e t worse instead of b e t t e r a l l of the t i m e .

J u s t the s e t t i n g up of the design of the experiment t o

The Food and Drug Administra-

DR. PRICE: Thank you. If there a r e no more questions, I w i l l turn t h i s back t o you, Bob.

DR. SAFFLE: Thank you, J i m . Our second topic is Experimental Techniques f o r the Evaluation of Processing Equipment. processing a rea up u n t i l ten years ago we saw l i t t l e new machinery coming on the market. However, t h i s has changed and i n the l as t ten years, par- t i c u l a r l y i n the l a s t f i v e years, we have seen a tremendous change i n new machinery f o r processing; thus it becomes more important t o a l l of us t o have some method of evaluating the new machinery which is coming on the market. We asked Walter Urbain from Michigan Sta te University t o cover t h i s area and immediately following him R. B. Sleeth of Armour and Company w i l l handle the discussion period. Walter.

I think i n the

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pesticide residues in mammalian tissues, problems

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