Document DDde1MzGvyoR22JyK0kaYLgVd

METABOLISM ML DISTRIBUTION OF RADIOACTIVE AND STABLE LEAD IN MAN E. DI FERRANTE and Ph. BOUHDEAU, Units Scientifique "Nuisances", Directorate General III, Commission of the European Communities, Brussels, Abstract The literature concerning the metabolism and distribution of radio active and stable lead in animal and human organisms was reviewed. All the available data have been summarized in tables so that a com parison between results obtained using either radioisotopes of lead or stable lead could be made. The purpose of such comparison was to ascertain whether the information obtained with radiolead could clari fy the metabolic processes of stable lead in man. The usefulness of the experiments performed with radioactive tracers seems unquestionable s the results of the experiments performed in order to study the reten tion and excretion of radiolead in animals and in humans are, in general, confirmed by direct observations made on the behaviour of Btable lead in man. Some inconsistencies might be due to differences in the experimental conditions. However, the critical examination of the literature on both radioactive and stable lead reveals that the mechanism of lead absorption in man is not completely known. Precise information, for instance, on transfer coefficients of lead through the respiratory and gastro-intestinal tracts is not reported in the literature. The analysis of the various studies on metabolism of lead has permitted to discover where additional research is needed. Some specific, points to be clarified, also through experiments with radiolead, are suggested. The present paper was prepared on the basis of published information on the metabolism and distribution of radioactive and stable lead in man and experimental animals. The objective of this review was to perform a comparative analysis of the available data and ascertain whether and to what extent results obtained for very small concentrations of radiolead are also valid for stable lead. Furthermore it was aimed at pointing out which aspects of the problem of environmental .lead contamination require additional research. RADIOACTIVE LEAD Horiuchi and Horiuchi^studied the fate of ^'L0Pb in the organism of rats which had already been poisoned with lead acetate. Radiolead was given by means of subcutaneous injection, parenteral administration and inhalation. The level of 2l0pnj in -the urine and feces was measured daily. Twenty days after subcutaneous injection, about 20 i of the radiolead was excreted and 24 % absorbed within the body. After paren teral administration excretion was about 87 % and absorption 5 % , while an. excretion of 46 % and an absorption of 32 i was observed after inMation. Most of the absorbed 210pb was accumulated in bones and teeth. Regardless of the mode of administration, lead circulating in blood was found in greater amounts in red cells than in plasma. Holtzman(v o ' 'determined the 210Po and the 210Fb content of bone samp les from professionally unexposed people. The average ratio 2l0pb/2l0po was found to be equal to unity. The distribution of 210pb waB as follows ; Tissue l jo of body burden Liver Muscle Other tissues Bone (Rib) 1.7 17.0 18.0 63.O According to Holtzman most of the radiolead in bone, comes from potable water (0.022 pCi/g ash) and from the atmosphere (0.073 pCi/g ajfh). He reports also the fractions of the daily ingested lead retai ned by the organs (fw) and the fractions of lead entering the organs <. from blood (f'o) obtained by other authors for rats, injected with 203pb. Tissue fw f'g Bone Liver .Kidney 0.022 ,0.28 0.0064 O.O8 0.013 0,14 Castellino and Aloj'^'studied the kinetics of the distribution and excretion of lead in rats for 14 days following single intravenous injections of lead acetate (with an activity of about 1 /iCi of ^lOpb, The highest concentrations were found in the kidneys and, in decrea sing order, in liver, bone, whole blood, lung,spleen, muscle and heart. In bone tissue the concentration did not wary, or at least very little, with time, while in all the other tissues the disap pearance of lead was very rapid during the first three days and slowed down afterwards. During the whole period lead in the blood was bound mostly to the red cells (96 $) while only 4 $ was in the plasma. At the end of the experiment, fourteen days after injection, 44* & . of the in jected dose was still retained. Excretion occurred through feces and urine. Over the whole 14 day., period, the fecal excretion of 210pb was 36 % of initial dose, while 16 $ was excreted with the urine. Hie ex cretion curves show that the ratio Peces/Urine wae approaching unity in the final stage of the experiment. Jaworowski ( 'in a study on stable and radioactive lead, reports data of his own and of other authors on the distribution of 210pb in human organism^ DUP050058797 Averaged, values are : Tissue . $ of body burden Kidney Spleen Liver Muscle Blood Soft tissues (all) Bone 0.13 0.14 2.00 13.00 2.00 30.00 70.00 ll ~3 It must be noted that the soft tissue*data were derived from a limited number of analysis. The contribution of the non-osseous portion of the organism to the total burden of lead-210 is, therefore,' estimated with less certainty than of bone tissue"', which, on the contrary, has been frequently analyzed. The data presented by Jaworowski indicate that an increase in the 210^ levels of human bone occurred between 1952 and 1964 to reach a mean concentration of 0.04 pCi/g wet bone. A possible correlation between 210pb in bone and age suggested by some authors was not confirmed. On the basis of data from other authors, Jaworowski also states that in normal and contaminated humans, excretion of lead-210 through feces and urine is roughly equal. In experimental animals excretion rates were more than twice as high in feces as in urine shortly after administra tion, but the ratio approached unity with time. Another route of excre tion is hair in which the concentration of radiolead, according to Jaworowski*s experiments with animals, is related to the amount adminis tered and reflects blood concentration at the time of its formation. Cohen and Howells^in reviewing the literature from 1947 to 1968 con cerning the metabolism of 210j5f have realized that little information was available on the absorption, distribution, retention and excretion of trace quantities of carrier-free ^lOpb in tie animal and human orga nisms. Some studies have been performed in an attempt to .characterize those parameters, but only for abnormal intakes leading to toxicity. Cohen and Howells present a model, valid also for .stable lead, of the metabolic pathways of 210Pb (Pig.l) in which the main steps are s l) intake, 2; absorption, i.e. transport of ingested lead across the intestinal mucosa or direct passage of inhaled lead in .0 the blood stream, 3) transport in the body fluids from the sites; of absorption to the tissues and then to excretory sites, 4) lead uptake by various tissues, including deposition in bone, 5) removal from sites of uptake and deposition including bone resorption 6) excretion via the kidney, the intestine and other routes such as hair and sweat glands. Several investigations of these various steps, especially those numbered 2 through 5 have been made by using radioisotopes of lead in various chemical forms, but, according to Cohen and Howells, results for a par ticular animal species have been inconsistent and, therefore, further studies are required. The use of trace quantities of 210pb would also help in the study of the movement and fate of stable lead in the environ - DUP050058798 Several studies have also been performed by various authors in the to find out whether analyses of hiood could provide an indication exposure levels or of body burden. The data are unfortunately still sufficient to establish the type of relationship that may exist. The e thing can be said for excreta, especially urine samples, in which e concentration of radio lead may vary according to mocte of intake* 'ii- uberfc and White(v7' )'and Lucas and Stanford-(g) , whose studies are report in Cohen and Howells1 review, obtained urine to fecal ratios of tout 1 for rats injected with carrier-free Lucas and Stanford their experiment also found, in agreement with other authors, that " of the lead in blood was in the red cells* (9) bhen,Howells, Wrenn and Eisenbudw'have studied the metabolism of in-- acted ?10pn in the adult baboon in the hope that extrapolation of data man might be more reliable. Most of the experiments are still under Excretion studies have revealed that after an initial period during iich some differences were observed, the ratio of total 21^Pb excreted i urine and feces was about 1. irsh^^perfornied an experiment with three beagle, dogs which were made > inhale "Opb aerosols with a stable lead content of 0*006 to 0.018/xg er liter air. The particles had a mean diameter of 0.25yu. Retentions 25 and 15 % were measured on two dogs. Complete excreta collection made yielding a fecal to urinary lead ratio of about 1*25. The dogs re sacrificed at 2,11 and 31 days j and the tissues and blood were *alyzed. The higher fractions of the lead absorbed were found in bone, ver and red cells* ^lo; Mays and Atherton.'("`H"`''ai lso studied the distribution and retention -' Opb in beagle dogs. The percentage of radiolead retained at dif ferent .times after intravenous injection, was indirectly calculated on the basis of lead blood removal and excretion data. After three weeks le retention was about 49 f of the injected dose. The excretion values Obtained during Che-first three weeks give a ratio F/u = 3 with no apjlreftt tendency toward equal fecal and urine excretions of radiolead, "iis faot is irf contrast with the-observations of other authors who,, at ater stages of experiments on animals of different species, found the ^excretion ratio equal or close to unity. A total retention of 37*6 f of ^injected 210pij was found for one dog sacrificed 28 days after injection. '%he distribution Values were the following : Tissue fo of body burden Bone 63 Liver 20 i*. Blood Other tissues 8 9 The retention data, calculated from excreta measurements were confirmed by tissue analysis performed at sacrifice. .Another study on the retention and excretion of 210pb in dogs had been previously performed by Blackl1^). The animals were exposed to an atmos- U- S phere containing radon and its daughters. The fraction of the calculated -?10pb body burden retained after one year was about 25 %. The ratio of the daily fecal excretion to the daily urinary excretion radio varied from 2 to 8.7 for a period of about two years after exposure. This is another case of higher fecal excretion at late stages of experiment. Blanchard and Moore('13)/have analyzed tissues of 41 uranium miners and 11 .unexposed people for the 210po content. The concentrations for exposed people were 5 "to 50 times higher than in normal population. l)istribution studies gave the following results : Tissue % of body burden 210P. c* 210Fb Bone Lungs Muscle Kidney Liver Blood 77.0 5.6 4.0 1.3 - - 79.0 4.9 4.4 - 2.2 1.6 The average value of the 2Xu0Po/2Xu0Fb body ratio was 0*74 in both exposed and non-exposed subjects. In general the relative distribution of the two nuclides in the body is similar among individuals of a population group. For some tissues though, due to differences in the degree and avenue of exposure, the relative concentrations may vary within k group* For instance, the concentrations of radiolead and polonium found in the lungs of miners wore much higher than those observed for unexposed people in relation to the concentrations of other "tissues* Good correlations seem to exist between the concentration in blood and that m bone and liver and between the 210po concentration in blood and ` .hat in bone, liver kidney and spleen. The results indicate that in this case blood concentrations were a good index of the 210po an& 210pb body burdens. In the case of miners, when the exposure is interrupted, there is a removal from bone of 210po and. 210pb which pass into other holy compartments until an equilibrium is established between skeleton, b'!:o! and soft tissues* Hursh and Suomela(v14)'administered carrier-free 212Pb to three nunian subjects to determine the fraction of radiolead takeij into the alimen tary canal that enters the blood* The retention of ^ ^Fb was calculated by comparing the amount excreted in the urine during the first 24 hours 'with that of two subjects who received the radiolead by intravenous in jection* The validity of this indirect method depends on the assumption that the fraction of the systemic 212pb excreted in the urine is the same whether the mode of administration is by ingestion or intravenous injection. The retention values found by Hursh and Suomela for the three subjects were : 1*3, 8.1 and 16.0 % of the administered dose with an average value of 8 % which is equal to that used by ICRP^1*/^ rj^e results seem indicate a decrease in absorption with age* Excretion values given by the authors for experiments in which 212pb was injected intravenously indicate a higher excretion in urine in relation to that m feces : 4*9 and 3*4 % of the dose appeared in the *24 hr urine col lection of two subjects, while the fecal excretions during the first DUP050058800 only 0.29 and 0.25 % This might due to the fact that Hursh Ifela carried out a short-term experiment because of the short lfe of 212pb and therefore the observations had to be made within two days following administration. Vitro0 experiment conducted b^the same authors with heparinized ;||hcubated in the presence of zlzFh, showed that after 16 minutes 3ake by the red cells was 99 I Schraub, Sattler and Hoffmann.-(16'1performed a study on the deposi1 translocation and excretion of inhaled 212pb in humans. An average lung retention of 25 $ of the amount inhaled was found with a sub- eht recovery of 3 $ in the feces. The average 24 hr urinary excretion iPadiolead was 2.8 %. The authors estimated that 50 $ of the lung bur- distributed. to systemic tissues in 6.5 hrs. (]7) er, Chamberlain, Newton and Stott' 'studied the fate of inhaled and toted 212pb in two human volunteers. The inhalation experiment was formed with 212pb generated from a source of ^Th. and administered ___ attached tc submicron particles or as vapour. For the particulate |d-212, initial retentions of 60 % and 34 % were observed for the two jects respectively. After 24 hrs, 75 % of the activity passed into the tod with a subsequent slow removal from it. An excretion of only 2-3 % fthe feces was observed after 72 hrs. When ^Fb was inhaled as a jpibur, in one experiment, the fecal excretion was 37 i of retained dose, er 72 hrs. This was due to vapour deposited in the upper respiratory ct and subsequent passage, through swallowing, into the gastro intestinal tract. p. ~ V*n| the experiment in which ^ nFb, was injected viith 10jag of Fb(H0i)9 'to carrier, an increase in the activity of blood, with more than 90 % 'It associated with the red cells, occurred during thee first few hours, I'A^similar observation was made by Hursh and.Suomelav14)i]n the experiment } With humans already mentioned and by Stover'1"'who injected 212p^ in dogs. ` |n' their experiment Booker et al. could not ascertain the ultimate fate of inhaled and injected lead-212. An increasing activity in the legs of f,fc6ne subject between 24 and 60 hrB after administration (injection and ^inhalation), seems to suggest an accumulation of in hone. An -excretion in urine of 4*4 and 5.6 % of dose was observed in the first |*24 hrs after injection which is in good agreement with the figures of f 4*9 and 3.4 $ found by Hursh and Suomela'1^'. Because of slow transfer I from the lungs, excretion of inhaled 212pb was lower, V' -STABLE LEAD (?) Holtzman' 'gives the following values for the distribution of stable lead in human body : Tissue % of body burden Bone Muscle Liver Blood 83.2 4.6 . 3.1 -Or! DUP050 U - ? He calculated a total "body "burden of 111 mg for unexposed people. At equilibrium the daily intake of lead acquired through alimentary and respiratory absorption is equal to the daily urinary and fecal excre tion, Holtzman calculated an intake of 0,46. ing/day of.Fb, He gives a value of 0,08 for the fraction of the daily ingested lead entering the blood, Kehoe(' l9 * 20) studied the metabolism of lead in man under normal and abnormal conditions. Considering a normal daily intake of 0,33 mg, he states that the output of lead in the feces corresponds to the lead in food, 0,3 mg/day, while the output of lead in the urine is about 0,03 mg/day. Somewhat less than 10 % of the normally ingested Pb is absorbed ; some of this may go back to alimentary canal and excreted. Of the inhaled Pb, 70-75 % is discharged in the expired air, 25-30 % is retained. According to Kehoe, there is little evidence of retention or accumulation of lead in the body of the normal indi vidual even though lead is found in all human tissues. Most of it is found in the skeleton. A progressive increase of lead body burden with age under normal environmental conditions is excluded by Kehoe, In order to get information on absorption, excretion and retention of lead under occupational or abnormal conditions, Kehoe carried out experiments in humans with ingested and inhaled lead. With daily intake varying from 0.3 to 3*0 mg, added to the amount of lead nor mally introduced in the organism, he observed a prompt increase in the Pb concentration of urine.A smaller and more gradual increase was also observed in the lead concentration of blood and of all tissues. The increase would continue at a steady rate as long as the alimen tary absorption of lead was being maintained at a constant rate. At the termination of the experimental ingestion of lead, there was a decrease in theconcentration of lead in urine and blood. Kehoe found that the loss of lead accumulated in the body depended more upon the length of time over which the accumulation occurred than upon the quan tity accumulated. The inhalation experiments were carried out with particles of diameter varying from 0,05 to 1.2 /*. The retention of lead ranged from 35 to 54 % according to particle dimensions. A prompt increase in the lead concentration of urine was observed, but the most significant result was that the increase reached a peak above which it did not go sub sequently, When most of the particles had diameters above 1 /a, the quantity of lead excreted in the feces increased, because of deposi tion in the upper respiratory tract and passage into the gastro intestinal tract, Kehoe states that the severity of occupational ex posure is related to the concentration of lead in blood,which, therer*-\ fore, may be an index of body burden, in agreement with Blanchard*s' J observations. Patterson(' 2i)'describing the contaminated and natural environments of man, states that toxic tresholds of lead concentrations in the blood may be better defined than toxic tresholds for total body burdens. The amount of lead present in the blood reflects that absorbed during a very short period ; over longer periods the blood concentration of lead tends to increase only with increased rates of absorption* Lead consent of urine reflects better short-term fluctuations in lead ab DUP050058802 H- S sorption. Patterson estimated that in the USA, because of industrial contamina tion, absorption rates are about 30 times higher than natural rates, yielding body burdens of about 200 mg/70 kg and blood concentrations of 0. 25 ppm* Mehani ( 22)'performed an experimental study on the retention of lead in workers exposed to a contaminated atmosphere. The average percentages of lead retained in relation to the amount inhaled were 39 47 % for two different types of workers. The values are not much different from those given by Kehoev1?). Despite the rather good agreement bet- * ween results of different, event.though similar, experiments, Mehani affirms that the percentages of lead retention represent only appro ximate orders of magnitude because of difficulty in the measurements. The interaction of various factors (e.g. : particle size and density,'-, respiratory frequency., exposure, duration. .), might affect the results. Schroeder and Tipton('23)'analyzed human tissues collected .between 1952 and 1957 in various localities of the United Statestiand other countries in .Older to determine the lead content. Concentrations in U.S. subjects were, in general, higher than in those from Africa and the Par East. The lead concentration of some tissues, e.g. : aorta, kidney, liver, lung, bone, appeared to increase with age in Americans. For nonAmericans lead increased with age only in aorta. The aialysis of bone revealed that the skeletal content was `higher for Ame rican subjects, about 91 % of total body burden. The authors affirm that lead exposures from food and water probably declined in recent years, while those from air increased. Correlations of* concentrations of lead in lungs and in other tissues indicate that soft tissue lead reflects pulmonary lead and that lead deposited in the lungs is ab- sorbed into the rest of the body. Jaworowski^in his study on stable and radioactive lead in the environ^ ment. and in the human body, on the basis of data of his own and from other authors, estimates that the world mean body burden for stable lead is 240 mg/70 kg. He reports the following fractions of total body burden (source ICRP) : Tissue of body burden Bone Muscle Skin and subcutaneous tissue Liver Pat Blood Lungs G.I. tract Bone marrow Brain Kidneys Lymphoid tissue Heart Spleen Other_______________ _ Total tody 69.5 7.7 5.1 5.1 3.0 2.4 1.1 0.9 0.9 0.9 0.6 0.2 0.2 0.2 2.1 100.0 DUP050058803 Data of Hofreuter et al. ^are also reported in Jaworovfki's review as an indication of existing differences in 'blood lead concentration in relation to residential area, sex and Bmoking habits. Group Mean blood concentration ppm Fb Urban areas Rural areas Hale Female Smokers Nonsmokers 0.21 0.16 0.21 0.17 0,16 0.10 0.17 0.11 No correlation between blood levels and age was observed ; however, according to 6ther authors, there is such .a correlation for the lead content of bone and of some other organs (e.g. liver). JaworowBki cal culated the mean concentrationbof lead in bone of professionally expo sed humans : Boneppm Fb Cortical Trabecular 24.2 7.4 He suggests the use of hair, which reflects the blood levels of lead existing during its growth, for the detection and evaluation of inter nal contamination. He gives a mean concentration of 8.9 jug/g hair for unexposed people and 79 7 jug/g hair for professionally exposed people and found an average hair/bone concentration ratio of 3.84 analyzing samples from the same individuals. Hammond(''25")in describing the metabolism of lead mentions the two prin cipal routes of entry into the organism : gastrointestinal tract and lungs. Absorption through the skin is insignificant for inorganic lead, quite important on the contrary for alkyl lead compounds. It is known that under conditions of normal intake, absorption of ingested lead in humanB is less than 10 $ but, acoording to Hammond, knowledge is lacking about the transfer mechanism of lead across, the gut mucosa into the blood. Calcium in the diet plays an important role on the degree of absorption/ Retention of inhaled lead, estimated by different authors not to exceed the 5 % of the amount introduced in the organism, is influenced by particle size. The affinity of lead.for bone is also known, (90 fo of total body burden) but Hammond points out that the mechanism of deposition and removal of lead in bone requires further investigations. Studies on the distribution of lead in soft tissues revealed a considerable range of concentrations. Hammond, on the basis of the findings of other authors, confirms an increase in lead concentration of bone and of various soft tissues with age at least through the fifth decade of life. He reports results of the "Three-city stfedy" (26) performed in USA in 1961-1962 from which it is evident that l) the concentration of lead in blood and urine did not increase over a period of 5 years, 2) the concentration of lead increases in relation to automobile traffic, 3/ smoking habits influence blood and urine concentration of lead 4) levels of lead observed are well*within the accepted range of concentrations considered non-dangerous for humans. DUP050058804 [[-Ao Barry and Mosaman('27)'have determined lead concentrations in human tis sues of 69 individuals from an area characterized hy increasing indus trialization over a period of more than 100 years. A consistent dif ference was observed in the Fb concentration of bones from individuals of- both sexes. Adult male bones were found to contain concentrations as high as 30 times that in females. This was not valid for soft tissues. The concentrations of lead appeared to increase with age only for bone samples. Total body burdens presen ted great variations. Ninety five $ of lead content was in bone (70 % in cortical bone). In some occupationally exposed subjects lead content of bones was higher than in unexposed subjects, but no difference was .observed in soft tissues. Examples of Fb mean concentrations of tissues from unexposed and exposed people are s Tissue occupational exposure ppm Po non-occupational exposure ppm Fb Bone (Tibia) Liver Lung Blood Muscle 59.20 1.17 0,29 0.17 0.04 32.65 1.11 0.30 0.22 0.06 Values found for lead body burdens, whose non-occupational range is 108-352 mg, are comparable to those of earlier investigators. They indicate, therefore, according to Barry and Mossman, that the present population is not exposed to higher levels of lead. Blokker^^in a very recent review concerning the health aspects of lead emissions from gasoline engines, has studied, among other topics, the presence of lead in the human organism, He states that the main hazard resulting from exposure to >small amounts of lead resides in its gradual accumulation in the body of exposed people during their life time. Data gathered by the California Public Health Department*^)and by Patterson*reported in Blokker*s review, indicate that for urban residents the total quantity of lead absorbed from the respiratory traot is of the same order Of magnitude as that absorbed from the gastro intestinal tract. Goldsmith and Hexter^^confirm this fact. According to them, increasing respiratory exposure may cause an increased storage of lead in the body. Kehoe*^-'in a recent study denies this possibility. In regard to the use of blood lead as indication of total body burden, Blokker reports what is stated, in a publication of the California Public Health Dept.' that repeated blood analyses from the same individual may give quite different results, while total body burden does not change. However, .blood may be a reliable indicator of body burden in population studies where individual variations average out. Blokker inoludes in his review also some results of the "Three-city study" v"), already mentioned by Hammond(25), and "The Los-Angeles Free-way study"* 32. Such results dearly indicate that a correlation exists between lead air levels and blood concentrations of lead. For instance, to an exposure of 2.2 /ig/m3 for employees of Pasadena corresponds a mean blood lead of 19 /ig/lOO g. A correlation between inhaled lead and lead concentration in hone was observed diring experiments with animals. DUP050058805 Blokker reports the results of Lutmer et al. who in mice exposed to auto-exhausts found a hone content 40 % higher than in unexposed animals. CONCLUSIONS The analysis of various studies has revealed that many experiments have been performed to investigate the problem of radioactive and stable lead contamination of huinans. Despite the relative abundance of data the lite rature, transfer coefficients of lead through the respiratory and gastro intestinal tracts, are not known with a sufficient degree of precision. Data on storage of lead in the different compartments of the organism are also far from being consistent. The absorption and retention values given by some authors have always a range of variation, sometimes rather large ; they do not provide, therefore, a completely satisfactory basis for the establishment of permissible levels of exposure. With regard to the principal aim of the present review which was to as certain whether experiments performed with radioisotopes of lead in animals and humans, may provide useful information on the metabolism of stable lead in man, recapitulative tables with data on radioactive and stable lead are presented (see Tables 1 and 2). It seems evident, in general, that the results of experiments performed with radioactive tracers are confirmed by those on the behaviour of stable lead in man. However, metabolic differences may occur for carrier-free radiolead and for stable lead introduced into the organism at normal or abnormal levels, let, many important questions concerning the toxioological aspects of environmental contamination due totlead are still without satisfactory answer. The.experiments with lead radioisotopes which in the past were performed with the aim of estimating the degree of exposure to radioledd for the establishment of radioprotective rules, might be usefully continued to fill in the subsisting gaps concerning stable lead. The choice of the radioisotope and the experimental conditions should be, of course, carefullv studied in order to obtain results and conclusions which give a valid contribution to the elucidation of'the toxicity mechanism of lead. The analysis of the different studies on metabolism of lead, has shown where additional research is required. The following list includes the main.subjects to be further studied also with the use of radiolead : 1) Form of Fb circulating in plasma (in vivo"studies not performed). Nature of binding to plasma constituents. 2) Relationship between Fb in blood end in soft tissues and between Fb in blood and in total exchangeable Fb pool. Factors influencing the relation of Fb in blood to Fb in soft tissues e.g. age, sex, blood type, etc... .3) Mechanism of Fb transportation across the intestinal mucosa into syste mic circulation. 4) Mechanism of deposition of Fb in bone or metabolic factors modyifing interaction of Fb with bone. 5) Effects of interruption of Fb absorption on reduction of Fb body burden Factors influencing mobilisation of Fb in the body. 6) Fate of inhaled Fb. Absorption rates for particles of less than l/i (radioisotopes of lead could be particularly useful). 7) Effects of lead on enzymatic systems. References tl- A% (X) I Horiuohi and S. Horiuchi. The fate of lead in the body. Experiment with RaD. AEC-tr-4482. pp, 751-67 (1958), (2) R.B. Holt&man, Critique on the half-lives of lead and RaD in the human hody. ANL-6297. pp. 67-80 (196I). (3) R,B. Holtzman. Health Physics 9 385 (1963). (4) N. Castellino and 3. Alo.i, Brit, Joum. Industr, Med, 21, 308 (1964), (5) 2, Jaworowski. Stable and radioactive lead in environment and human body. Nuclear Energy information Center, Warsaw. Review Report n 29 (1967), (6) N. Cohen and G.P. Howells. A review of Fb-210 metabolism. Institute of Environmental Medicine. Progress Report NyO-3086-8 (N.Y. Univer sity) III-l (1968). (7) J. Schubert and M.J. White. Joum. of Laboratory Clin. Medi'c. 39, 260 (1952). (8) H.F, Lucas and J.E, Stanford. Excretion and retention of lead-210 in rats. ANL-7360, pp. 105-110 (1967). (9) N. Cohen, S.P. Howells, M.E. Wrenn and M. Eisenhud. Metabolic studies of Fb-210 in the adult baboon. Institute of Environmental Medicine. Progress Report NYO-3086-8 (N.Y. University) IV-1 ( 1968). (10) J.B. Hursh. Half-life and tissue distribution of Fb-210 in dogs. Paper presented at the Symposium on "Biology and Ecology of Polo nium and Radiolead" Sutton, U.K. 30 April-1 May I970. DUP050058807 13 R.D. Lloyd. C.W. Mays, D.R. Atherton and F.K, Bruenger. Distribution land retention of injected Fb-210 in the beagle. Paper presented at the Symposium on ''Biology and Ecology of Polonium and Radiolead" Button, U.K. 30 April-1 May 1970. . j|: S.C. Black. Archives of Environ. Health 5, 423 (1962). f|e)r R.L. Blanchard and J.P. Moore. Body burden, distribution and internal dose of Pb-210 and Po-210 in a uranium miner population. Paper presented at the II Intern, Congress of IRPA. Brighton, U.K. 4-8 May 1970. fe) J.B. Hurgh and <T. SuOmela. Acta Radiologies 7, 108 |5) International Commission on Radiological Protection. Report II on Permissible Dose, for Internal Radiation. ICRP Publication 2 (i960). 16) J.B. Hursh. A. Sohraub, E.L. Battler and H.P. Hoffmann. Health Physics 16, 257 (1969)* If17) D.V-. Booker. A.C. Chamberlain and P. flewton. Brit. Joum. Radiol. 42 457 (1969). ||j[l8) B,J, Stover# Proc* Soc. expl* Biol* Med* 100, 269 (1959)* ' ^'(19) R.A. Kehoe. Archives of Environ. Health 8, 232 (1964)* |: (20) R.A. Kehoe. Archives of Environ. Health 8, 235 (1964). (21) C.C. Patterson. Archives of Environ. Health 11, 344 (l9$|| (22) S. Mehani. Ann. Occup. Hyg. 9, 165 (1966). ; (23) h .A. Schroe^Ar and I.H. Tipton. Archives of Environ. Health 17, 965 (1968) DUP050058808 It - A If (24) D.H. Hofreuter, E.J. Catcott. R.Q. Keenan and C. Xintaras. Archives of Environ. Health 3, 563 (1961). (25) P.B, HannnonA. Lead poisoning. An old problem with a new dimension, in "Essays in toxicology"' Vol.j Academic Press pp, II5-I55 (1969). (26) IT. S. Public Health Service. Survey of lead in the atmosphere of three urban communities. Public, n 999* AP, 12 (1965)* (27) P.S.I. Barry and D.B. Mossman. 1970. Journ. industr. Medicine 27, 339 (1970), (28) P.0, Blokker. 1972. Atmospheric Environment 6, (1972). (29) California Public Health Department. Lead in,the environment and its effects on humans. Report prepared by'the Divisions of'Environemental Sanitation and Laboratories. Berkeley, California (i.967). (30) J.R. 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DUP050058809 FIGURE : 1 W" 4S Metabolic pathways of radiolead in human organism INGESTION -RADON 4oam s DUP050058810  H" A{o TABLE I Distribution of radioactive and stable lead in wan Tissue % of body burden 210 Pb Stable Fb 0 N reference (see list) 111""" Bone 63.0 58.0 80,0 79.0 80.O 83*0 70.0 90,0 91.0 95.0 2| 3 5 5 (other authors) 13 13 (other author) 5 (ICRP) 12 (other author) 23 27 Liver Spleen 1.7 2.8 1.5 2.2 0.14 3.1 5.1 0.2 2, 5 5 (other author) 5 (other author) 13 5 (ICRP) 5 5 (ICRP) Muscle Soft tis sues (all) 17.0 13.0 4.4 30.0 4.6 7.7 30,0 2 5 (other authors) 13 2 5 (ICRP) 5 5 (ICRP) Blood 2.0 1.6 2.4 5 13 5 (ICRP) DUP050058811 lim p; d e p o s itio n in h a la tio n minus e x h a la tio n , as s p e c ifie d by authors DUP050058812