Document 3NkDj5NaQagMvGEr97BG3xJD6

f thyroid logy and wilh the ale value iposium. Hamster, in, 1972. # British !. Unwin Edited by ime. I and 11. Ralkovi. ime. >. Plenum -im Press, W First A Ciba ed Scien- Fd Comet. Toxicol. Vol. II, pp 1)1-144. Pergxmon Press 197) Printed in Orest Britain Information Section 1 ARTICLES OF GENERAL INTEREST , IF ALL THE SEA WERE PCB . . . The polychlorinated biphenyls (PCBs) have now well and truly lined up with DDT and mercury in the ranks of materials recognized as important environmental contaminants. The qualifications for membership of this group are widespread occurrence, relatively high toxicity and, most imporianlly, non-biodegradability. The PCBs score well in all these categories, a fact borne out by the large number of review articles wnitefc on the subject of PCB pollution during the past year or so (Edwards, Chemy Ind. 1971, p.'l340; Pea kail A Lincer, BioSctence 1970, 20, 958, Hammond, Science, N.Y. 1972, 175, 1J5; Tinker, New Sclent <4 Scl J 1971. 50, 16). ` In simple terms, the problem seems to be that the PCBs, used inter alia as plasticizers and solvents in paints, sealants, adhesives and printing inks, are escaping into the environ ment, probably from sewage combined with industrial effluent, and are slowly accumu lating in rivers and sea areas. The structure of the biological food-chains then ensures that these PCBs are widely distributed throughout the animal kingdom, including man This much is fact (Cited in F.C T. 1971, 9, 568). The exact toxicological significance of PCB residues is not fully understood, however, although any marked accumulation of even a metabolically inert compound must be considered cause for concern. This concern was somewhat alleviated last year by the decision of the Monsanto group, sole producers of PCBs in ihe USA and Ihe UK, to restrict PCB sales to those destined for use tn enclosed applications, such as capacitors and transformers, providing a minimal possibility of leakage into the environment (ibid 1971, 9, 571) As PCBs have been known to cause poisoning tn man (Kuratsune et at. HSMHA Hlth Reps 1971, 86, 1083) and as they are clearly accumu lating in the environment from some of the less controllable sources, this decision represents an important advance in reducing the potential hazard proffered by these compounds Levels of PCB residues Aquatic animals and the birds feeding on them are the obvious material to use as a starting point for a survey of PCB contamination Furthermore, as the PCBs, especially the more highly chlorinated ones, have an extremely low solubility in water, one would expect them to be principally associated with the sediment on the bottom of seas and to enter into food chains via bottom-living organisms. Practical verification of this theory has come from Escambia Bay, Florida, where PCB residues of up to 120 and I 5 ppm have been found in shrimps and crabs respectively (Nimmo et al. Nature, Loud. 1971, 231, 50). The PCBs. which were mainly located in the sediments of the bay, originated from an up-stream chemical plant. Samples taken from 1)1 MOMS 208542 132 ARTICLES OF GENERAL INTEREST places up-stream from the plant were unpolluted Experimental work, involving exposure of shrimps and crabs to polluted sediment in the laboratory for 30 days, confirmed that both species were capable of absorbing PCBs from ttteir environment to such an extent ihat the final residue level in the animals after 30 days often exceeded that in the sediment itself. A similar conclusion was reached by Wildish & Zitko {Mar. Biol 1971. 9, 213). using the small shrimp, Caimiorus oceanictts. In this case, exposure was for shorter periods measured in hours rather than days. The uptake of PCB& was found to depend on both the external PCB concentration and the total exposure period, but after 4 hours there was a reduction in the rate of uptake In another study (Sanders & Chandler, Butt mu. contam, A Toxicol. (U.S) 1972, 7, 257), eight invertebrate species, including shrimps, crayfish and several types of immature aquatic insect, were exposed to PCB at concen trations below 3 ppb*. a level Similar to that found in the waters of Escambia Bay After exposure for 4 days, total body concentrations ranged from 0 2 ppm in crayfish to 16 ppm in the glass shrimp and 52 ppm in daphnia In scud (Cammarus pseudolunnacus) exposed to 1*6 ppm PCB, the concentration in the organism reached equilibrium in 14 days and was then 27,500 times higher than the concentration in the water. As one might expect, the levels found in fish are somewhat less, most commonly in the O-l ppm range. In a Canadian survey of fish taken from lakes, rivers and the sea and reported by Zitko (ibid 1971,6,464), values of 0-3-0-4 ppm were most common but levels up to 1 01 ppm were recorded for some samples. Much higher residue levels were seen in fish kept experimentally in water containing known concentrations of PCBs (Hansen et al ibid 1971, 6, 113). For example, a concentration of 5 ppb resulted in levels of over 100 ppm in both pinfish and spot; furthermore this concentration was fatal to some 50-60% of the fish A level of 1 ppb PCB was tolerated, however, even though residue levels of around 30 ppm were recorded after 30 days and the livers of these animals contained up to 200 ppm PCB. Interestingly, after 84 days in non-polluted water, the PCB levels of the whole fish fell by some 73% Similar figures have been reported in a review of PCB contamination by Zitko & Choi (Fisheries Research Board of Canada Technical Report no. 272, 1971). Once again the levels in fish were generally less than 1 ppm, although occasionally figures as high as 10-20 ppm were recorded from waiert near highly industrial areas. In aquatic birds, and especially their eggs, higher levels were found, figures of 1-10 ppm being not uncommon Fish-eating birds seem to have particularly high PCB levels, occasionally in excess of 100 ppm. Other animals have also been shown to accumulate PCBs The blubber of grey seals, for instance, commonly contains 10-50 ppm PCB, and one sample was found to have a level as high as 1800 ppm. Of greater importance to man, however, is the finding of up to 3 ppm PCBs in some commercial fish oils and of 0 18, 0-21 and 0-47 ppm in mar garines manufactured, respectively, from 100% vegetable oils and 60 and 80% marine oils. In view of the known environmental contamination, it is not surprising that PCBs are to be found in man. Two samples of adipose tissue analysed by Biros et al {Bull e>w. contam. it Toxicol. {U.S) 1970, 5, 317) yielded 200 and 600 ppm PCB and further work has delected PCBs at a concentration of 0 103 fig/ml (or 3 5 ppm based on the milk fa;) m human milk. In the latter case, fatty tissue was also examined and found to contain 5 7 ppm PCB (Acker & Schulte, Naturwissenschaften 1970, 57, 497). However, a survey of 79 lactatjng women, 32 from villages in New Guinea and 47 from cities in Texas, failed to * b " 10* throuchoul ihtj article. HONS 208543 --r exposure uied that xtentthat sediment 9, 213). T periods ] on both urs I here luit env. shrimps, coiicenay After o 16 ppm exposed and was ily in the reported pto 1*01 fish kept ' al. ibid ) ppm in \ of the f around 200 ppm hole fish & Choi gain the high as rds, and ommon xcess of of grey ound to ndmg of in mar* marine CBs are nii rnn er work k fat) in 5 7 ppm y of 79 aiied to ARTICLES OF GENERAL INTEREST 111 confirm these findings (Dyment er at. Bull. env. contam. & Toxicol. (US.) 1971, 6, 532) While residues of chlorinated hydrocarbon pesticides were present, there was no evidence I of PCBs in the milk of any of these women j Toxicity ofPCBs ; The results of Hansen et al. (toe cit) suggest that the,threshold of toxicity of the PCBs i to fish lies around I ppb. The pink shrimp, Peitaeus duorarum, seems equally sensitive ' (Nimmo et al. Mar. Biol. 1971, 11, 191). The adults were killed within 17-53 days by Aroclor 1254 concentrations of from 2-4-4-3 ppb, but the juvenile shrimps were found to be less resistant and failed to tolerate even I ppb There were indications that a simitar increase in susceptibility to PCBs occurred during moulting. Accumulation (up to 510 ppm) occurred in the hepatopancreas of the animals but subsequently the material was trans ferred to other tissues and eventually lost. There was very little indication of how or why the animals died, but in vitro inhibition of fish ATPase by PCBs was recently reported (Yap et al. Nature, Land 1971, 233, 61; Desaiah et al Biocftem Pharmac. 1972, 21, 857) I and the possibility that this may also occur in vivo perhaps deserves further study. ; The signs of PCB poisoning are more apparent in birds. For example, chicks fed a diet containing known quantities of PCB have presented with a characteristic group of reac1 tions. Levels of 100-150 ppm PCB (Aroclor 1248) in the diet for up to 5 wk have been shown to depress weight gain, cause oedema, breathlessness, hydro pericardium and internal haemorrhages, depress secondary sexual characteristics and increase liver weight (Rehfeld ! et al. Poult. Sci. 1971, 50, 1090). At 50 ppm these effects were lest marked and al 10 ppm j they were absent. Month-old cockerels fed a diet containing 500 ppm Aroclor 1254 for i up to 12 weeks showed a significant decrease m the size of combs and testicles, a reduction 1 in body weight, an increase in liver weight and an accumulation of PCB principally in (adipose tissue, kidney, liver, brain, muscle and blood (Platonow &. Funnell, Can. J comp. Med 1972, 36, 89) Tissue levels increased linearly with time Behavioural effects . have been seen in caged robins receiving as little as 5 pg PCB (Clophen A50) daily, how ever. After 20 or so dayi of treatment, the experimental birds were significantly more active than the controls and residue levels in breast muscle (0-1-O'4 ppm) were four times higher (Ulfstrand er al. Nature, Lond. 1971, 231, 467). ! Other effects of PCBi in birds include an increase tn susceptibility to viral hepatitis seen in ducks challenged with the virus 5 days after the termination of a 10-day course of feeding , with diets containing 25-100 ppm Aroclor 1254 (Friend & Trainer, Science, N. Y. 1970,170, 1314). In pigeons and quails fed wheat dressed with 250-500 ppm Aroclor 1242 or 1254 for 20-28 days, residue levels have been found varying from over 100 ppm in fat to less than 10 ppm in heart and brain (Bailey Sc Bunyan, Nature, Lond, 1972, 236, 34). The most important result of this work, however, was the finding that PCBs with a relatively low degree of chlorination are fairly rapidly metabolized and are not as persistent as the more highly chlorinated compounds. The anomaly therefore arises that the less widely used compounds, the highly chlorinated PCBs, are more common in the environment than their ^technologically more popular relations. The metabolism of an orally administered PCB with a fairly high mean chlorine content (Aroclor 1254) has been studied in the rat by Grant et al. (Bull env. contam. & Toxicol (US.) 1971,6,102) The PCB used consisted of six components recognizable by gas chroma tography. in line wtih the results of Bailey & Bunyon (loc at.), tissue residues of the less chlorinated components were significantly lower than the residues of the more chlorinated MOMS 208544 134 ARTICLES OF GENERAL INTEREST ones. In addition, total residue figures were increased by treatment of the rats with carbon tetrachloride, a result which, when considered alongside the increase in liver weight observed in this and several other studies, suggests that the liver may be the site of PCB metabolism An increase in the activity of the microsomal processing enzymes of the liver has been observed in PCB-treated birds (Bailey & Bunyon, loc. cit.), rabbits (Vilieneuve et al Bull. env. contam A. Toxicol. (U.S.) 1971, 6, 120) and rats (Bickers et al. Res. Conunun. ckem Path. Phamtac. 1972, 3, 505). The more highly chlorinated biphenyls were the most potent inducers, producing a statistically significant and long-lasting effect in both species Reduction of pentobarbitone sleeping time in rats by a number of PCBs has been shown to increase with the degree of chlorination of the compound and the extent of its storage in fatty tissues (Vilieneuve et al. Bull. ettv. contam. A Toxicol. {U.S.) 1972,7, 264), In the rabbit study (Vilieneuve et al. 1971, loc, at.) pregnant animals were used, so that additional data were generated showing that 10 mg PCB/kg/day was without effect on this mammalian reproductive system However, daily doses of 12-5 mg Aroclor 1254/kg or more given to rabbits on days 1-28 of gestation led to an increase in abortions, maternal deaths and stillbirths, although the dead foetuses showed no consistent skeletal abnor malities. The rat appeared to be less sensitive, since doses up to 100 mg/kg/day caused no foetal deaths or malformations (Vilieneuve et al. Envir. Physiol. 1971, 1, 67), Placental transfer of the PCBs was verified by human experience during the PCB poisoning incident in Japan (Kuratsune et al. loc cit). Pregnant women suffering from the poisoning gave birth to generally small babies with a characteristic brown discoloration of the skm. especially around the groin, dark-coloured natls and discharging eyes. The condition disappeared within a few months. An increase in the metabolic activity of the liver is associated with an increase in smooth endoplasmic reticulum (SER) Proliferation of SER and hyaline degeneration have been observed in the livers of PCB-treated mice and monkeys (Nishizumi, Archs envir. Hlth 1970, 21, 620). Associated with these effects were disturbances in lipid metabolism and a reduction in Jiver-glycogen stores. Similar results have been reported in rabbits following the percutaneous absorption of several PCB preparations (Vos & Bcems, Toxic, appl. Pharmac. 1971,19,617). Besides liver hypertrophy, damage to the kidney tubules, lymphopenia and atropy of the thymus were noted. The quantities of PCBs involved, 118 mg applied five times weekly for 38 days, also had a marked effect on the skin. The lesions induced were typified by hyperplasia and hyperkeratosis of the epidermal and follicular epithclia. However, as some PCB prepara tion* produced more severe symptoms than others, the possibility that these effects may have been caused by toxic impurities such as benzofurans must be borne in mind The sources and the hazard to man _ Monsanto's recent refusal to sell PCBs for "open" applications and for use in food processing plants will clearly, in the long term, reduce the potential hazard of these com pounds. At present, however, PCBs are present in human food. The levels involved are low--a recent US estimate pul the average daily intake of a person on a high-consumption diet at only O'I ^g/kg/day {Food Chemical News 1972,13(51), 36). neverlheiessthe biological characteristics of the PCBs warrant the continued monitoring of man's exposure to them Fish remains man's prime source of PCBs (ibid 1971,13 (40). 34). Indeed, it is difficult to see how this situation can change in the foreseeable future because, once polluted, the oceans must take a considerable time to recover. Other sources of PCBs can more easily HONS 208545 )carbon *RBT*d lbidicin as been * a *1 momun, be most 9KCt ) %t*y*s anape ia tothai 09 UllS </** or aicnul aboorned do kccotal arident penally speared BDOOlb e been r. Hlth l and a tion of In liver us were ys. also iia and ueparant may i foode comed are mpiion logical > them, icult to ed, the ; easily ARTICLES OF GENERAL INTEREST ns be reduced and eventually eradicated. The finding of PCB residues in poultry and eggs (ibid 1971, 13 (23), 3) should gradually diminish as PCB-containmg meal is removed from the market and the use of biphenyls in food plants is discontinued. Similarly, careful control over the use of PCBs as silo sealants (Skrentny et at. Bull. env. coniam. & Toxicol. (U.S.) 1971, 6, 409) should reduce ihe possibility of residues in milk. PCBs have been found in the milk of cows fed contaminated silage (Food Chemical News 1971, 13 (9), 22), and Saschenbrecker (Vet. Rec 1972, 90, 100) has shown that milk is by far the most impor tant route of excretion of ingested PCB in the lactating cow. After cows have been removed from any PCB contamination, ihe rate of reduction in ihe residue level in milk has been found to be similar to that of DDT in the same circumstances (Fries et al. Bull, env coniam. A Toxicol. (U.S.) 1972, 7. 252). The other important source of dietary PCBs has been food-packaging materials manu factured from recycled papers containing carbonless copy paper (Masuda et at. Nature, bond, 1972, 237, 41) and printing inks (Food Chemical News 1971, 13 (28), 3). Nevertheless, while PCB levels in packages have occasionally been very high, food itself seems to be only rarely contaminated to any significant extent (ibid 1972, 13 (51), 36). In the UK, manufacturers of carbonless copy paper have stressed that alternative solvents are now used (Lister Sc Bennett, Nature, Lond. 1972, 237, 414). In the USA, the FDA has set a tentative acceptable daily intake for the PCBs of 150-300 fig (Food Chemical News 1971,13 (26), 12). The actual daily intake, even before the recent tolerance levels set for various foodstuffs in America (ibid 1972, 13 (52), 38), was well below this As PCB residue levels are now likely to fall, it seems that man at least should not suffer unduly from this particular environmental hazard. The effect of PCBs on oceans, lakes and rivers and their flora and fauna may be anothe; Question. LITHIUM: USEFUL DRUG OR HAZARDOUS TERATOGEN? Lithium (Li), or strictly speaking the Li* ion, has only recently aroused the interest of toxicologists. The discovery that it is an effective treatment for manic-depressive psychiatric disorders has resulted in the exposure of many individuals to relatively high serum levels of Li, and this has led to a corresponding expansion in the literature on the likely sideeflects of such treatment. Serum levels and acute toxicity The dose of Li given in psychiatric treatment is critical. It must be such that the serum- or plasma-Li level is on the one hand above 0-6 m-equiv./htre, the lowest therapeutically effective level, and yet. on the other, below the toxic threshold of 1-6 m-equiv./litre (Schou, Acta psychiat. ueuroi. scand. 1969, 45 (Suppl, 207), 49). Plasma monitoring is one way in which the necessary control may be maintained Fry Sc Marks (Lancet 1971,1, 886) have successfully used this technique in a group of 100 patients on Li therapy but, somewhat disappointingly, they found that only 29 of them had plasma concentrations within [he optimum range of 0 8-1-2 m-equiv./lure Of the rest, 18 were probably receiving insufficient HONS 208546