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FOOD AND COSMETICS TOXICOLOGY An International Journal publishedfor the British Industrial Biological Research Association Editor L. GoLbirg. Chemical Industry Institute of Toxicology, Robert ,\f. Hanes Memorial Bldg. P.O. Box 12137, Research Triangle Park, North Carolina 27709, USA Assistant Editor A. M. SEELEY, BIBRA, Woodnwnsterne Road, Carshahon, Surrey Editorial Board R. J. L. Allen, Brentford ' R. F. Crampton, Carshahon J. W. Daniel. Ingatestone P. Ei.iaj, Karlsruhe W. G. Flamm, Bcthesda, Md. P. Giusso, Carshahon P. N. Magee, London J. McL. Philp, Lontion F. J. C. Roe, London A. N. Worden, Huntingdon Regional Editors G. Dflla Porta, Milan for Italy Y. Ikeda, Tokyo for Japan H. C. Grice, Ottawa for Canada D, L. Opdyke, New York for USA Editorial Board M. Kramer, Frankfurt for Germany H. C. Spencer, Midland, Mich, for USA J. Tremoherei, Paris for France G. J. VAN Esch, Bihhocen for tlie Netherlands Honorary Advisory Board E. Abramson, Stockholm F. Bar, Berlin F. 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PERGAMON PRESS LIMITED IIFADfNTil ON HILL HALL - MAXWELL HOUSE, FAIRVIEW PARK fi t u'r, ,ih > c j - n v r > *' QSW 032538 STLCOPCB4016500 V'ol |4. pp w MH fVfjjmon PfC\ 197A PfinlrJ m Rriljrft i REPRODUCTIVE DYSFUNCTION IN RHESUS MONKEYS EXPOSED TO LOW LEVELS OF POLYCHLORINATED BIPHENYLS (AROCLOR 1243) D. A. Baksotti. R. J. Marlak and J. R. Allin Department of Pathology. Uniiersity of Wisconsin Medical School, Department tif Food Micmhiology anJ Tocicolaov. and Regional Primate Research Center, Unteersity of Wisconsin, Mailison, IVi.vi nn.uu 5J7u6, USA (Recoiled 5 September 7V7<) Abstract Eighteen female anil f-uir male adult rhesus monkeys were fed the polychlorinated biphenyl (PCB) Aroclor 1248 at Its els of either 2 5 or 5 0 rpm in the diet. These levels are equal to. and 50",, of. the concentration allowed in certain foods destined for human consumption After consuming these diets for 2 months, some of the females developed acne, alopecia, cruhcmn and swelling of the eyelids and by (> months all females exhibited these changes to some degree. Modifications in scrum/finals ) developed gradually, with a trend towards hvnocholestcrolaemia. hvpolipidacmia and decreased serum In addition there was a shift in the plasma albumin globulin ratio and an increase tn serum glutamic-pyruvic transaminase activity. Analysis of subcutaneous fat showed an accumulation of the PCB isomers tn the adipose tissue The concentrations in this tissue reached a plateau, after which only slight variations were observed. Within 4 months, menstrual cycles were altered: menostasis and menorrhagia occurred frequently and at times amenorrhoca was apparent. The ability of the animals to maintain pregnancy was impaired, as indicated hy frequent resorptions and abortions When infants were born they were small, and the transplacental movement ol PCBs was evident from analyses of skin biopsies of neonates and of autopsy tissue from one stillhorn. Moreover, additional accumulation of PCBs occurred in infants during breast feeding. All males fed 5 0 ppm PCB exhibited only slight periorbiLil oedema and erythema after 14 months on the diet and showed no alterations in their breeding capacities The data presented indicate that long-term, low-level exposure of female non-human primates to PCBs can affect many important biological parameters INTROIH C HON Polychlorinated biphenyls (PCBs) are some of the more widespread and injurious environmental con taminants. These industrially produced compounds have been used extensively, because of their heat re sistance. dielectric properties and extreme stability. The properties that ensure their usefulness to industry also make them very resistant to biodegradation. The main routes of environmental contamination by these compounds include open burning, vaporization, acci dental spillage and waste disposal in sewage. In addi tion to acne, which is a fairly constant complication in most mammalian species exposed to PCBs. these compounds have caused reproductive failure in mink of the Great Takes region (Aulerich, Ringer & hvamoto. 1973: Ringer. Aulerich & Zabik. 19721. in sea lions on the Pacific Coast (DeLong. Gilmarttn & Simpson. 1973). in birds in many areas of the world (Rtscbrough, Riccho. Peakall. Herman & Kirven. 1968) and in man following the industrial contami nation of rice oil in Japan iKuratsune, Yosliimura. Matsu/aka & Yamagucln, 1972) In the Japanese inci dent, the occurrence of abortions, stillbirths and un dersized infants was attributed to the transplacental movement or the PCBs. Subsequent research (Allen. Carstens A Har.sotli. 1974a; Curley. Burse. Grim. Jen nings & Timler. 1971) tus shown that the l'CBs do. in fact, pass across the placental barrier and are excreted in the milk of lactating niothets (Miller it Fox. 197.1; Musi.11. Mui/inger. Zitko A t rocker. 19741 Although the utilization of PCBs hjs been limited to closed systems, the level of contamination, particu larly in bodies of water adjacent to densely populated areas, is not declining and in many instances appears to be increasing. Thus, the PCBs remain a major en vironmental contaminant of significance to health. In the present report some of the possible ramifications of low-level, long-term exposure to PCBs are pre sented. Even at the levels currently permitted in foods destined for human consumption, the PCBs are cap able of producing widespread harmful effects in female primates. EXPERIMENTAL Anitmilx ittul diets. Thirty female and ten male adult rhesus monkey s were housed in a controlled environ ment simulating the light, humidity and temperature conditions of the breeding season for these fetal ani mals in India. During the 6 months prior to the administration of (he experimental diets, the men strual cycles, sperm counts and morphological fea tures of the spermatozoa were evaluated in these ani mals. The monkeys were subsequently placed m ilucc grottps. a control group of 12 females and six males given a commercial diet iKulstoti-Pinina Co. St Toms. Mo ), a second group of nine females receiving a similar diet to which 2 5 ppm PCB t Arojor 124s. Monsanto Co. Inc.. Si loins. Mo I was added, ami a tliiid gioupol nine females and loin ni.ikw receiving a similar diet containin'.' s O p;un l'( It !' .'V"'-. DSW 032539 STLCOPCB4016501 100 D. A. B.vp.soiti. R. J. Makiar ami J. R. Amis ink-in.il Jicis were prepared by adding the appro priate levels of PCB to a finely powdered meal and subsequently pelleting the mixture into 0 5 x 1-25 in. cylmdrie.il pellets. Periodically, samples were ana lysed by gas liquid chromatography to confirm the PCH level. The females on the experimental and con trol diets received 200 g daily, while all males received 300 g of their respective diets daily. All diets were supplemented with fresh fruit and the animals received water ml lib. The food left in the feeder was removes! and weighed daily for calculation of intake. Ba-iiliih/ sti/Jv. After 7 months on the experimental diets, the eight surviv ing females from the 2 5-ppnt group, eight females from the 5-ppm group and the 12 control females were allowed to breed. Ovulation was predicted from observation of menses and pre vious menstrual cycle length (Valerio. 1969). In gen eral. the experimental females were housed with con trol males for 5 days during the appropriate time of oxidation, and the experimental males were housed with control females for a similar period. Pregnancytests on females were performed according to Wilson. Fradkm & Hardman (1972). The findings were con firmed by rectal palpation of the uterus at TO days of gestation. Obsemitions ami iinaly.n's. Throughout the exper iment. animals were observed daily for any physical change and were weighed monthly. Serum triglycer ides. cholesterol, scrum glutamic pyruvic transa minase (SGPT). albumin globulin ratios, total lipid and haemograms were determined monthly in all animals (Allen. Norback & Hsu. !974b). fn addition, every 3 months an inguinal subcutaneous fat biopsy taken from selected animals in each group (Allen cf al. 197-tu) was extracted and evaluated for PCBs according to a modification of the procedure ori ginally presented by Curley rr al. (I972|. For chroma tographic analysis, fat samples were homogenized in hexane (500 mg 20 mil and subsequently evaporated under dry nitrogen in a 40 C waterbath. Clean-up of the extracted material prior to analysis was carried out in a disposable pipette microcolumn containing silica gel 60 M>5 0-2 mml by elution with a benzene hexane (1:1. v v) mixture. Levels of PCBs were esti mated in a Hewlett-Packard 7620A chromatograph employing a *JNi electron-capture detector. A pyrex column packed with Gaschrom Q (80- lOOmcsh) coaled with 2",, SE-30 was operated at 170 C with argon-methane (95:5) as the carrier gas and at a flow rate of 40 ml min. Table I. Changes in the hody weight of female monk,'is receiving a diet ci'iiuiinint/ 2 5 or SO ppm Aroelor I'-t.t Time on diet (months) Moan body weight (kg) Control group Experimental group 0 4-50 0 68 5 57 4 0 55 1 4 89 060 5 47 + 0-5R 2 4 86 + 041 5 28 4- 0 55 3 5 00 055 5 38 4-0 60 4 5 00 051 5 38 + OoO 5 5 01 059 4 84 + 048 Values are means + standard deviation for groups of 12 control or ISPCB-fed (2.5 or 5 ppm) animals. RfiSU-TS During the first 6 months that the females received PCBs in their diets, the intake was relatively constant, with the animals ingesting an average of 90 and 180 mg PCB on the 2-5 and 5 0 ppm diets, respect ively. Despite normal food consumption, both exper imental groups lost an average of I5T,, of their initial body weight (Table 1). Within 2 months of the start of the experiment and when 30-60 mg PCB had been consumed, individual animals began to show the typi cal signs of PCB intoxication, including loss of hair, acne of the face and neck, and erythema and swelling of the eyelids. At 6 months all females exhibited these signs to some degree. Skin biopsies revealed afTected hair follicles with prominent keratinization. The haematological changes developed more gradually. Hae mograms remained relatively normal throughout the period, but the concentrations of serum triglyceride, cholesterol and total lipids decreased progressively (Table 2). although only the decrease in total lipids was statistically significant. There was also a shift in the albumin'globulin ratio and a progressive increase in SGPT activity (Table 2). The data obtained from the fat biopsies on the female animals (Table 3) showed an accumulation of PCB isomers in the adipose tissue. After a 6-monih exposure period, the PCB level in the adipose tissue of the animals receiving 5 ppm attained a plateau, subsequent values varying little with continued con sumption of the diet. A similar level was attained in I yr by the group given 2-5 ppm PCB After 4 months on the experimental diets and con sumption of a total of 60-120 mg PCB, menstrual Table 2. Modifieutums in the serum chemistry nf /emote monkeys given a diet containing 2 5 or S O ppm Aroelor ! '4fi Time on diet (months} Scrum levels (mg |00ml) Trig1>ceridcs Cholesterol Total lipids Albumin/ globulin ratio SGPT activity IRFU) 0 75 4 IX 166 + 28 582 90 1 20 019 14 + 3 2 93 4- 4H 152 + 28 573 98 1 23 + 0 20 24+7 3 75 4 24 159+ 24 581 4 97 1 30 + 0 21 21 8 4 51 4 20 1*6 - 26 451 + 74 1 23 016 214-9 8 61 z 2<t 15h r 22 470 + Mt 1 08 019* 31 7** Stxi'T * Svrmn .! 'M { *f .1 ic Ir.m ..mini .-e Rl l1 =:: Rcitm.tn-f-runkcl unis It! ! t, 1 r., tv it- i- i -in p. ' ? ppm artvl eipM 5 Oppm P( III iiin, I I j | * it j DSW 032540 STLCOPCB4016502 Effects of PCBs cin reproduction in primates |Q! Table .V 7dint in/uke unit adipose-tissui' ti t ch of PCBs in fen:.lie monkey!, con\unui,,/ a diet contuminij 2 5 or 5 0 ppm Aroclor td4X Values after administration of PCB diets* for Dietary level (ppm) of PCB 2-5 50 No. of animats 4t 3 1 month Total PCB intake (mg) Tissue content of PCBs 0<g g) 15 63 2 63 3095 + 1 06 5 06 3 50 16 39 4 49 6 months Total PCB intake (mg) Tissue content of PCBs (;ig g) X5-29 8 07 171 36 4 24 32 69 15 97 71-30 31 56 Data have not been included on the PCB levels of fat obtained from the control animals because in all instances the minor peaks recorded in the gas-chromatographic analysis could not be stated to be PC'Bs. Furthermore the amount the) represented was infinitesimally small. tOne animal in this group showed lesions carl) in the experiment and gas-chromatographs of its adispose tissue revealed that the PCB concentrations were closer to those of the animals fed M) ppm despite the lower intake of PCB This animal was not included in the calculations. Values are means + standard deviation for the numbers of animals show n. V cycles were decidedly altered, particularly in the group receiving the 5-ppm diet. There were increases in the duration of menses and in menstrual bleeding. Menses were 5- 7 days longer in the experimental group than in the controls. Several of the experimen tal animals exhibited occasional absence of menstrual bleeding. ' Conception rates for the control animals and for those fed 2-5 ppm PCB were essentially the same. but. the conception rate in the animals receiving 5 ppm was decreased. As shown in Table 4. eight animals on the 2-5-ppm diet became pregnant, as determined by the level of chorionic gonadotropin in mouse bioassays, but shortly afterwards three of these ani mals rcsorbed their embryos. In these animals, im plantation bleeding, which usually occurs 17 days after conception, was replaced by profuse uterine hae morrhage. In the 5-0-ppm group, six of the animals were impregnated. The remaining two animals were bred five times without success. Of the animals that conceived in this group, there were abortions at 46, 67 and 107 days of gestation, one resorption, one still born and one uncomplicated birth. Viable infants bom to the experimental animals were small II 2 standard deviations from the normal established by Kerr. Schetflcr & Waistnan, 1969). but were otherwise normal. These observations are in contrast to those in the control animals, all of which conceived and gave birth to normal infants (Table 4). One adult female on the 2 5-ppm diet and one on the 5 0-ppm diet died after i 73 and 310 days of feed ing, respectively. At autopsy, these animals showed the typical signs and tissue alterations of PCB intoxi cation. The major gross findings at autopsy included generalized alopecia, subcutaneous oedema and acne. Microscopically, in addition to hyperplasia of the fol licular epithelium and inflammation of the surround ing tissue, hair follicles were lilted with keratin. Throughout the liver there were focal areas of nec rosis. Hcpatocyles were enlarged and contained numerous small lipid droplets Large lipid droplets prevailed in the cytoplasm of the KuplTcr cells. In addition, both animals developed terminally a severe enleritis from which Sluyetla flesr.eri type IV was iso lated. This organism is known to be a common pathogen of primates, but is generally sensitive to treatment. Even following treatment, the animals in this study experienced shigellosis on numerous occa sions. a finding consistent with previous observations that PCB-mtoxicated animals appear to be more sus ceptible to this opportune pathogen. The distribution of PCBs in the tissues of the two females that died, as well as in those of the dead infant born to a mother on the 5 0-ppm diet, is shown in Table 5. The affinity of PCB for lipid-containing tissue is readily apparent and a transplacental move ment of PCBs is indicated by the high concentration in the tissues of the stillborn infant. Furthermore the levels of PCBs in the other infants continued to increase after birth as a result of the high concentrations in the milk of the mothers (2750 + 121-5 ngg milk). The level of PCB in the skin obtained by biopsy on the day of birth from infants born to the mothers on the 2-5-ppm PCB diet Table 4 Modifn ittnut in r^pnului (ion in prmuil\'\ expovt/ to Arm lor /J-fs in f/v thtf No. recorded in w;roup fed diets containing PCB IcwU IppnW of Reproduction 0 2-5 5 0 parameter No. of anim.ik croup. 12 8 K Total impic^'iuti/d Resorptions or alnutions SnllN'i n 12 8 6 0 34 0 0\ DSW 032541 STLCOPCB4016503 h>: D. A. Bvkvoiii. R. J. Maui vk .iih! J R. Amis Table 5. PCB content of tissues ohlnincit at autopsy from mo adult fenaU monl.cvs ami a stillborn tnjont PCB content (/ig g) in tissues from Tissue Adults fed dietary levels (ppm) or 2 5* 50f Stillborn infant^ Pancreax Liver Adrcinil Kidnev Spleen Small intestine Stomach Brain Lung Muscle Skin 0-16 561 309 0-60 l 55 0-77 268 . I 58 3 20 0-19 0-98 53 89 24 38 40 18 52 77 3015 322 47 45 21 41 869 17-66 too? 63 85 2.47 24 85 247 1252 15 00 18 96 031 99-36 443 0001 Aroclor 12-18 intake: 75-3 mg over !?1 days. t.Aroelor 12-IN intake. 284 56 mg out 310 days. JAroclor 124S intake, by motlu-r: .'94 3 mg over 401 days on 50-ppm diet v i was 2 8 1-4 /;g e tissue. This value had increased 10 1116 + 29 0 y,g g skin after breast-feeding had con tinued for 3 months. Otic of the male animals given 5 0 ppm PCB exhi bited a slight periorbital oedema and erythema of the eyes after 6 months (total PCB intake. 300 mg I. Only the consumption of approximately 620mu PCB over 14 months resulted in the development of slight to moderate periorbital oedema and congestion in all of the expos'd males. Levels of PCB continued to increase in the adipose tissue of the males with time. In spile of these rises there was no alteration in their gross breeding capabilities (sperm couttl or breeding success), control females conceived at the same rate whether bred to ex|vrimental or control males. DISCUSSION ` The levels of PCB that were incorporated in the diets of experimental animals were selected to rep resent concentrations equal to or half as great as those permitted in certain foods destined Tor human consumption. Previous experiments reported from this laboratory have shown that PCB concentrations as low as 25 ppm in the diet of non-human primates may produce morbidity and mortality after 2 months of exposure (Allen cl til. 1974a). Skin changes appeared in animals receiving 2-5 or 5 0 ppm PCB as rapidly as in the animals fed larger doses (Allen cl nl. 1974a; Allen & Norhuck, I973). In fad. these skin changes were recorded in some animals after a total of only 30 50 mg PCB lud !>ecn ingested These data suggest that only short exposure to PCBs is fcmtir-d to stimulate follienl.tr epithelial hyperplasia, block.me of the sebaceous duels and ker- almi/alion of the hair follicles. The early heavy locali zation of PCB in the skin of alTcclcd animals (Yo-dii- murj ik Oshitrta. 1771) is undoubtedly responsible for such tissue changes. [he values for SCiP I. albumin globulin ratios anil total Itpi.U were significantly tlilleivnt Irom the out ' ' 'll s \ ' ,-l- lli-ic vie 1C I 111! Iv'.l t o 'Ms tal diets before changes in the scrum triglyceride and cholesterol concentrations were statistically signifi cant. These observations substantiate the findings or Allen el nl. (1974a) who recorded similar changes in (he scrum chemistry of monkeys fed 25 ppnt PCB for 2 months. Male monkeys led a diet containing 5 0 ppm PCB invariably ate more food and attained higher levels of PCB in the adipose tissue than their fem.de counterparts. However, ihe female monkeys devel oped signs of PCB intoxication within 2 months whereas only minor skin alterations developed in males after 1 yr. One explanation for this difference in PCB response between the two seves may be related to the total reservoir of fat tissue. Since the males were much larger than the females, they hud a greater quantity of adipose tissue in which the in gested PCB could be sequestered. Plulonovv & Karstad (1973) described similar differences in the toxic response of mink to PCB. noting that male mink at all treatment levels were less severely affected, sur vived longer and produced abundant, viable sperma tozoa throughout the experiment. Gish & Chora (1970) observed that heavier quail survred longer than lighter ones when treated with DDT. One of the must serous results of PCB exposure in the adult female monkey was the effect on repro duction Lven with low dietary levels of PCBs. the menstrual cycles were irregular and there was exces sive and ptuiunycd menstrual bleeding In addition, animals that conceived showed a burlier incidence of resorption and early abortion even w hen compared with the It)",, abortions and stillbirths recorded each year in the breeding colony. A likely explanation for these changes is related to an oestrogen-progesterone imbalance in these animals, these hormones being re sponsible for niensiiu.il llow anil the maintenance of pregn.UK>. Preliminary observations from this labor atory suggest an endocrine disturbance resulting from PCB intoxication tn females When females are fed PCB in their diets they invariably li.uc much higher levels of urinary kcioslcmids than control mmtkeis osw 03254-2 STLCOPCB4016504 Effects of PCBs on reproduction in primates 103 Another intcicsling observation was the reduced size of the infant', horn ;tl term to PCB-fcJ monkevsT TKesc findings are in agreement with reports from Japan. where the children horn to exposed mothers wore reduced in size (Kurutsune el at. 1972). Even though the infant monkeys had shorter long hones, smaller head circumference and reduced crown-torump lengths, the osscus development as viewed radiographically was similar to that in the control infants (unpublished observations). Histologically, there was also normal development of the tissues in day-old infants born to PCB-fed mothers (Allen cl at. 1974a). Recently it has been shown that at least a portion of the PCBs are metabolized through an arene oxide intermediate (Hsu. Van Miller & Allen. 1975). There is a distinct possibility that mam of the effects that have been recorded in this experiment may be related to an interaction of these epoxides w ith cellular mac romolecules These findings also suggest that PCB exposure may have long-range effects in primate spe cies, since.epoxides are known to be capable of pro ducing necrogenic, carcinogenic and mutagenic changes in mammalian tissues. It is unlikely that man will be exposed to levels of 2-5 or 5-0 ppm PCBs on a continuous basis in his diet However, there may be instances when the in take of PCBs may exceed these concentrations for short periods or when exposure over a prolonged period may give rise to toxic concentrations in the tissues. Whether human exposure to the PCBs is suffi ciently great to produce serous effects such as repro ductive insufficiency or modifications in the functional capacities of certain cellular macromoleculcs hits not been determined. However, the data presented in this report suggest that present levels of PCB contami nation may be sufficient to cause such effects. Acknowledge"*, mi- -This investigation (Primate Center Publication no. 15-017) was supported in part by US Pub lic Health Service grants FS-VXU72. FS-00958 and R R -00167 and Pathology Graduate Training Grant GM-lX)l 30 from the National Institutes of Health, and by the University of Wisconsin Sea Grant Program. Part of this research was conducted in the University of Wi-wonsin-Madison Biotron. a controlled environmental research facility supported by the National Science f oundation and the University of Wisconsin The authors thank Ms J. Schelfter and Ms. L. Carstens for their technical assistance. REFERENCES Alien, J. K . Carstens. L A & Barsotti. I). A. (1974a) Resi dual effects of short-term, low-level exposure of nonliuman prim.lies lo |xilycliloriuuicd biphenyls. To vie. appl Phannac. 30. 44(1. Allen. J. R. & Norhach (7. M. 11973). Polyetdoiinaleil biphenyl- and triplienyl-induced gastric mueo-.it hyper plasia in primates. S< ienee. ,V>; 179. 49.S. Alien, J. R.. Norhutk. O II. Ac Hsu. I. ( . (I974b|. Tissue modifications in monkeys as related to absorption, dis tribution and excretion of polychlorinated biphenyls. Arch Environ. Contain. & Turner/. 2. 86. Aulcrich, K J.. Ruiger. R. K & Iwamoto. S (1973). Repro ductive failure and mortality in mink fed on Great Lakes fish J. Hcprotl Pert Snppl. 19. p. 365. Barsotti. D. A. & Allen. J. R. 11975). Effects of polychlor inated biphenyls on reproduction in the primate. Fain Pruc. Fcdn .-tin. Sm\ ,\p. lUol. 34, 33x. Curley. A . Burse, V W. Grim, M. E , Jennings. R W & Linder. R. E. (197)). Polychlorinated biphenyls: Dis tribution and storage in body fluids and tissues of Sher man rais. Emir. Res. 4, 4X1. DeLong. R. I... Gilmartin. W. G. & Simpson. J. G. 119731. Prcmaiure births in California sea lions: Association with high oreanochlorine polluunt residue levels. Science. .VV. IHI. 116X. Gish, C. D & Chura. N J. (1970). Toxicity of DDT lo Japanese' quail as influenced by body weight, breeding condition, and sex. Tiimc. appl Phannac. 17. 740 Hsu. 1. C. Van Miller. J. P. & Allen. J. R. (1975) Metabolic fate of JH 2.5.2 .5 -ictrachlorobiphcnyl in infani nonhu man primates. Buff cm. comum. & Toxicol. IE S.) 14. 233. Kerr. G. R.. Schcfflcr. G & Waisman. H. A. (1969). Growth and development of infant Macaca mnlaiia fed standar dized diet Growth 33. 185. Kutalsune. M.. Yoshimura. T.. Malsuzaka. J. & Yamagu- chi. A, (1973). Epidemiologic study on X usho. a poison ing caused by ingestion of rice oil contaminated wuh a commercial brand of polychlorinated biphenyls. En viron. Health Per.spcct. 1. 119. Miller. G. J. & Fox. J. A (1973). Chlorinated hydroearhon pesticide residues in Queensland human milks. Mat. J .4ir.vt. 2. 261 Musial. C. J.. Hutzinger. O.. Zitko. V & Crocker. J 11974|. Presence of PCB. DDL and DDT in human milk in th provinces of New Brunswick and Nova Scotia. Canada. Ihill. vnv. cnnlton. & Toxicol (C S.l 12. 25S Platonow. N. S. & Karstad. L. H. It973i. Dictarv effects of polvchlorinatcd hiplicnvl on mink. Can. J. comp. Mai. 37. 391. ` Ringer. R K.. Autcrich, R. J. & Zabik. M (1972). Effect of dietary polychlorinated biphenyls on growth and reproduction of nlmk Pror. tin. them. Soc. 12. 149. Risebrough. R. \V,, Rieche. P.. Peakall. D B, Herman. S. G. & Kirven. St. N. (1968). Polychlorinated biphenvK in the global ecosystem. .Vinurc. Land. 220. I09S Valerio. D. A. (|9ra)). Breeding Mac.n a inulaita in a labora tory environment Gi/i. .4mm llandh 4. 223 Wilson. J. G . I Yadkin. R. & Hardman. A 11972). Breeding and pregnancy in rhesus monkeys used for teratologieal testing. Tcratoloiiy 3. 59. Yoshimura. H. & Osluma. M. 11971) Studies on the tissue distribution and elimination of several components of KC-41S) (clilorohiphenv 1st m mice Fukuoka t<M mat. 62. 5 ' DSW 032543