Document e94ZyN0KeExxyGY2QXVXw7Dq

t v:i>n j id It' vtU'l vl.ul' Epidemiological Bases for Possible Air Quality Criteria for Lead John R. Goldsmith State of California, Department of Public Health Vw .<* ;v Km irul i-m I, %]nY In at least some urban areas, population exposure to elevated atmospheric lead levels is associated with in creased blood lead. No reasonable alternative explana tion exists other than that the increased levels of lead pollution are causing increased lead storage in the body. The study of lead body burdens in U. S. populations indi cates an increasing concentration with age in liver, spleen, pancreas, kidney, and lung. No such increase is found in samples of residents from foreign countries. The effect of increased storage of lead on porphyrin metabolism is in urgent need of investigation. Higher levels of lead exposure may interfere with hemoglobin synthesis. Using WHO categories for air quality guides (criteria), a level I criterion far two micrograms of lead per cubic meter of air for a long-term average can be proposed. It would apply to pollution largely derived from motor vehicular sources. Lead is widely distributed in man's environment. It is found in his food, his water, and in the air he breathes, Some of this lead derives from the industrial and technological activities of man. Technological uses of lead have changed over time. At present, two of the principal applications are for storage bat teries and gasoline additives; substantial amounts are also used in pigments, pesticides, and plumbing. Pottery glazes and solder are important as sources of human absorption. Almost all foods contain detectable amounts of lead. Sources include: uptake and concentration by the organism from soil or fodder; contamination through aerial fallout; use oflead compounds in agriculture and direct contamination during processing, storage, and preparation. Lead enters drinking water from a number of sources. The. most important are lead pipe, cisterns, solder, paints, atmospheric fallout into Uncovered reservoirs, and industrial sewage.1 Routes of Exposure For most individuals, the diet 1s the major source of lead exposure. While estimates vary, the average dietary intake in-the United States and in Europe is usually placed at about 0,30 mg per day.1 In some .areas, drinking water may be a major source, particularly in old urban areas where lead pipes or storage cisterns may still be in use. Tobacco smoke con tains lead, apparently derived from soil residues of insecticide sprays used many years ago, and this source may contribute to total body burden in smokers.5 Until recently, community pollution was largely neglected because it was thought to contribute little to population exposures. 714 Since a large proportion (90-95%) of orally ingested hwl ; excreted in the feces, most of the ingested lead is not Mils absorbed into the metabolic pool of the body. Metaboli absorption (as opposed to ingestion) may result in ihcre:i-r.! body burden regardless of the route of intake. Sonic of tiiiis excreted in the urine. Increased storage is likely when ex posures are persistently increased. Decreased storage omirwhen exposures decrease. From what is known about turn over rates of isotopes in bone, where much of the body burden of lead is stored, the processes associated with decreases in storage may have a slower half-time than those associated with increase. This needs to be further investigated, how ever. The amount absorbed by the respiratory tract is a function of particle size, solubility and route. Of inhaled lead derived from motor vehicle exhaust pollution, from 25 to 50% ithought to be absorbed; airborne lead from other industrial. sources generally has a larger particle size and a smaller jusportion is absorbed. Because of the difference in absorption ratios, the amounts absorbed by the body via the oral and tlm respiratory routes may be similar in magnitude even though the total ingested with food and water is usually several timethe total inspired with air. Health Effects of Lead Inorganic lead in sufficient amounts is implicated as a causative agent in decreased hemoglobin synthesis, liver ami kidney damage, mental retardation in children and in ab normalities of fertility and pregnancy.1-*-4 Claims that load is a carcinogen have not been sustained by occupational stud ies. Clinical observations are often used in denoting tineffects of undue lead exposure and it is against the onset clinical pathology in occupational exposure situations haadults, that blood and urine levels of inorganic lead have established in setting presumed "normal" values.5 Adults who have less than 0.0S mg of lead per 100 g m' blood, and excrete less than 0,15 mg of lead per liter in 21hour urine specimens, are considered to be within "normal" limits.4 They ordinarily do not show clinical lead intoxi'ntion even though metabolic effects of lead exposure may be mfleeted in blood and urine. There is evidence that exposure to moderately low lead levels may produce abnormalities in the synthesis of phyrins.* The most specific, but not the only, site of damage i-' porphyrin biosynthesis is the inhibition of delta-simim^ levulinic acid (d-ALA) dehydrase. This inhibition leads to in creased blood and urine levels of d-ALA; this increase may appear before any change is noted in blood or urine lend levels.7,8 In one study of occupationally exposed workers, a considerable increase in d-ALA in blood was the first sign Journo! of the Air Pollution Control Association lt*vt urii -to It* v\'i nVL Thi : i.it ( X H m z 4k o si to .siv* The pathway of porphyrin synthesis, with known the total body burden in relationship to lead exposure should t ,1f lead inhibition, is shown in Figure 1. provide an important index of this effect. Schroedev and " i Vitdren are said to be more susceptible to lead intoxica- Tipton1* have recently reviewed the available data. /ihan adults. Encephalopathy and mental deterioration Their basic approach was to collect organ weights aud > ,..u|.poisoned children have been well-documented. One |v disclosed that 200 normal children had blood lead levels it.iU-t to 0:030 mg per 100 g while mentally defective samples from U.S. decedents with sudden accidental death, in cooperation with medical examiners' offices in nine major U.S. cities. The specimens were analyzed by emission spec I in n showed 0.04 to 0.08 mg per 100 g of blood.10 Amino* troscopy. Specimens from foreign countries were also ob- i dime acid levels in the blood of these latter children were . tamed, but only about half were from deaths due to accident. 5 ,,> high. While it has been assumed that the elevated lead However, only tissues showing no gross pathology were | ', ,.| was a causal factor in mental deficiency,11 it is possible, analysed for both U.S. and foreign subjects. Unfortunately, i course, that the mental deficiency might have contributed not all organs from all locations could therefore be used. I ;iii increased intake of lead; e.g., from pica or chewing of Otherwise, comparable sampling aud analytical procedures I vied paint, rather than the other way around. Gordon, were used throughout. 1 and Mackay12 did not find significantly higher blood I ,in children who were mentally deficient compared with Table I shows the basic source and variation of data for the U.S. accidental death group. Table II shows the geo I mrols. I Lead is deposited mostly in bone with lesser amounts in -ft tissues. Once deposited, lead appears to be released at a {. rate over extended periods of time. Lead workers re eved several years from exposure still have shown high I els of porphyrins in their blood and of d-ALA in blood and graphical comparison between U.S. populations and foreign ones. African samples were mostly (41 out of 54) from decedents who had lived most of their lives under primitive conditions. Switzerland data shows the lowest body burden of all. Although the number of samples is small, they are of particular interest because lead additives for gasoline were d lead J .fine,1* Presumably, sufficient lead was released slowly fnroomt used in Switzerland until 1947, while in U.S. and many lot trv. ? ' emulated reserves to sustain the interference with por- other countries, they were used since 1923, fetalw ncrca- I e of t! i when ( I m occu- ^ hyrin metabolism. Because of this equilibration with bone -d other tissues and because direct measurement of lead ,,'r;lSe 18 nt possible, blood lead levels are generally taken ' *n indicator of total body storage for living populations, re" though values for an individual may fluctuate widely In liver, spleen, pancreas, kidney and lung, there is an in crease in lead concentration with age up to the fifth decade in the U.S. sample but no such increase was found in foreign samples. Both U.S. and foreign samples showed increased aortic lead concentrations with age. This suggests that >ut turi I >-``Ttlme. lT Kiirili. I reases : The Human Body Burden of Lead foreign adult subjects were in a steady state whereas the U.S. subjects continued to add to lead storage in soft tissues. Similar increases -were observed with age in bone lead con isociati Since one of the goals of air quality criteria for lead is to centrations up to the fourth decade in U.S. populations; 2d, ' ievent any increase in storage of this material in the body> with increasing age beyond 40 years, however, jt declined. funepi: l derive 50% Iadustri:. tiler pri >sorpticK i and tin f r thougl ral tinir- :ed as sliver and * d in al>| that lest! | tial stud- ] ting the | onset oi * tions for ave been; f 100 g ot er in 24` normal" intosiw- r iay be re- j* low ' vl - ~s Si f damage | a-amiu'>- | ads to in-1 ease may i fine lead j orkccs, k f fiist sign I f 715 DUP050083108 TEH 0 4 7 0 2 9 0 Table I. The body burden of lead, adult tissues from United States 150 accidental deaths, wet weight Total in organ Tissue Organ weight fe) Muscle 28 000 Fat 12 500 Skeleton 10000 Blood 5500 Skin 4900 Dense connective tissue 2300 Liver 1800 Brain 1430 <3,1, tract 1200 Lungs 1000 Heart 350 Kidneys 310 Spleen 180 Pancreas 100 Aorta 100 Hair 15 Other 315 Total body (ppm) 70000 Total soft tissue (ppm) 60000 $0% Mean Total range* Rangeb (mg) (mg) (mg) 1.7 0-179.2 0-5.9 0.60 0.1-1.5 0.22-3.6 110.0 7.5-195 48-170 1.4 0.22-2.7 0.3-2.4 1,5 0-11.8 0.4-4.8 1,08 0-4.8 0-5.5 3.1 0.72-13.5 1.3-6.3 0.14 0-8.8 0-2.0 0.15 0-3.1 0,05-0.52 0.39 0.05-5.1 0.09-0.86 0,02 0-0.4 0-0.07 0.34 0.003-2.0 0.14-0.74 0.06 0-2.2 0.02-0.24 0.06 0-1.1 0.02-0.17 0.22 0.15-1.0 0.04-0.55 0.75 0.05-1.5 0.06-1.3 0.08 0-0.2 0-0.1 121.59 9,55-434.9 50.7-205.1 1.73 0,14-6.25 0.72-2.93 11.59 2.05-239.9 2.7-35.1 0.19 0.03-4.0 0.05-0.59 * Total range of 258 cases. b Range of 150 cases. Source: Arch. Environ. Health, 17, December 1968. The authors conclude: "Therefore, Kehoe's hypothesis of a balance between absorption and excretion appeared to hold for most foreign subjects but not for Americans. This idea is not valid for bone and aorta in either group." Mathematical Distribution of Blood Lead Levels Published epidemiologic data on blood lead levels generally show the mean but not the distribution of the observations; means for nonoceupationally exposed populations are usually between 0.015 and 0.025 mg per 100 g of blood. Estimated standard deviations, when given, are highly variable, but are usually proportional to the mean. Proportionality between mean and standard deviation is characteristic of log-normal Table II. Lead in adult human tissues according to geographical area median values, ppm ash. Nine U.S. cities San Swit Fran zer. Middle Far cisco' land Africa East East No. cases 150 27 9 54 37 74 Aorta 140 220 32b 71 140 91 (%)* Liver 95 130 160 59 64i> 70b 97 (.%) Kidney 99 98 54 45 36b 62b 62 <%) 96 Pancreas 49 69 42 24 34b 39 Lungs 47 38 32 28b 42 43 (%) Testes 98 99 12 20 23 29 32b 35b (%) Heart 95 5 10 14 5 24b 19b (%) Brain 57 65 95 5 5 5 5 14b 10 <%) Spleen 69 96 71 88 81 27 44 20 21 40 33 (%) Bone 96 43 80 95 26b 30b (%) Total body (mgy 121.6 137,2 61.9 63.2 95 94 78,4 93.7 * Percent of samples in which lead was found. When blank, lead was present in all samples. Data calculated from Tipton, et al.13 b Differs from nine U.S. cities, P< 6.001. Estimated by comparison of values. 716 distributions, commonly encountered in biological work, an,] logarithmic scales have been recommended for analysis !(f this type of data.u-u A range of 0,015 to 0.040 mg per 100 g has been considered to be average for nonoccupationally ex- posed persons.5 ' A recent study of Los Angeles County residents by Thomas, et al,u proyided a striking demonstration of the relation be tween blood lead and place of residence which presumably re flects respiratory exposure for nonoccupationally exposed groups. Blood lead levels were measured for persons living near freeways (within 250 feet) and for persons near the coast (at least one mile from a freeway). Blood lead levels in the former group were markedly higher than those in the latter group but were higher, though not significantly so compared with the population values previously obtained from inland Los Angeles County, where atmospheric lead levels are generally high (Table III, Figure 2). Goldsmith and Hexter13-19" have presented data including that pf Thomas, el al. which they feel demonstrates that, for population groups, blood lead levels are epidemiologically re lated to estimated respiratory exposure in areas with high levels of motor vehicle pollution. This is based on epidemiclogical studies of general and occupational groups and the relation is similar to that from experimental exposures.*' This relationship assumes generally similar dietary and beverage ingestions in the several populations13'30 (Tables III and IV, Figure 3). This, in turn, implies that total body burden is, in part, a function of respiratory exposure. A reasonable interpretation of this epidemiological and ex- perimental data, is that continued respiratory exposures to ambient air levels already attained in some cities could re- suit in increased body storage as indicated by blood lead. i ^ l J. 1 i j f \ j { i j i s j j j j Table III. Blood lead levels and estimated ambient air and occupatlonal exposures of selected populations" Estimated exposure Uig/m!) Mean blood lead (pg/100 g) Type of population Occu- pa- Am- Aver- Fe- tional blent age5 Male male Populations without known occupational exposures Remote California mountain residents 0.12 12 9 Los Angeles residents near ocean 0.34 16 10 Composite rural U.S. 0.5 16 10 Suburban Philadelphia 1.0 13 13 Composite urban U.S. 1.0 21 16 Los Angeles aircraft workers 1.9 19 17 Pasadena city employees 2,2 19 12 Downtown Philadelphia 2.4 24 IS Los Angeles residents near free- 2.5 23 17 way Populations with known occupational exposures Cincinnati policemen (all) 4.7 1.4 2.1 25 Cincinnati traffic policemen 12.8 1.4 3.8 30 Cincinnati auto test lane Inspectors 14.8 1.4 4.2 31 Los Angeles traffic policemen 16.5 2.2 5.2 21 Cincinnati garage workers 21,1 1.4 5.5 31 Boston Sumner Tunnel employees 44.5 1.1 5,3 30 Source: U.S. Public Health Service, Survey of Lead In the At mosphere of Three Urban Communities, Publication No. 999-AP-12. January 1965. State of California, Department of Public Health. Environmental Hazards Evaluation Unit. b For populations with known occupational exposures, the aver age Is a weighted average of presumed occupational and ambient exposure. Ambient exposures are estimated only and were not necessarily measured at the same times and places at which the population s were exposed. > -{ ! , i 1 I < Journal of the Air Pollution Control Association DUP050083109 TEH 0 4 7 0 2 9 1 r es id en c e n ear f r eew ay r-z = 15.7 -- S.D.==7.0 35 WOMEN J k. 8 16 24 BLOOD LEAD, MICROGRAMS PER 100 GRAMS 32 40 RESIDENCE NOT NEAR FREEWAY pC = 9-9 s n = ac 30 WOMEN l---- 1 i --\ 16 24 32 40 BLOOD LEAD, MICROGRAMS PER .100 GRAMS Figure t. Frequency distribution of sample population by blood lead, sex and residence: Los Angeles County, 1966. PARTICLE SIZE (/> --*-- TOTAL RETENTION -------o-- LOWER RETENTION ----- o------UPPER RETENTION Figure 4. Relation between particle size and retention rate, total and regional retention for respiration rate. Source Nozaki, K. ESTIMATED AVERAGE RESPIRATORY EXPOSURE (,,g Pb/m3) Figure 3. Mean blood lead for epidemiologic and experimental res piratory exposures with regression from epidemiologic data only. Another experimental study which is highly relevant to epidemiology is of the relation of particle size to respiratory retention1 (Figure 4). The importance of this derives from the particle sis distribution of community airborne lead (Table V). An experimental study of human respiratory exposure pro vides evidence that hematopoiesis is altered by respiratory exposures somewhat greater than those likely in community air pollution. Two subjects inhaled a mist containing dilute lead acetate solution through a special nebulizer, with doses of 0.589,1.120, and 1.389 mg of lead per day for 61, 31, and 50 days, respectively. The amounts of lead inhaled, expired, and residual (in saliva) were measured and the net respiratory dose was found by difference. Over 80% retention was noted for this soluble salt, compared to 25-50% estimated for the Table IV. Mean blood lead for experimental exposures to atmospheric lead (ug lead per 100 g of blood). Respiratory exposure Observed blood lead Exposure level (mb Pb/m) Number of hours per week Estimated average* OigPb/m5) Average blood lead O*g/l00g) Number of periods1' Average blood lead Oig/100g) Number of period sb Expected blood lead* Cfg/lOOg) Subject NK Subject SS 10 0 10.5 21.0 31.5 42.0 62.5 63.0 73.5 1,4 20.4 7 18.6 5 20.2 1.9 21.4 4 19.3 6 21.7 2.5 21.7 6 20.2 4 23.1 3.0 23.2 4 19.8 4 24.1 3.6 24.6 4 20.2 4 25.1 4.1 - 26.5d 4 23,0* 4 25.9 4.6 28.5 4 ' 25.5 4 26.6 5.2 28.5 4 23.8 4 27.4 Subject LD Subject JS 150 0 1.4 22.4 21 24.5 13 20.2 10.5 10.7 26.0 4 28.5 4 32.4 21.0 20:0 39.2 4 38.2 4 37.4 * 31.5 29.3 40.8 4 39.8 4 40.9 42.0 38,6 43.5 4 44.8 4 43.6 * Estimated average for each experimental period assumes 1.4 ug of lead per m> in ambiert air between experimental exposure sessions. b Each period consists of 28 days with eight determinations of blood lead; only the average for these eight determinations was shown in the Source. The averages given here are the averages of the period averages. 0 Expected blood lead in fig per 100 g of blood calculated from the regression derived from the Three-City Study data (login blood lead = 1.271 + 0-2323 log, atmospheric exposure). 11A 14-day "vacation" interrupted exposure just prior-to this experimental period, A 21-day "vacation" interrupted exposure fust prior to this experimental period. Source: Kehoe, R. A., "Criteria for Human Safety from the Contamination of the Ambient Atmosphere with Lead," Proc. XV Congr. Intern. Med.Travail, Vienna, 1966, Vol. i II, p. 83. State of California, Department of Public Health, Environmental Hazards Evaluation Unit. September 1969 Volume 19, No. 9 717 DUP050083110 TEH 0 4 7 0 2 9 2 table V. Lead content of atmospheric particles by size, Berkeley, I960." Median equivalent diameter ftp Total, all sizes 20 9 4 3 1.5 1 <1 Percent of total atmospheric lead (by weight)' too 2-4 2-6 3-6 1-6 4-25 2-15 50-80 * Source: State of California, Department of Public Health, Air and Industrial Hygiene Laboratory. finely divided, but insoluble, inorganic lead particles from automobile exhaust. The daily absorbed dose for the first dosage level was about 0.50 mg; this produced a noticeable decrease in red blood cell count and hemoglobin count within two months, while urine coproporphyrin rose sharply within two weeks.' This work re-emphasizes the importance of urinary ex cretion of d-aminolevulinic acid in study of lead exposed populations. So far, the sensitivity of this test has been shown for industrially exposed populations*2 (Figure 5), but not for populations with community exposures. This should be considered a high priority problem for investigation. It is proposed that air quality criteria should include a criterion based on d-ALA excretion if and when it can be shpwn to be related to community air pollution exposure. Possible Criteria Reference is made to the report of the WHO Expert Com mittee on Atmospheric Pollution, WHO Technical Report Series No. 271 (1964), which suggested four levels of concen trations and exposure times for air quality criteria*5: "In the light of present knowledge, guides to air quality may be presented as four categories of concentrations, ex- 100 1,000 10,000 100,000 1,000,000 ADJUSTED URINARY ALA (mgm ALA/gm CREATININE) Figure 5. A group of men occupationally exposed to lead fn various industries in California had blood and urine samples taken. Since the urine samples varied in their dilution, the urinary concentration of d*ALA was corrected for the amount of creatinine in the urine. The logarithmic relation is represented by a correlation coefficient of ft =* +0.67. Source: Bureau of Occupational Health and Environmental Epidemiology Unit* and Air and Industrial Hygiene Laboratory, Cali fornia State Department of Public Health. 718 posure times and corresponding effects. These four categories are defined by limiting values which may vary for a given pollutant according to the anticipated effect or the criteria used and in relation to other eo-cxisting pollutants and the relevant physical factors, and which take into account the. varying responses of different groups of human beings. The Symposium agreed to define the four categories in terms of the following levels : "Level I, Concentration and exposure time at or below which according to present knowledge, neither direct nor indirect effects (including alteration of reflexes or of adaptive or protective reactions) have been observed. "Level II. Concentrations and exposure times at and above which there is likely to be irritation of the sensory organs, harmful effects on vegetation, visibility reduction, or other adverse effects on the environment. "Level HI. Concentrations and exposure times at and above which there is likely to be impairment of vital physiological functions or changes that may lead to chronic diseases or shortening of life. "Level IV. Concentrations and exposure times at and above which there is likely to be Scute illness or death iu susceptible groups of the population." Using these criteria as guides, there are several questions which may be appropriate for consideration: ?1 } t j , : i | | j. j j \ t I j j ' j J ) s j ; ; 1. What constitutes an effect? Is storage an effect? 2. Should "effect" be defined in terms of altered hlood or urine levels of porphyrins, delta-aminolevulinic acid, or other metabolites? What constitutes an altered level? 3. Does an altered level of a metabolite indicate an impair ment of a vital physiological function? 4. Is it possible, or desirable, to define a concentration and exposure time corresponding to Level II? 5. Should adoption of numerical guides await further population studies, such as studies to determine the re lationships, if any, between blood and urine levels of lead and of d-ALA in population groups exposed to vary ing intensities of urban air pollution? What groups? By whom should these studies be carried out? j In considering these questions, it is suggested that: 1. Definitions of criteria for Level I might be amended by adding, "significantly increased storage in the body of potentially toxic materials," as an example of a direct or indirect effect, 2. Definitions of criteria for Level II might be amended by adding, "significant alteration of an essential metabolic process (such as porphyrin metabolism)." Alternatively, this might be considered to be an example of a direct of indirect effect, in Level 1. 3. Significant alteration in hematopoiesis be considered an example of an impairment of a vital physiological func tion, in Level III, In view of the available data, and the above suggestions, it appears that a reasonable numerical guide for a Level I criteria would be long-term average exposure to 2.0 ag of lead per cubic meter of air, where pollution is largely from motor vehicular sources. There may not be sufficient data to support numerical .guides for criteria at- higher levels. Acknowledgment This work was supported in part by a contract from the National Air Pollution Control Administration of the De partment of Health, Education and Welfare. Journal of the Air Pollution Control Association DUP050083111 TEH 0 4 7 0 2 9 3 l\iT. i Kofsrencos . -Symposium on Environmental Lead Contamination," I'.tj. Public Health Service, Publication No. 1440 (1906). "Survey of Lead in the Atmosphere of Three Urban Com- inanities)," U.S- Public Health Service, Publication No. ill!) -AP-12 (1905). Tlsiencs, C. IT., and Haley, T. J., "Clinical Toxicology," Lea & i''ebiger, Philadelphia; 1964. I "A Textbook' of Medicine," Cecil, R. L. and Loqb, R. F., i-t-n eels., W. B. Saunders, Philadelphia, 1959. (loldwater, L. J. and Hoover, A. W. "An International r j :j - Study of `Normal' Levels of Load in Blood and Urine," ,lre?i. Environ. Health IS, 60-63 (1967). , JCehoe, R. A., "The Metabolism of Lead in Man in Health and Disease, 'Hie Harben Lectures, 1960," J. Boy. Inst. nmi { Public Health Hyg., 24,81-97,101-20,129-43,177-203 (1961). '"r;* I i 7. Diene, D., et al., "Dclta-Amino-Levuliuic Acid As Early Sign of Lead Exposure," Med. Lavoro, 57, 161-1C6 (1966). s. Iloriuchi, K., eial., "Studies on the Industrial Lead Poison ing," Osaka City Med. J., 57,151-169 (1962). y. Efe, S., "Studies on Urinary Excretion on Delta-Aminolevul y-> i 'iv inic Acid in Cases of Saturnism and in Plumb "Workers," New Istanbul CorUrib. Clin. Sci., 7,209-26 (1964). 10. Koumidis, Q.t "Lead Poisoning as n Cause of Mental Retar i ;tn> ] ' I !.!; i dation in Children," in: "Forensic Immunology. Medicine, Pathology and Toxicology," Report of the Third Inter national Meeting (1963). International Congress Series No. 80, Amsterdam Excerpta Medica Foundation, 1964, p. 97, | 11. Moncrieff, A. A., Roumides, O. P., Clayton, B. E., Patrick Oil- A., Renwick, A. G. C., and Roberts, G. H., Arch. Die. Chil dren, 39,1 (1964). 12. Gordon, H,, King, E., and Mackay, R. I., Bril. Med. J., 1,480 (1967). 13. Saita, G., e< al, "Determination of Blood and Urinary Delta- AminolevuKnic Acid in the Diagnosis of Past Lead Poisoning," Med. Laroro, 55, 357-64 (1961). 14. Schrocdcr, II. A, and 110101), L TI., Arch. Environ. Health, 17, 965 (1968). 15. Ruslagi, J. S., "Stochastic Behavior of Trace Substances," Arch. Environ. Health, 8,68-76 (1964). 16- Finney, D. J., "Statistical Method in Biological Assay," TMtTuJoivf*r-, .u%vuc.s7uvjieTvy<TM> ssrvWn A..wLzxrvj IflM 17. Finney, D. ,J.. "Propit Analysis," Cambridge University Press, Cambridge, England, 1952. TO Thnniae T-T V al nl I nncl a P Pnv.snno T iTHnn Vnnsi Freeways," Arch, Environ. Health, 15,695-702 (1967), 19. Goldsmith, J. R. and Hexter, A., "Respiratory Exposure to Lead: Epidemiological and Experimental Do3e-Response Re lationships," Science, 158, 132-134 (1967); 19a. Science, 159, 1000 (1968). 20. Kehoe, R. A., "Criteria for Human Safety from the Contam ination of the Ambient Atmosphere with Lead," Proc. Congr. Intern. Med. Travail 15th, Vienna, 1966,3,83. 21. Npzaki, K., "Method for Studies on Inhaled Particles in Human Respiratory System and Retention of Load Fume," tnd. Health, 4,118-128 (1966). 22. Stoops, G. J., "Symposium on Air Quality Criteria--Lead," J. Occupational Med,, 10,55C-564 (1968). 23. "Atmospheric Pollutants," Report of WHO Expert Com mittee, World Health Organization Technical Report Series No. .271, (1964). or or iir- * u'r a- * \ of A V- ? 1 l i >y of \ rl 5 *y w Discussion Gordon J. Stopps Assistant Director Haskell Laboratory E. 1. du Pont de Nemours & Co. Wilmington, Delaware * Dr. Goldsmith states quite correctly that lead is widely distributed in man's environment, and that probably the diet is ,1 the major source of lead exposure; but it is not an element present only in the urban diet because lead is part of the earth's1 crust and is present in almost all food. This results in a eer- j tain base line level of lead being found in all human beings j wherever they were sampled. We at Du Pont have been able to 1 analyze the blood of groups of people in remote portions of the r > world, far removed from cities and man-made sources of load. In South America, we were fortunate to obtain specimens from I the Caraja tribe in the Xingu National Park area of central Brazil. Eleven male Indians had blood samples drawn and an'. \ alyzed and the average blood lead concentration of these 11 subjects was found to bp 23 yg per 100 g of blood. In south eastern Peru, on the eastern slopes of the Andes, live, tribes of Indians who have seldom seen a white man. They are completely self-sufficient in regard to their food supply and are ^ hundreds of miles away from any man-made sources of air pollution other than their wood fires used for cooking, * Samples obtained from 39 Indians hod an average blood- ' fs. i i a. ?. ... - ift at. a lead level of 18 /ig per 100 g of blood. Moving from South America to the bushmen of the Kalahari region of Bechuanaland now called Botswana., 63 bushmen from widely-scattered family groups had blood samples taken and the average bloodlead value was found to be 16 ng per 100 g of blood. Moving east and north from the Kalahari Desert, we were fortunate to find an expedition that was seeking out pockets of primitive people as yet largely untouched by Western civilization. From these people in portions of Kenya, Malawi, and Rhodesia, 63 blood specimens were obtained and the lead concentration was found to bo 12 #ig per 100 g of blood. Even further west wc were able to obtain 28 samples of blood from Elcho Islanders off the northern coast of Australia, These people have little or no contact with white people, being from an isolated group of islands in Eastern Arnhem LandA total of 28 blood samples were analyzed and the average blood lead concentration was found to be 17.5 eg per 100 g of blood. These blood lead levels from persons living in remote areas With very little or no local exposure to artifactual lead, no DUP050083112 TEH 0 4 7 0 2 9 4 range from 12 to 23 jug per 100 g, In North America, using the same laboratory for the analyses and the same analytical technique, over 6000 working men and women are being sampled on a yearly basis at 25 different locations ranging from Michigan to Florida and New York to Los Angeles. The average blood lead value for these men in 1968 Was 20 Mg per 100 g of whole blood; and for the women in thesameyear was 17 Mg per 100 g .of whole blood. This data is presented because it suggests that there are no gross differences between the blood lead levels of persons living in remote areas of the world away from automobiles and those of an industrial pop ulation, most of whom live in cities and commute to work by car. These figures also suggest, to the somewhat limited extent that remote primitive tribes resemble our own an cestors, that- such blood lead levels have been present in man for long periods of time. Dr. Goldsmith then goes on to mention drinking water, and tobacco smoke as possible sources of lead. In the case of drinking water, this is an unimportant source in North America, and is rapidly becoming so in other parts of the world. In the case of tobacco smoke, I will have more to say about this as a source of lead later in the discussion In dis cussing ingested lead, Dr. Goldsmith points out that, lead taken in by mouth is largely excreted in the feces and in a topological sense has not entered the body; and in a similar fashion, lead which has entered the lung and has not yet been absorbed into the blood through the alveolar wall, can also be regarded as outside the body. The amount of lead that will be absorbed into the blood from that deposited or retained in the lung, is a function of the particle size, density, solubility, and concentration. Because of the difficulties of experimen tation, very little is known about the amount of lead aerosol retained in the lung under realistic conditions; and even less about the amount of lead absorbed from the lead so retained, since lead, like any other particle coming to rest in the lung, can be removed from the lung by phagocytosis or by ciliary action, or by a combination of the two. From a review of the literature, it appears that the quantity of lead deposited in the lung from the type of aerosol produced by the automobile is probably less than had been previously thought. The amount of lead deposited rises with increasing volume of air takenin with each breath and falls as the rate of breathing in creases. D.C.F. Muir and C.N. Davies, reporting in Arm. Occupa tional Hyg., V 10,161-174 (1967),found that during exercise, the fraction of deposition of 0.5 m diameter particles is about 10% of the inhaled concentration at all work loads. At slower hreathing frequencies, increased deposition is found in accord with the concept that the particles are slowly diffusing and sedimenting and that the chances of a particle encountering the wall of an airway increase with time. These workers found that the fractional deposition remained virtually constant and that the total weight of malarial deposited in the lung is directly proportional to the minute ventilation. The particle size having the minimal retention in the iung is of the order of 0.2 m mass median diameter; and this is also the approximate mass median diameter of the lead aerosol found in the atmosphere. At the lower respiratory rates associated with nonexercising subjects, the total deposition of particles in the 0.2 m mass median diameter size range varies with different experimental techniques, but ranges between 20 and 30% of the amount of aerosol inhaled. The higher total retention rates for lead fume in the paper by Nozaki, quoted by Dr. Goldsmith, may be due to factors: The use of carbon dioxide in the exhaled atr as a tracer for partitioning dead space in alveolar air as this technique has been shown to probably over-estimate the retention of aerosols. All of the work which has dealt with the retention and absorption of pnriculate lead aerosols lias heen conducted with lead sesquioxide or lead from industrial sources; and there Is reason to believe that the lead in the urban atmosphere might be less readily absorbed due to its particular mass median equivalent dia meter, which leads to minimal retention in the lung and its relatively poor solubility in water. In dealing with the health effects of lead, Dr. Goldsmith states that metabolic effects of lead exposure may be reflected in the blood and urine at blood and urine load levels that are considered to be within normal limits. This statement is natu rally disturbing because if it is true, it moans that we cannot place reliance on the blood and urine lead levels to guide us in assessing the health risk from exposure to lead. In the context of Dr, Goldsmith's paper the metabolic disturbance to which he is referring is the depression of delta-aminolevulinic acid dehydrase with the consequent blocking of the condensation of two molecules of delta-aminolevulinic acid to form porphobilinogen. This block in the synthetic pathway of hemoglobin leads to an increase of delta-aminolevulinic acid in the blood and subsequently a spill-over of this material into the urine. This process has been well studied in animals and the time course -of these events in both animals and man is fairly well understood. If the level of inorganic lead intake by the body is substantially raised above the normal level, first the urine and later the blood will reflect this increased intake by showing an increased concentration of lead, After this rise in blood ; ., > i : j \ , ( lead has occurred, and if it is sufficiently great, the level of delta-aminolevulinic dehydrase will be depressed and this In turn is followed by a rise in the ALA levels in the blood and urine. If now the lead intake is reduced to normal, the blood and urine values will return to their normal values at a rate which is dependent upon the degree and duration of the provious elevation. The enzymatic depression will take longer to return to normal and will lag behind the fall in the blood and urine lead values. If the lead levels have been elevated for a period of months or yearn, the ALA levels may remain ele } j ; ; ! j vated for several months to a year after the lead levels have fallen to normal. With this background, if we reexamine Dr. Goldsmith's statement we cau see that high ALA levels could be found in the presence of normal blood and urine lead values, if the person had previously had a fairly severe lead exposure. The confusion on this point has probably arisen because most of the studies of ALA levels have been earned out in popula- ' tions with an abnormal exposure to lead. This point is illustrated in Figure 1 which superimposes two sets of data, one from lead-exposed workers, and one from office workers with no occupational lead exposure. It can be seen that for the same range of urine lead values, the lead-exposed workers tend to have higher ALA values. A further point worth making about studies of the relationship of gradually increasing levelof lead intake to an index of metabolic derangement such as urinary and ALA concentrations, is that such relationships tend to be curvilinear, so that there is a range of lead intake which has ho biologically significant effect on the ALA level and then as the level of lead intake rises above this "no effect" ; ; ; ] ; j ; i ' Figure 1. Relationship of AtA to load in the Urine. TEH 0 4 7 0 2 9 5 720 Journal of the Air Pollution Control Association DUP050083113 V 1. . -4 I A.. i . .' ^ ' I. Figure 193 man exposed to inorganic lead regression: ALA on lead in the urine. ' ! > t. nrl;.. , j.-wfou, a rise in ALA concentration takes place at a rate '"`hi greater than the rate of increase of the lead intake. This Y.-uccpt of a level of lead intake belpw which no biologically ..a'tiificant effect occurs is open to some philosophical argu- : au.i i :;.enfs; but as a practical guide in regulating the use of food additives in controlling pollutants and in setting safe levels of iVmical exposures in industry, it has served us well. ran- Figure 2 shows the type of curve derived from measure |>r< - ments made on lead-exposed workers, with the virtually hori zontal portion of the curve covering the range of lead values '1`u.hi found in the normal population. A curve of a somewhat (i for' : different nature is shown in the paper by Dr. Goldsmith, which ell- relates estimated 24-hour air lead levels to blood lead levels of l.v.e groups of persons in different parts of North America, This Dr-, enrve may be a tme representation of the relationship between rtlM average* air lead concentration and blood lead level, but in the iur.f ` absence of evidence that the individual groups used in con- mv.' i structing tl^e regression line were properly investigated to see im-t , , whether group averages could, in fact, be used; judgment on u!:t- , the value of the Goldsmith Hcxtcr line must be deferred. To !:>- allow such group averages to be used to calculate a linear re- i gression line, individual regression lines should have been lit ted to each erf the groups of data points comprising the popu lation representing each subpopulation. These individual regression lines should then be subject ed to the following three , tests before a single regression line can be fitted: (1) the variance aboti t each of the regression lines must be similar; (2) if l the slopes of the regression lines must be the same, that is to rips ' say, they can be considered parallel; (3) the separate parallel like hues must be shown.to be segments of.one straight line. To Vil : perform these three tests, the individual data points are reCl" | quired. It is a much more powerful statistical technique to 4- use all of the individual data points at- one time rather than to j take group averages. This statistical argument is not to deny ? that there is a relationship between high levels of lead in the air and blood lead levels. Such a relationship has been demon strated and used for years in safeguarding the health of in dustrial populations. What seems more open to question is I the form of the relationship in persons exposed only to the | relatively low levels of lead encountered in the community air. 1 To further illustrate the difficulty of making general state- ' (nents about the relationship between the quantity of lead in- f haled and the amount absorbed, it has been generally assumed . - for some years that smoking cigarettes caused an elevation of blood lead levels. t In 1907, however, G. Lehnert (Intern. Arch. Gewerbepalkol. ') V/ Giwerbehijg'., 23,353-363) published a paper showing no dif- * fereiiCe in the blood lend levels of 110 .men between 20 and 22 ) Jiears of age living under identical environmental conditions 1 and eating similar food*. Seventy-one of the subjects were | smokers and 45 were nonsmokers. The average blood lead i levels for the nohsinokers was,16.3 //g of lead per 100 g of blood; % andforthcsmokers l6.4jugof lead pcrlOOgof blood. Since the in | September 1969 Volume 19, No. 9 average number of cigarettes smoked wasl7, tbiswould give an average Vtluc of 13,64 ag of lead inhaled .in the smoke; there fore an appreciable amount of lead was presented to the lungs in a very finely divided form, but this did not result in an in crease in the blood lead level. Being intrigued by these re sults, wo investigated the smoking habits of our industrial population referred to earlier and attempted to correlate the smoking habits with the blood lead levels. The lead level of smokers was 19,71 pg of lead per 100 g of blood and the lead level of nonsmokers was 19.78. Thus we have confirmed that in our series there is no difference between smokers and nonsmokers in blood lead level and that this holds whether a par son smokes four packs of cigarettes per day or none at all. In a similar fashion, pipe and cigar smoking was found to be with out effect on the blood lead level. These results run eouuter to those found in the Three Cities Survey and no immediate explanation is apparent; but if confirmed, it suggests that amounts of inhaled lead originating from cigarettes, up to about 64 ng per day, for the four pack per day smoker, have no effect on the blood lead level. This result is in contrast with the apparent effect on the blood lead level of living near a freeway in Los Angeles, with an average lead concentration of 2.5 fig per m3. Such a person might breathe between 15 and 20 m3 of air per day, giving a daily intake of between 37.5 and 50 fig of lead. This digression into the effects of smoking is intended to underline the apparent importance of the form and composition of the lead aerosol in determining absorption. Dr. Goldsmith has demonstrated that an aqueous lead acetate aerosol is easily absorbed, as one would predict, but we still know far less than we need to know about the retention and absorption of finely-divided solids in the lungs. Dr, Goldsmith's proposal that air quality criteria should include a criterion based on ALA excretion, if and when it can be shown to be related to community air pollution exposure, sounds to the author suspiciously like a man who has made up his mind that the present level of lead in the community air is harmful; and that if the ALA levels of the population are not affected by it, then ALA levels as a criterion should be re jected and the search continued for some index that is influ enced by the present level of lead in the air. I hope I am do ing Dr. Goldsmith a disservice in drawing this conclusion and that he is more open-minded than my interpretation would suggest. With regard to the suggestion that increased storage by itself be a criterion; this seems illogical, since body lead levels appear in general to follow the environmental lead levels in a passive manner and since lead has presumably always been present in the diet, a range of blood lead values must therefore be considered normal. If one accepts this premise, then an increase of storage may be perfectly acceptable if it occurs within the normal range; but at some point above this range an effect on health will occur. It is the level of this transition zone between safe and unsafe levels which causes so much debate. The debate drags on because we lack vital data on the long-term effects of various tissue levels of lead or dis turbances of porphyrin metabolism. Here, the epidemiol ogists who numbered Dr. Goldsmith amongst their number must help by studying populations with moderately elevated ALA levels and comparing the health of such groups with those without raised ALA levels. If there is no difference in the health of the two groups, I can see no reason to use a slightly elevated ALA level as a criterion for setting an air quality standard. Of course, the problem I have posed, is the measurement of health, and this is not really such a semantic slough of despond that some would have us believe; and in fact, is the daily bread and butter of the epidemiologist. What is important here is that we keep our eyes firmly fixed gu the functioning of the whole man rather than on individual enzyme systems. In conclusion, since I must reject the premise upon which Dr. Goldsmith bases his air quality standard, I must also re ject the number he offers. 721 DUP050083114 TEH 0 4 7 0 2 9 6