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(1981) Exposure of children to heavy metals from smelters: epidemiology and toxic consequences. Environmental Research 25: 204-224. Landrigan, P.M.; Baker, E.L., Jr.; Feldman, R.G.; Cox, D.H.; Eden, K.V.; Orenstein, W.A.; Mather, J.A.; Yankel, A.J.; von Lindern, I.H. (1976) Increased lead absorption with anemia and slowed nerve conduction in children near a lead smelter. 0. Pediatr, (St. Louis) 89: 904-910. Landrigan, P.J.; Gehlbach, S.H.; Rosenblum, B.F.; Shoults, J.M.; Candelaria, R.M.; Barthel, W.F.; Liddle, J.A.; Smrek, A.L.; Staehling, N.W.; Sanders, J.F. (1975) Epidemic lead absorption near an ore smelter: the role of particulate lead. N. Engl. 0. Med. 292: 123-129. Lane, S.D.; Martin, E.S.; Garrod, J.F, (1978) Lead toxicity effects on indole-3-ylacetic acid-induced cell elongation. Planta 144: 79-84. Lau, W.M.; Wong, H.M. (1982) An ecological survey of lead contents in roadside dusts and soils in Hong Kong. Environ. Res. 28: 39-54. Lauwerys, R.; Buchet, J-P.; Roels, H.A.; Materne, D. (1974) Relationship between urinary 6-aminolevulinic acid excretion and the Inhibition of red cell 6-ami no!evulinate dehydratase by lead. Clin. Toxicol. 7: 383-388. Lawrence, D.A. (1981) Heavy metal modulation of lymphocyte activities: I* in vitro effects of heavy metals on primary humoral immune responses, ioxicol. Appl. Pharmacol. 57: 439-451. TEH 0413771 DUP050454693 28 Laxen, D.P.H.; Harrison, R.M, (1977) The highway as a source of water pollution: an appraisal with the heavy metal lead. Water Res. 11: 1-11. Lepow, M.L.; Bruckman, L.; Gillette, M.; Markowitz, S,; Robino, R.; Kapish, J. (1975) Investigations into sources of lead in the environment of urban children. Environ. Res. 10: 415-426. Lepow, M.L.; Bruckman, L,, Rubino, R.A., Markowitz, S., Gillette, M.; Kapish, J. (1974) Role of airborne lead in increased body burden of lead in Hartford children. Env. Health Perspect. 7: 99-102. Levander, O.A.; Welsh, S.O.; Morris, V.C. (1980) Erythrocyte deformability as affected by vitamin E deficiency and lead toxicity. Ann. N.Y, Acad. Sci. 355: 227-239. j -'* Levin, E.D.; Bowman, R.E. (1983) The effect of pre- or postnatal lead exposure on Hamilton search task in monkeys. Neuro. Toxicol, Teratol. 5: 391-394. Liang, C.N.; Tabatabai, M.A. (1978) Effects of trace elements on nitrification in soils. ^J. Environ. Qua!. 7: 291-293. tills, R. (1981) Long-term occupational lead exposure, chronic nephropathy, and renal cancer: a case report. Am. 0. Med. 2: 293-297. Lilis, R.; Fischbein, A.; Eisinger, <J.; Blumberg, W.E.; Diamond, S.; . Anderson, H.A.; Rom, W.; Rice, C.; Sarkozi, L.; Kon, S.; Selikoff, I.J. (1977) Prevalence of lead disease among secondary lead smelter workers and biological indicators of lead exposure. Environ. Res. 14: 255-285. Lilis, R.; Gavrilescu, N.; Nestorescu, B.; Dumitriu, C.; Roventa, A. (1968) Nephropathy in chronic lead poisoning. 8r. J. Ind. Med. 25: 196-202. Lindberg, S.E.; Harriss, R.C. (1981) The role of atmospheric deposition in an eastern U.S. deciduous forest. Water Air Soil Pollut. 16: 13-31, Lin-Fu, J.S. (1972) Undue absorption of lead among children - a new look at an old problem. N. Engl. 0. Med. 286: 702-710, Lioy, R.J.; Mellon, R.P.; Kneip, T.J. (1980) Long-term trends in total suspended particulates, vanadium, manganese, and lead at near street level and elevated sites in New York City. J. Air Pollut. Control Assoc. 30: 153-156. Litman, Q.A.; Correia, M.A. (1983) L-tryptophan: a common denominator of biochemical and neurological events of acute hepatic porphyrias? Science (Washington, D.C.) 222: 1031-1033, Lucchi, l.; Memo, M.; Airaghi, M.L.; Spano, P.F.; Trabucchi, M. (1981) Chronic lead treatment induces in rat a specific and differential effect on dopamine receptors in different brain areas. Brain Res. 213: 397-404. TEH 0413772 DUP050454694 Madden, N.A., (1980). Environmental influrneces on mouthing in children with lead intoxication. J. Ped. Psych. 5: 207. Mahaffey, K.R.; Annest, J.L. (1985). Association of blood lead level, handto-mouth activity and pica among young children. 69th Annual Meeting of the Federation of American Societies for Experimental Biology. Anaheim, CA; USA April 21-26, 1985. Fed. Proc. 44: 752. Manatfey, K.R.; Annest, O.L.; Roberts, 0.; Murphy, R.S. (1982) National estimates of blood lead levels: United States, 1976-1980: association with selected demographic and socio-economic factors. N. Engl. J. Med. . 307: 573-579. Mahaffey, K.R.; Michael son, I.A. (1980) The interaction between lead and nutrition, in: Needleman, H.L., ea. Low level lead exposure: the clini cal implications of current research. New York, NY: Raven Press; pp. 159-200. Mahaffey, K.R.; Rosen, J.F.; Chesney, R.W.; Peeler, J.T.; Smith, C.M.; UeLuca, H.F. (1982) Association between age, blood lead concentration, and serum 1,25-dihydroxycholecalciferol levels in children. Am. J. Clin. Nutr. 35: 1327-1331. Mahaffey-Six, K.; Goyer, R.A. (1970) Experimental enhancement of lead toxicity by low dietary calcium. J. Lab. Clin. Med. 76: 933-942, Mahaffey-Six, K.; Goyer, R.A. (1972) The influence of iron deficiency on tissue content and toxicity of ingested lead in the rat. J. Lab. Clin. Med. 79: 128-136. Maisin, U.R.; Oade, O.M.; Lambiet-Collier, M. (1975) Progress report on morphological studies of the toxic effects of lead on the reproductive organs and embryos. Economic Community and Europe; Contract no.' U80-74-/; Env. B. Brussels, Belgium; ECE. Maker, H.S.; Lehrer, G.M.; Silides, D.J. (1975) The effect of lead on mouse brain development. Environ. Res. 10: 76-91. Mallon, R.P. (1983) A metabolic model of lead kinetics based upon measured organ Durdens during chronic exposure experiments with infant and juvenile baboons. Doctoral Dissertation, New York University. Manton, W.I. (1977) Sources of lead in blood: identification by stable isotopes. Arch. Environ. Health 32: 149-159. Manton, W.I.; Cook, J.D. (1984) High accuracy (stable isotope dilution) measurements of lead in serum and cerebrospinal fluid. Brit. J. Ind. Med. 41: 313-319. Marcus, A.H. (1984) Testing alternative nonlinear kinetic models in compartmental analysis. In: Eisenfield, J.; Delisi, C., eds. Proceedings, second IMACS international symposium in biomedical systems modelling, Amsterdam, The Netherlands: Elsevier Science, New York, pp. 259-268. TEH 0413773 DUP050454695 30 Marcus, A.H. (1985) Multicompartment kinetic models for lead: part III, lead in blood plasma and erythrocytes. Environ. Res.: 36: 473-489. Martin, M.H.; Coughtrey, P.J. (1981) Impact of metals on ecosystem function and productivity. In: Lepp, N.W., ed. Effect of heavy metal pollution on plants. Vol. 2: Metals in the environment. Barking, United Kingdom: Applied Science Publishers, Ltd.; pp. 119-158. (Mellanby, K., ed. Pollution monitoring series). Martonen, T.B. (1983) Measurement of particle dose distribution in a model of human larynx and tracheobronchial tree. J. Aerosol Sci. 14: 11-22. Maxwell, O.D.; Meyer, U.A. (1976) Effect of lead on hepatic 6-aminolavulinic acid synthetase activity in the rat: a model for drug sensitivity in intermittent acute porphyria. Eur. J. Clin. Invest. 6: 373-379. McBride, W.G.; Black, B.P.; English, B.J. (1982) 81ood lead levels and behaviour of 400 preschool children. Med. J. Aust. 2: 26-29. McCauley, P.T.; Bull, R.J.; lutkenhoff, S.D. (1979) Association of altera tions In energy metabolism with lead-induced delays in rat cerebral cortical development. Neuropharmacology 18: 93-101. McCauley, P.T.; Bull, R.J.; Tonti, A.P.; Lutkenhoff, S.D.; Meister, M.V.; Doerger, J.U.; Stober, J.A. (1982), The effect of prenatal and postnatal lead exposure on neonatal synaptoge*nesis in rat cerebal cortex. 0. Toxicol. Environ. Health 10: 639-651. McElroy, F.F. (1984). Letter to Leonard Bruckman, Director, Air Compliance, Department of Environmental Protection, State of Connecticut concerning Connecticut's request for an equivalent method determination for low-volume lead sampler, May 30, 1984. McKeague, J.A.; Wolynetz, M.S. (1980) Background levels of minor elements in some Canadian soils. Geoderma 24: 299-307. McMichael, A.J.; Johnson, H.M. (1982) Long-term mortality profile of heavily-exposed lead smelter workers. J. Occup. Med, 24: 375-378. McNurney, J.M.; Larimore, R.W.; Wetzel, M.J. (1977) Distribution of lead in the sediments and fauna of a small midwestern stream. In: Drucker, H.; Wildung, R.E., eds. Biological implications of metals In the environment. Proceedings of the fifteenth annual Hanford life sciences symposium; September-Gctober 1975; Richland, WA. Energy Research and Development Administration, Technical Information Center. Available from: NTIS, Springfield, VA; C0NF-750929. Melgaard, 8.; Clausen, J.; Rastogi, S.C. (1976) Electromyographic changes in automechanics with increased heavy metal levels. Acta. Neurol. Scand. 54: 227-240. Mellins, R.B.; Jenkins, C.D. (1955) Epidemiological and psychological study of lead poisoning in children. J. Am. Med. Assoc. 158: 15-20. TEH 0413774 DUP050454696 D-42 1982b; Schlipkoter and Winneke, 1980; Fox et al., 1977, 1982; with embryonic nutrition through competition with calcium, iron, and zinc McCauley et al., 1982; Barrett and Livesy, 1985) Pregnant women who lived in homes with excessive drinking water lead concentrations (>800 ppm) bore a significantly higher proportion of .retarded infants (Beattie et al., 1975). Children of women who had worked and lived near a smelter during pregnancy had lower birthweights and an increased frequency of single and multiple malformations although the cause is unclear given the possible exposures both of the mothers and presumably, the fathers, to high concentrations of arsenic, mercury, cadmium, sulfur dioxide, as well as lead (Nordstrom et al., 1978; 1979a,b). An increased incidence in the overall number of minor congenital anomalies, such as benign tumors and cysts and minor skin defects, was reported in newborn children with mildly elevated umbilical cord lead levels (> 6.3 yg/dl) after controlling for other covariates, although no single anatomic defect was individually associated with lead (Needleman et al., 1984). This suggested to the authors that lead may interact with other teratogenic risk factors to enhance the possibility of an abnormal outcome. No association was found between cord PbB levels and increases in major congenital anomalies. Further investigation of lead's possible interactions with other teratogens at low levels is needed before definitive conclusions can be made. More subtle effects on the fetus and newborn, such as inhibited heme synthesis, may also be important consequences of maternal lead exposure below 30 pg/dl and transplacental transfer (Hubermont et al., 1976; Hayashi, 1983a,b; Gerber and Maes, 1978). Several mechanisms can explain lead's teratogenic activity: a) disturbance of DNA synthesis and cell proliferation; (Choie and Richter, 1974a; Sirover TEH 0413720 DUP050454697 0-43 and Loeb, 1976); b) chromosomal aberrations; (CD, Table 12-20); c) interference (Mahaffey and Michaelson, 1980); and d) interference with embryonic energy supply by depressing mitochondrial function and cytochrome synthesis (Holtzman and Shen Hsu, 1976). Lead also affects the male gamete. Industrial exposure of men resulting in PbB levels possibly as low as 40-50 pg/dl resulted in abnormal sperm number and vigor (Lancrajan et al., 1975; Wildt et al., 1983). Sperm abnormalities, reduced fertility, and altered testicular function have also been observed among male mice exposed to low doses of lead (Hilderbrand' et al., 1973; Maker et al., 1975; Wryobeck and Bruce, 1978; Donovan et al., 1980). Such changes may be related to observations of compromised viability of progeny to mice exposed to lead before conception (Stowe and Goyer, 1971). o Although the data base is limited, the available studies suggest that low level exposure of mothers and fathers to lead might induce post-natal developmental delays and increase the risk of reproductive abnormalities. OSHA reviewed the available literature in 1978 and concluded that men and women planning to have children should maintain PbB levels at or below 30 pg/dl (OSHA, 1978). Defining a PbB at which effects on other aspects of reproductive function (e.g., loss of vigor, erectile dysfunction) would begin to be of concern must await further research. 6, Possible Genotoxicity/Carcinogenicity At high concentrations (>500 ppm), dietary lead acetate induced renal tumors in experimental animals (Azar et al., 1973; see CD, Figure 12.5). A dietary lead acetate level of 500 ppm produced a PbB of 80 pg/dl in dogs within 2 years; defining a corresponding exposure level in humans is difficult to determine, however. TEH 0413721 DUP050454698 D-44 Since lead is capable of transforming cells directly in culture (Dipaolo et al., 1978; Casto et al., 1979) and affecting DNA-to-DNA and DNA-to-RNA transcription (Sirover and Loeb, 1976; Robinson et al., 1984), lead may serve as an initiator of carcinogenic activity. Lead's ability to induce chromosomal aberrations (CD, Table 12-20) is also indicative of its ability to initiate carcinogenic activity. In addition, lead may be a promoter of carcinogenesis, as indicated by its ability to increase DNA, RNA, and protein synthesis (Choie and Richter, 1974 a,b) and to enhance the development of renal tumors in rats previously treated with a known carcinogenic initiator (Hiasu et al., 1983). Lead's sequestration in the form of "inclusion bodies" in kidney cell nuclei may be linked to its carcinogenic effects (CD, p. 12-225). * Epidemiological studies of lead-exposed workers and children suggest that lead may induce chromosomal aberrations that may be associated with certain forms of cancer (Grandjean et al., 1983; Dalpra et al., 1983). Little can be reliably concluded from the conflicting occupational findings on kidney tumor incidence and excess cancer mortality (Cooper and Gaffey, 1975; Kang et al., 1980; Baker et al., 1980; Lilis, 1981; Cooper, 1981,1984; McMichael and Johnson, 1982; Sheffet et al., 1982; Selevan et al., 1984), although the significant elevations in respiratory and digestive tract cancer in workers exposed to lead and other agents warrant concern (CD, p. 12-225). These latter findings should not be over-interpreted given differences in age distributions among the populations studied and inadequate controls for factors such as smoking, diet, ethnicity, and geographical location. Furthermore, these studies provide no specific information on the long-term lead exposure levels or the lead compounds to which workers were exposed. Lead emissions from other smelters and refineries include lead sulfate and oxides of lead while windblown dust from stored TEH 0413722 DUP050454699 D-45 ore concentrate and contaminated soil is predominantly lead sulfide (dennett et al., 1977). Exposure to even relatively insoluble lead compounds (e.g. lead sulfide) however, could account for the observed gastrointestinal and respiratory cancers (CO, p. 12-206). The criteria document concludes that: "Since lead acetate can produce renal tumors in some experimental animals, it seems reasonable to conclude that at least that particular lead compound should be regarded and treated as a human carcinogen (as per recommendations of the International Agency for Research on Carcinogenicity). However, this statement is qualified by noting that lead has been seen to increase tumori- genesis rates in animals only at relatively high concentrations, and therefore does not seem a potent carcinogen. In vitro studies further support the genotoxic and carcinogenic role of lead, but also indicate that lead is not potent in these systems1' (CO, p. 12-268). *' It is important to note that the IARC recommendations were published in 1980 and do not necessarily reflect findings from several recent experimental and occupational studies cited ijn the criteria document that continue to'focus attention on lead acetate and other inorganic leaTd compounds as possible carcinogens. It appears, therefore, that there is some need for caution and further research on the carcinogenicity of lead compounds that are present in the atmosphere and other exposure media. 7. Effects on the Immune System Lead interferes with host immune defense mechanisms as indicated by increased susceptibility to infectious agents (CD, Table 12-22), endotoxins (Cook et al., 1974), and increased incidence of tumors (CD, Section 12.8.2.2), in lead-exposed animals. There is suggestive evidence that human resistance to infection may be lowered by elevated lead exposure (Sachs, 1978; Ewers et al., 1982), although no dose-response information is available. Lead- induced immunosuppression, possibly through direct interference with macrophage function (Lawrence, 1981) occurs at low-level exposures in animals (PbB levels of TEH 0413723 DUP050454700 D-46 20-40 pg/dl) (CD. p. 12-268). Although these effects do not induce overt toxicity, they, nevertheless, may be detrimental to health and lead's immunosuppressive capabilty "should be carefully considered" (CD, p. 12-241). 8. Effects on the Hepatic System The metabolic breakdown by the liver of some pharmacologically active substances {e.g., drugs, hormones, environmental toxins) depends on the availability of the hemoprotein, cytochrome p-450 and consequently, the synthesis of heme (Remmer et al., 1966). Lead exposure impairs the detoxification capabilities of experimental animals, while drug metabolism and liver function in children appear to be affected at fairly high exposures (>40 pg/dl) (Alvares et al., 1975; Saenger et al., 1984). As discussed in Appendix D.l(b), in the absence of conclusive data it must be assumed that any indication of significantly altered heme biosynthesis (e.g., elevated EP) may also indicate * a possible inhibition of liver detoxification function. 9. Effects on the Gastrointestinal System Typical gastrointestinal signs and symptoms caused by lead intoxication include constipation or diarrhea, abdominal pain, nausea, indigestion, and anorexia. Mild symptoms have been associated with PbB levels in the 50 to 70 pg/dl range, and as low as 30 pg/dl (Haenninen et al., 1979; Fischbein et al., 1980), There is insufficient information, however, to establish a clear dose effect relationship for the general population at ambient exposure levels (CD, p. 12-247). 10. Effects on the Endocrine System Relatively high level lead exposures affect various endocrine processes (e.g., impaired thyroid function) (Sandstead and Galloway, 1967; Sandstead et al., 1969, 1970). Apart from the previously discussed studies showing alterations in vitamin D hormone metabolism that is secondary to interference TEH 0413724 DUP050454701 0-47 with heme synthesis, there have been few neuroendocrine studies in humans or animals at low levels of lead. A recent analysis of the NHANES II data (Angle et al., 1985) shows a significant negative correlation of stature With childhood blood lead. Sex, race, dietary protein and calories, blood lead and hematocrit accounted for 9U of the variance in height of 2695 children 6 months through 7 years. The correlation was not improved by the inclusion of the variables of income; urbanization; dietary carbohydrate, fat calcium, potassium, phosphorus. Vitamin A,-Vitamin C, niacin, thiamine and riboflavin; serum albumin, copper iron and zinc. Although lead may be a surrogate for multiple environmental factors not defined by the NHANES data, the authors propose consideration of endocrine toxicity such as that mediated by inhibition of calcium activated receptors for TRH or of hypothalamic dopaminergic and a adrenergic receptors. TEH 0413725 DUP050454702 APPENDIX E. THE LONG-TERM ACCUMULATION OF LEAD IN SOIL IN RURAL AREAS This appendix presents a simple linear model to predict the long term accumulation of lead in soil in rural areas. This model was developed as a tool to assess the potential long-term impact of lead in rural terrestrial ecosystems based on the predicted increases in soil lead concentration. Dry deposition rates that are associated with various air lead levels are the bases for estimating the long-term increase in soil lead concentrations. The contribution of wet deposition is included to approximate total lead deposition. Model predictions are based on a fixed lead particle size distribution and dry deposition velocity that are representative of rural areas only. Model outputs apply to typical rural terrestrial ecosystems with low natural soil lead levels, but do. not represent rural areas that are impacted by point source emissions of lead or possibly certain rural areas that may experience unusually high deposition rates of lead, e.g., rural mountain areas at high elevations. Model predictions do not apply to urban or roadway areas where soil lead concentrations may already exceed levels of concern. 1. Model Structure/Inputs A simple linear equation is used to estimate total soil lead concen tration: Soil Lead Concentration (pg Pb/g soil) Initial Soil Lead Concentration (16 pg Pb/g soil) Dry deposition flux (pg Pb/m2day) x (Volume soil/surface area)"1 (m2/cm3) x Soil density"* Days (cm3/1.5 g soil) x Year x Years. This equation is based on the following assumptions: 1) leaching of lead is negligible (CD, p. 8-13; Tyler, 1978); 2) a steady TEH 0413726 DU P050454703 E-2 state relationship exists between the resuspension and deposition of lead particles so that there is no net loss due to resuspension; 3) mechanisms that remove lead from vegetation before it reaches the soil are insignifi cant, e.g., no net loss due to grazing or harvesting; and 4) any lead taken up by plant roots or accumulated on or in leaves is recycled to the soil. Although these simplifying assumptions are reasonably appropriate for long-term predictions concerning large-scale natural ecosystems, they introduce uncertainty for model predictions. Dry deposition flux (pg Pb/m2*day) is a function of air lead concen tration (pg Pb/m3) x dry deposition velocity {cm/sec). A range of dry deposition velocities that are representative of lead particles are used to compute the dry deposition flux under alternative air lead level's. For one scenario, a particle size distribution weighted dry deposition velocity (Vq ) is used to compute the dry deposition flux of lead. This Vg of 0.56 cm/sec is weighted by the mass of lead particles in each particle size range based on an average particle size distribution of lead in rural areas (Milford and Davidson, 1985), and predicted Vg from the Davidson et al. (1982) model (Figure -1). The lead particle size distribution data are an average for 6 rural/remote sites for the time period 1973-1980. The particle size aerodynamic diameter of this average distribution ranged between 0.05-40 pm, with approximately 63S of the mass of lead particles in the submicron fraction. Each fraction of airborne lead mass in a size interval was assigned a dry deposition velocity based on the Davidson et al. model (Table E-l). In this way, a particle size distribution weighted Vg was computed. The Davidson et al. TEH 0413727 DUP050454704 amnuxsegt u <si V* S3 u c 4! eC VI <C3. U, ca awMawawugwBi E-3 swswjsssjj Pirtids Aerodynamic Diameter, pm icura E-1. Predicted particle dry deposition velocity for wild grass canopies. Wind profile and canooy characterization data for 5 wild crass canopies: surface roughness height 4-14 cm, wind spaed 2.4-5.3 m/sac, friction velocity 32-S4"cm/sac, maximum canopy height 30-100 cm. Source: Davidson at al., 1332. Tinia E-l. Estimation of ?arcic!a Size Distribution iieijntao Dry Denosition Velocity ?s.rtisl* sirs 1/ttsr**14, iorsaynoitne rti asterir 0.05 - 3.1 ua 0.1 - 3 a -st 3.5 1.3 'fit 1J - 1.5 4* 1.5 - 4 J rat - SJ '3* 5.3 - 3.2 -jt S.Z - 7.3 isi TJ - 3.1 tsi 9.1 - 10 ta ia - u.2 ta T*4 - !3 i TflO 1-S 0.3 o.m 302 ac 3.43 3.14 3.32 a.37 0.39 0.3*1 0.132 0.45 Fres!s s1 atriam* "ass in sirs frrtar-Ml 122 353 153 35 133 S3 0.33 23 23 3.33 2.SS 4t flry risasiilsn vtiaet*y. Vc: a/*K 0.11 3.43 0.17 0.22 8.S15 a.3 1.035 1.25 1.55 1.3 2-7 5<2S ?rs1sls sir* rtlst.-r button wugbtaa V' aa/tes 0.53 *arstci sirs aita fna .if Tfort wit Jlviijqn (12351. 11 i lag a, log A. sue - log a- am, wiopra a1*, tsaux ana itrtn arma. rssBeerlvaiy. ts naainua ana aintsua jareiei* Mrs (iori asrsaynaote itasosargf ra jsrelef* sir* intarvsi. Javtsan at at. (13321. tyaigntaa Sy nass In raeit gireiel* sites rang*. Y (tt.miQ.13) * (0.03HQ,ttSl * (a.lT!(Q.lS) * (8JBH0JS) *(0.5131(0.131 * (0.31(0.331 * a.aasKa,ao3) *u j b u 8j b ) * ii.s3K0.32i * (UKa-oat) * (Z-.'Ka-izs) (5-251(0.041 0.53 <svtoe TEH 0413728 DUP050454705 E-4 dry deposition model predicts dry deposition velocity as a function of particle size, windspeed and surface characteristics of wild grass canopies. Because this model predicts Vp as a function of the effective depositional area, i.e., detailed measurements of vegetative structure and surface area are input into the model to approximate the canopy collection efficiency for particles, it is an appropriate model to estimate dry deposition flux in rural areas. Soil lead concentrations predicted for the weighted Vp of 0.56 cm/sec are presented in Table E-2. The Vp of 0.2 cm/sec that is used to compute the dry deposition flux of lead represents calculations of particle dry deposition velocity based on field data of lead deposition onto artificial surfaces (Davidson et a!., 1985; Elias and Davidson, 1980; Davidson, 1977). Soil lead concentrations predicted for this Vp are presented in Table E-3. For both dry deposition velocities, the model predicts soil lead concentrations for three scenarios of lead immobilization, i.e., within the upper 2-5 cm of an undisturbed soil profile (CD, p..7-28), and for a cultivated soil profile (lead uniformly mixed to a plow depth of 18 cm; Ewing and Pearson, 1974). Soil lead concentrations are predicted for rural areas for the 100 year period following the introduction of lead additives to gasoline. 2, Model Results Tables E-2 and E-3 describe soil lead concentrations (pg Pb/g soil) predicted for rural areas for the 100 year period following the introduction of lead additives to gasoline. These predictions are made for two dry deposition velocities (0.56 and 0.2 cm/sec), and for a range of air lead levels (0.05-1.5 pg Pb/m^). The predicted total soil lead concentrations TEH 0413729 DUP050454706 E-5 TABLE E-2. ESTIMATION OF L0N6-TERK ACCUMULATION OF LEAO IN SOIL IK RURAL AREAS BASED ON DRY DEPOSITION FLUX UNDER DIFFERENT AIR LEAO LEVELS Dry Deposition Velocity, Vg* cm/sec Air Lead Level uq Pb/m3 0.059 0.;*' 0.2S Dry Deposition Flux3 yq Pb/m2.dav 25 50 120 5 years 20 d I7e 16f 20 d 17* 16' 25d 20 17' 10 years 20d 17e 16' 20 d 18 17' 30 20 13' Soil Lead Concentration 'J9 Pb/g soil 25 years 50 years 75 vears 25 30 40 19 22* 25 e 17' 18' 19' 3Q 4$d SO 22 28 34e iar 19' 20' 50 90 130 30 45 50e 20' 25' 30' 100 vears 45 28 19' 75 40* 25' ISO 75* 30' 0.56 cn/sac 0.5 240 30 45d 30 ISO 240 310 2Qe 30 45 75 105 135 ia' isf 25' 30' 40' 50' 0.75 1.0 1.25 380 . 480 500 40d 50 130 240 340 450 25* 35* SO* 105 ISO 190 iaf 20' 30' 40' 55' 65' 45d 75 150 310 450 600 30 4Qe 75 135 190 250e 20f 25' 30' 50' 85' 30' 50d 90 200 330 550 750 30s 45 soe ISO 235 310 20f 25' 35' 15' 75' 95' 1.5 730 50d 105 ' 240 460d 880 900 35 5Qe IQ5e 195* 285 3?oe 2Qf 25' 40' 55' 90' US' Particle size distribution weighted v0 (weighted by mass In each particle size range), based on average particle size distribution of lead in rural areas (Milford and Oavidson, 1985) and predicted Yg from Davidson et al. (1982). hflux ug Pb/n.day * Vg cra/sac x air concentration yg Pb/m3, sSee text; years are the number of years following the introduction of lead additives to gasoline, Lead immobilized within upper 2 cm of undisturbed soil profile, eLead immobilized within upper 5 cm of undisturbed soil profile. fLead immobilized within upper 18 an of cultivated soil profile. gRepresents lower bound of range of geometric mean quarterly lead concentrations at nonurban stations 1974-80 (CO, Table 7A-2). hRegresent5 yjjpe^ bound of range of geometric mean quarterly lead concentrations at nonurban stations 1974-80 TEH 0413730 DUP050454707 TA8LE E-3. ESTIMATION OF LONG-TERM ACCUMULATION OF LEAD IN SOU. IN RURAL AREAS 3ASEO ON 0Hr DEPOSITION FLUX UNOER DIFFERENT AIR LEAD LEVELS Ory OeDosition Velocity, Vg as/ sec Air Lead Level uo Pb/m* 0.059 0.1b 0.25 0.2 cm/sec 0.5 0.75 1,0 1.25 1.5 Ory Deposition Flux' uo Pb/m4.dav 10 20 45 90 130 170 220 260 5 years I7d lo 16f 174 17* ISf 2Qd 17* 1ST 20d I8e 1?T 24d 19 !7f 30 20* 171" 30d 20 iaf 30d 20 I8T 10 years 17d 17 ISf 13d 17 1ST 20d ia 17f 25d 20 17f 32d 22 iaf 40d 25 1ST 4Sd 30 I9f Sod 30e 20T Soil Lead ConeantrationC U9 Pb/g soil 25 years 50 years 75 years 19d 22 25 17 iae 20 1ST 17f 17T 22 28 35 18 21* 23e 17f 17T UT aod 45 SO 22 27* 32* 18T 19T 21T 45 7Qd 100 2Se 40e 50* 19f 22T 2Sf 55d 96 135 30 50 65 20T 25T 3QT 70 120 17Q 35 SO* 80 22f 30T 3ST 85 150 220 45 70e 100 23f 30f 4flf 95 175 250 50e 80e UOe 2ST 35* 40T 100 years 28 2ie 17T 40 26 19f 70 3ae 22f 125 60 28f 175 SO 35* 225 1008 4QT 280 123 45f 330 145 50 T ^Calculated dry deposition velocity from field studies that measured lead deposition onto artificial surfaces. FTux us Pb/n^.day * VD cm/see x air concentration us Pb/m3. tSee text; years are the number of years following the Introduction of lead additives to .gasoline. Lead Immobilized within upper 2 cm of undisturbed soil profile. Lead Immobilized within upper S cm of undisturbed soil profile. fLead Immobilized within upper 18 ca of cultivatedsoil profile. ^Represents lower bound of range of geometric mean quarterly lead concentrations at nonurban stations 1974-80 (CD, Table 7A-2). ^Represents upper bound of range of geometric mean quarterly lead concentrations at nonurban stations 1974-30 (CD, Table 7A-2). TEH 0413731 DUP050454708 E-7 in Tables E-2 and E-3 represent the contribution of dry deposition only. Although the relative importance of dry and wet deposition varies both spatially and temporally, on a global and long-term, e.g., annual as contrasted with daily basis, dry deposition has been estimated to account for approximately 50% of total lead deposition (CD, p. 6-27). This estimate is consistent with the limited data available of the relative contri bution of wet and dry deposition of lead in rural areas (NAS, 1980; Lindberg and Harriss, 1981). For model predictions that are based solely on dry deposition flux, the estimated net increase in soil lead concentration above a natural soil lead level of 16 pg Pb/g soil is, therefore, doubled to approximate the contribution of wet deposition to the total atmospheric deposition of lead. A doubling of the estimate of dry deposition flux to account for total lead deposition requires the simplifying assumption that a steady state exists between the addition and removal of particulate lead from the atmosphere. It is also assumed that the atmospheric residence time of lead is long relative to the duration of rain events. These seem to be reasonable assumptions given that a dynamic model best represents reality and lead aerosols have atmospheric residence times of approximately 1-2 weeks (NAS, 1980; Nriagu, 1978; Shirahata et al., 1980). Although the sources of lead in rural areas are not entirely certain, the historical accumulation of anthropogenic lead in soil in these areas, remote from point sources. Is attributed primarily to the long-range transport of fine lead particles that originate from mobile sources. Fine lead particles (aerodynamic diameter < 2 pm) have relatively long atmospheric residence times and have the potential for long-range transport (CD, p. 5-10, 6-16). Point source emissions of lead tend to have a more TEH 0413732 DUP050454709 E-8 localized impact on air and soil lead concentrations with background levels typically reached within 5-10 km (Landrigan and 8aker, 1981; Jennett et al., 1977; CD, p. 8-40; Battye et al., 1985). Given that rural areas may be impacted by local sources of lead emissions, these model predictions of the long-term accumulation of lead in soil best apply to rural areas not within 10 km of point sources. Lead-alkyls were first added to gasoline in the 1920*s (CD, p. 5-1). The plausibility of the estimates of the long-term accumulation of lead (Tables E-2 and E-3) is, therefore, evaluated by comparing current field measurements of soil lead concentrations in rural areas to model predictions at 50-75 years into the simulation, i.e., time period following the introduc tion of lead additives to gasoline. Current soil lead concentrations in rural-areas are estimated to range from 5-50 pg Pb/g soil (NAS, 1980; CO, p. 7-31; Nriagu, 1978; Getz et al., 1977; Jackson and Watson, 1977; Palmer and Kucera, 1980). At air lead levels that are most representative of rural areas in theU.S. (0.05-0.1 pg/m^; CD, Table 7A-2, 7A-3), and with the immobilization of lead in the upper 5 cm of the soil profile, model predictions of the long-term accumulation of lead in rural areas (Tables E-2 and E-3) appear plausible as order of magnitude estimates. For example, under an air lead level of 0.05 pg/n>3 and with a dry deposition velocity of 0.56 cm/sec, the model predicts an increase in soil lead concentration (associated with dry deposition flux) from a background level of 16 pg Pb/g soil to 22-25 pg Pb/g soil at 50-75 years into the simulation (Table E-2). For the same scenario, under an air lead level of 0.1 pg/m^ the model predicts a soil lead concentration of 28-34 pg Pb/g soil (Table E-2). For these two air TEH 0413733 DUP050454710 E-9 lead levels, a doubling of the dry deposition flux to account for the contribution of wet deposition gives an estimated soil lead concentration of 28-34 and 40-52 pg Pb/g soil. Similarly, model predictions based on a lower bound dry deposition velocity of 0.2 cm/sec (Table E-3) are plausible order of magnitude estimates of soil lead concentrations in rural areas. As an alternative to doubling the estimate of the dry deposition flux to account for total lead deposition, empirical data of lead concentration in precipitation and precipitation rates in rural areas are used to calculate wet deposition rates of lead. These estimates are then added to the model's predicted dry deposition rates to approximate total lead deposition. Although concentrations of lead in precipitation are highly variable making it difficult to assign a representative concentration value (Galloway et a!., 1982; CD, p. 6-25), wet deposition flux is estimated based on a median concentration of lead in precipitation of 8 pg Pb/1 for rural areas in the U.S. (Galloway et al., 1980; Galloway et al., 1982). For a lead concentration of 8 pg/1 and precipitation rates of 20-140 cm/year that represent the range observed in different geographic regions of the U.S. (Climatic Atlas of the U.S., 1968), the wet deposition rate of lead is 4 and 31 pg/m2*day, respectively. Estimated total soil lead concentrations that are associated with the sum of these average wet deposition rates and the dry deposition rates predicted by the model appear plausible, and the soil lead concentra tions predicted by either method are comparable as order of magnitude estimates. For example, for dry deposition velocities of 0.2 and 0.56 cm/sec, air lead levels of 0.05 and 0.1 pg/m^, and with the immobilization of lead in the upper 2-5 cm, predicted soil lead concentrations at 50-75 TEH 04T3734 DUP050454711 years following the introduction of lead additives to gasoline range from 20-90 pg Pb/g soil (Table E-4). Although concentrations of lead in precipitation are highly variable, these calculations that are based on a median concentration of lead in precipitation and a range of precipitation rates give some indication of the appropriateness of doubling the dry deposition flux to account for total lead deposition. As expected, the average wet deposition rates suggest that a doubling of the dry deposition flux predicted by the model to account for the total deposition of lead overestimates the contribution of wet deposition in the more arid rural areas of the U.S. In rural areas that experience relatively high annual precipitation rates, a doubling of the dry deposition flux based on a Vq of 0.56 cm/sec is a reasonable approx imation to total lead deposition. A doubling of this estimate, however, would tend to overestimate total deposition in areas with moderate precipi tation rates. A doubling of the dry deposition flux that is associated with a Vq of 0.2 cm/sec likely underestimates the contribution of wet deposition in areas with moderate to high annual precipitation rates. Although the model estimates under the above scenarios appear plausible, it should be noted that the plausibility check was based on model predictions for air lead levels representative of rural areas between 1974-1980, i.e., 0,05-0.1 pg/m3. In the absence of reliable data of air lead levels in rural areas from 1920 through the mid 196G's, it is difficult to evaluate the predictive power of the model with respect to the historical accumulation of lead in soil. Air lead levels in rural areas can, however, be estimated based on past emission data. Because anthropogenic lead in rural areas is TEH 0413735 DUP050454712 TABLE -4. ESTIMATED SOIL LEAD CONCENTRATION IN AURAL AREAS EASED ON NOOEL PREDICTS ORY DEPOSITION PUiX FOR AIR LEAD LEVELS REPRESENTATIVE OF RURAL AREAS ANQ ESTIMATED AVERAGE MET DEPOSITION FLUX Ory Deposition Velocity, Vcm/see Air lead Level ,, uo 'h/nr O.OS O.SS cm/sec4 0.1 0.2 em/sae" O.OS 0.1 Qry Deposition Flux' uo Pb/mE.dav Wet Deposition Flux ws Bb/m2.dav Total Lead Deposition' uo Pb/m2.dav Soil Lead Concentrations ug Pb/g soil 50 vears 75 years 23 4d 29 35h 40" 251 30* 203 203 25 31* 53 50" TO" 301 40i 203 203 50 Ad SA SO" 38" 3Qi 351 203 203 50 31* 81 S5h 90" ... 35* 451 203 253 10 W ii* -- 2N 19* 21* 173 173 10 31* 41 40" 55" 251 . 30* ewe-ms-- 20i M.----------------a 203 20 24 30" 40" 2Qi 25* 203 203 20 31* 51 SO" 55" 30< 35* 203 203 4Particle size distribucion weighteo Vg (weighted by mass In each particle size range), based on average particle size distribution of lead in rural areas (Milford and Davidson, 198S) and predicted Vq from Oavidson et al. (1932). ''Calculated dry deposition velocity from field studies.that measured lead deposition onto artificial surfaces. eOry deposition fluxug Pb/m?-day 0 ea/see x air Pb concentration ug PS/m3. "Wet deposition flux ug Pb/m^.day * 3 ug Pb/1 x 20 cm/year precipitation. Wet deposition fluxug Pb/m^-day 8 ug Pb/1 x 140 cm/year precipitation. fTotal lead daposttion ug Pb/ra^-day * Ory deposition flux + wet deposition flux. SYsars are the number of years following the Introduction of lead additives to gasoline. "Lead immobilized within upper Z cm of undisturbed soil profile. *Lead Immobilized within upper 5 cm of undisturbed soil profile. iLead Immobilized within upper 13 cm of cultiveted soil profile. TEH 0413736 DUP050454713 E-12 attributed to mobile source emissions, historical data of lead consumption in gasoline (U.S. Bureau of Mines Minerals Yearbook, 1929-1983) can be used to estimate past air lead levels. This was done by comparing data of yearly lead consumption in gasoline (Table E-5) to the level of consumption during 1974-1980, 8ased on the data of lead consumption in gasoline (Table E-5), air lead levels in rural areas during the late 192Q`s through the early 1960's are estimated to have been less than or approximately equal to air lead concentrations that are representative of rural areas between 1974-80, Air lead levels during 1966-73 may have' averaged 30% higher than concen trations in 1974-80. Deposition rates that would be expected during these time periods are directly proportional to air lead concentration. As a result, model predictions of soil Head concentration that are based on deposition fluxes associated with 1974-80 rural air lead, concentrations may overpredict deposition flux for the time period since the introduction of lead additives to gasoline through the early 1960's, but may underpredict deposition flux for the 8 year period between 1966-73. The magnitude of this underprediction appears small, however, as Indicated by the dry deposi tion flux associated with a 30% increase in air lead concentration (above the upper bound level of 0.1 pg/m3), and dry deposition velocities of 0.56 and 0.2 cm/sec, i.e., 63 and 22 pg/Si2-day, respectively. This small Increase in dry deposition flux (from 50 to 63 pg/m2*day and from 20 to 22 pg/m2*day; Tables E-2 and E-3) over a relatively short period of time would not signi ficantly change soil lead concentrations predicted by the model. The net effect of using a constant air lead level (0.05-0.1 pg/m3) as representative TEH 0413737 DUP050454714 E-13 TABLE E-5. ANNUAL CONSUMPTION OF LEAO IN GASOLINE ADOITIVIES IN THE UNITED STATES FROM 1929-1983 Year 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 Consumption 16,329 9,979 5,443 3,175 4,536 6,622 9,072 10,070 10,886 5,443 8,074 9,979 43,841 45,497 59,257 75,357 '68,846 43,513 71,014 Metric Tons Year Consumption 1948 76,030 1949 85,859 1950 103,279 1951 116,488 1952 133,104 1953 147,365 1954 145,544 1955 149,805 1956 174,169 1957 160,572 1957 144,615 1959 . 145,167 1960 148,620 1961 154,041 1962 153,246 1963 174,914 1964 202,724 1965 204,300 Year 1966 1967 1968 1969 1970 1971 1972 1973 1974 ` 1975 1976 1977 1978 1979 1980 1981 1982 1983 Consumption 223,964 224,228 237,588 245,962 252,654 239,713 252,504 248,939 227,250 189,242 217,504 211,291 161,778 169,593 116,031 101,030 108,167 80,846 SOURCE: U.S. Bureau of Minesi Mineral Yearbook, 1929 -1983. ! TEH 0413738 DUP050454715 E--14 of rural areas most likely is to overpredict soil lead concentration given the relatively long time period during which rural air lead levels are estimated to have been less than or equal to 1974-80 levels. The alternative method to estimate total lead deposition relies on dry deposition flux predicted by the model and average wet deposition rates of lead. The concentration of 8 yg Pb/1 precipitation- represents a median value of lead concentration in precipitation for the time period 1975-1980, Applying the same .rationale stated above, it is likely that soil lead concentrations predicted for an average wet deposition flux of lead (associated with a concentration of 8 yg Pb/1) are overestimates, given the relatively long time period during which lead concentrations in precipitation are estimated to have been less than or equal to concen trations measured during 1975-1980. Empirical data of soil samples collected from cultivated fields in Illinois show an increase in soil lead concentration from 13 yg Pb/g soil in the 1920's to 26 yg Pb/g soil in the late 1960's (Ewing and Pearson, 1974). Model predictions of soil lead concentration for cultivated soil (Tables E-2 and -3) underestimate soil lead concentration using these field data for empirical validation. Under air lead levels most representative of rural areas and with dry deposition velocities of 0.2 and 0.56 cm/sec, based on a doubling of the estimated dry deposition flux, the model predicts an increase in soil lead concentration from a natural background level of 16 yg Pb/g soil to 18-22 yg Pb/g soil for the time period 1920-1970, i.e., 50 years into the simulation. Alternatively, soil lead concentration can be estimated based on the sum of the dry deposition flux predicted by the model and the estimated average wet deposition flux for rural areas. For this same scenario, this summation yields a similar soil lead concen- TEH 0413739 DUP050454716 E-15 tration of 17-20 pg Pb/g soil (Table E-4). Either method results in an underprediction of soil lead concentration compared to empirical data collected in Illinois. The low levels predicted are, in part, due to the dilution effect of uniformly distributing the lead concentration through an 18 cm soil depth. It is possible that the higher soil lead concentrations measured in Illinois may represent the continual addition of fertilizers containing lead to these agricultural fields. For the model scenario associated with maximum soil lead concentration {Vq 0.56 cm/sec, lead immobilization within the upper 2 cm of an undisturbed soil profile) and for the range of air lead concentration that is most representative of rural areas (0.05-0.1 pg/m3), an increase in soil lead concentration from a natural background level of 16 pg Pb/g soil in 1920 to 75-135 pg Pb/g soil is predicted for rural areas for the 100 year period following the introduction of lead additives to gasoline (Table E-2). These levels are well below total soil lead concentrations that are associated with adverse effects in plants and soil microbes, i.e., 1000 pg Pb/g soil and 750-1000 pg Pb/g soil, respectively. Although soil lead concentrations predicted by the model for rural areas are not anticipated to approach levels associated with adverse effects in terrestrial biota, there is much uncertainty in assessing potential environmental impact in terms of total soil lead concentration. This is due to the varying capacity of different soil types to immobilize lead and the lack of a clear quantitative relation ship between total soil lead concentration and biologically available lead. With the recently revised phasedown schedule for lead in gasoline, it is estimated that by 1990 the annual average air lead level for neighborhood TEH 0413740 DUP050454717 E-16 scale monitoring sites, due only to mobile source impacts, will be 0.02 pg/m3 (Battye et al., 1985). Although impacts for remote and rural monitoring sites were not projected, air lead levels in rural areas should be no higher than 0.02 pg/m3 and will likely be much lower. Assuming a similar particle size distribution of lead in rural areas in the future, at such low air lead levels the anticipated rate of increase in soil lead concentra tion in most rural areas, based on this linear model and dry deposition velocities of 0.2 and 0.56 cm/sec, is quite small and it appears unlikely that total soil lead concentrations will reach levels of concern within the next several decades. Rural areas that have already experienced significant increases in soil lead concentration or have elevated natural soil lead concentration may be approaching levels of concern. These model predictions may not apply to rural areas at high elevations that appear to be more * rapidly approaching soil lead concentrations of concern (Johnson et al., 1982). The more- rapid accumulation of lead might be explained by increased precipitation due to orographic effects, and by the nature of the soil in certain high elevation forests. It appears that there may be an effect in high elevation forests that requires further research. 3. Model Uncertainties These model predictions must be considered, at best, as crude estimates of the long-term accumulation of lead in soil. Predicted soil lead concen trations are dependent on both the dry deposition model selected and the particle size distribution data that determine the dry deposition velocity and the resulting deposition flux. As a result, predicted soil lead concen trations are highly uncertain due to the complex interaction of parameters that influence particle deposition and that are not entirely well-defined, the high degree of uncertainty associated with dry deposition velocities. TEH 0413741 DUP050454718 E-17 the questionable accuracy of particle size distribution data, and the reliance on model assumptions and predictions that are difficult to validate. The dry deposition velocity curves of Figure E-l, for example, have not been validated experimentally. The range of dry deposition velocities predicted by models are comparable with dry deposition velocities that are calculated from field measurements of deposition onto surrogate and natural surfaces. Either method of estimating dry deposition velocity, however, gives highly variable results with dry deposition velocities varying by several orders of magnitude. This reflects the actual variations and also the uncertainties associated with these estimates (Davidson et al., 1982; SI inn, 1982; Sehmal, 1980). Much uncertainty is associated with calculating or predicting particle dry deposition velocity which is a .function of many variables. The weighted Vp (0.56 cm/sec) that is derived from the Davidson et al. model is considered here to be an upper-bound that may overpredict the dry deposition flux and accumulation of lead in soil due to the relatively greater surface roughness heights (4-14 cm) and plant geometry that increase collection efficiency and result in higher deposition velocities for grass canopies compared to bare soil. This weighted Vg may possibly underpredict dry deposition flux for forest canopies that are characterized by higher deposition velocities compared to grasslands (CD, p. 6-28). To the extent that a Vg of 0,56 cm/sec is an upper-bound, a doubling of the estimate of dry deposition flux to account for the contribution of wet deposition may compound this overestimation, especially in areas with low to moderate annual precipitation rates. In addition, the Davidson et al. model predictions are specific for meteorological TEH 0413742 DUP050454719 D-29 Thus, while any individual child's IQ score may fluctuate over time, the implications of a 5 point average deficit among children are serious (see Figure D-2). Considerable uncertainty exists regarding lead's impact on IQ scores of children with PbB levels below 40 pg/dl. This uncertainty largely stems from the complex interaction between lead exposure over time, social factors, and intelligence scores, and from the statistical and methodological limitations of cross-sectional studies to untangle these variables, and the range of interpretations that result from these studies. For example, Ernhart (1983, 1984) reanalyzed previously-published data on a group of children whose average PbB level dropped from 35.2 to 26.9 pg/dl over 5 years (Perino and Ernhart, 1974; Ernhart et al1981) and found that after partialling out the effects of sex, parental IQ, and parental education (but not socio-economic status), the proportion of variance explained by lead was no greater than 5% on any one of the IQ measures. With the exception of General Cognitive Index and Verbal Scale scores, the effects of early lead exposure on IQ scores appeared to be neither statistically significant nor persistent throughout childhood. It is possible, as with other studies, that by control ling for one variable such as parental IQ, which may be affected by lead exposure, the effects of lead on children's IQ is diminished. Ernhart (1983) concluded that although these data do not support an inference for an association between neuropsychologic deficits and lead exposures at the levels experienced by the children in this study, the rather low statistical power of the reanalyses does not allow for a definitive conclusion of ''noeffect", either. Nevertheless, the results from these analyses are reasonably consistent with those from other Investigators; namely that PbB levels above 30 pg/dl, compared to lower levels, show a small, but significant, association with some measures of IQ after controlling for confounding variables. TEH 0413707 DUP050454720 0-30 The criteria document concluded from the Needleman et al. (1979) study and subsequent re-analyses (Needleman, 1984) that, after controlling for confounding variables including pica, average IQ decrements of about 4 points and other neurobehavioral deficits appear to be associated with lead exposures of U.S. children resulting in dentine lead values that exceed 20-30 ppm and likely average PbB levels in the 30-50 pg/dl range (CO, p.1274 to 12-80). Needleman et al. (1982) calculated that a 4 point decrement in the mean IQ of a normal population distribution would be associated with a three-fold increase in the number of children with severe deficits (IQ .< 80) along with a 5% reduction in the number of children who attain superior function (IQ > 125) (see Figure.0-2). Figure 0-2. Cumulative Frequency Distribution of Verbal IQ Scores in Subjects with Low or High Levels of Lead (Source: Needleman et al., 1982). Bellinger et al. (1984) followed up on the academic performance of a subset of the children initially evaluated by Needleman et al. (1979) and TEH 0413708 DUP050454721 0-31 found that only grade retention was clearly associated with past dentine lead levels; other outcomes (e.g., remedial instruction, classroom behavior) tended to be in the predicted direction of effect but generally at p values between 0.5 and 0.15. It is of interest to note that two pilot studies (Yule et a!., 1981; Winneke et al., 1982a) that included children with PbB levels below 30-35 pg/dl (Rutter, 1983) living near lead smelters In Europe found IQ deficits (4.5 to 7 points) similar to those observed by Needleman et al. (1979) be tween high and low exposure groups after correction for confounding variables. However, the relatively crude controls for social variables provided in these latter two pilot studies prevent conclusive interpretation of the observed associations (CD, p. 12-86). Initial assessment of 104 lower SES children, aged 10 months to 6.5 years showed an inverse linear relationship of PbB and IQ across concentrations t from 6 to 59 pg/dl after controlling for SES, quality of the care-giving environment, maternal IQ, and other social factors (Schroeder et al., 1985). In addition, a dissociation of maternal and child IQ was found (r= 0.058; the expected normal mother-child IQ correlation Is about 0.50) in children below 30 months of age with PbB levels above 30 pg/dl, consistent with other studies (Perino and Ernhart, 1974; Bellinger and Needleman, 1983). Five years later, the PbB levels of the 50 children retested had dropped to below 30 pg/dl and the correlation between maternal and child IQ returned to a nearly normal value (r= 0.45). Furthermore, the effect of either contemporary or initial PbB levels on 5-year follow-up IQ scores was not significant after covariates were accounted for in the regression model (Schroeder et al., 1985). TEH 0413709 DUP050454722 D-32 A replication of the above study using 75 low SES children between 2 and 3 years of age showed the same continuous linear decrease in IQ with increasing PbB across a wide range (6-47 pg/dl) with 78% of subjects having PbB levels below 30 pg/dl (Schroeder and Hawk, 1986). The effect was almost equally as strong regardless of whether contemporary, past maximum, or mean PbB levels were used in the analysis. The potentially confounding factor of SES was effectively controlled by selecting a very homogeneous group of children. Studies of European children with lower lead exposures (mean PbB 815 pg/dl) have generally found only 1-2 point, and statistically non-signifi cant differences in various IQ scores at Pb8 levels In the 15-30 pg/dl range after controlling for confounding variables (Smith et al., 1983; Harvey et al., 1983, 1984; Yule et al., 1983; Yule and- Landsdown, 1983; Winneke et al., 1983, 1984). CThe study by Silva et al.(1986) on 11-year old New Zealand children with a mean PbB of 11 pg/dl found no effects of lead on IQ but significant associations between PbB and various behavioral measures. These results on older children are difficult to relate to the other studies cited here on young children]. Smith et al. (1983) commented that if differences exist in neuropsychological performance attributable to lead at the levels they studied (<25 pg/dl), then the sensitivity of psychological tests and other currently available measures and statistical procedures do not allow these differences to be detected with any degree of certainty. An important finding from several of these studies that tested for interactive effects (Yule and Landsdown, 1983; Winneke et al., 1983; Harvey et al., 1983) was that neurobehavioral deficits associated with lead were enhanced in, or even largely confined to, socially disadvantaged TEH 0413710 DUP050454723 D-33 children or those of manual working class fathers compared to those from more middle class backgrounds. These findings suggest that low level lead exposure, in combination with other factors associated with low socio-economic status (e.g., undernutrition) may predispose a child to psychological impairment. The findings by Schroeder et al. (1985) and Schroeder and Hawk (1986) of significant dose-response relationships down to very low PbB levels after controlling for social factors may be attributable to the uniformly low SES of the children studied. Although SES was not a significant covariate in Schroeder and Hawk (1986), quality of the home environment (which may be linked to IQ) was a significant predictor of lead exposure, consistent with other work (Milar et al., 1980; Dietrich et al., 1985). This close relationship between SES, home environment, and lead exposure suggests that SES may not be the sole determinant of increasesd risk for cognitive impairment. Further research is needed to investigate the possibility that any effects of low levels of lead (PbB < 30 pg/dl) on IQ are due, not to some "pure" form of permanent damage to the brain, as much as to the effects of lead as part of a more complex set of interacting influences including social and nutritional factors. 5) Electrophysiological Effects As discussed earlier, in addition to its varied effects on neuronal development and chemically-mediated synaptic transmission, lead impairs peripheral nerve conduction velocities, at levels possibly as low'as 30 pg/dl (Appendix D.2.a). Similarly, lead exposure affects brain morphology and metabolism, interferes with neurotransmission in central nervous system tissue (e.g., cerebellum, retina) (Palmer et al., 1981; Fox and Sillman, 1979; Sillman et al., 1982), and depresses conduction velocities in the visual pathways of rats accompanied by persistent decreases in t e h 04137H DUP050454724 0-34 visual acuity and spatial resolution (Fox et al., 1977; Cooper et al., 1980; Winneke, 1980; Impelman et al., 1982; Fox and Wright, 1982). Consistent with these findings are those from neurological assessments of children and adult workers which indicate that a wide range of lead levels may be associated with impaired function in the visual-motor and auditory systems (Repko, 1979; Haenninen et al., 1978; Needleman et al, 1979; Winneke et al., 1983; see discussion below). It has also been demonstrated that electrical activity in the brain itself, determined by electroencephalograms (EES), is disrupted in animals and humans suffering from lead intoxication (Cooper et al., 1980). More subtle abnormalities in EES patterns (increased delta/decreased alpha activity) were detected in a subset of children from the Needleman et al. (1979) study with high tooth lead levels (Burchfiel et al., 1980), The lower amounts of alpha activity in the high lead children (PbB levels 30-50 gg/dl; CO, p. 12-92) might signify that brain maturation was somewhat delayed by lead since such activity tends to increase with age in children (Beningnus et al., 1981), The brain wave patterns (indexed by slow cortical potentials elicited by classical conditioning) of 1-6 year old children varied as a linear function of PbB (ranging from 6-59 pg/dl) with no evidence of a threshold, although the slope changed systematically with age (Otto et al., 1981). Slow wave voltage tended to be positive in children less than 5 years old and negative in children over 5 years. [Psychometric evaluation revealed a significant lead-related IQ decrement at the time of initial testing (Schroeder et al., 1985); no relation between blood lead and hyperactive behavior was noted in these children (Milar et al., 1981).] Neurophysiological evidence suggests that slow surface-positive potentials in very young children may reflect TEH 0413712 DUP050454725 D-35 axodendritic inhibitory processes (Otto and Reiter, 1984). The relative amplitude of synchronized electrical activity between the left and right hemispheres of the brain varied as a cubic function of Pb8 levels in these children, with inflection points at 15 pg/dl and 40 pg/dl (Benignus et al., 1981). Increased synchrony and relative amplitude of the EEG at these PbB levels could indicate an Increase in the amount of Information being processed and, perhaps, that an Increased effort Is required to assimilate this information (Rostron, 1982). The clinical nor the functional significance of this measure has yet to be established, however. In a subsample of these children assessed 2 years later, slow-wave voltage during sensory conditioning again varied linearly with PbB with no apparent threshold over a range of 11-39 pg/dl (Otto et al., 1982). This relationship was constant whether PbB levels from the initial or follow-up study were analyzed, suggesting a change that persisted over time despite a substantial decline in mean PbB from 32.5 to 21.1 pg/dl. In a five-year follow-up on a subset of the same children, slow-wave voltage varied as a function of current PbB level during active conditioning, but not during the passive conditioning test used in earlier studies (Otto et al., 1985). Measurements of pattern-reversal visual-evoked potential (PREP) revealed increased amplitude and decreased latency of certain components as a linear function of original PbB level, which is contrary to predictions but consistent with results of Winneke etal. (1984). Significant associations were also found between PbB levels and increased latencies in brainstem auditory evoked potentials (8AEP), indicative of auditory nerve conduction slowing (Otto et al., 1985). Results of a replication study in an independent group of children 3-7 years old indicate that contrary to earlier findings (Otto et al., 1981,1982), TEH 0413713 DUP050454726 slow-wave voltage did not vary with PbB level. Although age differences between the two groups studied (1-6 versus 3-7 years) and their different exposure routes may account for these inconsistencies, earlier findings must be inter preted cautiously in the absence of further study. [Psychometric evaluation of these children revealed a continuous linear decrease in IQ with increasing PbB level across the range of 6-47 pg/dl (Schroeder and Hawk, 1986).] Only one PREP amplitude measure varied systematically with PbB levels and this was in the opposite direction of earlier findings. In contrast to the 5-year follow-up study in which a simple linear relationship was observed, several BAEP latency measures showed a curvilinear relationship to maximal PbB levels in the replication such that latencies decreased as PbB levels rose from 6 to 25 yg/dl, but increased at higher PbB levels (Otto, 1985; Robinson et al., 1985). In addition, latency of central transmission time in the auditory pathway increased directly with PbB as did hearing threshold, a reflection of peripheral auditory ' function. The latter finding is inconsistent with earlier findings (Otto et al., 1985), although it warrants concern in view of other reports suggesting impaired auditory processing (along with performance deficiencies) in leadexposed school-age children (Perino and Ernhart, 1974; Needleman et al., 1979). Given that the clinical and functional significance of many of the electrophysfological measures used are presently considered experimental and given the inconsistent correlations between PbB and the various measures, the current electrophysiological evidence concerning lead exposure and brain function in children is too fragmentary to draw any firm conclusions. Nevertheless, the criteria document concludes that these findings suggest the possibility of altered CNS functioning associated with relatively low level lead exposure at PbB levels in the 15-30 yg/dl range, and perhaps, below (CD, p. 12-157). TEH 0413714 DUP050454727 D--37 3. Effects on the Cardiovascular System Symptoms consistent with cardiac disease, such as degenerative changes in heart muscle (Kline, 1960), abnormal electrocardiograms (ECG) (Silver and Rodriquez-Torres, 1968) and increased cerebrovascular mortality (Dingwall-Fordyce and Lane, 1963) have been associated with high human lead exposures. Cardiotoxicity has been.reproduced in experimental animals acutely exposed to high concentrations of lead. Effects include depression in contractility, increased susceptibility to norepinephrine-induced arrhythmias (exaggerated in neonates), and decreased cardiac protein phosphyrlation (Kopp et al., 1980b; Williams et a!., 1977 a,b). It appears that effects may persist in immature rats even after cessation of lead exposure (Williams et al., 1977b). Chronic administration of lead resulting in PbB levels as low as 40 pg/dl caused structural changes in the myocardium of mice, and ECG abnormalities that are likely due to nerve conduction disturbances (Khan et al., 1977, Kopp et al., 1980 a,b). Besides affecting cardiac output, low levels of lead exposure have produced increased vascular responsiveness to contractile agents such as noradrenaline, and significant elevations in systolic blood pressure in rats with PbB levels around 40 pg/dl (and possibly lower) (Webb et al., 1981; Victery et al., 1982; Perry and Erl anger, 1979; Kopp, 1980a). These changes may be linked to reduced energy availability due to heme synthesis inhibition (Kopp, 1980a) or to altered nerve transmission caused by changes in calcium availability (Webb et al., 1981), and suggest possible mechanisms by which lead may contribute to hypertension in humans. Excessive amounts of mobilizable lead have been measured in patients with hypertension (and renal, impairment of unknown cause) (Batuman et al.. TEH 0413715 DUP050454728 D-38 1983) and evidence of increased hypertension has been found among men occupationally exposed to high levels of lead (Inglis et al., 1978; Lilis et al., 1977), although there have been contrasting findings in similar populations (Richet et al., 1966; Cramer and Dahlberg, 1966;). Lower levels of exposure as indexed by PbB or urinary Pb levels, have been associated in some adult populations with hypertension prevalence (8eevers et al., 1976; Kromhout and Coulande, 1984) and blood pressure (Moreau et al., 1982; Pocock et al., 1984), but not in others (Staessen et al., 1984). Pocock et al. (1984) considered the weak (but statistically significant) correlation between lead exposure and hypertension at levels above 37 yg/dl to be of minor importance given the lower PbB levels typically found in * British men. However, an unpublished EPA reanalysis of the grouped data reported by Pocock et al. (1984) indicates that blood lead is a significant predictor of blood pressure'in their data, both before and after adjusting for covariates, when a regression of blood pressure is performed versus the log of blood lead for their reported group averages (U.S. EPA, 1985c). Furthermore, the regression coefficient indicated that the size of the effect was significant, suggesting a blood pressure increase of 3 mm Hg as blood lead increases from 5 to 15 pg/dl. Recent analyses of NHANES II data have demonstrated significant associations between blood pressure (systolic and diastolic) and PbB levels among males (not females) aged 12 to 74 years independent of other, potentially confounding variables (e.g., nutrition) (Harlan et al., .1985). Further analyses were conducted on white males aged 40 to 59 years to avoid the collinearity between blood pressure and blood lead evident at lower ages and because data relating cardiovascular disease to blood pressure are less extensive for non-whites (Pirkle et al., 1985). PbB levels were a significant predictor of blood pressure in this subgroup after including TEH 0413716 bU P050454729" D-39 in the multiple regression analyses all. known factors previously established as correlated with blood pressure and also when the relationship was tested against every dietary and serologic variable measured in the NHANES II survey (Pirkle et al., 1985). Including both curvilinear transformations and interaction terms had little effect on the blood lead coefficient. A threshold below which blood lead was not significantly related to blood' pressure could not be found across a range of adjusted PbB levels between 7 and 34 pg/dl. It is of interest to note that the dose-response relation ships found by Pirkle et al. '{1985} suggest a large initial effect, leveling off at higher PbB levels, which is consistent with the biphasic blood pressure response to PbB levels found in rats (Victery et al., 1982) and which may account for the inconsistent epidemiologic findings in persons with mild to moderate elevations of blood lead. Because of the complex inter-relationships among the multiple environmental, dietary, medical, socio-economic, and genetic factors that influence blood pressure, all of which may not be measurable, results from even the recent studies that employed thorough and extensive analyses and high quality data, must be interpreted cautiously. Nevertheless, the suggested relationships between blood lead and blood pressure among adults, even at PbB levels below 30 yg/dl, should continue to be carefully studied and be considered to have potentially important public health implications in terms of increased incidence of hypertension and more serious cardiovascular disease. Pending review of the most recent papers in the criteria document, their results are not reflected in the assessment of health risks associated with different PbB levels in determining an acceptable PbB level. TEH 0413717 DUP050454730 0-40 4. Effects on the Kidney Lead at high concentrations is concentrated in the kidneys by high affinity binding proteins (which form intranuclear inclusion bodies) and causes numerous types of changes in a variety of physiological processes associated with the kidney. At low dosages, lead affects renal mitochondrial structure (e.g., swelling) and function (e.g., altered respiratory rates, oxidative phosphorylation and synthesis of heme, proteins, nucleic acids and vitamin D hormone) (Goyer, 1968; Fowler et al., 1980, 1981 a,b; Silbergeld et al., 1982; Rosen and Chesney, 1983). Lead's interference with these biochemical processes in the kidney, particularly energy metabolism, might account for the transient decreases in renal tubular reabsorptive processes, as indicated by hyperaminoaciduria, glycosuria, and hyperphosphaturia, at PbB levels ranging from 40 to more than 100 pg/dl, and possibly as low as 30 ug/dl (See CD'; Sections 12.5.2 and 12.5.3; p. 12-170). Irreversible kidney damage (e.g., interstitial nephritis) ' appears to require prolonged high exposure, with PbB levels probably exceeding 70-pg/dl in adults although lead chelation is necessary to detect cumulative body stores that may contribute to the gradual develop ment of this disease <Li1is et al., 1968; Cramer et al., 1974; Wedeen et al., 1979). It should be noted that the effects of chronic, low-level lead exposure on renal dysfunction in children have not been adequately studied. There is limited evidence that elevated lead absorption contributes to renal disease in association with gout and hypertension (Emmerson, 1973; Batuman et al., 1981; Wedeen, 1982). The mild hypertension observed with chronic low-level lead exposure however, may be related to lead's ability to directly alter vascular reactivity (Webb et al., 1981; see Appen- TEH 0413718 DUP050454731 D-41 dix 0.3) and any contribution of lead-induced renal Impairment to this disorder, at low exposure levels, remains to be determined. 5. Effects on Reproduction and Development Lead compounds have been used as an abortifacient and lead poisoning has been shown to be accompanied by reduced fertility, miscarriages and stillbirths (Oliver, 1911). Little research has been*directed however, at whether subtoxic levels affect fertility or cause fetal Injuries in humans. In female animals, relatively low-level lead exposure has been shown to affect pubertal progression and hypothalmic-pituitary-ovarianuterine functions, as evidenced by ovarian abnormalities (Hilderbrand et al., 1973; Der et al., 1974), and delays in vaginal opening (Grant et al., 1980; Kimmel et al., 1980) and first conception (Maker et al., 1975). In addition, the ability of the placenta to support fetuses is compromised*in mice exposed to relatively low lead levels (Maisin et al., 1975; Jacquet et al., 1976). It is of particular concern that placental transfer of lead begins as early as the 12th week of gestation and continues to accumulate in the fetus throughout pregnancy (Barltrop, 1969) resulting in comparable PbB levels in the mother and newborn child (Alexander and Delves, 1981; Rabinowitz and Need!eman, 1982). Newborn rodents and monkeys whose mothers were exposed to lead during pregnancy showed compromised growth (Reiter et al., 1975), congenital malformations in the spinal cord (Carpenter and Ferm, 1977; Jacquet and Gerber, 1979) and delayed development of the CNS (e.g., cortical connections) and its functions (e.g., motor function, social behavior) (Klein et al., 1978; Bushnell and Bowman, 1979; Crofton 1977; et al., 1980; Grant et al., 1980; Overmann et al., 1981; Winneke et al., 1977; TEH 0413719 DUP050454732 APPENDIX D. HEALTH EFFECTS OF LEAD This appendix discusses and evaluates the information reviewed in detail in Chapter 11 of the criteria document on the various human health effects associated with lead exposure. The discussion is broken down into the major health effects areas of primary concern and is intended to support the assessment in Section VII.C(l) of health risks associated with various blood lead (PbB) levels for purposes of determining an appropriate lead' NAAQS. 1. Heme Biosynthesis and Related Functions Under normal circumstances, heme biosynthesis is a highly efficient and coordinated pathway, which produces only sufficient amounts of inter mediates and, ultimately, heme to service requirements for hemoglobin -the blood pigment responsible for transporting oxygen to the tissues -- as well as a multitude of functions mediated in most cells by heme-containing proteins. These hemoprotefns include myoglobin, the hemoglobin of muscle, and the mitochondrial respiratory pigments, cytochromes, responsible for cellular Energetics. Moderately elevated lead exposure has been demonstrated to disturb the biosynthetic sequence so as to produce large quantities of redundant intermediates that must then be excreted; more severe lead Intoxication may result in the development of anemia. Lead*s interference at susceptible stages of the biosynthetic pathway {illustrated in Figure D-l) may have Important Implications for a multitude of organs and systems, especially in the growing child, and is briefly reviewed below. i. The initial step of the heme synthetic pathway, the formation of delta-aminolevulinic acid (ALA) from succinyl-CoA and glycine by the mitochondrial enzyme delta-aminolevulinic acid synthetase (ALA-S), represents the control point of the pathway. During lead exposure, the activity of this rate-limiting enzyme Is increased through feedback TEH 0413679 DUP050454733 D-2 MITOCHONDRIAL MEMBRANE MITOCHONDRION GLYCINE SUCCINYLCoA HEME FERRO if CHELATASE Pb Fe - PROTOPORPHYRIN d-ALA SYNTHETASE (INCREASE) Pb (DIRECTLY OR BY OEREPRESSION) f d-ALA d-ALA OEHYDRASE (DECREASE) Pb r-" COPROPORPHYRIN (INCREASE) PORPHOBILINOGEN IPBG) Figure D-1 Lead effects on heme biosynthesis,from CD; Figure 6-1. TEH 0413680 DUP050454734 D-3 control apparently in an attempt to compensate for the diminished production of heme due to lead's interference (Maxwell and Meyer, 1976). ii. In the second step of the pathway, the zinc-requiring enzyme deltaaminolevulinic acid dehydrase (ALA-D), catalyzes the condensation of two molecules of ALA to form porphobilinogen. ALA-D is inactivated by lead without any apparent threshold, and in erythrocytes, its activity appears to be markedly reduced at a PbB around 15 yg/dl in both adults and children (Hernberg and Nikkanen, 1970; Wada et al., 1976; Nieberg et al., 1974; Secchi et al., 1974; Roels et al., 1975b). Based on several of these studies, Zielhuis (1975) calculated that the fraction of children with 40% reduction of ALA-D activity increases from about 10 to about 90% as PbB rises from 10 to 30 jjg/dl. The combination of increased ALA-S and decreased ALA-D activity accounts for the marked accumulation of ALA in the plasma and body fluids, and excess excretion of ALA irr urine. The rate of ALA excretion accelerates above a PbB of 40 yg/dl in adults and children (Cramer et al., 1974; Moore et al., 1980; O'Flaherty et al., 1980). Several studies indicate a continuous correlation between urinary ALA (ALA-U) and PbB down to levels around 20-25 yg/dl (Meredith et al., 1978; Selander and Cramer, 1970; Lauwerys et al., 1974; Chisolm et al., 1976). In light of conflicting findings from studies using different measurement techniques, it remains to be established whether Increases in ALA-U are preceded by elevations in circulating levels of ALA in plasma at PbB levels below 40 yg/dl (Meredith et al., 1978; O'Flaherty et al., 1980). The criteria document concludes that despite a positive bias in absolute ALA values due to measure ment contamination by aminoketones not correlated with blood lead, the relative changes in blood ALA detected by Meredith et al. (1978) "appear TEH 0413681 DUP050454735 D-4 to provide the most plausible basis for the observed correlations with Pb8 levels as low as 18 ug/dl`` (CD, p. 12-19). While blood indicators of erythropoietic effects of lead may be more accessible, they are not the only, nor necessarily the most sensitive indicators of heme biosynthesis derangement in other organs (CD, p. 12-26). At roughly comparable lead levels associated with such changes in blood ALA and ALA-D, inhibitions of ALA-0 and elevations in ALA are observed in the liver, kidneys, and spleen of adult rats and humans, and to a greater degree in the developing brain of young, compared to adult rodents (Millar et a!., 1970; Secchi et al., 1974; Gerber et al., 1978; Silbergeld et al., 1982). The impact that elevated ALA may have on the neurological system is discussed in Appendix D.l(d). It is important to note that because lead is preferentially deposited in bone (Appendix A), the concentrations of lead in the marrow will be , significantly-greater than in the blood during red blood cell formation and hemoglobin synthesis in the bone marrow (Albahary, 1972), and the developing red blood cells in the marrow will be particularly affected. 11 i. Another effect of lead on heme biosynthesis is its interference with the last step of this chain, i.e., insertion of iron into protoporphyrin. This is mediated by the enzyme ferrochelatase, which is located in the inner matrix of the mitochondria of most cells (Moore et al., 1980). Lead impairs the transmitochondrial transport of iron and Instead of producing heme, the mitochondria accumulate its precursor, protoporphyrin, which lacks iron and is incapable of performing its essential respiratory function. As a result of lead intoxication in newly forming erythrocytes, protoporphyrin (referred to as erythrocyte protoporphyrin or EP) takes the place of heme in the specific pocket of the hemoglobin molecule. As the red blood cells TEH 0413682 DUP050454736 JgJj D-5 remain in the circulation, zinc is rapidly chelated at the center of the molecule in the site normally occupied by iron (Piomelli et al., 1982). The resulting zinc protoporphyrin (ZPP) is tightly bound in the available heme pocket for the life of the erythrocyte, normally 120-130 days (Lamola et al., 1975). Thus, the content of protoporphyrin in circulating red blood cells represents what has accumulated during red blood cell maturation and consequently describes an effect that took place in the bone marrow, with a time lag of 3-4 months (Sassa et.al., 1973), With increasing blood lead, there is a rapid exponential increase of protoporphyrin, with significant accumulations over baseline at PbB levels of approximately 15 pg/dl in infants and children (Roels et al., 1976; Piomelli et al., 1977, 1982; Hammond et al., 1984; Rabinowitz et al., 1985) and 25-30 pg/dl in adults (Roels et al., 1975b; Grandjean and Lintrup, 1978; Odone et al., 1979; Herber, 1980). The population dose-response relationship between EP and blood lead in children aged 10-15 years indicated that EP levels were significantly higher (> 2 standard deviations) than the reference mean in 50% of the children at a PbB level of 25 pg/dl (Roels et al., 1976) . A study of 2004 children found that EP levels increased exponentially above a PbB of 18 pg/dl and that PbB levels of 29.9 and 35.2 pg/dl corresponded to EP elevations of more than 1 and 2 standard deviations, respectively, in 50% of the children studied (Piomelli et al., 1982). The health significance of EP or ZPP accumulation is attributed to the fact that it is evidence of impaired heme and hemoprotein formation in many tissues that results from lead's entry into mitochondria (CD, p. 12-46). Besides its role in the erythropoietic system in forming hemoglobin, heme is active in liver function, vitamin D metabolism, and the nervous system. These interactions, and lead's impact on them, are depicted back in Figure 7-1 and discussed below. TEH 0413683 DUP050454737 0-6 a) Effects of lead on Heme and Hemoglobin Synthesis and Erythrocytes Anemia is often the earliest manifestation of chronic and acute lead poisoning. It is defined as a hemoglobin concentration depressed below some clinically accepted level, usually about 9.5-11.0 grams of hemoglobin per dl blood. The symptoms of anemia in young children can include pallor, sallow complexion, fatigue, irritability, and decreased play activity. The anemia of lead poisoning is related to some combination of decreased heme and hemoglobin production and increased rate of red blood cell destruc tion. In 'addition to its inhibitory effects on heme synthesis, lead disturbs the biosynthesis of globin, the protein component of hemoglobin, disrupts enzymatic activities necessary for erythrocyte membrane stability and ultimately, cellular survival (e.g., pyrimidine nucleotidase, ATPase), and causes oxidative damage to the red blood cell membrane (White and Harvey, 1972; Dresner et al., 1982; Gelman et al., 1978; Secchi et al., 1973; Valentine and Pagliaj 1980; Angle and Hclntire, 1978; Moore et al., 1980; Levander et al., 1975). Although these effects on enzyme activity and globin synthesis are detectable at PbB levels as low as 10 and 20 yg/dl, respectively, their role, if any, in reduced hemoglobin synthesis and shortened erythrocyte survival at such levels is uncertain. In determining a PbB level of concern for anemia. It is important to distinguish the effects of lead from iron deficiency, which is prevalent in young children and could increase an individual's sensitivity to lead toxicity. Unfortunately, the available data do not provide sufficient information to separate this potentially confounding factor. In children with no obvious iron deficiencies, the incidence of anemia (defined as a hemoglobin concentration below 11 g/dl) rose sharply as the PbB levels increased from 37 to 100 pg/dl (Betts et al., 1973). At PbB levels below 36 gg/dl, 14% of the children were anemic, compared to 36% with levels i I TEH 0413684 DUP050454738 D-7 between 37 and 60 jjg/dl. The criteria document cites a threshold PbB for anemia in children of 40 pg/dl {WHO, 1977) and 50 yg/dl in adults (CO, p. 12-28). However, until additional dose-response information on large groups of children is available, with appropriate controls for iron deficiency, this "threshold" should not be considered definitive, h) Heme Synthesis and Liver Function A major fraction of heme synthesized in the liver is used in the hemoprotein, cytochrome P-450. This hamoprotein is the terminal oxidase of the microsomal mixed function oxidase system that is involved in the metabolism of a variety of drugs and foreign toxins, as well as endogenous substrates such as steroid hormones (Granick et al., 1978). Decreases in liver cytochrome P-45Q content and in drug detoxification rates have been observed following acute and chronic lead administration in animals and in lead-poisoned children and occupationally-exposed adults (Scoppa et al., 1973; Alvares et al., 1975, 1976; Meredith et al., 1977; Chow and Cornish, 1978). Lead-induced alterations and diminished cytochrome P-450 function are-also believed responsible for the decreased excretion of 6 Beta-Hydroxycortisol (6, s-OHF), a metabolite of cortisol, in young children with moderate elevations of blood lead (46 pg/dl)(Saenger et al., 1984). Because of children's vulnerability and exposure to drugs and foreign chemicals, and their high metabolic rates, these findings suggest that in the absence of conclusive data it should be assumed that any indication of significantly altered heme biosynthesis (e.g., elevated EP) may also indicate a possible inhibition of liver detoxification function, c) Heme and Vitamin D Metabolism Renal 1-hydroxylase, another heme-requiring cytochrome P-450 mediated mitochondrial enzyme system, converts 25-hydroxyvitamin D (which is formed in the liver from vitamin D) to the hormonal metabolite 1, 25-dihydroxy- TEH 0413685 DUP050454739 0-8 vitamin D {1*25-(OH)2 D) in the kidney. 1,25-{OH0 is the major active form of vitamin D in: 1) orchestrating the differentiation and turnover of cells in bone mineralization (CD, p. 12-41); 2) stimulating intestinal absorption of calcium and phosphorous (Sorell et a!., 1977; Rosen et al,, 1980); 3) maintaining extra- and intra-cellular calcium homeostasis essential for cellular integrity and function {including responses to hormonal and electrical stimuli, modulation of cyclic nucleotide metabolism, and regulation of several enzyme systems) (Cheung, 1980; Rasmussen and Waisman, 1983; Rosen and Chesney, 1983; Rosen, 1983); 4) mediating the activation of various immunoregulatory processes (Provvedini et al., 1983; Bhalla et al., 1983; Tsoukas et al., 1984); and 5) mediating pancreatic function and insulin secretion (Clark et al., 1981; Kadowski and Norman, 1984a,b). In addition to its reliance upon heme, the biosynthesis of the vitamin D hormone is controlled largely by the functional integrity of the renal mitochondria, by the ionic (calcium, phosphorus) environment of the exracellular fluid, and by the active uptake of calcium by mitochondria (CD, p.12-38). Given lead's toxic effects on mitochondria, cellular energetics, and cytochrome P-450 function, and the fact that ferrochelatase activity in kidneys is inhibited by lead just as it is in red blood cells (Fowler et al., 1980), it is not surprising that lowered 1,25-(0H)2 D levels occur at PbB levels corresponding to those associated with the onset of EP accumulation in erythropoietic tissue. For example, a strong negative correlation between children 1,25-(0H)2D and PbB levels was found over a range of 12-120 pg/dl (Mahaffey et al., 1982). In children with PbB levels over 33 pg/dl, the reductions in 1,25-{0H)2 0 were comparable to those observed in children with severe renal Insufficiency (i.e., lacking two-thirds of normal renal function), as well as in those children with a variety of in-borne metabolic disorders such as vitamin D-dependent rickets, oxalosis, and I TEH 0413686 DUP050454740 D-9 hypoparathyroidism (Rosen and Chesney, 1983; Chesney et al., 1983). Several other points should be made regarding the significance of lead- induced reductions in blood serum levels of 1,25-(0H)2 D: (1) Mahaffey et al. (1982) noted the possibility of a feedback mechanism in children by which lead-induced reductions in 1,25-(QH)2 D interfered with intestinal lead ab sorption. Short-term experimental studies with rats (Smith et al., 1981), how ever, indicate that: (i) dietary intake of vitamin D does not affect blood lead concentration; (ii) lead ingestion totally blocked calcium transport thereby enhancing lead absorption; and (iii) reduced 1,25-(QH)2 D levels do not protect target organs (e.g., kidney) by sequestering lead in bone. Furthermore, experimental data (Smith et al., 1981; Edelstein et al., 1984) confirm the inhibitory effects of lead on the conversion of 25 to 1,25-(0H)2 D in the kidney. (2) Although chelation of children with elevated PbB levels results in a rapid (within 2 days) return to normal 1,25-{0H)2 D levels (Rosen et al., 1980), the vitamin D system's ability to recover only after lead levels are reduced does not necessarily imply that the system is operating as a normal biological feedback mechanism. (3) Decreased calcium levels and increased parathyroid hormone (PTH), along with impaired bone mineralization -- conditions that typically accompany severe vitamin D deficiency (as e.g., in rickets) --are not evident in children with PbB levels below 62 pg/dl (Rosen et al., 1980). However, PTH and serum calcium levels typically are normal even in children with stage I rickets; these changes- are therefore not meaningful indicators of the signifiance of reduced 1,25-(0H)2 0 in children (Rosen and Chesney, 1983). The fact that the mineralization of bone matrix is impaired in vitamin D deficiency rickets but not in lead-induced 1,25-(OH)2 D deficiency is also not relevant since vitamin D deficient children may have normal or even elevated 1,25-(0H)2 D levels. TEH 0413687 DUP050454741 q-io The varied biological roles of 1,25-(0H>3 0 in the body, including extra- and intracellular calcium homeostasis, cell differentiation/ maturation, immunoregulatory function, and pancreatic function, e.g., insulin secretion (Kadowski and Norman, 1984a,b,; Clark et al., 1981) are becoming increasingly evident. Impairment of these activities that results from lead's depression of circulating 1,25-(0H)2 U levels may underlie many of the diverse effects of lead. The criteria document concludes that "It appears likely that lead-induced reductions in heme underlie the effects seen in the vitamin D-endocrine system. This origin would account for the similarities in "thresholds" for the effects of lead on both EP accumulation and decreases in levels of 1,25-(0H)2 0. It also typifies a cascade of biological effects among various organ and physiological systems of the body, a cascade that can ultimtely encompass the entire organism" (CD, p. 12-37) and "that impaired production of l,25-(OH)2 D can have profound and pervasive effects on tissues and cells of diverse type and function throughout the body" (CD, p. 12-49). d) Heme Synthesis and the Nervous System The nervous system, both central and peripheral, is recognized as a target of critical importance in the toxicity of lead. Behavioral, electrophysiological, morphological, and biochemical investigations have demonstrated alterations in brain function at relatively low levels of exposure, particularly when exposure occurs during early development. Mechanisms that explain the neurological effects of lead include (but are not limited to) direct alteration of sodium and calcium metabolism, inhibition of certain neuronal enzymes (Na, K-ATPase and adenyl cyclase), and a decrease in mitochondrial oxidative phosphorylation (Silbergeld et al., 1982). Other evidence suggests that some aspects of lead neurotoxicity may be mediated through its inhibition of heme synthesis by the following mechanisms: TEH 04 T3688 DUP050454742 (i) Interference with neurotransmission by the heme precursor, ALA The excessive accumulation of ALA is believed to be linked to the clinical and biochemical similarities (e.g., paralysis, psychiatric disturb ances, nerve demyelination) of lead intoxication and "porphyria", conditions in which elevated tissue concentrations of porphyrin precursors result from genetic or acquired deficiencies {Dagg et al., 1965; Moore et a!,, 1980). Excessive ALA levels in the brain may be responsible for some neurological dysfunctions associated with more mild lead exposure as well, since low levels of ALA in vitro can interfere at the neuromuscular junction or spinal cord with normal neurotransmission by y -aminobutyric acid (GA8A), which ALA closely resembles (Nicoll, 1976; Brennan and Cantrill, 1979; Silbergeld et al. 1980, 1982). Interference with GABA-ergic function by exposure to lead is consistent with such clinical and experimental signs of lead neuro toxicity as excitability, hyperactivity, hyperreactivity, and in severe' cases, convulsions (Silbergeld and Lamon, 1980). (ii) Heme deficiency and altered neurochemical synthesis Litman and Correia (1983) have reported that treatment of rats with a combination of phenobarbltal and ODER, to Induce depletion of the hepatic free "heme" pool, resulted in inhibition of the hepatic heme-requiring enzyme system, tryptophan pyrrolase, and in significantly elevated brain levels of tryptophan, 5-hydroxyindoleacetic acid, and the neurotransmitter, serotonin. With infusion of heme, these Increases were reversed. Elevated levels of tryptophan and its metabolites have been associated with human hepatic encephalopathy and with neurohistological and symptomatic changes seen in victims of acute porphyria attacks (e.g., alteration of brain neurons, axonal wasting, psychomotor disturbances) (Litman and Correia, 1983). It remains to be resolved, however, whether changes in this heme-dependent enzyme system alone can account for observed low-level lead neurotoxicity. ! TEH 0413689 DUP050454743 D-12 (iii) Impairment of heme availability in neural tissue Heme biosynthesis appears to be inhibited in nervous system tissues at dose ranges comparable to those which are toxic in erythroid and liver cells (Whetsell et al., 1978; Sassa et al., 1979). Co-administration of heme and lead prevented most of the neuro-morphological effects caused by lead alone, namely destruction of myelin and Schwann cells and structural alterations of neurons (Whetsell and Kappas, 1981; Whetsell et al., 1984). These results are suggestive of heme's possible role in neurotoxicity, but again, firm conclusions must await further research. (iv) Impairment of cytochrome function in brain energy metabolism Another possible heme-mediated mechanism of lead neurotoxicity is suggested by findings that production and operation of the electron transport cytochrome C respiratory chain in the developing cerebral cortex are impaired when neonatal rats are chronically exposed to low levels of lead (Holtzman and Shen Hsu, 1976; Bull et al., 1979). Disruption of energy metabolism has been implicated in developmental delays in the metabolically active nervous system of young animals exposed to relatively low levels of lead (McCauley et al., 1979; Crofton et al., 1980). These linkages between the biochemical effects of lead on heme synthesis and neurological function are primarily based on animal or in vitro experimental data. As such, it is difficult at this time to determine a lead exposure level of concern for heme-reTated neurological impairments in humans. Nevertheless, the common biochemical processes operating across neurological and hematological systems in mammalian species suggest that the abnormalities in heme synthesis caused by low level lead exposure in humans may also indicate some risk of neurobehavioral impairments. TEH 0413690 DUP050454744 2. Neurological Effects of Lead a) Acute Effects and Peripheral Nerve Damage The effects of lead on the nervous system are both structural and functional, involving various regions of the brain and spinal cord (i.e., the central nervous system) as well as the motor and sensory nerves leading to specific areas of the body (i.e., the peripheral nervous system). These effects can result in deterioration of intellectual, sensory, neuromuscular, and/or psychological functions. Acute encephalopathy (degenerative brain disease) is the most severe consequence of lead intoxication. Early features of the syndrome include lethargy, sporadic vomiting, irritabi1ity, loss of appetite, dizziness, poor attention span, muscular tremor, and memory loss. These signs can abruptly progress to delirium, convulsions, coma, and ultimately death (Cumings et al., 1959). Acute encephalopathy in adults usually is manifested at PbB levels of approximately 100-120 pg/dl (Chisolm and Harrison, 1956; Chisolm, 1965); scattered evidence (Gant et al., 1938; Smith et al; 1938; Bradley et al., 1956; Bradley and Baumgartner, 1958; Cumings, 1959; Rummo et al., 1979) suggests that this syndrome may be associated with PbB levels between 80 and 100 pg/dl in the most susceptible children (CO, p. 12-62). Severe lead poisoning with or without encephalopathy has permanent effects on the behavior-and intellectual functioning of children, even if subsequent lead exposure is minimized. Such sequelae range from mental retardation and cerebral palsy to sensorimotor deficits, short attention span, and optic atrophy (Byers and Lord, 1943; Chisolm and Harrison, 1956; Perlstein and Attala, 1966; Chisolm and Barltrop, 1979). TEH 0413691 DUP050454745 While encephalopathy occurs primarily fn children, peripheral nerve damage (neuropathy) due to high lead exposure is more commonly found in adults occupationally exposed to lead. Overt symptoms such as muscle tremor, palsy (e.g., "wrist drop") or weakness, muscle and joint pain, and gastrointestinal complaints have been observed in workers with PbB levels exceeding 40 pg/dl (Lilis et al., 1977; Spivey et al., 1979; Baker et al., 1979; Haenninen et al., 1979; Zimmerman-Tansella et al., 1983). The conduction velocity of electrically stimulated nerves in the arm or leg provides a readily accessible indication of neurophysiological function in sensory as well as motor nerves. Small reductions in nerve conduction velocities (NCVs) have been observed in some apparently asymptomatic workers with PbB levels as low as 30-50 pg/dl (Seppalainen et al., 1975, 1979, 1983; Araki and Honma, 1976; Melgaard et al., 1976; Bordo et^al., 1982; Johnson et al., 1980; Seppalainen and Hernberg, 1980, 1982; Singer et al., 1983; Triebig and Nottbohm, 1983; Rosen et al., 1983). It Is difficult to draw conclusions from these observations without further prospective studies and in light of contrasting, negative findings (Spivey et al., 1980; Triebig et al., 1984), as well as a lack of consistency in the nerves examined and in the significance of the results. Nevertheless, the preponderance of results have been positive, and of the various nerves examined, the most consistently decreased NCVs appear to Involve the median motor nerve in the arm. Although lead-induced impairment of nerve conduction may be reversible, at least in part by a reduction in PbB levels through chelation therapy (Feldman et al., 1977; Araki et al., 1980), it is not clear whether such effects reflect mild, fully reversible impacts of lead (Buchtal and Behse, 1981) or are early warning signals of progressively more serious neuropathy in otherwise undiagnosed lead intoxication (Feldman et al., 1977; Seppalainen and Hernberg, 1980), TEH 0413692 DUP050454746 1 D-15 Overt, lead-induced peripheral neuropathy has been documented in children with PbB levels above 60 pg/dl (Erenberg et al., 1974), and in some cases possibly as low as 40 pg/dl (CD, p. 12-95). Although more subtle signs of possible advancing neuropathy (i.e., slowed nerve conduction velocities) have been observed in children across a wide range of increasing PbB levels, (Landrigan et al., 1976), no clear threshold for abnormal function can be determined from the available data. In interpreting the effects of lead on the peripheral nervous system, it is important to note that: 1) Because these are chronic effects and PbB levels do not accurately reflect the long-term accumulation of body lead, it has not been determined if peak exposures prior to the time of study are responsible for the dysfunction, or the length of time that PbB must remain above a certain level to cause impairment; 2) The range of nerve conduction velocities in*humans is great, even when measured by a single investigator and, in almost all studies, most velocities among individuals are well within the range of normal values (although a statistical reduction in a population does indicate the need for reducing lead exposure; Seppalainen et al., 1975); and 3) Because peripheral nerves are able to regenerate, there is some dispute as to whether the observations of slowed nerve conduction velocities reflect mild, reversible impacts of lead (Buchtal and Behse, 1981) or are early warning signals of progressively more serious peripheral neuropathies that are important in the diagnosis of otherwise unrecognized toxic lead effects (Feldman et al., 1977; Seppalainen and Hernberg, 1980). The criteria document concludes "nevertheless it is clear that these effects represent departures from normal neurologic functioning and their potential relationship to other more serious effects argues for prudence in Interpreting their potential health significance." (CD, p.12-61) TEH 0413693 DUP050454747 0-16 b) Effects Associated with Chronic Low-Level Exposures Besides the severe pathophysiological changes observed in the central nervous system (CNS) associated with childhood lead intoxication, various maladaptive behaviors, neuropsychological deficits, and neuro-anatomical changes may be associated with chronic exposures to relatively low concentrations of lead. Below is a summary of the numerous biochemical, morphological, and functional effects of lead at low dosages and exposures that have been found in developing nervous systems. Although effects in adults are not the focus in this paper, the lead-induced CNS effects reported in non-overtly lead Intoxicated adults are important to note. Disturbances in oculomotor function, reaction time, visual-motor performance, hand dexterity, 10 scores, memory, learning ability, mood, nervousness, and "coping" have been observed in lead workers with PbB levels of 50-80 pg/dl, and In some cases, at time-weighted average levels as low as 27-52 pg/dl (Baloh et al., 1979; Spivey et al., 1980; Arnvig et al., 1980; Grandjean et al., 1978; Haenninen et al., 1978; Hogstedt et al., 1983; Mantere et.al., 1982; Baker et al., 1983; Valciukas et al, 1978). No single mechanism appears sufficient to account for the diverse effects of lead on neurological function, and it is more likely that lead acts at several cellular and sub-cellular sites. Although neurochemical changes may preceed observable effects on electrophysiology, morphology, and behavior in terms of dose, they are not separate from functional changes at higher levels. In those systems that have been examined pharmacologically in vitro (e;g., inhibition of adenyl cyclase, acetylcholine release, and Na,K-ATPase), a continuous dose-response relationship is suggested, best fitted by smooth curves with either no threshold or thresholds in the nanomolar range (Silbergeld, 1983). It should be noted that the findings from in vitro or animal studies TEH 0413694 DUP050454748 0-17 cannot be directly extrapolated to estimate PbB levels associated with changes in pediatric neurological functions because: a) the relatively short lifespans of experimental animals alters the relationship between dose and duration from that which may exist for humans; b) significant species differences exist for absorption, retention, and internal compart- mentalization of lead; and c) with some exceptions, the measurements of animal neurotoxicity are not comparable to those possible in studies of children (Silbergeld and Goldberg, 1980; Winneke et al., 1982b). Although in vitro or animal results should not be quantitatively applied to lead-induced effects in humanSjthe continuum of lead neurotoxic effects starting with biochemical changes at the lowest observed dose levels provides an important foundation in assessing the more overt effects reviewed in this section. 1) Brain Development o Lead readily enters the brain and appears to be selectively deposited in the hippocampus and cortex as well as in non-neuronal elements (e.g., glial cells, endothelial cells of brain capillaries) that are important in the maintenance of "blood-brain barrier" functions (Fjerdingstad et al., 1974; Grandjean, 1978; Stumpf et al., 1980). Once deposited, lead is retained in the brain for long periods of time even after external exposure ceases and PbB levels decline (Mykkanen et al., 1979; Goldstein et al., 1974). These spatial and temporal patterns of brain lead accumulation correspond to the following neurobehavioral and morphologic abnormalities associated with lead exposure: 1) pathologic studies of exposed animals and encephalopathic humans that indicate changes of a primarily vascular (e.g., endothelial and glial cell) nature (Michaelson and Sauerhoff, 1974); 2) animal studies that show effects on neuronal populations in the hippocampus and cortex and behavioral changes indicative of hippocampal and cerebellar TEH 0413695 DUP050454749 D-18 dysfunction (Campbell et al., 1982; Petit and Alfano, 1979; Bushnell and Bowman, 1979); and most importantly 3) electro-physiological and behavioral changes associated with lead exposure measured in young animals and children that persist long after exposure is reduced or ceases (Brown, 1975; Otto et al., 1982). The sensitivity of the brain during the period of maximal brain growth and differentiation in the first 2 years of life tends to magnify the severity of the long-term consequences of any toxin encountered during that period (Oobbing, 1974). The immaturity of specific brain tissues (i.e., hippocampus, cerebellum and neocortex) at birth and their relatively late development suggests that post-natal lead exposure could interfere with mitosis, cellular migration, differentiation of dendritic and axonal processes, synaptogenes.ls, and myelin production, as well as exerting biochemical and cytotoxic effects (Campbell et al., 1982). While the developing nervous system may possess-considerable reserve -for functional compensation (involving plasticity, regeneration, and redundancy of neural pathways), specific processes affected by lead apparently may not be reversed, either because lead is not removed from brain cells (Silbergeld, 1983) or because of interruption or damage to neurostructural elements undergoing rapid development at the time of the lead Insult. Rat pups exposed to low levels of lead during the pre-natal or neonatal period show retarded development in cerebral energy metabolic pathways, delayed cerebral cortex synaptogenesis, and reductions in hippocampal morphometric, dendritic, and axonal development (Bui 1 et al., 1979, 1983; McCauley et al., 1979, 1982; Petit and Alfano, 1979; Alfano and Petit, 1982; Petit and LeBoutillier, 1979; Averill and Needleman, 1980; Campbell et al., 1982). These biochemical and morphological disruptions are paralleled TEH 0413696 DUP050454750 0-19 by delays in the development of exploratory and locomotor activity, and by learning and behavioral deficits in young, lead-exposed animals (See CD, Tables 12-4 and 12-5). The effects of in utero or post-natal lead exposures on human infant neurological development have begun to be investigated. Mentally retarded children in Scotland were more likely by a factor of 1.7 to come from homes in which high levels of lead in drinking water (> 800 ppm) were present during pregnancy compared to controls (Beattie et al., 1975). PbB levels in a sample of these children at 2 weeks of age were 25.8 + 8.9 pg/dl compared to 20.9 * 7.9 (jg/dl in normal children (Moore et al., 1977). Although these are provocative findings, their quantitative value is uncertain given that the children were limited to those known to health care services (and hence not necessarily representative), the matching was imperfect, and the P.bB levels were available for only about 50% of the children. Preliminary results from recently initiated prospective studies suggest that low to moderate lead exposure (mean PbB 15 pg/dl) during the first two years of life may have a small impact on early and mental development (Bellinger et al., 1985; Dietrich et al., 1985). Assessment of the medical significance and persistence of these effects, if any, must await follow-up testing and replications from other longitudinal studies. 2) Motor Coordination and Reflexes Pre- and post-natally lead-exposed rats tend to show developmental delays in their ability to orient properly and respond to selected stimuli (Overmann, 1977; Overmann et al., 1979, 1981; Grant et al., 1980). Impaired performance was observed in rats with PbB levels as low as 35 pg/dl at 11 days of age although no significant' effects have been found at higher exposures in some studies using somewhat different measures of motor coordi nation and reflexes (Overmann et al., 1979; Zenick et al., 1979; Grant et TEH 0413697 DUP050454751 D-20 al., 1980). These contrasting results can probably be attributed to differences in body weight, age at testing, and in the test apparatus and procedures (Zenick et al., 1979). Lead-induced abnormalities in motor ability may be linked to preferential concentration of lead in the cerebellum where posture and movement is regulated, or to lead's damaging effects on peripheral nerves and at the neuromuscular junction (Cooper and Manalis, 1974; Silbergeld et al., 1974). Small deficits in perceptual motor integration and fine motor coordination have been reported in children with PbB levels of 50-60 pg/dl, and possibly as low as 30-40 pg/dl (de la Burde and Choate, 1972, 1975; Landrigan et'al., 1975; McBride et al., 1982; Needleman et al., 1979; Winneke et al., 1982a), or lower (Winneke et al., 1983). No significant lead-related deficits in performance have been found at comparable PbB levels (i.e., 30-60 pg/dl) (Rummo, 1974; Rummo et al., 1979; Perino and Ernhart, 1974) and at Pb8 levels below 25 pg/dl (Winneke et al., 1984). No differences in fine motor scores were found in another study, although the mean PbB levels for the control group (26 pg/dl) may have been too high to detect any effect in the exposed group (PbB 38 pg/dl) (Kotok, 1972; Kotok et al., 1977). These conflicting results are analogous to those found in animal experiments in which somewhat different measures of motor coordination and reflexes were also used. Nevertheless, any deficits in perceptual motor and fine motor coordination that are, in fact, related to lead may be functional evidence of lead-induced decrements in motor nerve function. This has been noted in children and in adults who exhibit conduction deficits in distal-extremity nerves at PbB levels above 30 pg/dl (See Appendix 0.2.a). Similarly, the findings of perceptual Inaccuracies associated with lead exposures have been Interpreted in terms of lead-induced attentional TEH 0413698 DUP050454752 D--21 deficits which are discussed below (Winneke et al., 1983). 3) Hyperactivity and Other Behavioral Disorders Since Byers and Lord (1943) reported hyperactivity as a possible sequel for children who had recovered from lead poisoning, there has emerged a large and controversial data base concerning possible associations between lead and hyperactivity and other behavioral disturbances. Hyper activity is a complex syndrome with respect to both cause and manifesta tion. Attention deficit disorder is generally thought to be the most salient manifestation of the condition (American Psychiatric Association, 1980). This disorder occurs with and without hyperkinesis, which refers more to inappropriate and/or random activity than it does to an increase in activity, although the latter is sometimes seen (David et al., 1983). Other symptoms frequently present are impulsivity, low frustration tolerance, hyperexcitability, and disturbances in conduct (Wender, 1971; David et al., 1983). Inconclusive findings of hyperkinesis have been reported in neonatally lead-exposed rodents (CD, Table 12-4). Attempts to collate these data are hampered by variability In the species, dose of lead, length and route of exposure, age, the methodology for activity testing and the presence of growth retardation. It has been proposed that a) the apparently discrepant findings on hyperkinesis are consistent with an explanation in terms of lead-induced, situation-specific, emotional or behavioral over-reactivity rather than hyperactivity per se (Hastings et al., 1977; Winneke et al., 1982b; Kishi et al., 1983); b) these behavioral disturbances are consistent with previously described disruptions in hippocampal morphology and function (Petit et al., 1983); and c) these behavioral effects may contribute to learning deficits observed in lead-exposed animals (see Appendix D.2(b)5). Despite these interesting analogies between some of the changes in j TEH 0413699 DUP050454753 developmental animal behavior and hyperactive abnormalities, it would be premature to extrapolate from simple animal models to this complex clinical syndrome in children. Multiple etiologic factors Including genetic influences, perinatal complications, covert cerebral insult, irregular brain maturation, maldevelopment and perhaps, most importantly, psychosocial factors can play a role in hyperactivity (David et al., 1983)j Some studies that have attempted to control for these etiological factors and pica (which may be a consequence rather than a cause of hyperactivity) have found consistently higher lead levels in hyperactive children (Baloh et al., 1975; David et al., 1976; 1977; 1985; Gittleman and Eskenazi, 1983) and mentally retarded children (Youroukas et al., 1978), while other studies have not (Rummo, 1974; Milan et al., 1981). Because of methodological limitations, conclusions from these studies are also limited. * In an experimental intrevention study designed to avoid some of these problems, David et al. (1983) found that reductions in hyperactive children's PbB levels (from 29.3 to 19.5 pg/dl) as a result of chelation therapy with penicillamine were associated with marked symptomatic and behavioral improvements, as assessed by teachers, parents, and treating physicians. Hyperactive children given a therapeutic drug to treat the syndrome, but whose PbB levels remained approximately the same, showed some similar improvements while children given a placebo exhibited no significant changes in behavior ratings or PbB levels. Several methodological problems have been noted in this study as well (Needleman and Bellinger, 1984; Rutter, 1983). The criteria document concludes that the above data are at best qualitatively suggestive and that if lead is indeed causally involved in the etiology or exacerbation of the behavioral abnormalities associated with hyperactivity, it is currently impossible to TEH 0413700 DUP050454754 0-23 state with confidence the levels, durations or critical periods of lead exposure that may have been important (CD, p. 12-89), There is somewhat more convincing evidence that low PbB levels may contribute to some other behavioral disorders such as attentional deficits and distractibility in essentially normal children not diagnosed as hyper active. Several analyses of classroom behavior have failed to adequately account for the influence of social class although they have produced consistent dose-response relationships in which teachers* ratings on several behavioral measures (e.g., '*distractabilityM, "not persistent", low overall functioning) increase parallel with tooth and PbB levels (de la Burde and Choate, 1972; Needleman et al., 1979; Yule et a!., 1984). A follow-up of the children studied by Needleman et al. (1979) suggests that other measures of classroom performance may show long-term effects of early lead exposure more effectively than IQ measures (Bellinger et al., 1984). Silva et al. (1986) found similar results on 11-year old children. As is the case for several other general population studies (Landrigan et al., 1975; Winneke et al., 1983), hyperactivity was noted in very few children and was generally not associated with lead levels. After adjusting for socio-economic and other potentially confounding factors, behavioral and attentional deficits as rated by teachers (e.g., disordered classroom activity, restless, easily distracted, not persistent, does not follow directions, low overall functioning) were significantly associated with children's tooth and PbB levels (Winneke et al., 1983). The criteria document has Interpreted this study, which also assessed lead-induced deficits in 10 and other psychometric tests, as showing overall neurobehavioral deficits at PbB levels possibly below 30 yg/dl (Winneke et al., 1983). In addition, lead levels in young children have been consistently TEH 0413701 DUP050454755 D-24 associated, following appropriate adjustments, with deficits in reaction time under varying intervals, which is an index of attentiveness (Needleman et al., 1979; Gillberg et al., 1982; Winneke et al., 1983; Yule and Landsdown, 1983; Hunter et al., 1983), and with reaction behavior (Winneke et al., 1984). The criteria document concludes that these findings appear to argue for probable effects of lead on attention and vigilance functions at PbB levels extending below 30 yg/dl, and possibly, down to as low as 15-20 jjg/dl (CD, p. 12-84). 4) Auditory and Language Processing Central nervous system damage caused by severe childhood lead poisoning is often associated with motor-speech and language disorders (Byers and Lord, 1943; Mellins and Jenkins, 1955). There is conflicting evidence on whether subtle cerebral Injury associated with chronic low-level lead absorption is manifested in impaired verbal behavior and auditory processing. Several studies have found no statistically significant lead-related differences on verbal subtests of standardized intelligence tests in children with PbB levels across a range front below 10 to above 60 yg/dl (de la Burde and Choate, 1975; Landrigan et al., 1975; Kotok et al., 1977; Yule and Landsdown, 1983; Yule et al., 1984; Smith et al., 1983; Winneke et al., 1982a, 1983, 1984), while other studies have (Kotok, 1972; Rummo et al., 1979; Needleman et al., 1979; Yule et al., 1981). Significant associations, however, have been detected between children's lead levels (possibly as low as 30-50 pg/dl PbB) and a more extensive battery of measures, including motor-speech behaviors, language comprehension, formulation behaviors (Needleman et al., 1979; 1984) and auditory processing tasks (de la Burde and Choate, 1975; Needleman et al., 1979). In addition to more specific measures of language and auditory function, these findings of lead-associated decrements TEH 0413702 \ DUP050454756 D-25 may be attributable to samples drawn from among children with relatively early exposures to lead. Although no conclusions can be drawn from these findings, it is clear that further research on low level lead effects in children should include sensitive measures of motor-speech behaviors and communication impairments. Because maturation of the auditory cortex, which plays a vital role in language processing, and the onset of competence in speech and language occurs within the second year of life (Shaheen, 1984), such research should include assessments of the effects of lead absorption in children prior to their second birthdays. 5) Cognitive Function In addition to deficits in behavioral functions, fine motor control, and auditory, language and speech development, there is evidence that low levels of lead may be associated with effects on some complex cognitive functions including learning, visual-perception skills, and IQ scores. In studies not confounded by nutritional or litter effects (a common problem in behavioral assays), rats exposed to lead in utero and/or through early development, resulting in PbB levels below 30 pg/dl and as low as 20 jjg/dl, display alterations in learning task performances (visual discrimination, shock avoidance, operant conditioning) (e.g., Winneke et al., 1977, 1982b; Cory-Slechta and Thompson, 1979; Gross-Selbeck and Gross-Selbeck, 1981; Bushnell and Levin, 1983; Cory-Slechta et al,, 1983, 1985; Alfano and Petit, 1985). Monkeys exposed for one year after birth to achieve PbB levels between 30 and 50 pg/dl were significantly retarded in their ability to learn spatial and discrimination tasks (Bushnell and Bowman, 1979) and in their ability to alter their behavior under changed learning conditions (Rice and Willes, 1979). After lead dosing ceased, the lead treated monkeys TEH 0413703 DUP050454757 D-26 at 2-3 years of age (PbB * 20 pg/dl) had higher response rates than controls to reinforced stimuli (Rice et al., 1979), and deficits in spatial memory persisted in these monkeys at 4-5 years of age when Pb8 levels had stabilized at 5 pg/dl (Levin and Bowman, 1983). Another series of studies on monkeys using conditioning tasks demonstrated consistently impaired learning ability, even in some cases where the peak PbB levels reached only 15 pg/dl and steady state levels were only 11 (jg/dl (Rice, 1985). Pb8 levels are presented for comparative purposes only and should not be extrapolated to human dose-response relationships. In considering these effects, it should be noted that performance in a learning task is based on a number of functional processes, such as motor functions, emotional-motivational conditions, sensory functions, and cognitive functions (namely memory and/or learning processes, i.e., the formation and retention of stimulus-response associations) (Sornschein et al., 1980; Winneke et al., 1982b). It has been suggested that the above findings, which include "improved" performance in lead-treated animals on some learned tasks where success was measured by rapid response, indicate an underlying tendency to respond excessively or a behavioral "over-reactivity," whether or not such response is appropriate (Winneke et al., 1982b). This interpretation corresponds to some extent to lead-induced increases in locomotor activity and responsedisinhibition (Overmann, 1977; Winneke et al., 1977; Rice and Willes, 1979; Schlipkoter and Winneke, 1980; Rice, 1985; Alfano and Petit, 1985). Taken together, these data indicate that lead exposure during early development is disruptive in attention-demanding, difficult discrimination learning and complex neuropsychological performance and reduces responsiveness to contingencies in the environment, but this exposure facilitates active avoidance and other simple learning tasks (Overmann, 1977; Winneke et al., 1982b). Although TEH 0413704 DUP050454758 D-27 these results cannot be quantitatively extrapolated to children, they are in agreement with findings from recent studies that lead at low doses may be associated with a spectrum of alterations in children's behavioral, academic, and possibly intellectual development (see below). These studies on children have attracted controversy because of difficulties associated with attributing subtle deficits in child development to lead ex posure rather than to effects due to genetics, nutrition, medical history, access to education; and parental and social influences, all of which interact in potentially complex ways to mold an individual (Pearson and Dietrich, 1985), Untangling these different sources of behavioral variance is complicated by the necessary focus on children from lower socioeconomic areas where lead exposure is elevated and learning and caregiving conditions often are not ideal. */ . Other difficulties encountered in the conduct and interpretation of childhood lead studies include: 1) accurately classifying exposure since PbB is an Index of recent, but not necessarily historical, lead exposure, and because the relationship between tooth and PbB levels is uncertain; 2) in appropriate measurement covariates (e.g., social class as an index of parental care and intellectual stimulation) that can bias regression analyses; 3) incomplete assessment of complex behavioral and intellectual processes; and 4) possible non-representativeness of study samples since most studies relied on information from either pre-selected clinic groups along with a selected "match" sample, or volunteers from the general population who may be more altruistic, interested, or better informed (Smith et a!., 1983). Based on five methodological criteria (adequate markers of lead exposure, sensitive measures of neurobehavioral function, appropriate subject selection, control of confounding covariates, and appropriate statistical analysis), the TEH 0413705 DUP050454759 D-28 criteria document has identified a group of neurobehavioral studies that "were conducted rigorously enough to warrant at least some consideration here" {CD, p. 12-65). As with other parameters of neuropsychological performance, there have been mixed findings regarding lead's association with children's scores on standardized IQ tests, which measure some combination of literacy, information, academic capacity, and intelligence (Flynn, 1984). Several well-controlled studies have found effects that are clearly statistically significant whereas others have found "non-significant" but borderline effects. It is important to note that: 1) the definition of "statistical significance" (p < 0.05) is somewhat arbitrary and should not be-used to totally exclude results that may have Important public health implications; and 2} given the likely subtle nature of the behavioral or neural effects probable at' low levels of lead exposure, the differential maturation patterns and sensitivities among different brain processes, and the many other factors that play a larger role in an individual's developmental trajectory, one would not expect to find striking differences in every study, especially in those that use standardized but non-specific measures of intelligence or academic capacity. The general indication from the better Investigations is that PbB levels persistently elevated in the range of 50-70 pg/dl tend to be associated, on average, with about a 5 point reduction in IQ, even among asymptomatic children and after controlling for potentially confounding variables (de la Burde and Choate, 1972, 1975; Rummo, 1974; Ruramo et al., 1979). A 5 point decrease in children's average IQ score, given the normal curve of distribution of intelligence, would be associated with a doubling In the number of children with IQ's below 70 (the level used to define mental retardation), as well as a reduction in the number of children with IQ's above 125 (Rutter, 1980). TEH 0413706 DUP050454760 8-11 Several of the studies for which data are not used to develop relationships require comment: a) Barltrop et al. (1975) surveyed a rural district in England with minimal air pollution, but with high natural soil lead levels as well as being contaminated by nearly 1900 years of mining activity. Thus, lead deposition on soil surfaces had probably been low for some time, in contrast to the other studies In which surface contamination was ongoing or had been recently reduced; b) Eight of the ten homes sampled by Lepow et al. (1975) were built prior to 1940 and apparently had significant sources of leaded paint that had been "corrected" for previous to the study. In addition, some of the homes were located close to heavily trafficked roadways, where street level air concentrations ranged between 2.2 and 7.7 pg/m3, thus lending uncertainty to a dust/air relationship from this study based on annual average air lead levels measured at centrally located monitors distant from the dust sampling sites; c) The smelter studied by Yankel et al. (197J) operated for several years with severely limited air pollution control capacity due to a baghouse fire in 1973. The very high soil and dust lead concentrations measured near the smelter would not be expected today with normally controlled emissions; d) The high indoor dust lead levels measured by Brunekreef et al. (1981) and Diemel et al. (1981) near the Belgian smelter were probably due, in part, to extremely high lead content (up to 40% by weight) in peeling paint in old houses (built around 1900; the children in these houses were excluded from analysis of blood lead levels); e) The relatively high soil and dust lead levels in relation to concurrent air lead concentration measured near the Bartlesville smelter by Hartwell et al. (1983) was probably due to a drastic reduction of total suspended particulate emissions, from 1600 tons/year to 15 tons/year, just prior to the onset of the study. TEH 0413659 DUP050454761 B-12 With these exceptions, the studies listed in Table B-l appear to have sampled a broad spectrum of homes (e.g., both low and middle class, old and modern, with and without leaded paint -- those with high paint lead levels were excluded) and neighborhoods that can be considered fairly representative of current U.S. conditions in urban and point source areas. Although far from conclusive, the available data suggest the generalized relationships between air lead and soil/dust lead concentrations presented in Table 8-2. The ranges represent boundaries that encompass the majority of observed and interpolated values and are used to estimate street dust/soil lead and indoor dust lead concentrations under alternative air lead levels. Interpolations were necessary because of the limited amount of data. For instance. Angle and Mclntire (1979) and DOE (1983) report outdoor soil/ dust lead concentrations in urban areas with an average air lead level of approximately 0.4 pg/m3 to be 81 and 260 ppm (pg Pb/g soil or dust), respectively. One of the rural control areas studied by Roels et al. (1978) had an outdoor soil/ dust lead concentration of 114 ppm corresponding to an air lead level of 0.45 pg/m3, The range of 80-350 ppm is thus estimated based on these data. For indoor dust, the former two studies report concentrations of 190 and 211 ppm; these were chosen as an upper bound estimate for 0.4 pg/m3 while the lower bound of 140 ppm was derived by multiplying by two the lower bound estimate for an urban/rural area with an air lead level of 0.2 pg/m3 (70 ppm from DOE, 1982). Outdoor soil/dust lead concentrations near point sources that can reasonably be associated with 0.4 pg/m3 were derived from Brunekreef/Oiemel et al., 1981 (690 ppm) and by interpolating the levels measured by Hartwell et al. (1983) concurrently with average air lead levels of around 0.25 - 0.28 pg/m3. The resulting estimate is 624 to 630 ppm and, when combined with the Brunekreef value, results in an upper TEH 0413660 DUP050454762 B-13 Table B-2. Generalized Relationships Between Lead Concentrations in Air and in Dusts and Soil! Air Lead (ljq/m3) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Outdoor Soil/Dust Lead (ug/g) General Near Point Source 5-30 20-100 20-90 50-300 40-150 80-450 70-250 125-600 100-350 200-700 150-500 350-800 200-650 450-1000 250-800 550-1150 Indoor Dust Lead (pg/g) General Near Point Source 5-30 20-100 40-100 40-200 70-200 70-400 100-250 250-600 200-300 300-650 250-400 350-700 300-500 400-750 350-600 500-800 0.8 300-950 650-1300 450-700 600-900 1.0 500-1150 750-1450 525-875 800-1150 `1.25 1.5 1.75 600-1250 700-1400 775-1450 850-1600 1000-1750 1075-1950 625-1000 750-1150 800-1200 1000-1400 1200-1700 1350-1900 ^Derived from environmental surveys in Table B-l. The ranges of dust and soil concentrations for each air lead level reflect differences in emission sources, distance of measurement sites from these sources (within 5 km for point sources) and characteristics of the homes (e.g., permeability, paint condition, etc.), and other variables assumed to be representative of real world conditions. Values that are underlined represent actual data (rounded off where necessary) listed in Table B-l, while the remainder are interpolations using the most representative and plausible data in Table B-l and an assumption that there is a directly proportional relationship between air lead and lead in dusts (both indoors and outdoors) and in the top layers of soil. 1 TEH 0413661 DUP050454763 B--14 bound estimate of 700 ppm. The lower bound estimate of 250 ppm is assumed based on the levels of 80 ppm observed by Hartwell et al. at 0.2 yg/m3, 466 ppm measured at 0.8 yg/m3 by Roels et al., and 337 ppm at 0.5 yg/m3 by Yankel'et al. This brief example at 0.4 yg/m3 only superficially illustrates the limitations of the available data and the judgments necessary to fill in gaps using various assumptions, such as the assumption of a direct and roughly linear relationship between air lead and surface concentrations. It must be emphasized that there is a great deal of uncertainty in these estimates. For instance, assuming that a decrease in air lead from 1.0 to 0.8 yg/m3 would result in reduced soil and dust lead concentrations may overestimate the impact that such a decrease in lead emissions would have on children's exposure, particularly because outdoor soil tends to retain lead for long periods of time. Dust lead levels would likely respond relatively more contemporaneously to reduced air emissions, but the necessary length of time is difficult to estimate. 14. It is estimated that a young child typically sleeps about 12 hours a day (Pope, 1986c), leaving approximately 12 waking hours in which he or she is capable of ingesting dirt. The time weighted concentration of lead in dust and soil that a child is exposed to is thus computed by: [(outdoor soll/dust lead concentration x time spent outdoors) + (indoor dust lead concentration x time spent indoors)] -f- 12 hours. 15. Amount of dirt ingested: Hand to mouth activity (e.g., thumb sucking and finger licking) and Immature dietary habits (i.e., the retrieval and subsequent consumption of food from dusty surfaces or soil), which are normal behavorial characteristics of children up to five years of age (Lin-Fu, 1972), make soil and dust major sources of ingested lead for children (Charney et al., 1983). There is little information on the amount | TEH 0413662 DUPO50454764 8--1S of dirt a child eats in the normal course of a day. Lepow et al., (1974) measured a mean of 10 ug of dirt on the hands of 22 young children which would be ingested with each episode of hand to mouth activity. Based on a small number of direct measurements. Day et al. (1975) estimated that under average urban conditions (and after 30 minutes of normal playground activity), 5 to 50 mg of dirt transferred from a child's hands to a typical "sticky sweet", and estimated that a daily intake of 2-20 sweets would lead to a dirt intake of 10-1000 mg. These authors estimated that a child puts its hand Into Its mouth ten times per day which would result in the Ingestion of 100 mg (0.1 g) of dust and soil per day. An average estimate of 100 mg of dirt ingested daily by young children has been used in several documents (Drill et al., 1979; NAS, 1980; CD, Table 7-23) and will be used here as well to represent a probable value for a "typical" child. It should be noted that this value probably underestimates the dirt' Ingestion rate for many children in certain circumstances. For example, among young children hospitalized for asymptomatic lead poisoning and exposed to three play environments which differed in their stimulus complexity (e.g., number and type of toys, availability of playmate), significantly more mouthing behavior occurred in the impoverished play setting (Madden et al., 1980). In particular, children with pica who display patterns of repetitive hand-to-mouth activity or deliberately Ingest paint, plaster, paper and other non-food items including dirt may be exposed to considerable amounts of lead compared to children who only inadvertantly ingest foreign substances. Pica occurs to some degree in a substantial percentage of young children. Data from NHANES II indicate that the percent of children with a history of pica is significantly higher for those 6 months through \ TEH 0413663 DUP050454765 3 years old (11.0%) than for those 4 through 5 years old (3.2%) and for children living in households with annual family incomes < $10,000 (11.9%) than for those in households with incomes > $10,000 (6.0%) (Mahaffey and Annest, 1985). Estimates for pica prevalence rates, based on more limited samples, range as high as approximately 10 to 30% in children 1 to 6 years old to 35-50% in those 1 to 3 years old (Milllcan et al., 1962; Barltrop, 1966), Children exhibiting pica for paint are of major concern because of the high levels of lead in some paints, with older painted surfaces containing lead In concentrations greater than 1 percent (10,000 ppm). [The allowable lead content of paint was set in 1978 by the Consumer Product Safety Commission at 0.06 percent lead (600 ppm)]. Pica for paint is believed to occur in episodes, possibly 2 to 3 times per week (NAS, 1972). It has been estimated that a child can consume somewhat greater than 1 gram within a 24 to 36 hour period, with cases reported of up to 20 grams within the same time period (Sachs, 1975) and that children with pica for paint may consume 1 to 3 grams per week (NAS, 1972). Estimates of daily lead uptake under alternative air lead levels are presented in Table 5-1 only for children without pica. In order to calculate the contribution of lead in paint to the total lead exposure of children with pica, the above range of 1 to 3 grams of paint chips consumed per week (i.e., approximately 140 to 430 mg/day) could be used. As discussed In Section VII, future reductions in airborne lead emissions are not likely to significantly alter pica exposure to lead over the next few years and other regulatory alternatives to protect these children must be considered. 16. Lead intake from dust and soil is computed by multiplying the time weighted concentration of indoor and outdoor soil/dust concentrations by 100 mg. TEH 0413664 DUP050454766 B-17 17. Gut absorption of dirt: As discussed in Appendix A, an absorption rate of 30% is assumed for ingested lead in dust and soil. 18. Total lead uptake from dust and soil is obtained by multiplying rows 16 and 17. 19. Total lead uptake is the sum of rows 8, 11, and 18. TEH 0413665 DUP050454767 APPENDIX C. UPTAKE AND BLOOD LEAD CONCENTRATION Several studies are available that provide the necessary linkages to relate the exposure/uptake estimates calculated under different air lead levels in the integrated uptake model (See Section V.A.l) to children's PbB levels. The re sults of these studies are summarized in Section V.A.2 and are discussed below. a) Dietary Lead Ingestion Studies in Infants Studies that have measured dietary lead intake concurrently with PbB levels among infants and toddlers are compared in the criteria document (CD, Table 11-49). Although precise estimates of dietary lead consumption can not be assumed, these studies (U.K. Central Directorate, 1982; Sherlock et al., 1982; Ryu et al., 1983) have several advantages: .1) careful control and analysis of dietary intake; 2) minimal lead exposure to sources other than the diet as the study population (infants) is relatively immobile; and 3) the impact of total lead exposure (i.e., from all sources) on blood lead can be estimated by applying intake/blood lead relationships because tracer studies (Chamberlain et al., 1978; Rabinowitz et al., 1976) show no differences in the distribution of lead to tissues whether taken up from lung or gut. Both the U.K. Central Directorate and the Sherlock et al. studies involved infants with relatively high PbB levels and high intakes. Because the PbB levels (< 20 pg/dl) and lead intakes of the Ryu Infants are more relevant, the criteria document concludes that the slope from this study is the best available estimate (CD, p. 11-126). The relationship between lead intake and infants' blood lead, derived by EPA's analysis of Ryu et al. (1983) is: PbB = A + 0.16 PbD, where "PbD*' represents dietary lead intake and "A" represents non-dietary lead. Applying the gastrointestinal absorption rates (42-53%) used in Section V.A.l to convert dietary intake levels TEH 0413666 DUP050454768 into uptake and assuming a background PbB of 4 yg/dl, based on a study of blood lead and lead intake in Boston infants (Rabinowitz et al., 1984b), yields two possible lead uptake/PbB relationships depending on the absorption rate. These relationships are illustrated In Figure 5-1 in the summary of uptake/PbB relationships. b) Application of Chamberlain and Heard Analysis An attempt to relate blood lead and absorbed lead was made by Chamberlain and Heard (1981) using epidemiological and clinical data on adult men (Williams et al., 1969; Kehoe, 1961; Nordman, 1975; Zurlo and Griffini, 1973; Fugas and Saric, 1979). Total;dietary and airborne lead uptake was estimated using calculations similar to those presented in the integrated lead uptake model in Section V.A. The resulting eye-fitted curve is shown in Figure C-l. The dashed curve is that previously derived in a NAS (1972) report. */ The straight line is the increase in blood lead to be expected from an increase in lead uptake based on the assumptions given in Chamberlain et al., (1978): a) a fraction, 0.55, of the uptake becomes attached to red blood cells; b) the biological half-life of lead in blood is 18 days; c) a factor, 1.3, is to be allowed for long-term resorption and re-entry into blood of some of the lead which is stored in bone; and d) the mass of blood is 5400 grams With these assumptions: 4 PbB 4 Uptake 0.55 x 18 x 1.3 * 0.34 pg/dl per pg/day 54 x 0.693 In order to apply this equation to children, several adjustments are required. For example, the mass of blood in young children is estimated to fall between 800 and 1500 grams (Wintrobe, 1979). It has been sugyesteed that the half-life of lead in children's blood is shorter than in adults (Duggan, 1983) although no direct measurements have been taken to allow a reliable estimate. TEH 0413667 DUP050454769 Figure C-1. Relationship between daily lead uptake and blood lead in adult men. From Chamberlain and Heard (1931). i TEH 0413668 DUP050454770 C-4 Because there is no information available on appropriate factors to adjust this specific equation to children, the derived relationship from adult data illustrated in Figure C-l is illustrated in Figure 5-1 only for comparative purposes, c) Lead Balance Studies: Compartmental Models To demonstrate a causal relationship between lead in the body and a biological change, it would be ideal to know the amount of lead present at the site and time of the effect. For instance, if lead is'suspected to induce neuropsychological changes, a measure of the lead level present in nerve cells when the change occurred would be desirable. Living tissues can rarely be sampled, and data obtained at necropsy cannot reveal the variations in exposure throughout the individual's life. For analytical simplicity, these tissues can be grouped together on the basis of lead distribution characteristics and body burdens of lead represented as a limited number of distinct, homogenous, and well-mixed pools or physiological compartments with similar kinetic properties. Mathematical biokinetic models have been fitted to data obtained in long-term balance studies and to lead isotope tracer experiments that estimate the rates of Input to, transfer between, and excretion from the different compartments (Rabinowitz et al., 1976, 1977; 8atschelet et al., 1979; Bernard, 1977; Mallon 1983; Harley and Kneip, 1985). Differences in the predictive lead models have been discussed by Bernard (1977) and Batschelet et al. (1979). Two models are shown schematically in Figure C-2. Compartments as defined kinetically are not necessarily congruent with specific tissues or organ systems; the three pool model of Rabinowitz et al. (1976) considers blood, the most labile soft tissues, and bone marrow (M. Rabinowitz, personal communication) as part of the central compartment where exchange takes place continuously with the second (soft tissues and labile bone) and TEH 0413669 DUP050454771 A ir Lead I I Sources paint) D iet, Sail/Dust, ss3o> eo<Uj ---*A$ <n <-- *ac3a cWbou.i *e**va* V *S a- v>> --+J _3e7> W8 a9** 41 S'S.'S-S" <e* (eQ ui w41 4o> j s ss ts * e kS^S'" WW c o S *285^ `dQoSi amSbdi*^W*J --<u wo v. 5 -Q U U >t9 4 aVa* iur e *a *w a *^* * ca 2aj^3'-3 a* tOWml MiA od+*CsaJ--t^--J.<5wo0ie*m ^'.09-ci--~00V4vAa1iIl*~0<U* *--4ya_g4-3'11**+6V4aa3*I ~**b*>4mei1iu3/-r?f ba. *> * -W ocg =55 (A 56 *i0o Pf ao +4*i --9e> a e+V >* ao 0toao-) oi w e 1 v a*fm*m aV* ao4--i j*4b a--v-V eQ 4 Oe tU *--C b. <9 <U*. Cb W*1 Q 41 C Wag** *W3a*< sU * 4C*asbd *j C9(/. MbC<56Q*o4S> ra a9. a a ab 4vu> eus 5g *u covi i 29 CD Up. (Oet .h9e.r, Lead in DUP050454772 C-6 third (immobile bone lead) pools. The five-compartment model proposed by Bernard (1977) consists of pools that are mainly blood, liver, kidney, and soft and hard bone. The choice of pools or level of aggregation in a model depends on the available experimental data, the appropriate time scale, and the pre dictive uses of the analysis, and is a compromise between accuracy and complexity. For example, blood can be broken down into plasma and erythrocytes and then further into plasma protein-bound lead, diffusible lead, extracellular fluid lead, and erythrocyte proteins. Soft tissues can be broken down into brain (hippocampus, medulla, etc.), kidneys, liver, hair, and so on. The hard tissue pools can be separated into compact (cortical) and cancellous (trabecular) bones, and teeth; within each of these, separate components may be needed to model distinct diffusion time scales (Marcus, 1985). Because the skeletal system in young children is rapidly developing and is both large and kinetically active, 'it is especially Important to model bone lead in children. Until such refinements are further tested, a relatively simple 3 - 5 pool model should provide a framework for predicting lead distributions in children. These models are helpful in predicting total body burden or equilibrium levels of lead over time in any of the presumed kinetic compartments under different exposure conditions. The basic assumption of the models is that the mass of lead in each of the compartments changes according to a system of coupled first-order linear differential equations with constant fractional transfer rates. Such models predict that when the lead intake changes from one constant level to another, there is a directly proportional change in the mass of lead in each compartment and the attainment of a new equilibrium. TEH 0413671 DUP050454773 C-7 The rates and magnitudes of these changes are dependent upon the rates of lead flux in the tissues and can theoretically be calculated from a compartmental model of the appropriate parameters. Support for a first order kinetic model for lead metabolism is demonstrated by calculations, using first order models of soft tissue and bone concentrations of lead, and other elements {calcium strontium, radium), that fit human measurements as well as by using more complex ones (Johnson and Myers, 1981; Mallon, 1983). PbB levels in adults after exposure for 5 and 19 years have been computer simulated by Hammond et al. (1981) based on predictions of the Rabinowitz and the Bernard models. The amount of lead absorbed each day into the systemic circulation was entered into the computer program as a single unit. This daily increment was allowed to be distributed and excreted in accordance with the magnitudes of the model rate constants. Table C-l gives the predicted PbB levels at the end of the specified exposure periods expressed as functions of the total amount of lead absorbed each day from all sources. It is assumed that these linear mathematical models with distinct rate constants for each lead compartment are, in general, valid for relatively low to moderate lead exposures (CD, p. Tl.A-2). The studies that have experimentally determined compartmental models in humans have used a very small number of subjects, however, all of whom were adult males, with a limited range of exposure conditions. Given the physiological and metabolic differences between children and adults, the projected PbB levels calculated in Table C-l have limited applicability and are used for comparative purposes only. k four-compartment biokinetic model of lead metabolism has been developed from data obtained In controlled single dose and chronic lead exposures of TEH 0413672 DUP050454774 C-8 Table C-l. IMPACT OF DIFFERENT LEVELS OF LEAD UPTAKE ON BLOOD LEAD AS PREDICTED BY 2 COMPARTMENTAL MODELS AND COMPUTED BY HAMMOND ET AL. (1981, 1982) Total Pb Absorbed { yq/da.y) 35.2 70 .A 105.6 140.8 176.0 211.2 PbB Predicted by Bernard Model { ug/dl) After 5 yr . After 19 yr. 13.5 16.5 30.5 34.2 48.4 52.4 66.7 70.9 85.2 89.6 103.9 108.3 PbB Predicted by Rabinowitz Model ( ug/dl) After 5 yr. After 19 , 13 14 26 36 39 45 52 60 65 76 78 91 TEH 0413673 DUP050454775 C-9 infant (9 months) and juvenile (22 months) baboons (Mallon, 1983; Kneip et al., 1983). Dynamic blood measurements and steady state blood and organ lead measurements were accurately fitted to predict concentrations of lead in blood, liver, and kidney, and bone (the four compartments in which 95% of total body lead is contained) (Heard and Chamberlain, 1984). Human metabolism and growth patterns were applied in a computer simulation of the model that was then successfully validated using human autopsy data. The model parameters were revised using measured metabolic data for each organ (e.g., bone turnover rates) for children and were used to simulate lead organ burdens and concentrations in children with constant lead exposures from birth (Harley and Kneip, 1985). Although complete model validation is not possible, the revised model is consistent with experi mental data on blood lead accumulation following dietary lead uptake among infants (Ziegler et at., 1978), and skeletal lead accumulation following controlled exposures in adults (Heard and Chamberlain, 1984), and, given the available data it appears to provide the best estimates of PbB levels in children with continuous lead uptake. Table C-2 presents PbB levels predicted by the model for male children under different exposures, or lead uptake levels. No differences were found between the sexes except at older ages, and predicted PbB levels were highest among 2-3 year olds, consistent with results of NHANES II and the New York City screening program (Billick et al., 1979). These results are applied to estimates of the integrated lead uptake model in Section VII.C.2(a) to estimate children's PbB levels under alternative air lead levels. d) Empirical Relationships 8etween Blood Lead and Lead in Individual Exposure Media One of the modeling approaches presented in Section V, and applied in TEH 0413674 DUP050454776 Table C-2 Predicted Equilibrated Blood Lead Levels (ug/dl) Over Time Among Children with Constant Lead Uptakes3 '' Lead Uptake (pg/day) Age T~ 2 3 4 5 6 7 8 9 10 10 20. 30 40 50 60 70 80 170 4.0 5.9 8.1 8.9 12.1 11.9 16.2 17.8 20.2 T7.8 24.2 20.8 28.3 23.8 32.3 3.7 3.5 3.6 3.5 3.3 2.5 2.3 2.6 7.3 7.0 7.3 6.9 6.5 5.0 4.6 5.2 11.0 10.5 10.9 10.4 9.8 7.4 6.9 7.8 14.6 14.0 14.5 13.8 13.0 9.9 9.3 10.4 18.3 17.5 18.1 17.3 16.3 12.4 11.6 13.0 22.0 21.0 21.8 20.7 19.5 14.9 13.9 15.6 25.6 24.5 25.a 24.2 22.8 17.4 16.2 18.2 29.3 28.0 29.0 27.6 26.0 19.9 18.5 20.8 aFrom Harley and Kneip (1985). TEH 0413675 DUP050454777 C-ll Section VII.C.2, to estimate PbB levels in children exposed to various air lead levels is referred to as the "disaggregate" model. In this model, for each exposure medium to which children are exposed to airborne lead (i.e., air, dust, soil, diet) separate empirical relationships derived from controlled experimental, observational of community studies, are applied so that a combined exposure function can be estimated under various air lead levels. The disaggregate model developed in the CD (Table 13-6) and presented here in Table 7-10 relies on the most relevant and reliable of the available mathematical relationships. The relationship {*1.97 pg/dl per pg/m^) between children's blood lead and inhaled air lead (derived from Angle and Mclntire, 1979; Roels et al., 190; and Yankel et al., 1977) has already been discussed in Section V. The studies used to derive the remaining relationships in the disaggregate model, betwee*n children's blood and lead in diet, soil, and dust, are summarized in Tables C-3, C-4, and C-5. TEH 0413676 DUP050454778 TEH 0413677 C-12 wi a ?i -si lie? mI A _3 3|llw Iso * 2 81 I5? fl N l aa O a A ^ (si pi si NN *4 fCOIJ <U JtZO \ DUP060454779 C-13 Table C*4. ESTIMATES OF THE CONTRIBUTION OF SOIL LEAD TO BLOOD LEAD Study Range of soil lead values (pg/g) Angle and Mclntire (1982) study of children in Omaha, NE 16-4792 Stark et al. (1982) study of children New Haven, CT 30 - 7000 (age 0-1) 30 - 7600 (age 2-3) Yankel et al. (1977) study of children In Kellogg, 10 50 - 24,600 Galke et al. (1975) study of chi Iren In Charleston, SC 9 - 7890 Barltrop et al. (1975) study of children In England 420 - 13,969 (group means) Nerl et al. (1978) study of children In British Columbia 22S-1800 (group means, age 1-3) 225-1800 (group means, age 2-3} Oepth of sample 2" V 3/4" 2" 2" NA NA Estimated slope (X10s) 6.8 Sample size 1075 2.2 153 2.0 334 1.1 860 1.5 9 0.6 194 82 7.6 87 4.6 103 R2 .198 .289 .300 .662 ,386 NA* NA NA "NA means Not Available. Source: CD, Table 11-63. Table C-5. ESTIMATES OF THE CONTRIBUTION OF HOUSIBUST TO BLOOO LEAD IN CHILOREN Study Range of dust Lead values (pg/g) Angle and Mclntire (1379) study In Omaha, NE 18-5571 Stark et al. (1982) study In New Haven, CT 70-7800 40-7600 9-4900 Yankel et al. (1977) study In Kellogg, ID 50-35,600 Age range In years 1-18 6-18 0-1 2-3 4-7 0-4 5-9 Estimated slope <X10a) 7.18 3.36 Sample Size 1074 832 R* .198 .262 4.02 1.82 0.62 0.19 0.20 153 .233 334 .300 439 .143 185 .721 246 .623 Source: CD, Table 11-64. TEH 0413678 DUP050454780 VII-S3 remedies specific to lead-based paint, as well as sustained funding, political support from the public and health and housing authorities, and financial incentives for "deleading11 and maintaining old housing in good condition by property owners (Farfel, 1985). Research on effective lead hazard abatement measures (in 1981 HUD's prevention research was terminated), including their cost-effectiveness, as well as continued screening programs and large-scale, population-based surveys are needed to support these efforts. Several studies have shown that in addition to environmental factors, sociodemographic factors are associated with Increased lead exposure (Stark et a!., 1982; Urban, 1976; Gilsinn, 1972; O'Hara, 1982), These include income, marital status of parents, disturbed mother-child relationships, frequent moves, education of parents, inadequate parental supervision and large family size. Although some or all of these variables may be confounded by lead exposure, it is necessary to advance educational programs on lead toxicity and sources of lead in homes, and sustain social-welfare programs as well as regulating environmental sources of lead. In addition to abatement of lead paint hazards, further efforts and source-specific control measures are also required for other high intensity exposure situations involving heavily-contaminated soils due to historical accumulations of deposited lead from smelters, roadways, and other sources, as well as homes with unusually high tap water concentrations due to the combination of soft, acidic (corrosive) water and lead plumbing. It is clear that Federal agencies regulating various sources of lead (EPA, FDA, HUD, HHS) need to better integrate their activities and address total lead exposure from multiple sources. TEH 0413611 DUP050454781 VII-84 0. Summary of Staff Conclusions and Recommendations on the Primary Standard The major staff conclusions and recommendations made in Section VII, A-C are briefly summarized below: 1) Based on available information, a monthly average appears to be the most appropriate health target; 2) The standard itself could be expressed as either a monthly average or as an appropriately adjusted quarterly average that would assure that the monthly average health target is achieved during periods and in areas of maximum concentration; 3) The standard, either as a monthly or quarterly average should be expressed in a statistical form; 4) Sampling frequency using the high volume sampler could vary depending on the averaging period and form of the standard, and the site type; 5) The use of "low-volume" samplers in lieu of the high-volume sampler as a modification to the Federal Reference Method for lead may be appropriate, but site-specific testing would be needed; 6) Lead affects many different organ systems and biochemical/physio logical processes across a wide range of exposure levels. These effects range from biochemical changes in energy metabolism, neurotransmission, and blood enzyme activity detectable at very low dosages with no apparent threshold on a subcellular-molecular level, to severe, irreversible central nervous system damage manifested by mental retardation, encephalopathy and possibly death at Pb8 levels above 80-100 pg/dl; 7) Based on recent studies, the PbB level of 30 pg/dl used as the maximum safe level for an individual child in setting the 1978 lead NAAQS / TEH 0413612 DUP050454782 VII-85 contains little or no margin of safety for children from several adverse health effects. Based on an assessment of the available health effects data, the staff concludes that a child with a PbB of 25-30 ug/dl is at risk of significant alterations in heme synthesis (as indicated by elevated EP), depression in vitamin 0 metabolism, and possibly neurobehavioral distur bances, which collectively may represent impaired functioning and depleted reserve capacities of many different tissues and organs. Below 25-30 pg/dl, the risk associated with observed reductions in heme and vitamin D hormone synthesis, as well as altered brain wave activity and small decrements in cognitive function and behavior have not been fully determined. The CDC has revised the PbB level used to identify children with excessive lead exposure in the lead poisoning prevention screening program from 30 to 25 yg/dl, a medical "intervention" level that represents a compromise between the amount of tolerable risk and the practical timits of effectively implementing the existing screening program. The staff concludes that a PbB for an individual child of 25 pg/dl appears to contain little or no margin of safety from significant risks of multi-organ impairments and possible neurological and behavioral functions. Conversely, it is felt that the risks of adverse effects are minimal for an individual child at a PbB level below 15 pg/dl. In order to avoid potentially significant risks among young children and to protect as many children as possible who can be protected by a lead NAAQS with an adequate margin of safety, the staff concludes that the maximum acceptable individual PbB level should be chosen from the range between 15 and 20 jjg/dl; 8) Fairly consistent results were provided by the three modeling approaches used to estimate PbB levels among children under alternative air lead concentrations, assumed to be maintained at constant levels: the TEH 0413613 DUP050454783 blood lead/air lead slope approach, and the disaggregate epidemiological approach presented in the criteria document. Conclusions discussed below pertain to estimates derived from applying a geometric standard deviation (GSD) for the child population of 1.42 to calculate blood lead distributions around mean PbB levels predicted by the models. In addition, these calculations pertain to children not excessively exposed to lead in paint or with a high degree of pica: a) At constant air lead concentrations at and above 1.0 yg/m3, 99.5% of young children would not be protected from reaching' PbB levels of 20 yg/dl, unless only children living away from lead point sources are considered in the integrated uptake/biokinetic model, or lower bound estimates only are considered in the aggregate model; b) If 20 yg/dl is chosen as the maximum acceptable PbB for an indi vidual child and assuming a goal of 99.5% protection for the population, the highest air lead concentration that should be permitted under a revised lead NAAQS is 0.75 yg/m3, according to the integrated uptake/biokinetic model and the lower to middle estimates of the aggregate model. If only the upper bound estimates of the aggregate model, or the criteria document disaggregate model is considered, an average air. lead level between 0.25 and 0.5 yg/m3 would be required to protect 99.5% of young children from PbB levels of 20 yg/dl; c) If 15 yg/dl is chosen as the maximum acceptable Pb8 for an individual child, an average air lead concentration of 0.5 yg/m3 would provide protection for 99.5% of young children according to the integrated uptake/biokinetic model. According to the other models, an average air lead level below 0.5 yg/m3 (0.25 yg/m3 and possibly lower) would be required to prevent PbB levels above 15 yg/dl, depending on which assumptions are relied upon. TEH 0413614 DUP050454784 VII-87 In order to model children with excessive exposures to non-air sources of lead, it would be necessary to account for a high degree of pica (i.e., repeated ingestion of non-food items) and/or to account for the impact of flaking and peeling lead-based paint, commonly found in homes built before 1960, or severely contaminated soils/dusts due to historical accumulations of point source emissions. Because of the large stock in the U.S. of-old, occupied housing con taining lead pigment paints which have deteriorated and will in the future continue to deteriorate, it seems likely that exposure to lead in old housing, in combination with poverty, sub-optimal nutrition, and parental stresses and limitations will constitute the major issue in childhood lead toxicity during the coming decades. It is important to recognize that any lead NMQS would not suffice in reducing health risks posed to children from lead-based paints and further coordinated, preventive measures by appropriate governmental activities to eliminate the hazards associated with lead-based paint (e.g., removal of severely contaminated soil, sealing or repainting surfaces) are needed. In addition to abatement of lead paint hazards, further efforts and source-specific control measures are also required for other high intensity exposure situations involving heavily-contaminated soils due to historical accumulations of deposited lead from smelters, roadways, and other sources, as well as homes with unusually high tap water concentrations due to the combination of soft, acidic (corrosive) water and lead plumbing. It is clear that Federal agencies regulating various sources of lead (EPA, FDA, HUD, and HHS) need to better integrate their activities and address total lead exposure from multiple sources. TEH 0413615 DUP050454785 VIII. CRITICAL ELEMENTS IN THE REVIEW OF THE SECONDARY STANDARD This section includes a discussion of information drawn from the criteria document that appears most relevant to the review and possible revision of the current secondary NAAQS for lead. It focuses on field and laboratory studies that identify potential effects of lead in biota of terrestrial and aquatic ecosystems at levels of exposure relevant to natural habitats. Within each category, the section presents 1) a brief summary of the relevant scientific information;'2) an evaluation of the potential quantitative relationships-between lead and its effects; and 3) an evaluation of the quantitative relationships between levels of lead in the natural habitat and biologically available lead. A staff recommendation, which recognizes the major uncertainties in the available data, is also presented that If it is judged that retention of a secondary standard is appropriate consideration should be given to making it equivalent to the primary standard in all respects. A. Terrestrial Ecosystems Anthropogenic emissions of lead deposit on terrestrial ecosystems via wet and dry deposition. After initial deposition on vegetation and other surfaces, the migration and distribution of lead in the soil reservoir depend on a number of environmental factors that Influence the immobilization of lead via precipitation, surface adsorption and ion exchange reactions (Zlmdahl and Skogerboe, 1977; Miller & McFee, 1983; Camerlynck A Kiekens, 1982). Once in the soil reservoir, lead is relatively insoluble and immobile (NAS, 1980; Nriagu, 1978) and is not readily removed by such mechanisms as leaching and stream run-off (CD, p. 8-7, 8-13). As a result, lead accumulates in the soil reservoir even when the deposition rate is relatively low. TEH 0413616 DU P050454786 VI11-2 1. Mobility and Bioavailability of Lead Zimdahl and Skogerboe (1977) identified soil pH and cation exchange capacity (CEC) as primary determinants of a soil's capacity to bind lead. Based on their empirically derived equation, the binding capacity for lead for various soil types was estimated. Although the reliability of this equation to predict soil binding capacity is questionable (due to its linear form which may not be appropriate for high CEC's), this analysis suggests that while the capacity of certain soils to immobilize lead is large, it is finite. When examining the potential impact of lead on terrestrial ecosystems, a distinction must be made between total soil lead content and the available or potentially available fractions. The fraction of soil lead that may be biologically available includes the potentially available lead (exchangeable forms determined by chemical extraction) an'd the actually available water soluble forms (lead in soil moisture) (CD, p. 6-29). The generally low solubility of lead and the apparently small percentage (1-12H) of total * soil lead that is exchangeable (Camerlynck and Kiekens, 1982; Miller and McFee, 1983; Hughes, 1981; Atkins et al., 1982) suggest that the bioavail ability of this pollutant Is quite limited. The potential effect of acid precipitation to increase the relative mobility of lead in soil (Tyler, 1978; Hutchinson, 1980) Is of clear concern as a mechanism that may increase the bioavailability of this heavy metal. Given the varying capacity of different soil types to immobilize lead under different environmental conditions and the limited usefulness of chanical extraction studies to provide reliable estimates of exchangeable soil lead fractions, it is difficult to predict the percentage of total soil lead that is biologically available (actual or potential). As a result, it is difficult to predict the magnitude of Increase in total soil lead concentration that TEH 04136t7 DUP050454787 T VIII-3 results in a soil moisture lead concentration associated with levels of biologically available lead that may cause adverse effects. 2. Effects in Terrestrial Biota This section, based on the scientific literature summarized in the criteria document, includes a review of the effect of lead in components of the terrestrial ecosystem, i.e., flora, microbes and fauna. The lowest levels of exposure at which effects have been observed in field and laboratory studies are emphasized. The biological or ecological significance of certain lead-induced effects is unclear. This is primarily due to the difficulty in determining the long-term significance of subtle changes in ecosystem structure and function. Given the available data, it is difficult to assess the extent to which lead-induced effects constitute short or long-term, adverse environmental impacts, a. Flora i) Exposure, Uptake and Translocation Plant exposure to lead occurs via root uptake from the nutrient medium (soil moisture) (CO, p. 8-14). Although 9015 or more of lead taken up via the roots may remain tightly bound in the roots (Koeppe, 1981), field and laboratory studies provide evidence that some lead is translocated to physiologically active tissues in vascular plants (CO, p. 8-15 to 8-17). Recent isotopic and mass balance studies suggest the mechanism of foliar uptake as another route of exposure of plants to lead (Facchetti and Geiss, 1982; Lindberg and Harriss, 1981). While the relative signifi cance of foliar uptake has not been clearly determined, it is potentially quite high since surface deposition of lead is estimated to account for 90% of total plant lead (CD, p. 8-38). Elevated lead burdens in plants near smelters and along roadsides, for example, have been attributed ; TEH 0413618 DUP050454788 VIII--4 primarily to surface deposition (Getz et al., 1977; Nriagu, 1978; Smith, 1976). Taken together, these studies suggest that the foliar uptake of lead deposited on vegetative surfaces may be of greater importance than previously thought. ii) Experimental Data from HydroponfcaUy Grown Plants Experimental data on lead-induced effects in plants are available primarily from laboratory studies of agricultural plants grown in artificial nutrient media (i.e., hydroponic solution). These studies (Table 8-1) report that at relatively low concentrations, ranging from 2-10 pg Pb/g solution, inhibition of photosynthesis, alteration in enzyme activity, and reduction in growth can occur. While the physiological and biochemical changes observed in these studies are biologically significant, the results cannot be readily extrapolated to the varied conditions present in natural habitats. Such factors as length of treatment (exposure), chemical form of lead, level of nutrients In solution, and age and species of plant can influence the experimental results (Koeppe, 1981; Paivoke, 1979) and limit the extrapolation of controlled experimental results to the natural habitat. The absence of data to clearly define the quantitative relationship between soil moisture lead and total soil lead further limits the usefulness of laboratory studies of hydroponically grown plants for environmental impact prediction. Due to the absence of data, it is difficult to accurately assess the potential effect of lead in terrestrial flora. Leadinduced effects have been evaluated for a limited number of plant processes (CD, p. 8-17) and the data base on effects in non-agricultural plants and trees (Smith, 1981) is inadequate. Ill) Experimental Data of Plants Grown in Lead-Amended Soils Studies involving the artificial addition of lead salts to soil have evaluated lead-induced changes in plants at specified soil lead concentrations. TEH 0413619 DUP050454789 Table 8 -1 . LEAD-INDUCED EFFECTS IN HYDROPQNICALLY GROWN VASCULAR PLANTS 3R ns X tn *a ns cao CM u TO 00 c C <31 f -* a> Pc o as 3: VII1--5 ___ f * o CM r**v r^. CO CT! 05 f'v i--* 'M_0> 05 ,*F 05 C F <0 ns / >- 44 T3 CU p C 03 <0 cn cu 03 05 f-- c c *F 10 3 s P CO c <F N TJ C -3 --s a c r* (0 O' pM* Q.W a. s X 05 r* 05 o > *F CL m c F F-- F 3 -o C f -"* F- 00 TO 05 e fw L. <3 PP oc X6 PP cn <0 c 41 &- H* p OP tn <0 co F O "D a. CO X tn >i <0 tj r- 03 P 3 C40 f C - <9 --3 t/> L. tn 3 >5 O <0 X T3 11 00 m 43 *0 +4 F c. uo 44 f f J cu 03 44 44 10 40 U L. 44 P *r- cC TO TJ TO TO ns ns a> 03 -J p P _i tn t- tn 9 >5 X TO CM CM F-- T3 F* P u oP Xu u o *o X cn tn >s 'O TO CM O T3 F P L. O L. FP X F oe T3 T3 C---* oc - o p *F <0 P L3 ca V) u c 05 o^ OX a. -o cr> SL 43 f" U 0) CL CO 44 u 03 P P U4 * a tn F-* U5 r* * co 1 CM r in o O V r"" o CM F-- CM CM 05 Ui </) C 05 44 F 05 c 1/3 F> e F pmr TO (A F tn o> t o CL Ol a e O c tn cn F 4) L. F cn F* M F" c tn e T5 *o F* 5 x 01 P tn |HM V> U 03 x> * TO tn tn C- o > tn j x tn >> 05 44 44 5 tn tn 10 (0 e > > F" C= 03 *o u p c 5 X *r- 3 as P 2E X F CO F~ O CL X c o F ep (0 XI L. c a. p >1 b p U (0 F- < o P C. C o <4- X <4- o o c_ O 44 c o> f x 10 F e e e O M-- P 44 O 3S P o ca e o co P P (T3 L3 3O T7 L. *f c o F 44 O -> P P i- C US j o o> f s c 05 L. J4 ox c P *f" F X 44 i* #0 p F- C u X2 3 f - 44 L O C CU r~ ** O ao Cft fi. XX C *f TO -C c c H 03 03 cn c. < 05 F4 P OS F-* U XX P P5 tn * Oo r- tn L. Im. cn T5 >* 05 cn f - tn oX O T3 PP p O c o >J tn X co r- P "O L. u |P p X1 1 F F F tn > O ot F" c >, >, tn x cc oo O XX f act L p 0 *F* F o <n p p POO c x 3; >i r-- F u C- c. F 0.0 0 X X 3 00 tn r-- x j F *F T5 F- F- 3rft O -- XX XX O X O CM c c as o u to cm- r- F< M c* 9 r- O X is DUP050454790 viii-6 In general, high concentrations of total soil lead are necessary before physiological effects in plants are observed. Khan and Frankland (1983) report significant growth reduction in radish plants with exposure to 1000 pg Pb/g soil and complete growth inhibition at 5000 pg Pb/g soil. These total soil lead concentrations are found in certain high lead environments, i.e., near roadsides and smelters (Wheeler and Rolfe, 1979; CO, p. 7-30; Atkins et al., 1982). It is unclear, however, whether lead-induced effects would occur under natural soil conditions where the availability of lead is influenced by nutrient levels, organic matter content, CEC, and pH of the soil (Koeppe, 1981). 1v) Field Evidence of Lead-Tolerance Further indication of the effect of lead is provided by the identification of lead tolerant plant communities near roadsides and point source emissions (CD, p. 8-38; Antonovics et al., 1971; Atkins et al., 1982). Potential changes in species composition in these areas have implications for the long-term effect of lead on ecosystem function and stability. At relatively low total soil lead concentrations (112 pg Pb/g soil), Atkins et al. (1982) suggest that selection pressure due to soil lead resulted in the evolution of lead tolerance in a roadside grass, b. Microbes Available data suggest that the impact of lead in terrestrial eco systems may be.evident first in the components of the soil and litter microcosm (e.g., fungi, bacteria and algae) (Tyler, 1972) that play a critical role in the decomposition of organic matter and in nutrient cycling (Doelman and Haanstra, 1979a; Doelman, 1978). i) Experimental Studies of Lead-Induced Effects Experimental studies provide evidence of lead-induced effects in TEH 0413621 DU P050454791 VI11-7 soil microbes at soil lead concentrations as low as 750-5000 yg Pb/g soil (Table 8-2). In the presence of lead (1500 pg Pb/g soil), the composition of microbe communities may shift to more lead-tolerant populations (Doelman and Haanstra, 1979b) and, at soil lead concentrations found near roadways and point sources (750-2000 pg Pb/g soil), soil microbial activity may be sufficiently reduced to Inhibit the decomposition and nitrification processes (Smith, 1981; Doelman and Haanstra, 1979a; Liang and Tabatabai, 1978). Inhibition of growth and activity in soil microbes has occurred at lead concentrations in solution of 10-50 pg Pb/ml (Table 8-2). While these data suggest that certain soil microbes can be affected by lead at soil lead concentrations found near roadsides and point sources, the data are inadequate to draw any general conclusions about the tolerance of soil microbes to lead (Doelman, 1978) and lead's effect onthis ecosystem component as a whole. The inhibitory effect of lead appears'to vary with different types of microbes (Johnson et al., 1982; Martin and Coughtrey, 1981), In addition, because microbes exhibit a diversity of functions that interact in ways that are not well defined (Swift et al., 1979; CD, p. 8-22, 8-23), a broader data base, encompassing various taxonomic groups, is required for environmental impact prediction. Environmental impact prediction of the effect of lead on soil microbes based on the findings of these experiments is constrained by experimental conditions that influence the bioavailability of lead and result in uncertainties associated with extrapolating laboratory results to the natural habitat. The long-term significance of lead-induced changes in soil microbial populations Is unclear and depends on whether the ecosystem has the ability to compensate for such perturbations. The critical role of soil TEH 0413622 DUP050454792 Table 8 -2 . EXPERIMENTAL EVIDENCE OF LEAD-INDUCED EFFECTS RELATING TO SOIL MICROBIAL ACTIVITY to r--* CO u<0cu3 3 l. X 03 p Pccu *r" s in <o L. P V) s to to X -a c ---> to to 3 c r-* to 3 S - U o a *--N 3 p** 3 r-- l-- to X <o p <o X lO p "O c to CP c to *!>-- p VIII-8 X 3* r*^. 3 ** to Cp V) e fO (O X 3 X to c to % o 3 u r^. 3 * IM to p <u vs 6 to PM* r* 2 3 P^. r3~m ---- >) p IM P o P CO -a c to X o 1* X to ca r-- o <rt co 3 x Ql , pfC CP 3. ooucc o o o X 1 o o o o CM r-- f* V) or XI a. 3 p 3 3O tO r-- i-- X o ] * 3 tO to !** P rmm r O VI 3 0J ^P X <0 a. p 3O X to O T3 O to o p r- o to 3T5 "S. *r-- X cc. o r--" 3X =3. O 33 3 <0 ix >-- p X 0) r-- p S to P X <u CL O <o 3 XT to 3 <U to P X i-** & ^ a> XP CL to t. 3P ZL -r- C o X3 1 <0 o *-- p CO CM CO CrOo \ 1 I LU H 01 to to to * r f" XI 5- L. L. o 0) uP P p uo U o <0 to ro CO 3 20 p o c o r- P rX) `f c Xo e: i- p r* 03 VI *-- o X CL i- S v) O V) <J O o- -a 1 S v> O * oc a; s -o o a. p5 oo u s oo 1-- *t-- Pc -f- to X3 r L. XO c p o 53 sc to o >*P #0 l" r-- vs o o CL c o I-- p to o r P " Sp r* c p o e o *p" p p X r X c r-- <o to f* t. u <13 r-- 01 P 3P 3 U eu c CO 3 <0 3 X u. ca Ul . t oc t- o o r-- p 6U 01 P r-- O 03 CO C^-- O *-*'* f- to VI P - c *r-- t0 *r" vs aj to o > u CL P 5 CO VI o U L- P <U X e p to 'f- P C- to 03 03 -- 3 to O fc P lO o X 1-- P OP o pM <0 r-- X L. O r* & P O 3 X c c o P vs c X 'r~ 1-- to XL P >--< V> X p 2 o _ 3 P C o r P r* X 'r** X C *-+ cCVaJ COt oc .p2 Pe Oon S c 3 *r- OC OO r- tO p i-- ro TPC<mU. PUc<y o c co r- Ta3j -ao; c<tVS )XaOr DUP050454793 vm-9 microbes in terrestrial ecosystem processes (decomposition and nutrient cycling) suggests, however, the serious nature of the potential inhibition of microbial activity by lead and indicates the need for additional research to more clearly define the effect of lead in this ecosystem component. il) Field Evidence of Altered Microbial Activity Reduced abundance and altered composition of microflora populations have been observed in the vicinity of point source emissions of lead and in an area contaminated with metal mine waste. Corresponding to these changes, the accumulation of litter and alterations in soil parameters have been reported. Lead was the predominant heavy metal contaminant in these areas (Jackson and Watson, 1977; 8isessar, 1982; Williams et a!., 1977c). Although these field observations suggest the inhibitory effect of lead on microbial activity In certain heavily contaminated areas, their usefulness in assessing the environmental Impact of lead is limited for the following reasons: a) the inability to isolate the effect of lead from the confounding effects associated with other components of point source emissions and other heavy metals; and b) the lack of quantitative information concerning the effect of other environmental factors that influence the decomposition rate, e.g., temperature and moisture conditions (Smith, 1981). c. Fauna i) Exposure The principal pathway of exposure for fauna is through dietary Intake (CD, p. 8-26). Animals of the grazing food-chain are affected most directly by deposition of lead on vegetation. Others, such as predators, are affected more indirectly by lead moving through the food-chain, thus 1 TEH 0413624 DUP050454794 viii-io raising concerns about the potential accumulation and biomagnification of lead at higher trophic levels. While biomagnification (biological concentration of lead from one trophic level to the next) has not been observed in vertebrate food-chains (NAS, 1980; Williamson and Evans, 1972) , available data suggest that the biomagnification of lead does occur in invertebrate food-chains (NAS, 1980; Getz et al., 1977; Wade et al., 1980; Watson et al., 1976), Thus, non-toxic levels of lead taken up and accumulated by invertebrates may produce toxic effects in their predators. Although support for this potential route of exposure is provided (Bull et al., 1983a; Getz et al., 1977; Gish and Christensen, 1973) , the occurrence of lead burdens in prey high enough to cause toxic effects in predators is variable (Wade et al., 1980). ii) Field and Laboratory Evidence of Lead-Induced Effects The available data on lead-induced effects in invertebrates are very limited and are not sufficient to establish quantitative relationships. Decreased soil invertebrate abundance, that may result in potentially significant alterations In soil decomposition processes, has been observed, however, in the vicinity of point source emissions of lead and in the area of a metal mine waste site (Watson et al., 1976; Williams et al., 1977c; Bisessar, 1982). Due to the presence of other pollutants and heavy metals in these areas, it Is not possible to attribute the observed reductions to lead alone. Very few field studies reporting lead exposures, body burdens and associated effects in wildlife are available. Unusually high lead exposures resulting in toxic effects have occurred primarily in waterfowl and livestock. Sources of these exposures have typically Included lead wastes, paint and spent lead shot (unrelated to airborne lead emissions), and contaminated TEH 0413625 DUP050454795 forage near lead smelters (NAS, 1980; Forbes and Sanderson, 1978). With the exception of cattle and waterfowl, incidence rates of lead poisoning in terrestrial fauna are generally unavailable (Forbes and Sanderson, 1978; Botts, 1977) and difficult to verify. Although lead burdens in mammals are elevated relative to natural background levels (CD, p. 8-29, 8-30), with burdens positively correlated with proximity to roadways (Williamson and Evans, 1972; Quarles et al., 1974), it is uncertain whether exposures are resulting in animal burdens high enough to be of concern. This uncertainty results from a limited data base of field observations that report conflicting findings. Body burdens of lead that have been identified to cause effects In animals have not been observed in certain high lead environments, i.e., roadsides and smelter areas (Forbes and Sanderson, 1978; Getz et al., 1977). Other studies, however, indicate that elevated lead burdens associated with effects may occur in livestock grazing near smelters and In small mammals in areas adjacent to highways, mining sites and smelters (NAS, 1980; Clark, 1979; Quarles et al., 1974). When assessing the effects of lead on domestic animals and wildlife, it is important to consider the more subtle effects that are not readily discernible in field observational studies. Drawing on animal toxicological studies discussed in the CD and referred to in Appendix D, it is clear that lead can affect a wide range of critical functions such as heme synthesis, neurobehavioral function, and reproduction and development. Investigation of these effects has been limited, however, primarily to laboratory animals. In part because of species differences in suscepti bility (Forbes and Sanderson, 1978) and a lack of sufficient quantitative exposure/uptake/response data in natural habitats, results from controlled TEH 0413626 DUP050454796 animal studies have not been extrapolated to animals In natural environments. While current analyses and understanding of the potential effects of lead in domestic animals and wildlife species are considerably less definitive than for humans, the available data strongly suggest that animals may be at risk. When assessing much of the same data in 1980, the Committee on Lead in the Human Environment of the National Academy of Sciences concluded that animal sensitivity to lead might equal or exceed that of man (NAS, 1980). 3. Long-term Impact of Lead in Terrestrial Ecosystems The persistence and continued accumulation of anthropogenic sources of lead in the soil reservoir raise concern about the long-term environ mental impact of this pollutant In terrestrial ecosystems. With a net increase in soil lead concentration over the long-term, even under relatively low deposition rates, it is anticipated that at some unknown future time concentrations that exceed a soil's capacity to bind lead may be reached. In some geographical areas this binding capacity may already be exceeded. Model predictions of the long-term accumulation of lead in soil in rural areas suggest that it is unlikely that soil lead concentrations will reach levels of concern in the immediate future in most rural areas (Appendix E). This is indicated by the small rate of increase in soil lead concentration predicted for air lead levels that are representative of rural areas. Model predictions apply to typical rural terrestrial ecosystems with low natural soil lead levels, but do not represent rural areas that are Impacted by point source emissions of lead or possibly rural/remote areas that are Impacted by unusually high deposition rates, e.g., high elevation forests (Johnson et al., 1982). Although model predictions give some indication of the potential long-term impact of TEH 0413627 DUP050454797 VI11--13 lead in rural terrestrial ecosystems, predictions are highly uncertain given the many assumptions and limitations of the model. The structure and results of the model, in addition to its many uncertainties, are discussed in Appendix E. B. Aquatic Ecosystems 1. Behavior of Lead in Water and in Sediments The capacity of surface waters to retain lead in solution at equilibrium is dependent upon the physical and chemical water quality parameters of the particular aquatic environment (NAS, 1980). In addition to physical and chemical parameters that determine lead's solubility, biological conditions can influence the behavior of lead in aquatic systems (Rickard and Nriagu, 1978), and, hence, its availability and potential impact in aquatic biota. Although lead is readily complexed in natural water systems (CD, p. 6-33), concentrations exceeding 100 pg Pb/1 (lead in solution) have been "reported for surface waters receiving urban runoff and sewage and industrial effluents (NAS, 1980). Due to the lack of major exports of lead from freshwater ecosystems, these systems function as potential sinks for lead loading (McNurney et al., 1977; Getz et al., 1977), with the sediment as the primary sink for lead similar to soil in terrestrial ecosystems (Rickard and Nriagu, 1978). The sedimentation of lead depends on a number of environmental factors (CO, p. 8-13), and the retention of this heavy metal within the sediment is influenced by the substrate type (McNurney et al., 1977; Wershaw, 1976; Newman and McIntosh, 1982). Over the past century, a trend of increasing deposition of lead in the sediments of freshwater systems has been observed (CD, p. 5-1, Figure 5-1), with elevated lead TEH 0413628 DUP050454798 concentrations observed in sediments draining urban areas relative to rural areas (McNurney et al., 1977; Getz et al., 1977). As a result of the accumulation of lead in the sediments of fresh water systems, the soluble fraction comprises only a small percentage of the total lead burden (Rickard and Nriagu, 1978; Wershaw, 1976). 8ecause of potential regeneration, however, the reservoir of lead in the sediment can become a source of soluble lead even after the discontinuation of lead inputs {Wershaw, 1976). The significance of this mechanism to increase the availability of waterborne lead to aquatic biota may be most pronounced in water bodies in which complexed lead in the sediment remains at the water-sediment interface. Field observations indicate that this situation does occur (Getz et al., 1977). 2. Effects in Aquatic Biota This discussion of the effects of lead in aquatic biota focuses on vertebrates (fish) because this component of aquatic ecosystems appears most sensitive to this heavy metal and, relative to other taxonomic groups, a more extensive data base is available. There is some evidence, however, of effects of lead in other aquatic biota at low concentrations of waterborne lead. Although the data are limited, lead-induced effects (e.g., increased mortality, impaired reproduction) in certain aquatic Invertebrates have been reported at concentrations as low as 19-30 pg Pb/1 (CO, p. 8-33, 8-34; Borgmann et al., 1978; Biesinger and Christensen, 1972). Hematological and neurological changes have been observed in fish exposed under laboratory conditions to waterborne lead concentrations between 8-120 pg Pb/1 (Table 8-3). While the hematological system of fish may be capable of compensating for lead-induced changes, the neurological effects, black tails (an early indicator of spinal deformity) and spinal TEH 0413629 DUP050454799 Table 8 - 3 . EFFECTS OF WATERBORHE LEAD Id AQUATIC VERTEBRATES (FISH) VIZI-15 .01 0 coy sc 32 cs -' o ci vi rs. 'SS 0) cn 0.09 Q.OI 32 4a-> Us <tS <0 w rtgis vOcf Oc<oj *3.>B i-1* "CO CJ Oo- o x<Q <<Ao--U-lZa. v</ii o{** 4e)oOo<o VI O'* v* 01 Ou VI 04 t - i-. (.01 CO C fj Io <VI u 4f S VI CO vi vi ; 01 <009 <0 CO z UJ 1-- 3- X&f2l.r VI <o O > -- i_r S3 aIQ wV. XVS 4>->4O5J i--1 > A <9~ <J ** G fU O Q 4-> 1/ <oss- l>nS>--j =&e<o s<eU Cci *CJu= V )9 WZ <0 Q. 45 VI J <0 a# S?~ = *-- AC *4 2uOL3=.c*--Uiap U<>ab0 X e^ o. ** 3 O3 O (J t* t - ta Ocn<M s? " 83 C. VI 44 3^a-3w If ss o C** 44 mi a. o s J3- 9vi Ocu~- 04 CM OO VOI -.FX- * a- IS: vi *"*. CL -O aa>t 9 3; ui j4X*1..oea.n. 4> _ 01 CO 3PU> 9 I 4u934 11 a % 5**- CJ <J Cp<0.J*O--Q V<a0tI <4V9I **>4 1 ev u uv c j C u *- j: w1* S. -o1 ^q5j y<a u n*"o 0o144 >--ou u<o Z3L--sa- ' <o *- Ol U > C ^-4- -- 40 4- -as n CJ 7S-- i-- <o <o 01 v--. 44 C. Cl-- fu01 h. 0cs ea 44 w -3 2>V4o1I --~42/e04 o *4c34*. oci >i--SfQ--*T40=4J1 43O145 DUP050454800 VI11-16 ; curvature (which Increases mortality and prevents successful reproduction) are of clear concern (Hodson et al., 1978a). These findings are conservative because sensitivity to lead is species-specific and trout exhibit increased susceptibility to lead relative to other fish (Wong et al., 1978), and the effects observed at the lower limits of the concentration range may have been enhanced by the relatively soft water conditions used in the experiments (Davies et al., 1976). Extrapolating these results to natural systems is constrained by the many factors that influence the toxicity and bioavailability of lead, i.e., form of lead, route and length of exposure, pH, hardness and temperature of water, and life stage of organism (Hodson, 1979; Hodson et al., 1978b, 1979; Wong et al., 1978). Decreased pH level appears to increase the uptake of waterborne lead by fish although the precise mechanism of action is unclear (Hodson et al., 1978b). These data suggest that lead has its greatest effect on fish in soft water, low pH aquatic systems because these systems have a greater capacity to retain lead in solution at equilibrium before reaching chemical saturation (Hem, 1976), and the adverse effects of lead in fish are closely related to dissolved lead content (Hodson et al., 1978b; Wong et al., 1978). The U.S. EPA Office of Water Regulations and Standards has published new ambient water quality criteria for lead to protect aquatic life. These criteria concentrations are expressed as a function of water hardness and indicate the need to consider the influence of this chemical water quality parameter on the bioavail ability and toxicity of lead. For example, at hardnesses of 50, 100, and 200 mg/1 as CaCOj the 4-day average criteria concentrations of lead for freshwater systems are 1.3, 3.2, and 7.7 pg/1, respectively, and the one-hour average concentrations are 34, 83, and 200 pg/1 (50 FR 30791). TEH 0413631 DUP050454801 VI11-17 C. Staff Conclusions and Recommendations The available laboratory and field data indicate that at concentra tions at or below those found In certain high lead environments, lead can: 1).affect certain plants (e.g., inhibition of photosynthesis, reduced growth, changes in composition), microbes (e.g., reduced abundance), and fish (e.g., neurological changes); and 2) alter the composition of microbial communities and inhibit invertebrate activity resulting in delayed decomposition, reduced nutrient supply, and altered soil properties (e.g., lower organic content). With respect to domestic animals and wildlife, a qualitative assessment of the available field studies and animal toxicological data suggests that animals may be as susceptible to the effects of lead as humans. The available data also'raise concern about the continuing accumulation of lead in the soil reservoir that functions as a finite sink of undefined capacity. Due to the persistence of lead in the environment, such accumula tions are expected to continue as long as inputs exceed outputs. Thus, even at relatively low deposition rates lead could affect the ecosystem over the long-term. This concern is primarily directed to urban and point source areas that may already be approaching or have exceeded their soil capacity to bind lead. Rural or remote areas that may experience un usually high deposition rates (e.g., high elevation forests) are areas of special concern for the continued accumulation of lead. The available data are limited, however, and do not permit any definitive findings with respect to concentration-response functions associated with the observed effects or provide clear quantitative relationships between concentrations of lead in the natural habitat and biologically TEH 0413632 DUP050454802 VI11-18 available lead. Data are not available to determine quantitative relationships between ambient concentrations of lead and effects in the biota of terrestrial and aquatic ecosystems. These limited data do suggest, however, that effects of lead on these ecosystems can be significant, although poorly defined, particularly with respect to their long-term implications. The effects of lead on ecosystems are probably more closely related to the deposition and long-term accumulation of lead than to current ambient air quality levels. This suggests that a secondary standard for lead in the form of a deposition rate may be more appropriate than one expressed as an airborne concentration level. Such a deposition standard is conceptually appealing because it could be a more effective method to provide protection against the welfare Impacts of lead. Its application at this time is constrained, however, by practical considerations such as the absence of sufficient data to develop appropriate deposition targets and the lack of reliable methods for measuring both wet and dry deposition. The limited data base of the ecosystem effects of lead and the lack of a clear quantitative relationship between total soil lead concentration and biologically available lead prevent the identification of an appropriate deposition target. This results from the inability to identify the effects on terrestrial biota that would be associated with Incremental additions of lead to total soil lead concentration for different soil types. If the data were available to develop such a target, its implementation would be constrained by the lack of reliable methods for measuring deposition. The model discussed above and in Appendix E that predicts the long-term accumulation of lead in rural areas relies on current methods to measure dry deposition. The questionable reliability of dry deposition measurements and the resulting highly variable calculations of dry deposition velocity are identified as sources of uncertainty in these model predictions. TEH 0413633 DUP050454803 VIII-19 In summary, the available data clearly indicate that the potential ecosystem effects are of real concern. The data are limited, however, and do not permit any definitive finding as to the level of a secondary standard in either the form of an ambient concentration or as a deposition rate. A key question in determining the need for a separate secondary standard is whether the levels considered for the primary lead NAAQS discussed in Section VII would provide adequate welfare protection. While this question cannot be answered definitively, the levels considered for the primary standard would reduce current ambient lead loading. These reductions, particularly when coupled with reductions achieved by the continued phase-down of lead in gasoline (gasoline combustion through the early 198Q's has accounted for 85-90% of total airborne lead emissions), would likely mitigate or delay the potential risks of lead-induced ecosystem effects occurring in most areas of the country. In urban centers, along roadsides, and in the immediate vicinity of major point sources that have experienced a long-term, historical accumulation of lead, and where the natural soil sinks for lead may be approaching or have exceeded their capacity to bind lead, the more sensitive components of the ecosystem (e.g., soil microbes) may remain at some risk that is difficult to quantify at present. Although the available data are quite limited and do not provide a clear basis for specifying the level and form of a secondary standard, they do suggest that the levels considered for the primary standard, coupled with the ambient lead reductions associated with the continued phasedown of lead in gasoline, should minimize the Incremental risk of lead-induced ecosystem effects in the short-term. Therefore, until a stronger data base is developed that more accurately assesses the TEH 0413634 DUP050454804 vm-19 In summary, the available data clearly indicate that the potential ecosystem effects are of real concern. The data are limited, however, and do not permit any definitive finding as to the level of a secondary standard in either the form of an ambient concentration or as a deposition rate. A key question in determining the need for a separate secondary standard is whether the levels considered for the primary lead NAAQS discussed in Section VII would provide adequate welfare protection. While this question cannot be answered definitively, the levels considered for the primary standard would reduce current ambient lead loading. These reductions, particularly when coupled with reductions achieved by the continued phase-down of lead in gasoline (gasoline combustion through the early 1980's has accounted for 85-90% of total airborne lead emissions), would likely mitigate or delay the potential risks of lead-induced ecosystem effects occurring in most areas of the country. In urban centers, along roadsides, and in the immediate vicinity of major point sources that have experienced a long-term, historical accumulation of lead, and where the natural soil sinks for lead may be approaching or have exceeded their capacity to bind lead, the more sensitive components of the ecosystem (e.g., soil microbes) may remain at some risk that is difficult to quantify at present. Although the available data are quite limited and do not provide a clear basis for specifying the level and form of a secondary standard, they do suggest that the levels considered for the primary standard, coupled with the ambient lead reductions associated with the continued phasedown of lead in gasoline, should minimize the incremental risk of lead-induced ecosystem effects in the short-term. Therefore, until a stronger data base is developed that more accurately assesses the TEH 0413634 DUP050454804 VI11-20 environmental impact of lead, it is largely a matter of judgment as to whether a separate secondary standard should be retained. If it is judged that retention of the secondary standard Is appropriate, the staff recommends that consideration be given to making it equivalent to the primary standard in all respects. TEH 0413635 DUP050454805 APPENDIX A. LEAD METABOLISM AND PHYSIOLOGICAL MEASUREMENT 1. Lead Absorption Environmental lead compounds can be absorbed into the bloodstream from the lung after inhalation, from the gastrointestinal tract after ingestion, or to a limited extent from direct dermal contact. In addition, fetuses absorb lead through the placenta. Some lead that is inhaled or ingested passes out of the body before being absorbed, and some lead that is absorbed from the lungs or the gut is removed from the blood and excreted. The absorption kinetics for each pathway are dependent upon a number of factors, including the physical and chemical nature of the lead compounds at the time of exposure and the presence of other modifying agents (e.g., dietary constituents, other pollutants). Once inorganic lead is abosrbed into the bloodstream it is readily transported to other locations in the body and does not normally retain any characteristics associated with its exposure or absorption route. Dermal absorption is potentially significant only for high organic.lead exposure in occupational settings or other special circumstances. This route, therefore, will not be addressed further. a) Respiratory Absorption Although lead aerosols in ambient air encompass a broad size range depending on proximity to sources and meteorological conditions, most urban and rural airborne lead mass is associated with submicron particles, with a distinct peak of large particles in the upper end of many of the size distri butions (Davidson and Osborn, 1984). Particle size distributions of airborne lead mass, collected from various urban, rural and industrial areas (MMAD = u.53 pm) were combined with recent lung deposition data (Chan and Lippmann, 1980) to estimate the mass fraction deposited in each TEH 0413636 DUP050454806 A-2 compartment of a mouth-breathing adult's respiratory tract (Davidson and Osborn, 1984). Based on these calculations, it is estimated that on average, about 26 to 42% of inhaled airborne lead particles in these different locations are capable of deposition into the respiratory tract of adults. This is generally consistent with deposition data on lead particles generated'in laboratory chambers (Kehoe, 1961; Gross, 1981; Nozaki, 1966; Chamberlain et al., 1978) and near a highway (Chamberlain et al., 1978) in resting adults breathing through mouthpieces. It is estimated that 10-26% of these submicron particles deposit in the alveolar region (Davidson and Osborn, 1984) where absorption into the bloodstream appears to be rapid and nearly complete, regardless of the chemical form of the inhaled lead particles (Chamberlain et al., 1978; Rabinowitz et al., 1977; Morrow et al., 1980; Barry, 1975). The remaining 16% of the lead particles, mainly In the coarse mode (>2.5 pm) are estimated to deposit in the nasopharyngeal and tracheobronchial compartments of the respiratory tract. Clearance of most of this material to the esophagous may be rapid, except for non-hygroscopic particles lodged in the tracheo bronchial region. From the esophagous, the lead particles are either expectorated or swallowed. Lead absorption into the blood through the gut is about 40% by mass of coarse-mode inhaled particles (MMED-v- 2.9 pm) (Kehoe, 1961). Total respiratory absorption of inhaled lead particles for adults can be calculated by adding the products of deposition and absorption rates for each region of the respiratory tract. Thus, (10 to 26% x 100%) for the alveolar region is added to (16% x 40%) for the combination of nasopharyngeal and tracheobronchial regions, yielding an estimate of 16-32% for total respiratory absorption of inhaled lead particles among TEH 0413637 DUP050454807  ' A-3 adults In various U.S. atmospheres. For present purposes, this range will be rounded off to 15-30%. Given that lead particles larger than 1 pm which are prevalent near lead smelters (within 2-5 km) and other stationary sources (Landrigan et al., 1975; Dorn et a!., 1976; Davidson and Osborn, 1984) are likely to deposit in the respiratory tract with increasing efficiency as particle size increases up to about 8 pm (Chan and Lfppmann, 1980), the above estimates may underestimate respiratory deposition and absorption of lead particles in these areas. For example, it is estimated that 15-55% of 5 pm particles by mass deposit in the alveolar region and 8-45% deposit in the tracheobronchial region of mouth-breathing adults (Chan and Lippman, 1980). The upper bounds of these ranges are 2-3 times higher than those estimated for airborne lead particles in various urban, rural, and Industrial atmospheres, previously discussed. In the absence of extensive lead particle size data around lead point sources that would allow a separate analysis to calculate respiratory deposition and absorption for these areas specifically, it is assumed that for adults, total respiratory absorption of inhaled lead particles Is more efficient (i.e., 20-40%) around point sources compared to the general case representing typical urban, rural, and urban industrial areas (15-30%). Because atmospheric particle size distributions and individual deposition characteristics (e.g., mouth versus oronasal breathers) as well as other factors (e.g., ventilation rates) vary widely, the above discussion may not address potentially important exposure/deposition cases. This is especially true for children, whose respiratory deposition and absorption characteristics have not been studied experimentally. Age-dependent differences in respiratory' geometry, air flow conditions, lung clearance mechanisms. TEH 0413638 DUP050454808 A-4 and body compartment weight must be applied to make projections from adult data. Mathematical predictions of particle deposition in tracheobronchial airways of children have been developed based on morphological measurements on airway casts of people aged 11 days to 21 years (Phalen et al.9 1985). Airflow rates for different physical activity states and different particle sizes (0.05, 0.5 and 5.0 pm) were used for modeling purposes. The computed particle deposition efficiencies indicate that under most circumstances smaller (younger) people will have greater tracheobronchial deposition efficiencies than larger (older) people. For example, Phalen et al. (1985) predicted that in 2 year old 'children at light exertion levels (20 L/min) about 50% of 5.0 pm particles deposit in the tracheobronchial .region as compared to about 40% in 18 year olds. For 0.5 pm particles, 2 year old children at light activity levels are estimated to have 5% tracheobroncial deposition in contrast to about 2% in 18 year olds. In general, the age-related differences in tracheobronchial deposition efficiencies estimated by Phalen et al. (1985) are not large except for 5.0 pm particles at light activity levels and it will be assumed that these patterns hold for alveolar and nasopharyngeal deposition as well. Therefore, the previously derived range for total respiratory absorption rates in adults living in typical urban/rural atmospheres (15-30%) will be applied to young children in those areas. Near point sources, there is In general a greater fraction of large particles in the ambient air that appear to deposit with greater efficiency in young children. Based on the model of Phalen et al. for 5.0 pm particles, it is estimated that these larger particles deposit in 2 year old children 25% more efficiently than in adults. Furthermore, it appears that lead particles greater than 1 pm TEH 0413639 DUP050454809 comprise between 50-70% of the total airborne lead mass near point sources (Landrigan eta!., 1975; Dorn et al., 1976). By incorporating these factors, the range of respiratory deposition rates of airborne lead particles estimated for adults living near point sources (20-40%) is adjusted upwards to 35 to 60% for 2 year old children. b) Gastrointestinal Absorption The absorption in the gastrointestinal (GI) tract of lead-containing compounds present in food, water, soil, dust, paint chips, or other materials that a child may Ingest is dependent upon the physical/chemical form of the material, the composition of the diet, and the age and physiological status of the individual. Young children have a higher intake.of lead on a body weight basis because of higher requirements for calories, fluid, and air (Mahaffey and Michaelson, 1980). In addition to ingesting more'lead, young children absorb between 42 and 53% of ingested dietary lead compared with 7 to 15% in adults (Alexander et al., 1973; Ziegler et al., 1978; Kehoe, 1961; Chamberlain et al., 1978; Rabinowitz et al., 1980). These rates do not reflect the wide degree of inter-subject variability observed in the studies nor other factors that influence absorption in children. For example, absorption rates 2 to 4 times higher were observed in adults following fasting periods of 4 to 16 hours (Blake, 1976; Chamberlain et al., 1978; Heard and Chamberlain, 1982; Rabinowitz et al., 1980). Such increases can be expected among children who skip meals, a particular problem among lower income groups (Koh and Caples, 1977). Regular eating patterns do not insure minimized dietary lead absorption, however. Based on several animal studies, clinical investigations, and epidemiological surveys, children with diets deficient in calcium, iron, phosphate, zinc. TEH 0413640 DUP050454810 A-6 copper, vitamin D, protein, lipids, or lactose can be expected to absorb and retain lead to a greater degree (Mahaffey and Michaelson, 1980; Rosen et a!., 1981; Chilsolm, 1981; Heard and Chamberlain, 1982; CD, Table 10-4). This phenomenon may partially explain the enhanced neurotoxicity of lead in animals with nutritional deficits (Mahaffey and Michaelson, 1980),, The importance of nutritional interactions with lead absorption and possibly toxicity is particularly significant for young children because of their large fluxes in relative nutrient status. These interactions can only be estimated qualitatively with present information, however. Although nutritional deficiencies are more pronounced among lower income children (Mahaffey and Michaelson, 1980; Owen and Lippmann, 1977; Hambidge, 1977), they exist in children of all socio-economic strata (CD, p. 10-41). The ingestion of non-food items such as dust, soil and dirt through normal hand-to-mouth activities in children constitutes the greatest contribution of atmospheric lead to a typical child's total lead exposure (CD, Table 7-25). Animal experiments indicate that lead of variable chemical form in soil or dust is as available for absorption as food lead (Dacre and Ter Haar, 1977) and in vitro studies demonstrate that the acidity of the human stomach is adequate to extensively solubilize lead assimilated from soil and dust (Day et al., 1979; Harrison, 1979; Duggan and Williams, 1977). Based on these data and the fact that ingestion of such materials occurs other than at mealtimes, allowing for potentially enhanced absorption due to the previously discussed fasting factor, the CD estimates that 30% of the lead ingested in dust and soil is absorbed in a child (CD, p. 10--10)- An inverse relationship was found between particle size and gastrointestinal absorption of lead, especially in the range of 1-100 pm, such that a 6 pm dietary lead particle was absorbed five times as efficiently as a 197 pm TEH 0413641 DUP050454811 A-7 particle (Barltrop and Meek, 1975). `There is little information to assess whether the conversion in the physical form of atmospheric lead-containing particles once inside the complex geochemical matrix of soil or as dust would affect their bioavailability and, consequently, toxicity. Thus, all atmospheric lead particles that have deposited are considered to have the same absorption rate (30%) if ingested. 2. Transplacental Transfer Lead uptake via this pathway occurs rapidly beginning in the twelfth week of gestation and increases throughout development (Barltrop, 1969). Cord PbB levels are slightly lower than maternal levels and are significantly correlated with maternal exposure (Alexander and Delves, 1981; Rabinowitz and Needleman, -1982; Ryu et a!., 1978). 3. Physiological Retention, Distribution, and Excretion The initial uptake of lead from the lungs or gut is to plasma, where it is rapidly distributed to red blood cells, bone, and virtually all of the organs and tissues of the body (Chamberlain et al., 1978). The level of lead at any one site and time is determined by complex, dynamic interchanges among the various tissues and fluids that affect their respective affinities for lead. With consistent exposure for an extended period, a near steady-state distribution within the body is achieved (CD, p. 10-13). A primary goal of more refined lead uptake estimates to be used in conjunction with the biokinetic model discussed in Section V.A.2 will be to assess how short-term exposures superimposed on a long-term uptake pattern affect this steady-state distribution in children. a) Retention and Excretion In children, 47 to 58% of ingested lead on average is eliminated in the feces without prior gastrointestinal absorption (Alexander et al., 1973; Ziegler et al., 1978), while at least as great a percentage of inhaled TEH 0413642 DUP050454812 lead particles fail to deposit in a child's respiratory tract. In adults, 40-60% of the lead absorbed from the gut or lungs into the blood is excreted in urine with a half-life between 18 and 37 days depending on initial blood lead or dosage (Chamberlain et al., 1978; Rabinowitz et a!., 1976; Griffin et al., 1975). This rapidly excreted fraction is estimated to be only 16% of the absorbed lead in infants (CO, Table 10-3, based on Ziegler et al., 1978). Lead is excreted into the urine by the kidneys, both by glomerular filtration and transtubular flow (Goyer, 1968). Lead-induced renal effects (Appendix D.4; CD, Section 12-5) may compound toxicity by interfering with urinary lead excretion. Absorbed lead can also pass from the blood through the intestinal wall into the gut and be eliminated with the feces, as is the ingested and inhaled lead that is swallowed and not absorbed (Chamberlain et al., 1978). The excretion rate of this "endogenous" fecal lead appears to be roughly equal in children and in adults (CD, Table 10-3). A small portion of absorbed lead is excreted in sweat and milk, or is stored in tissues that are later shed (e.g., hair, nails, deciduous teeth) (Rabinowitz et al., 1973). The balance of the absorbed lead is transported to soft tissues and bones where it may be stored for months to years or reabsorbed into the blood. In adults, between 1 and 4% of daily lead intake is retained in the body (Chamberlain et al., 1978; Rabinowitz et al., 1977; CD, Table 10-3) while children (2 months to 8 years of age) are estimated to retain between 18 and 33% (Alexander et al., 1973; Ziegler et al., 1978; CD, Table 10-3). b) Distribution Lead that remains in the body can be divided conceptually into separate physiological pools- The largest pool is skeletal (i.e., bones and teeth) which accounts for about 94% of total body lead in adults and about TEH 0413643 DUP050454813 A-9 73% in children under 16 years of age (Rabinowitz et al., 1974; Barry, 1975). The remaining body burden of lead resides in soft tissue and blood. Under typical conditions, more than 99% of blood lead is bound within red blood cells, primarily to hemoglobin (DeSilva, 1981), although it is the very small fraction transported in plasma and extracellular fluid that carries lead'to the various body organs (Bdloh, 1974). The selective accumulation of lead in the heart (aorta), kidney cortex, and liver (Barry, 1975, 1981; Gross et al., 1975) may be associated with the sensitivity of these organs to elevated lead exposure. The greater capacity of young animals to retain lead in their tissues, particularly in the brain, may help to account for the persistence of neurotoxic effects of various types in young animals (CD, 12.4.3.1.5) and children (CD, 12.4.2.2.2) long after external lead exposure has ceased and PbB levels have declineci to "normal". Furthermore, relative uptake characteristics and distribution patterns of lead among the regions of the brain may be factors in lead neuropathology (Grandjean, 1978; Klein and Koch, 1981). Within the cell, there is selective uptake of lead into nuclear inclusion bodies and mitochondria (Barltrop, et al., 1971; Castellino and Aloj, 1969), which is consistent with lead-induced interference of normal processes in these organelles such as disrupted energy metabolism and ion transport, and possible genotoxicity (CD, 12.2.1 and 12.7). 4. Kinetics and Physiological Indices of Lead Exposure Skeletal lead is relatively inactive physiologically, with an approximate biological half-time in normally exposed humans of 17-28 years (Rabinowitz et al., 1976). When lead exposure is reduced or terminated, lead is released from the skeleton so that the declines in blood lead levels and TEH 0413644 DUP050454814 A-10 excretion rates are less than would be predicted for the amount absorbed. This is especially evident in occupationally exposed adults {O'Flaherty et al., 1982). Lead turnover rates in dense cortical bones (e.g., teeth, tibia, femur) are substantially slower than in spongy trabecular bones (e.g. rib, vertebrae) (Steenhout, 1982). Long-term resorption rates of lead stored in the skeleton, though difficult to measure, have been derived from isotopic ratio and radiolabel tracer studies (Chamberlain et al., 1978; Manton, 1977). About 25% of an adult's PbB is estimated to result from eventual re-entry of skeletal lead (Chamberlain et al., 1978). Chamberlain (1983) proposes that the blood lead/air lead ratios discussed in Section V.B. be multiplied by a factor of 1.3 to allow for possible * re-entry intothe blood of lead transferred to bone or other long-term storage. The release of lead from the skeleton may be accelerated under some stressful conditions, such as chelation'therapy, nutritional deficiencies, hormonal imbalances, bacterial infections, and possibly lactation with subsequent transfer of both lead and calcium from mother to fetus or newborn (Bethea and Bethea, 1975; Rosen and Wexler, 1977; Keller and Doherty, 1980; Gross and Pfitzer, 1974). As a result, children, whose skeletal systems are more prone to some of these demineralizing conditions, are at increased risk of remobilization of skeletal lead. The lead content of deciduous teeth provides an index of historical exposure over several years since teeth accumulate lead up to the time of shedding or extraction. Tooth lead levels appear to be proportional to exposure (Needleman and Shapiro, 1974; Steenhout and Pourtois, 1981) and to blood lead levels (Shapiro et al., 1978), and are becoming more commonly used as an exposure index in population studies of lead health effects in children (e.g., Needleman et al., 1979; Winneke et al., 1982a, 1983; TEH 0413645 DUP050454815 A-ll Ernhart et al., 1981; Smith et al., 1983). Uniform measurement techniques are required to insure comparability in future studies since the absorption of lead varies depending on the type of tooth (e.g., incisor versus molar) and the constituent matrix within the tooth (e.g., primary and secondary dentine, enamel). Although tooth lead levels are not useful in appraising current exposure, reliable techniques of in situ tooth analysis are being developed such as X-ray fluorescence (Shapiro et al., 1978) which, when combined with serial blood measurements, could provide indices of ongoing uptake of lead in target organs. While most of the body burden of lead appears to be toxicologically inactive due to its storage in bone and other possibly "protective" pools in soft tissue such as nuclear inclusions and atherosclerotic plaque deposits (Cramer et al., 1974; Barry, 1975), the fraction of mobile lead in soft tissue and blood available to biological sites of action determines the degree of potential toxicity to the organism. The most useful index of this active fraction and of imminent toxicity may be the amount that is excreted in response to administration of a chelating agent, such as EDTA or penicillamine (CDC, 1985; Chilsom et al., 1976; Chilsom and Barltrop, 1979; Saenger et al., 1982; Piomelli et al., 1984). Chelatable lead apparently comprises a fairly large labile body pool made up of soft tissue lead and a mobile compartment within bone (CO, p. 10-25). In contrast to skeletal lead, turnover fn soft tissues and blood is rapid, with a residence time of four to six weeks in adults (Rabinowitz et al., 1976; Griffin et al., 1975), and possibly much shorter in children (Duggan, 1983). Despite this transience, lead added to and removed from these pools reaches equilibrium with relatively constant exposure. A change in lead exposure and absorption shifts the balance to a new ! TEH 0413646 DUP050454816 A-12 steady state of dynamic equilibrium within about 60 days although changes in PbB levels may be noted immediately {Tola et a!., 1973; Rabinowitz et al., 1973; Griffin et al., 1975), The equilibration period in children may be quite different given their accelerated skeletal metabolism and apparently increased lead resorption rates from bone, as well as the shorter half-life of lead in their blood (Duggan, 1983). It does not appear that with continuous dosing lead accumulates in the blood, although it may do so in other tissues (Kehoe, 1961; Purser et al., 1983). In contrast to tooth lead measurements which reflect lead exposures integrated over years, a single blood lead measurement is limited to reflecting primarily steady state exposures over recent months, although a PbB level may respond to short-term changes in exposure in proportion to the initial PbB content. Linder conditions of intermittent exposures and rapid growth, as is the case with children, blood lead provides only a static picture of a dynamic process that includes intake, excretion, storage, and mobilization. A high degree of variability in PbB levels was frequently observed in children sampled semi-annually from birth through two years of age (Rabinowitz et al., 1984a), while older children (4-12 years) display greater stability (David et al., 1982). In addition, blood lead is only an indirect indicator of lead levels at critical sites In the various organs and tissues (Azar et al., 1973; Grant et al., 1980). For instance, levels of mobilizable lead (CaNa2 - EDTA) in 26% of "asymptomatic" children with moderate elevations in blood lead (30-49 yg/dl) were similar to chelatable lead values obtained in children with overt lead toxicity (Piomelli et al., 1984). Again, this limitation of blood lead as an index is especially evident with abrupt changes in exposure because of lead's shorter retention time in blood compared with other TEH 0413647 DUP050454817 A-T 3 parts of the body, particularly in the brain-of the developing organism (Bjorklund et al., 1981; Momcliovic and Kostial, 1974). Despite the limitations, blood lead has been the most widely used index of exposure because of the ease and relative safety of its collection and measurement. In future research there should be increased use of serial blood measurements in combination with tooth lead analysis, or other indices that reflect changes in tissue lead burdens with changes in exposure. ii TEH 0413648 DUP050454818 APPENDIX 8. ESHMATES OF LEAD UPTAKE For each of the numbered lines in Table 5-1 in the integrated lead uptake/ biokinetic model, the assumptions and estimates used in calculating average lead uptake for children from the various exposure pathways are discussed in the correspondingly numbered paragraphs below. 1. Outdoor air lead: For purposes of this analysis, it is assumed that each air lead concentration analyzed is maintained at a constant level and therefore represents the maximum average (e.g., either quarterly or monthly) allowable under any given concentration. The possible impact of daily variations in air concentrations on uptake is assumed to be small given the equilibration period for lead in blood (2 months in adults), the relatively small contribution direct inhalation of lead has on total exposure, and the modulation of lead levels after deposition and integration of lead particles in the environment. It is also necessary to address potential differences between lead levels monitored by stationary samplers and actual exposures of children to airborne lead. Such differences arise from various vertical and horizontal disper'sion patterns of lead over complex micrometeorological conditions (e.g., urban street canyons). For instance, lead levels decrease significantly with distance and with height near roadways and point sources (Huntzicker et al., 1975; landrigan et al., 1975; PEDCo, 1977, 1981). Short- and long-term roof-top lead levels in New York City were about 60-80% of street level readings (Lioy et al., 1980; Bauman et al., 1982). Despite such spatial gradients and inter-site variability, it is assumed that the currently designed lead monitoring network will adequately differentiate pollutant variability and instances of significant excursions, and that given the relatively small contribution of Inhaled outdoor airborne lead to total exposure to atmospheric lead, the level monitored by a fixed sampler is a reasonable representation of outdoor, inhalable lead exposure. TEH 0413649 DUP050454819 B-2 2. Indoor air lead: The penetration of atmospheric lead into residential structures depends on the size of the lead particles, meteorological conditions, and the permeability of the windows, doors, and walls of the home, A range of indoor/outdoor ratios has been found (0.3-0.8) for different cities and structures (Yocom et al., 1971; Yocom, 1982; General Electric Company, 1972; Moscheandras et al., 1981; Halpern, 1978; Berk et al., 1981; Tasteson et al., 1982) and is applied to the urban situation. Near point sources where large airborne particles are more prevalent and infiltration into homes is low, the ratio appears to be closer to 0.3 (Cohen and Cohen, 1980). 3. Time spent outdoors: The amount of time spent between indoor and outdoor environments varies among young children depending on their stage of development (i.e., infant, toddler, pre-school), season, geographical location, and family behavior. For present purposes a range of 2-4 hours per day spent outdoors (and therefore 20-22 hours spent indoors) is considered a reasonable average (CD, p. 7-42). 4. Time weighted air lead concentrations for each level is estimated by: [(outdoor concentration x time spent outdoors) + (indoor concentration x time spent indoors)] * 24 hours. 5. The volume of air breathed each day is dependent on age, body size, lung capacity, altitude, and activity of the child. For instance, ventilatory volume can increase three-fold during strenuous exercise (Cotes, 1979). Phalen et al. (1985) determined average ventilation rates for males and females from birth through age 18 from graphical fits of published tabulated data (Altman and Dittmer, 1971, 1972). For example, a two-year old at "low activity" is estimated to have a minute ventilation rate of 2.75 liters/minute, which corresponds to an average daily rate of approximately 4 m^/day while a three-year old is estimated to have a daily TEH 0413650 DUP050454820 R-3 rate of 4,3 m3/day. Other estimates that appear In the 'literature are 4.7 m^/day (ICRP, 1575) and 4 to 6 m^/day (Nutrition Foundation, 1532) for active one-year olds, and 4.7 m^/day for a three-year old (Nutrition Foundation, 1982). These values combined with those determined by Phalen et al. are used to construct a range for the average daily ventilation rate for a typical 2 year old child of 4 to 5 m^/day. 6. The range of total lead Intake by inhalation for each air lead level is computed by multiplying both the estimated upper and lower bound time-weighted average concentrations of air lead by upper and lower bound estimates of the volume of air respired per day. 7. Respiratory deposition and absorption: Only a portion of inhaled lead is deposited in the lungs and subsequently absorbed into the bloodstream. The deposition efficiency of lead particles depends primarily on their size and the physiology and rate of breathing of the individual. In Appendix A (Section la), a respiratory deposition/absorption rate of 15 to 30% is calculated for young children living in typical urban/rural areas, while a rate of 35 to 60% is calculated for those living near point sources. 8. Total lead uptake from the air is the product of total Intake and the lung deposition/absorption factor. 9. Average dietary lead consumption: Given the wide spatial and temporal distribution of atmospheric lead to different populations via the food pathway, it is difficult to reliably estimate current and future contributions of lead to the diet under alternative air lead levels. Estimates of current (1982-1984) mean dietary lead intake are, however, provided in the criteria document (CO, Table 7-25). Based on FDA data on the lead content of various foods and beverages both before and after processing, packaging, and preparation, and on food consumption TEH 0413651 DUP050454821 8-4 patterns (Beloian and McDowell, 1981; Jelinek, 1982; National Food Processors Association, 1982, Pennington, 1983; Wolnik et a!., 1983; U.S. FDA, 1984), the CD estimates that, on the average, 25.1 yg of dietary lead are ingested daily by a 2-year old child through food, water and beverage consumption. The direct atmospheric deposition of lead accounts for 10.3 pg of this daily intake. The remaining 14.8 yg/day is attributed to natural lead (0.7 pg/day), indirect atmospheric lead, i.e., lead previously incorporated into soil (1.7 yg/day), lead solder (11.2 yg/day), and undetermined sources (1.2 yg/day). It is likely that further research will show that the lead estimated to be from undetermined sources is part atmospheric in origin and part from industrial metals (CD, p. 7-51). The 11.2 yg/day of dietary lead intake attributed to lead in solder Includes that contained in food, beverages and water. Based on the percentage of lead in water that is solder lead (CD, Table 7-23) and on the average water consumption in a 2 year old (CD, Table 7-22), it is estimated that water distribution systems (solder lead) currently contribute an average of 1.2 yg/day to the typical dietary intake of lead. In order to estimate the future contribution of the water distribution system to dietary lead intake, the impact of a revised lead drinking water standard that is expected to be promulgated in the near future must be projected. The U.S. EPA Office of Drinking Water currently anticipates that this standard will be revised to a level of approximately 20 yg Pb/1, which represents a 60? reduction in the lead content of drinking water relative to the current standard of 50 yg Pb/1 (W. Coniglio, personal communication, November 14, 1985). Assuming that there will be a 5 year period before the impact of this standard is observed (W. Coniglio, personal communication, November 14, 1985), it is estimated that the dietary intake of lead from water will be 0.48 yg/day in l TEH 0413652 DUP050454822 B-5 1990. This projection assumes that the revised drinking water standard, which applies to a lead concentration at the tap, is attainable, although water treatment will be required in many areas nationwide to achieve the level of the new standard (P. Lassovszky, personal communication, November 14, 1985). The remaining 10 pg/day of the current dietary intake of lead attributed to solder is associated with food and beverage consumption. Because the U.S. FDA, in conjunction with the National Food Processors Association, is actively pursuing programs to further reduce lead in foods, it is estimated that lead in adult canned foods should eventually decline by 70% from pre-1978 level's as a result of the efforts of the two major U.S. can manufacturers (CO, p. 7-48). With the combined efforts of the leading and smaller can manufacturers, the removal of 90% of solder lead from the diet is expected over the next decade (CD, p. 7-51). Based on this projection and the 50% reduction in the usage of lead soldered cans that has already occurred between 1979-1983 (Jelinek, 1984), it is estimated that the contribution of solder lead to the dietary intake of food lead in a 2 year old child will decline to 3.3 pg/day in 1990. The remaining source of lead in the diet that requires a projection to account For future trends is direct atmospheric lead. In estimating the direct atmospheric lead contribution to dietary lead intake, it appears reasonable to make several assumptions that do not account for spatial and temporal variations in the contamination of foods by atmospheric sources of lead. For example, with the exception of self-sufficient households, most food is raised, packaged, and consumed in different locations, thereby blending the effects of different atmospheric lead levels from around the country. Furthermore, there may be a time lag between lead's introduction into the TEH 0413653 DUP050454823 B-6 atmosphere and its incorporation into, and ingestion via the diet. Neverthe less, it is clear from the most recent data that the surface deposition of lead and its uptake into foliage and crops is a significant source of animal and human exposure to atmospheric lead throughout the country (CO, Table 7-18). The average lead contribution to a 2-year old's diet from direct atmospheric deposition is estimated in the criteria document to be 10.3 yg/day and is derived from data on the lead content of foods consumed in the U.S. during 1982-84 (CO, Table 7-25). A portion of the food consumed during this period represents crops that were grown and animals that were raised prior to 1982. The annual average lead concentration in non-urban areas in the late 1970's was as high as 0.2 pg/m^ (CD, Table 7A-3). Most crops are grown, and most animals are raised in rural areas where atmospheric lead has been primarily attributed to mobile source emissions of lead. The recent EPA revisions to the gasoline lead phasedown schedule (EPA, 1985b) that lower the allowable lead content from 1.10 grams per gallon of leaded gasoline (gplg) to 0.10 gplg, effective January 1, 1986, are expected to reduce dietary lead consumption in relation to reduced atmospheric lead deposition nationwide. It is necessary, therefore, to estimate the impact of the recent revisions to the lead-in-gasoline phasedown schedule so that future trends in dietary lead consumption can be estimated. By 1990, the average annual lead concentration due only to mobile source impacts for neighborhood scale monitoring sites is estimated under the revised phasedown program to be approximately 0.02 pg/m3 (Battye et al., 1985). Mobile source impacts for remote or rural areas were not projected. Based on the projections for neighborhood scale monitors, it is clear that independent of the level of the lead NAAQS, the average air lead levels in areas away from TEH 0413654 DUP050454824 8-7 point sources (where food is generally grown and raised) will be below current rural air lead levels. Battye (1985d) has made year-specific estimates of the future mobile source contribution to ambient lead concentration in urban areas. Although these estimates were made for urban areas, the same relative reduction in the mobile source contribution is expected in rural areas. 8ased on this relative reduction, the dietary lead intake due to direct atmospheric lead was estimated to be 0.36 pg/day in 1990. This estimate is rounded off to 0.4 pg/day and represents the direct atmospheric lead contribution to calculate exposures under each of the air lead levels presented in Table 5-1. The total average dietary lead intake under alternative air lead levels can then be calculated by adding the atmospheric contribution to the estimated lead intake from solder, natural soil lead, indirect atmospheric lead, and undetermined sources. 10. Gut absorption: Only a portion of ingested lead is absorbed into the bloodstream. As discussed in Appendix A, the percentage of absorption of lead varies greatly depending' on the contents of the gut and the nutritional status of the child. A range of absorption rates between 42 and 537. (Ziegler et a!., 1978; Alexander et al., 1973) is assumed for children. 11. Daily dietary lead uptake is obtained by multiplying rows 10 and 9. 12. and 13. Dust/soll concentrations: As discussed in Section IV, the accumulation of lead in street and household dusts and soils appears to be directly related to the volume of traffic, and inversely related to distance from neighborhood streets and roads, distance from lead-based painted and brick houses and buildings, and distance from lead point sources. Despite these observations, there is little information on the relationship between different air lead levels and dust levels over time. Predicting such a relationship would require the inclusion of many complex variables such as deposition TEH 0413655 DUP050454825 B-8 rates, chemical and physical characteristics of the lead particles and soils, topographic and meteorological conditions, frequency of street washings and precipitation, background dust concentrations, and Information on transport of dust and soil into homes and buildings. Given current data, there would be an extremely large amount of uncertainty surrounding any one of these variables for different locations. In order to predict outdoor and Indoor dust concentrations under alternative air lead concentrations, reliance is placed on available studies that include measurements of both air levels and dust and/or surface soil concentrations (see Table B-l). These data are limited in that samples were collected from a small number of locations. It is assumed, however, that both the air and dust measurements were representative of lead levels in those areas and that the studies employed comparable sampling and analytical techniques. Because of historical accumulations of relatively large lead particles near primary and secondary lead smelters and other point sources, outdoor soi.l and dust lead concentrations, and consequently potential exposures, are significantly greater in these areas, regardless of ongoing emission controls. Therefore, separate exposure estimates for Individuals living near point sources under alternative air lead levels are required. Data collected near lead point sources where emissions were comparable to current situations will be used to develop outdoor soil/dust lead levels for point sources meeting different air lead concentrations. TEH 0413656 DUP050454826 B-9 Table B-l. Summary of Environmental Lead Measurements from Various Locations Average Air Lead (yg/m3) 0.20 0.40 0.28 0.34 Average Outdoor Soil/ Oust Lead (uq/q) 43 336 518 4,881 0.22 0.04 0.32 0.46 80 91. 591 260 1.6 - 2.0 1,200 0.13 0.20 0.30 0.31 0.14 0.18 0.09 0.26 0.09 o.n 0.19 0.26 0.36 0,56 0.13 0.28 35 243 829 821 75 115 294 424 58 65 77 95 532 117 326 331 0.30 0.45 0.8 3.67 114 112 466 2.560 Average Indoor Dust Lead (ug/g) Location/Reference 70 Various Sites in U.K. 190 (DOf. 1983) 565 1,803 Derbyshire, U.K. (lead mining area) (Barltrop et al., 1975) "Post-control"a (1973-1976) measurements in Omaha neighborhoods: 215 suburban 162 280 mixed (battery plant in resi dential neighborhood) 470 commercial (Angle and Mclntire, 1979; Angle, 1985)_______________ : 11,000 Hartford (Lepow et al., 1975) Distance range (km) from zinc or copper smelters in: 241 (3.5 - 24.0) 409 (1.3 - 3.7) Bartlesville, OK; 386 (0.8 - 4.3) 441 (0.8 - 1.5) 235 (10.0 - 26.0) 164 ( 3.5 - 21.0) Anaconda, MT; 210 ( 2.0 - 11.0) 398 ( 2.0 - 3.5) 75 ( 3.4 - 68.0) 60 ( 1.0 - 6.4) Ajo, AZ; 65 ( 0.5 - 2.3) 116 ( 0.5 - 1.3) 263 (11.0 - 26.0) 201 ( 5.4 - 14.5) Palmerton, PA 198 ( 3.3 - 9.9) 438 ( 0.3 - 2.8) (Hartwell et al., 1983) m "Post-control"a measurements (1976) - in rural area, Brussels, and near - lead smelter, Belgium (Roels et - al., 1980) TEH 0413657 DUP050454827 8--10 Table 8-1. Summary of Environmental Lead Measurements from Various Locations (Continued) Average Air Lead (U9/m3) 0.41 0.82 3.01 1.3 2.7b Average Outdoor Soil/ Average Indoor Dust Lead Dust Lead (ug/g).......................... (ug/g) 690 (street dust) 1,239 240 (soil) 924 2,416 427 948c 713 1,550 1,479 8.623C Location/Reference Near Arnheim secondary lead smelter, Holland (Brunkreef et a!., 1981; Dlemel et al., 1981) Near Toronto secondary lead smelters and in city (Roberts et al,, 1974) Near El Paso primary lead smelter "Post-control"a "Pre-control" (Morse et al., 1979) 0.5 0.5 0.7 3.0 6.6 14.2 16.8 337 700 2,300 1,400 1,250 3,300 7.470 1,800 3,900 3,400 3,300 2,400 10,300 11.700 Near Silver Valley, Idaho, primary lead smelter; Pre-control3 (Yankel et al.. 1977; Idaho Dept. Health and Welfare, 1977) a"Post-control" refers to the period of time following the application or increase in emission controls at the lead point source(s) involved'in the particular study. Conversely, "pre-control" refers to the period of time before the application or increase in emission controls. ^Geometric annual mean of air lead levels measured within 5 km of smelter CGeometric mean of dust and soil lead levels within 6.4 km of smelter TEH 0413658 DUP050454828 VII-56 level under alternative lead NAAQS. For comparative purposes, the calculations of blood lead distributions under various air lead levels using the three models presented below will use the GSD of 1.42 as well as values of 1.34 and 1.39 that are derived for homogeneous sub-populations of children. Analytical variation which exists in any measurement has an impact on the bias and precision of statistical estimates such as the GSDs derived from NHANES II. For this reason, it is important to recognize the magnitude of analytical variation in blood lead measurements due to measurement variation (i.e., between measurements run at the same time) and variation created by analyzing blood samples at different times (CD, p. 11-26). For example, correcting the GSDs for homogeneous subpopulations of children (1.34 - 1.39) for the overall estimate of analytical variation for the NHANES II study (0.02083) yields estimated GSOs in the range of 1.29 to 1.34, Using GSOs corrected in such a way, although providing a more accurate characterization of a given blood lead distribution, may not be appropriate for this assessment because the health effects studies used to define a maximum acceptable PbB did not correct their'PbB measurements for analytical variance. These studies, like NHANES II, generally employed the best available measurement techniques and quality control. Using "corrected" GSDs on one hand to predict the distribution of children's Pb8 levels around a mean population PbB, and then matching those predicted PbB levels with "uncorrected" PbB levels derived from health studies in order to assess the risks associated with that population mean PbB, would result in a somewhat biased assessment. Therefore, the range of GSOs presented in the CO from NHANE5 II that are not corrected for analytical variance will be used in further calculations. In setting the current lead NAAQS in 1978, EPA estimated that in order to protect 99.5% of U.S. children from attaining a PbB of 30 ug/dl. TEH 0413584 DUP050454829 VII-57 a target population mean PbB would be approximately 15 yg/dl assuming a GSD of 1.3. Similar calculations can be made for other percentages of the population if different protection "goals1' are chosen, e.g., 99.9 or 99.0%. Given a population mean PbB level the relationship between different percentiles in the corresponding blood lead distribution is illustrated in Figure 7-6. The population mean PbB levels used in this example are the lower bound estimates from the integrated lead uptake/biokinetic model for children living near lead point sources under specified constant air lead levels. The GSD used to calculate the different percentiles is 1.42. It is clear that for a given population mean PbB as one moves higher in the lognormal blood lead distribution, a progressively greater change in predicted blood lead levels is observed. For example, at an average air lead of 0.75 pg/m3, the integrated uptake/biokinetic model predicts a population mean of approximately 8.2 pg/dl. Given that population mean and assuming a GSD of 1.42, 99.0% of the population would be below 18.5 yg/dl, 99.5% would be below 20.2 pg/dl, and 99.9% would be below 24.2 pg/dl. So, if a protection target of 99.9% is chosen, and given-a maximum acceptable PbB level of 20 pg/dl, inadequate protection would be provided at this air lead level. If a protection target of 99.0 or 99.5% is chosen, then acceptable protection would be assumed. It is important to recognize how sensitive the decision on a lead NAAQS is to the choice of an appropriate protection target. Table 7-9 presents the population mean PbB levels that would be required to protect 99.5% of U.S. children from reaching various PbB levels given the range of uncorrected GSDs derived from NHANES II for homogeneous subpopulations (1.34 - 1.39) and for the entire mix of children excluding those with PbB levels above 40 pg/dl (1.42). (Mean PbB levels necessary j TEH 0413585 DUP050454830 vr 1-58 illo w l le<ul (m'J/iI I ) Figure 7-6 . Distribution of children's blood lead levels as a function of population mean blood lead level under different air lead concentrations. Illustrative population nean blood lead levels are lower bound estimates of integrated uptake/biokinetic model for 2-year old children living near a lead point source. Per centiles in blood lead distribution for each population mean blood lead are calculated assuming lognorr.iality and a GSD of 1.4-2. (Lines drawn through the datagoi/its were fitted by eye and not through regression techniques.)* Range of maximum acceptable blood lead levels was derived by staff based on health effects information in criteria document (see Section 7.C.1). TEH 0413586 DUP050454831 to provide 99,9% protection would be somewhat lower; conversely, they would be higher for 99.0% protection). These values were calculated using the formula given to describe a lognormal distribution (Yankel et al., 1977): Mg * GSDn * On where: Mg * geometric mean PbB GSO * geometric standard deviation n = the number of standard deviations On * value of PbB at a standard deviation. Table 7-9. POPULATION MEAN BLOOD LEAD LEVELS (yg/dl) REQUIRED TO PREVENT 99.5% OF U.S. CHILDREN FROM EXCEEDING SPECIFIED BLOOD LEAD LEVELS (Assuming GSDs of 1.34, 1.39, 1.42) GSD 1.42 1.39 1.34 Maximum Acceptable Individual Blood Lead Level (pg/dl). 25 20 15 10 10.1 8.1 6.1 4.1 10.7 8.6 6.4 4.3 11.8 9.4 7.1 4.7 a) Integrated Lead Uptake/Biokinetic Model Table 7-10 presents the upper and lower bound estimates of average daily lead uptake derived in the Integrated Lead Uptake Model in Section V.A.I for point sources and general urban/rural areas under different average air lead concentrations, along with the corresponding PbB levels predicted for 2 year old children by the biokinetic model presented in Section V.A.2 (Harley and Kneip, 1985). TEH 0413587 DUP050454832 VII-60 Table 7-10. AVERAGE 8L000 LEAD LEVELS FOR CHILDREN UNDER CONSTANT AIR LEAD LEVELS (ESTIMATED USING INTEGRATED LEAD UPTAKE/BIOKI NET!C MODEL) Average Air Lead (uq/m5)1 Type of Area Average Lead Uptake (us/day)2 ............ Average Blood 1Lead (pg/dl)3 0.25 General Pt. Source 5.9 - 11.0 7.9 - 19.6 2.4 - 4.4 3.2 - 7.9 0.50 General Pt. Source 10.4 - 17.2 '14.1 - 26.8 4.2 - 7.0 5.6 - 10.8 0.75 General Pt. Source 14.9 - 25.6 20.3 - 34.4 6.0 - 10.3 8.2 - 13.9 General 1.0 Pt. Source 19.1 - 34.4 27.6 - 42.9 7.7 - 13.9 11.1 - 17.4 1.25 General Pt. Source 22.2 - 38.1 33.5 - 49.7 9.0 - 15.4 13.5 - 20.1 General 1.5 Pt. Source 25.9 - 43.0 39.4 - 57.5 10.4 - 17.4 16.0 - 23.2 3-Air lead levels that were used to calculate daily uptake levels were assumed to be constant and therefore can represent either monthly or calendar quarterly averages, ^Uptake estimates derived in Table 5-1. Range under each air lead level and location reflects upper and lower bounds of estimates used to calculate uptake levels. 3PbB levels for 2 year old children derived from lead biokinetic model (Harley and Kneip, 1985) discussed in Section V.A.2. Range under each air lead level and location reflects uncertainties in uptake estimates. TEH 0413588 DUP050454833 pen VII-61 Several uncertainties associated with these estimates are discussed in Section V.A.l and Appendix 8. It is important to emphasize that because air lead (and associated dietary, soil, and dust lead) levels were assumed to be constant at whatever air level was analyzed, the upper ends of these ranges in particular may represent "worst case" population mean uptake and PbB estimates for each air lead concentration. The staff believes, therefore, that given the available data and necessary assumptions used in this model, the lower ends of the ranges of Pb8 levels for the different air lead levels reflect the best estimates of lead exposure, uptake, and metabolism among children In different locations within the population. Furthermore, estimated PbB levels at 2 years of age were selected in order to predict the maximum impacts on young children. At this age, PbB levels would be highest, assuming constant exposure, according to the biokinetic model (consistent with the NHANES II data). The lower bound estimates for 2-year old children will thus be used as the predicted mean PbB levels under each air level in later calculations. Finally, assuming lognormality with a geometric mean and GSO, it is possible to calculate for any mean PbB, the individual PbB exceeded by a specified percentage of the population. This calculation is illustrated below for the other two modeling approaches and the results are later summarized in Table 7-14.. b) Application of "Aggregate" Blood Lead/Air lead Relationships from Epidemiological Studies'" i) Blood/Air Lead Slope The epidemiological studies discussed in Section V.B. provide quantitative estimates of the relationship between air lead exposures and PbB levels in various populations of children. In assessing the total impact that atmospheric lead makes on total exposure, the aggregate modeling approach discussed in Section V.B.2 attempts to recognize the TEH 0413589 DUP050454834 VII-62 simultaneous presence of lead in multiple environmental media. Thus, the median blood/air lead inhalation (i.e., disaggregate) slope for children ( $ ) is estimated in the CD to be 1.92 from three major studies (Yankel et al., 1977; Roels et al., 1980; Angle and Mclntire, 1979), and aggregate slopes that include both direct (inhalation) and indirect (via soil, dust, etc.) air lead contributions typically yield values in the range 3-5 (CD, p. 11-105), To account for possible re-entry of lead into the blood transferred from bone or other long-term storage, Chamberlain (1983) estimates that blood/air lead relationships for adults must be multiplied by a factor of 1.3, yielding a range of aggregate slopes between 4 and 6 for total air lead exposure. It is possible that the rapid growth and high rate of turnover in children's skeletal systems would require-an even higher adjustment. Assuming that these slopes are reasonably accurate, and that at lower levels of exposure (< 30 pg/dl) a linear relationship applies (Chamberlain, 1983; CD, p. 11-64), a 1 pg/m3 change in the average air lead concentration would produce a corresponding Increase of between 4 and 6 pg/dl in the average equilibrated blood lead level of young children. ii) Contributions from Non-Air Sources of lead To predict PbB levels associated with alternative air lead levels using these aggregate slopes, it is necessary to estimate the contribution to total lead exposure from emission sources not subject to control by imple menting an air quality standard. These sources may include lead-soldered food cans, lead plumbing, lead-based paint, and indirect occupational exposures (i.e., from clothing and shoes of parents who work in lead-related TEH 0413590 DUP050454835 VII-63 industries). It should be noted that by using measured lead concentrations in dust from a wide range of locations and conditions, the integrated uptake model discussed in the previous section implicitly includes average contributions to total exposure from lead-based paint, but excludes from the analysis high level exposures associated with deteriorated lead-based painted housing. In addition, based on recent FDA data the criteria document directly provides estimates of the dietary contribution of non-air sources of lead which were used in the model. In attempting to explicitly estimate exposures from non-air sources of lead, which is necessary in applying the aggregate blood/air lead slopes to determine an appropriate lead NAAQS-, several difficulties arise: 1) With the exception of non-air lead in diet, few studies provide detailed information on the relative contribution of various sources to children.'s PbB levels in the U.S. Estimates must be made by inference from earlier survey data and theoretical calculations; and 2) Because non-air contributions to PbB levels probably vary widely In space and time among children, a single estimate for the average case may result in a lead NAAQS that is not protective for all children. [This can be expected, for example, for children who regularly ingest lead-based paint.] Conversely, the air standard will be overprotective in areas where lead from non-air sources is below the average. In setting the 1978 lead NAAQS, the Agendy estimated that non-air sources of lead contributed on average, 12 pg/dl to children's PbB levels. Since then, significant reductions in PbB levels have occurred, attributable not only to declines in atmospheric lead emissions but to the gradual TEH 0413591 DUP050454836 VII-64 conversion by manufacturers to non-lead soldered cans, the reduction In the number of old, lead-painted homes, cleaner working conditions, as well as efforts by parents and public health agencies to minimize children's lead exposure. It is not surprising, therefore, that the non-air lead contribution to average Pb8 levels appears to be lower today. In children sampled in NHANES II between 1976 and- 1980 living in rural areas where air emissions can be expected to be minimal, the measured geometric mean PbB was 13.9 pg/dl (Annest et al., 1982). After three adjustments are made to the NHANES II data, a true "non-air" PbB of 6.6 pg/dl is estimated for children that are living in the U.S. by the time a revised lead NAAQS can be expected to be implemented (i.e,, 1990): The rationale for the adjusted value is described below. 1) Although automobile and industrial emissions may be low, rural populations in the U.S. are still exposed to atmospheric lead through long-range transport from mobile sources and more localized impacts from point sources and indirectly from atmospheric deposition of lead on crops grown around the country that enters their diet. No data are available on U.S. children, although preliminary analyses of the Isotopic Lead Experiment, which manipulated the isotopic composition of gasoline sold in and around Turin, Italy, found that approximately 11.4% of the blood lead in adult men living in the countryside within 25 km of Turin can be directly and indirectly traced to gasoline lead locally consumed over 7 years (Facchetti and Geiss, 1982; Colombo and Fantechi; 1983). It can be reasonably assumed that the contribution of total atmospheric (not only gasoline) lead to active children who are regularly exposed to dirt and dust is likely to be significantly higher compared to adults. In the absence of direct data, the estimated average of 11.4% for rural Turin men is TEH 0413592 DUP050454837 VI1-65 multiplied by two, yielding an estimate of 23% for PbB related to gasoline lead and industrial sources in rural U.S. children. Thus, the remaining 77% of children's blood lead is assumed to be attributable to non-atmospheric sources. 2) .The NHANES II data are based on blood lead measurements made between 1976 and 1980. Since then, in addition to the phasedown of gasoline lead, efforts by the food industry to remove sources of lead consumed by young children have continued. The use of lead-soldered cans has decreased from 90% in 1979 to 50% in 1983 and as the switchover continues, lead in canned foods for children should decrease by as ' much as 70% of pre-1978 levels (CD, p. 7-48; Jelinek, 1984). Since lead from solder and other metals is estimated to account for approxi mately 24% of a typical child's background lead exposure (CD, Table 7-25), it is estimated that the average child's total PbB levels will decline by (0.24 x 0.7) or 17%. 3) The staff estimates that .ongoing efforts to reduce occupational exposures (and thereby reduce children's indirect exposures) and to prevent childhood lead poisoning, and the gradual reduction of lead exposure to lead-based paint in old homes will have resulted in a 25% reduction in the average Pb8 level in U.S. children from the 1976-1980 time period by 1990. Based on these three considerations, the NHANES II mean value of 13.9 pg/dl for rural children sampled between 1976 and 1980 is adjusted in the following calculation: 13.9 gg/dl x (0.77) x (0.83) x (0.75) = 6.6 pg/dl TEH 0413593 DUP050454838 VII-66 This estimate represents the mean PbB levels that would be expected in 1990 in U.S. children not exposed to atmospheric lead directly or indirectly, based on the data and assumptions presented above. Another method to estimate children's mean "non-air" PbB is to use available data on typical background levels of lead in food, water, dust, and soil ingested by U.S. children and the relationship between lead taken up through these media and children's PbB levels. Table 13-6 of the criteria document uses such data in calculating a mean PbB of 4,42 yg/dl to be expected at an air lead level of zero. Because this estimate is based on observations limited to a few studies not necessarily representative of all U.S. children, it will be used with and added to the estimates derived from the NHANES II survey to construct a range of PbB levels (4.4 to 6.6 yg/dl) predicted for U.S. children not exposed to atmospheric lead emissions, either directly or indirectly. It must be emphasized that these estimates for non-air contributions to average PbB levels represent average values. Many children may be at risk for significantly higher lead exposures that cannot be prevented by atmospheric emission controls. In particular, these include children who ingest paint chips and other non-food items containing leaded paint, children exposed to high drinking water lead levels from eroding lead pipes or solders in distribution systems, those living in deteriorated or recently resurfaced lead-painted housing who Inadvertently Ingest paint dust through normal mouthing activities, children of parents who work in lead-delated industries and are exposed to lead dust that is subsequently carried home on clothing, or children living near lead smelters and other point sources where historical accumulations of lead are excessive. The staff urges that other regulatory agencies and public health programs, including other EPA TEH 0413594 DUP050454839 V11-67 components, responsible for minimizing children's lead exposures from non-air sources, or from historical accumulations of atmospheric lead deposition, maintain or increase, where necessary, their efforts, iii) Calculation of Alternative Lead NAAQS Based on the conclusions reached in the preceeding sections, alternative target air lead levels can be derived using the "aggregate" modeling approach by: 1) determining a maximum acceptable PbB level for individual children (between 15-20 pg/dl) to protect against effects discussed in Sections VII.C.l and Appendix 0 with an adequate margin of safety; 2) calculating a target geometric mean PbB level for U.S. children based on placing a specified percentage below the maximum acceptable PbB: for purposes of the present discussion the goal is assumed to be 99.5% (Table 7-9); 3) estimating the PbB level attributed to non-air sources such as leaded paint and canned food (4.4-6.6 pg/dl). 4) subtracting the non-air contributions from the target geometric mean Pb8 level; and 5) dividing the remaining allowable contribution to blood lead from air sources by the aggregate blood lead/air lead slopes (4-6 yg/dl per iig/ra3) discussed in Section V.B. Tables 7-11, a-c present the alternative air lead levels derived from these calculations assuming a goal of protecting 99.5% of the population and GSDs of 1.42, 1.39 and 1.34, respectively. For purposes of this analysis, no distinction is made between monthly or quarterly averaging times because each air lead level is assumed to be constant. For each possible PbB that could be accepted as the level of concern, different target air lead values arise depending on which blood/air lead slope, which non-air blood iTEH 0413595 DUP050454840 VII-68 Taole 7-11. Air Lead Levels (yg/m^, monthly or quarterly average) Required to Protect 99.55 of Children from Exceeding Alternative Maximum Acceptable 31ood Lead Levels According to Aggregate Epidemiological Model for Different Non-Air Lead Contributions and Blood/Air Lead Slopes. a) GSD for Population Assumed to be 1.42 81ood/Air Lead Slope 4 5 6 10 yg/dl Non-Air PbB 4.4 6.6 - - --- Maximum Individual PbB 15 yg/dl 20 yg/dl Non-Air PbB 4.4 6.6 Non-Air PbB 4.4 6.6 0.4 - 0.9 0.4 0.3 - 0.7 0.3 0.3 - 0.6 0.3 o 25 yg/dl Non-Air PbB 4.4 6.6 1.4 0.9 1.0 0.6 b) GSO for Population Assumed to be 1.39 10 yg/dl Maximum Individual PbB 15 yg/dl 20 yg/dl 25 yg/dl ] Blood/Air Lead Non-Air PbB Non-Air PbB Non-Air i'bB Non-Air PbB Slope4^46;64j46^64^46_j5iA___________________________________________________ 6.6 4 -- 0.5 - 1.1 0.5 l.S 1.0 5 -- 0.4 - 0.8 0.4 1.3 0.8 6 -- 0.3 - 0.7 0.3 1.1 0.7 c) GSD for Population Assumed to be 1,34 Blood/Air Lead Slope 10 yg/dl Non-Air PbB 4.4 6.6 Maximum Individual PbB 15 yg/dl 20 yg/dl Non-Air PbB 4.4 6.6 Non-Air PbB 4.4 6.6 4 0.08 5 0.06 6 0.05 0.7 0.1 0.5 0.1 0.5 0.08 1.25 1.0 0.8 0.7 0.6 0.5 25 yg/dl Non-Air PbB 4.4 6.6 1.85 1.5 1.2 1.3 1.0 0.9 j TEH 0413596 DUP050454841 VTI-69 lead contribution, and which GSD is ultimately taken. For example, in order to protect 99.5% of the population of children from exceeding a Pb8 level of 20 pg/dl, and assuming a GSD of 1.42, a non-air blood contribution of 4.4 pg/dl, and a blood lead/air lead slope of 4, an.air lead level of 0.9 pg/m3 would be adequate. At this time, the staff does not attempt to judge which of the values in the ranges presented are most valid for these parameters (i.e., GSD, blood/air lead slope, non-air PbB) and awaits comment on these issues before discussing the margins of safety associated with alternative lead NAAQS. It is clear, however, that given a maximum acceptable Pb8 no higher than 20 pg/dl for an individual child, all of the air lead alternatives predicted as necessary for adequate protection (99.5%) by the aggregate epidemiological model are below the current standard level of 1.5 pg/m3. It is also clear that according to this model, even an air lead level close to zero' would not fully protect 99.5% of children from exceeding PbB levels of 10 pg/dl, and assuming a non-air contribution of 6.6 pg/dl, from exceeding 15 pg/dl. These results are compared in Table 7-14 with PbB levels predicted under various air lead levels by the other two models. In addition, it once again should be noted that none of these air lead levels can fully protect children who are excessively exposed to non-air sources of lead such as paint chips, and heavily contaminated soils and dusts. c) Predicting Blood Lead Levels Using "Disaggregated" Slopes for Individual Media Just as mathematical relationships have been derived between blood lead and air lead levels among different populations, various studies have investigated the relationship between blood lead levels in children and concentrations of lead in food, water, soil, and dust to which they are exposed. The CD has applied the most reliable and relevant of these relationships to currently representative concentrations of lead in these TEH 0413597 DUP050454842 VI1-70 Individual media in order to estimate proportional inputs to total PfaB levels in U.S. children (CD, Section 13.4,3). Table 7-12 (CD, Table 13-6) presents estimates for the direct and indirect contributions of air lead to children's (intended to represent 2-year olds) blood lead at different air lead levels and typical background levels of lead in food, water and dust. Calculations and assumptions used in deriving the estimates are summarized in footnotes to the table and are referenced to specific sections of the criteria*'document. This disaggregated analysis shares similarities to both approaches presented earlier in this paper that were used to estimate PbB levels under alternative air lead levels. For example, the integrated lead uptake/biokinetic model estimated the range of contributions that both atmospheric and non-atmospheric sources of lead make to total exposure, directly and indirectly, via the individual media pathways. The second "aggregate" blood lead/air lead approach relied on mathematical relationships derived from some of the same epidemiological studies relating blood lead and lead in the environment. It is of interest to note that after adjusting the estimated PbB in Table 7-12 for children exposed to 1.25 pg/m^ air lead to a level that would be expected given the dietary and background lead conditions during 1976-1980 when NHANES II was conducted, the result is roughly comparable to the mean PbB measured by the NHANES II survey for children living in U.S. urban areas which then had an average air level of approximately 1.20 pg/m^ (15.6 vs. 16.8 pg/dl) (CD, p. 13-26 to 13-28). The PbB levels listed under each air lead level in Table 7-12 represent the predicted population mean PbB levels for 2-year olds. Using the equation presented previously in this section, it is possible to estimate, given a geometric mean PbB level and known blood lead distribution TEH 0413598 DUP050454843 V11-71 TABLE 7-12. CONTRIBUTIONS FROM VARIOUS MEDIA TO BLOOD LEAD LEVEiS (Hg/d1) OF U.S. CHILDREN (AGE = 2 YEARS): BACKGROUND LEVELS AND INCREMENTAL CONTRIBUTIONS FROM AIR Source 0 Background-non air Food1 Water2 Dust3 Subtotal 1.55 .94 .30 2.79 Background-air Food4 Water5 Subtotal 1.47 .16 1.63 Ingested Oust (with Pb deposited from air)6 0.00 Inhaled air7 0.00 Total 4.42 .25 1.55 .94 .30 2.79 1.47 .16 1.63 1.57 .50 6.49 Air Lead (pg/m3) .50 .75 1.0 1.55 .94 .30 09 1.55 .94 .30 2.79 1.55 .94 .30 2.79 1.47 .16 1.63 1.47 .16 1.63 1.47 .16 1.63 3.09 1.00 8.51 4.70 1.50 10.62 6.27 2.00 12.69 1.25 1.55 .94 .30 2.79 1.47 .16 1.63 7.84 2.50 14.76 1.5 1.55 .94 .30 2.79 1.47 .16 1.63 9.40 3.00 16.82 lFrom Table 7-25, (18.9 - 9.2) pg/day x (0.16 from Ryu et al., 1983) = 1.55 (jg/d 1. 2From Table 7-25, (6.9 - 1.0) pg/day x (0.16 from Ryu et al., 1983) = 0.94 pg/dl. Alternatively, Tables 7-20, 7-21 give a weighted mean concentration of liquids as 0.012 pg/g. 1/7 is atmospheric, leaving 0.01 pg/g (10 pg/T) non-atmospheric. 10 x (0.06 from Pocock et al., 1983) * 0.6 pg/dl. 3From Chapter 7, 1/10 dust not atmospheric. JJsing Angle et al. (1984) low area (Area S) for soil and house dust and their regression equation, we have: (1/10) x (97 pg/g x 0.00681 + 324 pg/g x 0.00718) = 0.30 pg/dl. Alternatively, the consumption from non air would be (1/10) x (97 pg/g soil dust + 324 pg/g house dust) x 0.05 grams ingested of each * 2.1 pg ingested. Using Ryu et al. (1983), 2.1 x 0.16 = 0.34 pg/dl added to blood* 4As in 1 above, but using 9.2 instead of (18.9 - 9.2) yields 1.47 pg/dl. Values are derived for component of background Pb in food from past deposition from air onto soil and into other media leading into human food chain (not expected to change much except over long-term). sAs in 2 above, but using 1.0 instead of (5.9 - 1.0) yields 0.16 pg/dl. Values are derived for component of background Pb in food from past deposition from air onto soil and into other media leading into human food chain (not expected to change much except over long-term). 6The regression equations of Angle et al. (1984) are used, as well as levels of soil dust and house dust in the low area (S) and high area (C) of that study. For example, the increase at 1.0 pg/ma in air would result in Increases in soil as follows: 1.00 - 0.29 0.86 - 0.29 x (519 - 97) * 526 pg/g Similarly the increase in house dust would be: 1^Q0_-JL29 ,, (625 _ 324) _ 3?4 jjg/g 0.86 - 0.29 ` The effect on blood lead would be (526 x 0.00681) + (374 x 0.00718) = 6.27 pg/dl. 7Using the 2.0 slope from Angle et al. (1984), i.e., 1.93 rounded up. Source: CD, Table 13-6. TEH 0413599 DUP050454844 VI1-72 characteristics of the population, the individual PbB at a specified standard deviation. Table 7-9 for example, indicates that given a geometric mean PbB level between 8.1 and 9.4 pg/dl, 99.5% of the population of individual children would have PbB levels below 20 yg/dl (depending on which geometric standard deviation is chosen). Similarly, a population mean PbB of 8.51 for example (predicted under an air lead level of 0.50 pg/m3 in Table 7-12), would prevent 99.5% of the population from exceeding a PbB of either 18.1, 19.9 or 21.0 pg/dl (for GSD's of 1.34, 1.39, and 1.42, respectively). Table 7-13 lists the maximum individual PbB predicted in 99.5% of the population for each estimate of mean PbB predicted by the criteria document in Table 7-12. These results are presented in Table 7-14 for comparison with those of the other two modeling approaches. Table 7-13. Maximum Individual Blood Lead Levels for 99.5% of Children Under Different Air Lead Levels, Based on Mean PbB Predictions from CD Disaggregate Model (see Table 7-10) and Assuming Different Geometric Standard Deviations Air Lead (ug/m3) Predicted Geometric Mean PbB (pg/di) Maximum Individual PbB (pq/dl) GSO 1.34 1.39 1.42 0 4.42 9.4 10.3 10.9 0.25 6.49 13.8 15.1 16.0 0.50 8.51 18.1 19.9 21.0 0.75 10.62 22.5 24.8 26.2 1.0 12.69 26.9 29.6 31.3 1.25 14.76 31.3 34.4 36.4 1.50 16.82 35.7 39.2 41.5 d) Summary of Predicted PbB Levels under Alternative Air Lead Levels Table 7-14a presents the various estimates of PbB levels for children (both means and individual maxima for 99.5% of the population) under different TEH 0413600 DUP050454845 VII-73 J UP 3* UI -J Q < VU ed - < z UJ cd UJ u. u. a <Q oc v> Ui UJ o sc ss o o v) oc -J Cu j cu 3* < UJ -J a z o *-* C --J UI -J -J UI a OO as o --i US CO UQJ X UJ h- H" Si M |w< J-- V) OO UI u. o >oc* sX V5 *5 i-4 01 J<3Q vn *--i vr> o -X> CM r-- av VO CO r-- ID VO * lO CO p~ CO 1 1 r*- * o to *-- CM ^ CM vft CO r- ID Q- r-- CMtJD CM co m v c m o> CO CO CM w CO r-- 00 -- tr CO r~ 11 cm * co a> CM *-- *--s 01 01 <u0 01 > AS o u 0 4&-9. <Q 3 a u O > VD JZ *-> c O o a * CO s 1 P-** at r^. --4 -w- p--1 P- f--4 CM *-- w 00 sr vo w .*-- CM CM a co CM w to> 01 ** CM O CoS' . oJ p-- CO VO P-- N-- ns 01 -P pu-- < vCDM at at c m O V CM * co ^r* -- vc r-- CM CO r-- 11 ,r- *? 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V* > V5 0 C0 p-- <Q a 0X 0 6 0 0 4-1 C U 0 <p*f-- 4-4 Q 4-> tO U V> r-- f-- 0 0 a. o. 0 v- JK 0.0 4^ 0 0 4-5 0 0 C 4J U 0 <Q at VI S 0 0 *P- xs U 4-1 a. vt j z 0 ui cn L -- -C -a * e *-- iQ <a 0 > j= r-- 0 +J 0 r- -- N. 3 ax? vn 0. <Q c 4-5 0 0 V> C r-- U 0 XI XJ U P-- c .r- .p. -a 0 |Q JC C > u <o *r- C cn 0 0 -- > Ifl *r 0 - O O u atx; v> 0 4-> IQ XI V) 0 0 p- L*D -P 0 O0 > 4- i-- 0 0 O *i-- i-- xs c 6 0 -- 0 CO 0 4-> XI UP c a, x o o 0 0o p-- 0 U 0 U CO 0 JO xs a. u 0C <Q i-- 0 to E u 0 C . 0 pOl4P IQ U r-- 00 X= Q. - O *p- a. 0 4-1 C t.*- <0 > as c T- U > r O 1-- 4-5 s -73 o Cl i-- V5 0 in c m u <s<Q * 0 r-- >> CM O c vo 01 U V) X3 4J p-- r- U 0 *- 0 > r- 01 U <f- r- 0 pw U p- to to 3Q 3 X CX p-- IQ -- > > -- 0 *rX UX. cue r- 0 -f-- Q_ u cn S O0 t-P E *r V) i--* X 0 O0 p ag IQ 6 XJ** p* <o u> 4-5 0 * <n i-- a 0 at 0 4P m h -- +4 0 C 640 *-- 4-5 VX V) 0 0 vr> cn in i 0 0) CM U 4-> a. e c 0 f- 0 L U 4-5 iQ <n *# i-- 3 0C s> u -- 0 p--* m cn p" CO IQ 0 ja > (0a. t- r- cn 0 um 00 0.T 4-1 P-- c 0 cnNs W to =X CL VO C 1 n --< m p*-- 00 CL > O0 p-- 1-- cn CO JO iQ O. 0 IQ U0 *4" E 0 Ns O O -r 4-1 1-- 0 03 0 V * <n o. u 0 4-> 4P U 00 > to uo to CJ a. o 4P 4-> e 0 U0 * 0 in 4- 0 <u r-.CM 'Bf U i-- o <4* H-- 0O 3 V> -- CD 0 > * 0 J -n ^. > cl OVD a. VD d- I O -O' 0 <** p-- atw c> mc0 U j p- f-- tfl p pP 3 <0 UP 3 O'*- r--> L- "P" 4- 4- > 0 *-- U *i-- p-- CO ^, 0 5 >0-0 0 p*- U *p- *P- X co iq s t 6 a. c o 4- C ID -at Ol-^ct ^L CEO 1X^4^ OC 05 o Cl **-- CO JO a. c <Q 0 e p-- 4P iQ 1--" 3 CL Q. 4-5 U 0 > O u o 4P 0 3 CM *r p* 4- 3 VD CO 4-5 O 0 4-- 0 U 0 Up p i-- p- ai d: > O0 p-- p-- . 0 0 u to -- 0> >*-r~ CM *p~ 4P 6 00 0 #* LX a. 0 0 u ** VD 4-> at cs at o 4J -1- c r-- 0 4-5 0 e 00 JC 0 4- U a. 0 0w L. CL p-* 0 > -p-- 0 P- CO 0 . > CL 0 p- oCO ci--o x* X tu H \ DUP050454846 VI1-74 average (monthly or quarterly) air lead levels based on the three modeling approaches discussed in this section and using a population GSD value of 1.42. As discussed previously, the staff concludes that a GSD of 1.42 derived from NHANES II data is the most appropriate value to use in predict ing how the distribution of blood lead levels among U.S. children would be affected by incremental changes in air lead levels. For comparative purposes. Table 7--14b presents the same estimates using the three modeling approaches assuming that the GSD is between 1.34 and 1.39, the range calculated from NHANES II for homogeneous subpopulations of U.S. children. It must be emphasized that for present purposes, each of the air lead levels are considered constant. As discussed in the criteria document (Chapter 6) and in Section IV, airborne lead concentrations are highest near sources of lead emissions and decrease rapidly by dispersion or deposition. As a result, sharp downward gradients.in air lead levels are seen with increased distances from the immediate vicinities of highways and stationary lead sources (Roberts et al., 1974; EPA, 1984b), In reality, in an area that is in attainment with a standard, air lead levels at some points close to the source or directly downwind may be at the standard level, but the remaining locations will have concentrations below the standard. Consequently, assuming constant air lead quality at the level of a specified lead NAAQS in all locations would tend to over-predict the impacts expected for a wide area. Therefore these results from the models should be interpreted as conservative in the context of projections for large populations of children in point source (and non-point source) "areas". Analyses will be presented in a separate report to better represent actual exposures surrounding lead point sources in the future under alternative lead NAAQS. It should also be noted that the three exposure modeling approaches presented in Section V all employ data on indoor and outdoor dust and soil TEH 0413602 DUP050454847 tsi -J Us>J UJ UJ cc >--i < 3D Ui OC uuUJ.. o a v> UOJ UXJ o2S u>t-oji <oaOocc. <ac. Ui --l <3 3 UJ l -J UJ aoo ose -J Ui CC LQU Uxta--si Jcs--:' o2 vf--s Vo> UJ ou. *Js3t CO CO taf p- p -- tO CM a CO O i r--* c-- O VO f-- * * r-- CM **-* CM CO to *sr to to *-- co i t *-- o CM i-- CM*--' a to pH pmm tO CM O CO to CM * * t-4 as r*- co *w f-- OS G CO'*-' p4 CM u 0) > CTt r-- CM ^SCO f-- 11 O <3* .* OO CM*- > i-- l. o* os 4-> CO tft p"* L. o *--< <--% r*- CM p * * 2 * vo p C r-- r** * p vo -w CO *-- u --* CM ^ vo CTj CM CM i-- It oo * ?* * CO f--* *w^ >1 1-- JC 4-2 c o s o CM or> -- 9> OS --- to *-- CO s tO p- * 7o CO * p~ CM 1 9f CO CT o 3. vo CM W s4 pM CM -- 11 f** !* to r* **--' r4 .. *--w' p* MU>wJi -J -- * co^ CO P P--'- s c m I VO J i * os * uD 0*1 to c O p-- 'fcHP flW p c vo CM c m a> 1t to f* CO vo pmm < VO p-- LO# VO 9* r** c m to 1 i* CM p< CM 00 CO >*--* *w o to vo cy--> r"~ 00 * r-- 00 }1 vft -- to fM s, * C p~ j O L. ua =3 CC * 4M u 3c t- f- ao. too a 97 o a) 4-> as **--> s- a? c ^BW os jsi P -a o +t-t>> c: 4<c->0u*aof- s - ro co <u JU rtS Cf>u <u f * C- 0) cn-o a> o * s: CM * o> -** CO CM 1 CO r*. * vo to -- CO W co vo 1N CO * T r* r-- CO vo CM Ol JcrL * * CM VO " CM W CO CM CM 1 VO vn w* iM CM *--1 a> cr> 1 P- -- VO * 00 00 1-- %-x* p-- to iH i <rv C0 <o to (* '*--- T5 p 4- <U C X3 a> o 5S 3 u cu o +-> O 3 o> <0 4) p L t. or cn <Mr~ </! L p OO aj L. <U > * d> t/> ui `4~ O O t u oo *v to *J c: c cn o <3> U s -a 4J &|Q as <U JS CC *-- +J f- ce Q) T" > <o <r> *p- c l co o o -- W 1 13 v> a> 3 ML CO f-- 05 * CJ in p- > o <U Ou C *-- X <u <u a) eo 3: j o o j uo. > <y i" j o c v* <o </) W <3J QJ ego 3X (- c <u J o* > `P* C- +J o O <0 l/> r~ <9 wa- 3O..Pu. O CL US O. |p 4-- VO o > J <11 4M a> f-- <2 cu & tt3 P" W j j gj P VS 9 <9 UI S JC p - C3 4-> p* U> r-- J3 <u <u > <9 4J O Cf- *J 4P T3 *p " J2 C 42 03 p- C US 4} 42 L. L. L*p -0 CtrtJp 42 *r (. S 42 U o > C p* 42 cn u> r* 9 *0 -fj *s CL * os o us 3X4- -a Jj v> C -o P" o p ty, u o c C O - "O ax c > 4J +J o p O 0>4-> C f-- O p * 02 C O O u -a u 9 r-- p~ u> "O V) *p C 42 i-- 3r -M *p* <0 > cj e 4J <9 *p * *-- U f-- S 9 3 CQ p O 4J O *p p -* c n. c o f9 U O L2 f9 ea U JS 3 o. u **S. c c <9 JO s L. se o r-- *p * <9 <L> C <9 42 p *" C3 O. > a. u 4J JC u 4P p- > e c IfcM u >+J c p* PPI > cfs p CO p p-- 1 T3 -9* r- (O o !* US w u <9 - >> UI 3 CM *W US O c to CD L. - 4p *p jr O cn c p <9 IQ L * 3 US 9 Up P o >> p p- * 4- Pe r L p <9 L9 3 O C9 4* <9 p > US p VJ " p L C Q 3 *p S _ p V) *> 3 US 4-2 E C *p PX jj O 2 US CL E JO T3 ** to U ' C p - s o> vs as O t- 4- 4J a. o c *i-- t- s ^ us us p- to us 1 > CM JC 4-a r-- C C p ffl r l J -LS Xp 4 s 4-- C L *p Ui > U> re > os - *o p- L. US ra_ > p- T3 p*^ s CO =LJ5 CL MD tc *** ^ S CL C o p p US 4-2 9? p 3 CL P~ o O. L. -- 4-> ttS L. ^ T3 > C OO r- U CO o 4J V "O u US 4J 3 e^* > c CO <9 * CLp * 4-2 J <9u <o * 4- p 4-^ p TO US L. p4-- > US G 3 V) p* CD us p> p> p- p 9p JO -n . p p V) XflS US 3 O VO 95 CL *p * to > 4- 1 p O <9* * C. <5* -p G*-^ CS C3 - S *p *p US X 4> 3 IQ U -O -ip-- L. 4- VO C u o os OG U> p- G O J3 4M >a c p p* L P vs G J3 1 US ex. c 4- e 4-2 oe tOtO to C S CL *> fit QIC O 3*p O 4-2 CTi CO p 1 <o p-- US 3 US a to o 4-- US OSp > u pus 4J p * U 3 p- *o 4^ *p > U *p 93 --** C *p _ L. es * 3 p* E *p *p X O B - p- >5. to L. G as >s o 4J CM C -p 4-2 c US vs V) t- J= a-4-> e u c 4-2 CL oe o *p vs p p 93 > 4-2 i-- c cc US J3 a. L. Q- C vs s p c > -p p- 4M CQ p " -Q 3 CL CL 4-- Oa. o 4J L os c> c CSC 93 VJ co CO *? o X UJ I- DUP050454848 Vi i-76 lead concentrations measured in various locations where children were exposed. As best that can be determined from the studies, these data do not include measurements from in and around homes where peeling paint, holes in the walls, or other unsound conditions were reported. [Those data from homes with identified lead paint hazards are excluded from analysis; see Appendix B.] To the extent that the studies appeared to have sampled populations and dwellings representative of the study areas, a heterogeneous mix of homes are likely included and it is reasonable to assume that the data do include older homes with lead-based paint (but no overt hazards) and therefore may be suitable to represent average or "typical" lead exposures excluding those due to excessively high paint lead levels. In addition, where applicable, available information was used on the average rate of dirt ingestion through inadvertent hand-to-mouth activity in children. No attempt is made here to distinguish exposures to lead in children with a high degree of pica (i.e., abnormal tendency to repeatedly ingest non-food items) or who are excessively exposed to lead in paint from deteriorating housing conditions. Such children cannot be effectively protected from the hazards of lead in their environment by a lead NAAQS. Further discussion on this issue is provided at the end of this section. The ranges of PbB estimates under each air lead level reflect the differences among the available modeling approaches. For each air lead level and each GSO, the protection predicted for young children not excessively exposed to non-air sources of lead (e.g., paint lead) by the three models can be compared. For example, based on the criteria document's disaggregate model, at an average air lead level of 1.5 yg/nr* and a GSD of 1.42, 99.5% of exposed children (2 year olds) would have PbB levels below 41.5 yg/dl. The integrated uptake/biokinetic model predicts that the TEH 0413604 DUP050454849 VII-77 corresponding 99.5% cutoff would be 39.5 pg/dl among 2-year old children living near lead point source and 25.7 pg/dl among those in generalized urban/rural (i.e., non-point source) areas. (As discussed previously, all PbB estimates presented in this section for the integrated uptake/biokinetic model are those from the lower end of the calculated range since the assumption of constant air lead levels used in this model would tend to over-predict exposures.) The range of PbB levels calculated using the aggregate model at 1.5 pg/m3 encompasses that predicted-by the other two models at this air lead concentration. Relatively comparable results are also found among the three models at air lead levels of 1.0 and 1.25 pg/m3. It is clear that each model estimates that, given the range of PbB levels of concern (15-20 pg/dl), 99.5% of young children would not be adequately protected at an air lead level above 1.0 pg/m3. In fact, given a maximum acceptable PbB level for an individual child of 20 pg/dl, and a GSO of 1.42, the models predict that 99.5% of children would not be adequately protected at an average Vir lead level of 1.0 pg/m3, unless the least conservative parameter values of the aggregate model are accepted (i.e., blood/air lead slope ( 8 ) of 4, non-air background PbB of 4.4 pg/dl), or only children living away from lead point sources in the uptake/biokinetic model are considered. At 0.75 pg/ra3, however, 99.5% of 2-year old children not excessively exposed to paint lead would have PbB levels below 20.2 pg/dl according to the integrated uptake/biokinetic model (including point source areas) as well as the aggregate model, using low and mid-range parameter values [ 8 of 4 or 5, non-air background PbB of 4.4; a 8 of 5 and non-air PbB of 4.4 at an air lead level of 0.75 pg/m3 yields a mean PbB of 8.2 pg/dl, identical to that predicted by the integrated uptake model for point source areas and which would be associated with a 99.5 percentile PbB of 20.2 pg/dl.] Given that TEH 0413605 DUP050454850 VI1-78 20 pg/dl is the upper bound for a maximum acceptable PbB level for an individual child, the staff recommends based on this analysis that the upper bound of the range of air lead levels that should be permitted under a revised lead NAAQS should be no higher than 0.75 pg/m3. It must be noted that even at this air lead level, the criteria document's disaggregate model and the upper bound parameter values of the aggregate model do not predict adequate protection (99.5%) against individual blood lead levels of 20 pg/dl. At the lower air lead levels analyzed (0.25 and 0.5 pg/m3), the integrated uptake/biokinetic model predicts greater protection (i.e., lower PbB levels) than the other two models, especially at 0.25 pg/m3. This divergence may be related to the wider array of data sources employed in the integrated model. Specifically, the daily lead uptake estimates which determine the PbB estimates in the integrated uptake/biokinetic model are calculated at each air lead level in part from dust and soil lead'concentrations that were measured concurrently with air lead, even at low levels, at various locations. The epidemiological studies that were used in the aggregate and disaggregate models to derive relationships between air lead and blood lead and soil/dust lead and blood lead, on the other hand, were generally conducted during times and in areas where atmospheric air lead levels were relatively high compared to levels that would be predicted under a 0.25 or 0.5 pg/m3 lead NAAQS. As a result, relationships from these epidemiological models to predict PbB levels under low air lead levels are for the most part, extrapolations from higher pollution conditions. The dust and soil lead concentrations estimated at low air lead levels and thus the PbB levels predicted in the integrated uptake/biokinetic model are more directly derived from actual measurements closer to the scenario modeled and may therefore be more reliable than the PbB levels estimated by the aggregate or disaggregate models at these lower air lead levels. TEH 0413606 DUP050454851 VII-79 At 0.5 yg/m3 and with a GSD of 1.42, the integrated uptake/biokinetic model estimates that 99.5% of 2-year old children living near point sources and not excessively exposed to paint lead would have PbB levels below 15 |jg/dl, which is the lower bound PbB level of concern. In contrast, the other two models predict that a smaller fraction of children would be below 15 jjg/dl at 0.5 p^j/m3, but that 99.5% could be expected to have Pb8 levels below approximately 20 yg/dl, the upper bound PbB level of concern, under certain assumptions. For example, calculations using the aggregate model at 0.5 pg/m3 and a e of 5 and non-air background Pb8 of 4.4 yields a mean PbB of 6.9 pg/dl, which corresponds to a 99:.5 percentile of 17.0 yg/dl given a GSD of 1.42. The disaggregate model estimates that at 0.5 pg/m3, 99.5% of 2-year old children would have PbB levels below 21 yg/dl, given a GSD of 1.42. Only at air lead levels below 0.5 yg/m3 (e.g., 0.25 yg/m3) do all three models predict adequate protection (99.5%) from 20 yg/dl regardless of the assumptions employed. Even at 0.25 pg/ra3, however, inadequate protection from PbB levels of 15 pg/dl among young children is predicted by the middle to upper bound estimates in the aggregate model and by the disaggregate model, given a GSD of 1.42. In fact, given the mean non-air background PbB estimate used as an upper bound in the aggregate model (6.6 pg/dl), no air lead level considered would be calculated as providing adequate protection from PbB levels of 15 pg/dl among 99.5% of the population if the upper bound of the aggregate model is relied upon, e) Staff Conclusions With regard to Table 7-14a and 7-14b, the following conclusions can be made, all of which pertain to children not excessively exposed to lead in paint or with a high degree of pica: 1. At air lead concentrations at and above 1.0 yg/m3, 99.5% of young children would not be protected from reaching PbB levels of 20 pg/dl, TEH 0413607 DUP050454852 VI1-80 }i unless only children living away from lead point sources are considered in the integrated uptake/biokinetic model, or lower bound estimates only are considered in the aggregate model. 2. If 20 pg/dl is chosen as the maximum acceptable PbB for an individual child and 99.5% chosen as the protection target for the population, the highest air lead concentration that should be permitted under a revised lead NAAQS is 0.75 pg/m3, according to the integrated uptake/biokinetic model and the lower to middle estimates of the aggregate model. If only the upper bound estimates of the aggregate model, or the criteria document disaggregate model is considered, an average air lead level between 0.25 and 0.5 pg/m3 would be required to protect 99.5% of young children from PbB / levels of 20 pg/dl. 3. If 15 pg/dl is chosen as the maximum acceptable PbB for an individual child, an average air lead concentration of 0.5 pg/m3 would provide protection for 99.5% of young children according to the integrated uptake/biokinetic model. According to the other models, an average air lead level below 0.5 pg/m3 (0.25 pg/m3 and possibly lower) would be required to prevent Pb8 levels above 15 pg/dl, depending on which assumptions are relied upon. 4. The above conclusions pertain to estimates derived from applying a SSD of 1.42 to calculate blood lead distributions around mean PbB levels predicted by the model's. The staff concluded previously that this 6S0 appears to be the most appropriate GSO In determining a lead NAAQS that would protect the entire mix of U.S. children. If it is determined, however, that a GSD in the range of 1.34 to 1.39 is more appropriate, the results presented in Table 7-14b could be used to compare the relative protection provided under different air lead levels according to the three exposure models. 5. The above calculations all were presented in the context of keeping a constant fraction (99.5%) of the sensitive population below TEH 0413608 DUP050454853 VII-81 some critical PbB level. By estimating different parts of the tail end of the PbB distribution that corresponds to a given mean PbB, it is possible to predict the impacts of different air lead levels if different protection "goals" (e.g., 99.0 or 99.9%) are chosen. For example, given a mean PbB of 8.2 pg/dl (predicted by the integrated uptake/biokinetic model for children living near a lead point source under an average air lead level of 0.75 pg/m^) and a GSD of 1.42, the 99.9 percentile would be 24.2 pg/dl, compared to the 99.5 percentile of 20.2 pg/dl. The 99.0 percentile given-a mean PbB of 8.2 pg/dl is 18.5 pg/dl. It is clear that the percentage of children in the tail end of the PbB distribution is sensitive to small changes in the mean, and conversely, if a different protection goal besides 99.5% is chosen, a significantly different air lead level would be required to achieve that target. 6. Finally, It must be emphasized that the potential health risks posed to children with very high levels of exposure to lead contaminated dusts, soil, and paint are not accounted for in these analyses. Average blood lead estimates are calculated for the population of "typical" children and subsequently, blood lead levels of individuals are presented who are in the upper end of the "normal" distribution. In order to model children with excessive exposures to non-air sources of lead, it would be necessary, for example, to: a) assume a higher daily ingestion rate of dirt than 100 mg so as to account for a high degree of pica (i.e., repeated ingestion of non-food items); and/or b) assume a significantly higher concentration of lead in indoor dust and outdoor soil and dust in order to account for the impact of flaking and peeling lead-based paint commonly found in homes built before 1960, or severely contaminated soils/dusts due to historical accumulations of point source emissions. TEH 0413609 DUP050454854 V11-82 Because of the large stock in the tl.S. of old, occupied housing containing lead pigment paints which have deteriorated and will in the future continue to deteriorate, it seems likely that exposure to lead in old housing, in combination with poverty, sub-optimal nutrition, and parental stresses and limitations will constitute the major issue in childhood lead toxicity during the coming decades (Chisholm 1984; Mahaffey, 1980). It is important to recognize that any lead NAAQS would not suffice in reducing health risks posed to children from lead-based paints and further coordinated, preventive measures by appropriate governmental activities to eliminate the hazards associated with lead-based paint (e.g., removal of severely contaminated soil, sealing or repainting surfaces) are needed. Regulatory action directed at the large reservoir of existing lead in dust and paint In and about the older homes of urban children has had only limited impact because it pertains only to federally-assisted housing and the dwellings of children identified as lead-poisoned (Farfel, 1985; see Section IV.F). Together, these categories of housing constitute a small proportion of all housing. Only a few cities and states have enacted legislation requiring prophylatic removal of lead-based paint from dwellings, and the few abatement programs have had little impact due to a lack of commitment and capability for inspections and enforcement (Farfel, 1985). Although screening programs have been generally effective in the management of affected children at highest risk for symptomatic lead poisoning (CDC, 1985), primary rather than secondary preventive measures are required to address the vast majority of affected children with undue lead absorption who are at moderate risk. The elimination of lead hazards from all housing (not just the houses of identified, affected children) will require strong housing codes and legal TEH 0413610 DUP050454855 VII-18 In summary, the staff's assessment of the available information on the averaging period, form, and sampling frequency suggests the following: 1) Based on available information, a monthly average appears to be the most appropriate health target; 2) The standard itself could be expressed as either a monthly average or as an appropriately adjusted quarterly average that would assure the monthly average health target is achieved during periods and in areas of maximum concentration; 3) The standard, either as a monthly or quarterly average should be expressed in a statistical form. Of those examined, the expected highest 3 months (quarters) approach appears most appropriate; 4) Sampling frequency using the high volume sampler could vary depending on the averaging period and form of the standard, and the site type, from one-in-three days to everyday sampling (assuming a precision of +10%); and 5) The use of "low-volume" samplers In lieu of the high-volume sampler as a modification to the Federal Reference Method for lead may be appropriate, but site-specific testing would be needed. C. Level of the Standard To assess the degree of health protection that would be afforded by alternative lead NAAQS, it is necessary to predict the blood lead (PbB) levels associated with various concentrations of air lead for the sensitive populations and to determine the toxicological consequences associated with different PbB levels among young children. 1. Summary of Health Risks Associated with Different PbB Levels Table 7-5 summarizes the lowest observed effect levels (in terms of PbB levels) that the CD concludes to be thus far credibly associated with "unacceptable risk" for particular health effects of concern occurring among at least some children (CD, p. 13-32). Many Individuals may TEH 0413546 DUP050454856 VII-19 Table 7-5. s u mmar y o f l o w es t o bs er v ed e f f e c t l e v el s f o r k e y l ead -in q u c e o h e al t h e f f e c t s in c h il o r e n Lowest Observed Effect Level (PbB) 80-100 pg/dl 70 pg/dl SO pg/dl SO pg/dl 40 pg/dl 30 pg/dl IS pg/dl 10 pg/dl Heme Synthesis end Hematological Effects Frank anemia Reduced hemoglobin synthesis Elevated coproporphyrin Increased urinary ALA Erythrocyte protoporphyin elevation ALA-0 inhibition Py-5-N activity inhibition Neurological Effects Encephalopathic signs and symptoms Peripheral neuropathies 7 CNS cognitive effects (IQ deficits, etc.) Peripheral nerve dysfunction (slowed NCV's) Renal System Effects Chronic nephropathy (aminoaciduria, etc.) Gastrointestinal Effects Colic, other overt gastrointestinal symptoms 1 Altered CNS electrophysiological responses 7 Vitamin 0 metabolism interference t Abbreviations: PbS 3 blood lead concentrations; Py-S-N 3 pyrimidine-5'-nucleotidase. Source: CD, Table 13-8. ! TEH 0413547 DUP050454857 VII-20 not experience the stated effect until distinctly higher PbB levels are reached (CD, p. 13-32), or conversely may respond to even lower PbB levels due to wide ranges of individual biological susceptibility, variations in nutritional status, and other factors. It is clear, as discussed in Section VI and in Appendix D, that lead affects many different organ systems and biochemical/physiological processes across a wide range of exposure levels. These effects range from biochemical changes in energy metabolism and synaptic neurotransmission, with no apparent threshold on a subcellular molecular level, as well as alterations in blood enzyme activity detectable at PbB levels at or below 10-15 pg/dl (e.g., ALA-D, pyrimidine-5-nucleotidase) (CD, Table 12-9; Angle et al., 1982).to sevete, irreversible central nervous system damage manifested by mental retardation, encephalopathy (degenerative brain disease), and possibly, death at PbB levels starting between 80 and 100 pg/dl (CO, p. 12-62). Other overt neurological damage such as peripheral neuropathies have been observed at PbB levels as low as 40-60 pg/dl (CD, p. 12-95). Clearly adverse effects occur in other organ systems at these elevated levels (60-100 pg/dl) including chronic nephropathy, gastrointestinal symptoms, and frank anemia, which represents an extreme manifestation of reduced hemoglobin synthesis and which has been observed at PbB levels as low as 40 pg/dl (CD, p. 12-47). Less severe but Important signs of impairment in normal physiological function are evident at similar and lower exposure levels than those associated with overt intoxication. The nervous system is a critical target for low-level lead effects, which are summarized in Table 7-6. Alterations in neurochemistry (e.g., neurotransmission, brain mitochondrial function) are evident within minutes of exposure to submicromolar concentrations of lead in vitro and in vivo. Although the functional significance is difficult to assess and TEH 0413548 DUP050454858 *XCX- CS--P 0p*0* 'OC(0<CN3>D9- ^ 40 * Io- so <r> < 4-- -- VI > *-- v O i CcOi xre CO 01 Of ^1 Juu3Z nc--oni ---greoc--ot * -J <a n s* fi >*t0oi -- -3J0--03 c*> PC0--**O1 UWW )j O'9 `V cj -- CO W V11-21 X^ ereXea >co----o w- 3--e jo --e W . c>oco -co --<y wre. cmo re 4--LJi a. stOJs *eo <NCo----O H0<c3*i*]-i--r-e*i cCo*--mO o *---- wc --IoON* re U--<xu--raSraeel.o0cU p---mL*-i0(p4Co&--3--xo3>*il 4V Oo--> *4*-J3rree ere w SrBe wO> 4-> re 0c m3^- 4 ee*-- o- s *eo oEW> a3O**nwO-ao : . --QU,u>LO icl0fn0l re Fr-. Oi >re t -- C Si S *rMe* U4--3>reC rogeS9e 5^-- IaaSwi --* P-Ocoi re sua<0--oSL>t* 9s--C4u--rOer 9noPeio1----n>onI.9----_0r(C4e1 OPON''. COr.O*'L--i ---- CWoi <4* ca wi veAo at W 4-- o cl re re C--/JcoN401 01'O4C--Oi -- o c V> > V* INO XO CCOMOi C<OO--I uOcXX. oocc--oncC4--oM o4--i *a re o ns4- Li 3 v e o eo u--i --eoc>o ca -- o> ca CM IA -- eo co re cn ---- eo <-- 0^1 <--re *- _ --jemz -- po*i --1 eoo . 4-- O44oVV XCoCt OGI--O' re Li -'M<*'OCOi-OimZOS-i 1 co cn re O' -O w r0-1. rree < O' Oi4 -- (O a .* -- -- n o o mn *0' so co rN. --01 cn 0 -- e -- --< -* i- --03 --* > re cn re : > -- . e 3 s u ..x vc s e 3 I ore> 10 CO Vroe X Ui O vrO/>- w W Li *ree --o2i C iA irnes5--jco* O4 cm *cW0- * w S3 rWe ----*eeV *..4Mf-->itwI *>wss1erereoe -gr *l0j> eru-esee -jeoas we* *> JSt ^49 --JruZe l--u>. </ Vi "* riu>ne <w J--<cewoQ*Su-.. ^re Lo W c = (<401 _O --re > --> b w re 5UI sw i--/i Wi/i --* --**L *i *ej --*u t5< -- re < *j <JuC --.eWil*w*Esc-^Ie%* 1*>C5' i -vei wcre --ee w--LS O*w3S UoWV> F3 rere o o <--4--r--oe c n{Jrle> ! s. rXe Isw!] 59- i- --*re --VoovcIi --e >1 s *a- o3>i "3 oue ws --rse oe aXo*-.--reWe 1q&x41 U C VI CS wvi --rSe rreaes --v>t----vvi 4>re-,--V> b--O JwLS> C u* "S --J3 re? res re re H :-- o V* 1i S1 S > --l -Wre|iUre 3 --C:}--OI -- --ci--o tvf> >iiU co_ resi--uj AwU re -- O >i O II> 4OWV el --' 3 41 w os w * <_*--3 _:(A V>>1 sre <se jc 'r3tAe La--is 1 >ore vre VI3A 3S S>. 4" Li LS >3 o 01 re re s s *i -- 5s* 3?2-o *- . VI w* so CO > * e Ws --3c wo>t l e -- e vi ^ w re e 3 vi -- re --vi --re *r-e> 4-- c 3v w vi o -- se> <--re *Ajj c --40* re --* c c .l v ^ Li S --w C 3<-- 3 ! I| cnJ DUP050454859 V11-22 w* </> ra a (. Ol tss P-- Q. WNo' O af*t co ** ^ O' 4*J1oI>0So e<s0j -- co XCj * 4) 9f-- e(O It) *J ISB --<0l <-- X s- e c3o IcQnsr *-- JC f"-5*toe. cno Cee xa; -jj o> --3 c"Sss c3i5 to j*t CO v 04 -- U4 * * Q s Ex 39 t)NS t4-5>r--^>4*r>t.o-f-Cr"mO> at co -- at QO 04 *--` <+m . X IQ -r- ** > V* ** lO O 45 - 3 <*4 *> U ioe j : r U CoO * CO <o p-- vi QU cxo 35 3o fit -- -- oso~ah*x-* _ X * *. -- ot VO) t(oA 2 *-> he- e * > -- Xt (W0 i-- - *.?. ?3S 0* =.ut to (* n ec.u4i o x *"* ^m l Q) VO C 03 > e cn u --X X* XcoXo 0C0O4: t 04 t *- Ui X tft M* o T W CO ^o> CCO4 *r*0*4 u 4J -- -- o 04 uxo as ---t 1 X X <U/l :: XC --* -- >>wtX0--4I >: t0e>eors-t 4o>su=li - >.v c*c-. # e c0Uo44 *--|Q ^ a. iQ s ** > u <n IQ CO X X <* *--04 BS CO x x 4 K-- 4J TO -- eo e CO --04 J -- x e --v ^O* >.** ^9 X X -- _X*-* <* >|C U4 V) 04 < *D omI VOeI ._ P- 6 ---- js w 04 C. * 04 X >sf-i e > --94 u * L s e *" *s > CXf ><3o p-- ..-o * - -- <uQ CmO nocsen X X 04 MOO L. r 8 --21 t/4 t 04 S -- U4 <n o O' v x cs |Q VO IB S ---- ^Ot i=n ^j-r e c nut4M 4(3 It3 CT4 <B U C U 04 Oe ifi- 5in> w T* o X Ui H o < 01 -u> c sj a. co 5 o o cn a <o x i.y x i .5 o e JUS s|4S- >"**< ex Cc'W o 04 v i e UU 3 U L. O X > tfl VJ e 2*i O ( 4JV> >4 V ! to u 3 U U 4J 4e-> -- 3 *91 =oi c-- 1v * I <! u *-P- tm 04 i- a.-- C 2s * *- * zi 2i -- VI o 2 5* *4V<*4> Cm <C 3 * IB C I-- cwt -- t! *3s e -- so>J Zj \ --X | x Vt x*4 X o Ml L. 3 X C S u DUP050454860 VII-23 estimates of PbB levels at which such effects occur in humans, cannot be made, these neurochemical changes (e.g., inhibition of acetylcholine release and Na,K-ATPase activity) exhibit continuous dose-response relationships which may form the bases of delayed brain development and disrupted neurobehavioral function (Silbergeld, 1983). Indications of sensory and peripheral motor nerve dysfunction, such as slowed nerve conduction velocities (NCV), have been observed in adults with PbB levels as low as 30-50 pg/dl (CD, p. 12-61). Significant delays in neurological development and persistent alterations in neurobehavior have been found in young animals exposed to relatively low levels of lead (See Appendix D.2). Determining the subtle interactive effects of low level lead exposure on children's neuropsychological development in relation to social (especially caregiving), genetic, nutritional, and other influential variables over time, and controlling for experimental and analytical biases have proved to be difficult, however, and have generated contrasting interpretations. Problems encountered In the conduct and interpretation of childhood lead studies are discussed in the criteria document and in Appendix 0.2. The criteria document concludes that: "none of the available studies on the subject, individually, can be said to prove conclusively that significant cognitive (IQ) or behavioral effects occur in children at PbB levels < 30 pg/dl. Rather, the collective neurobehavioral studies can probably now be most reasonably interpreted as being clearly indicative of likely associations between neuropsychologic deficits and low level lead exposures in young children resulting in PbB levels ranging to as low as 30-50 pg/dl. The magnitude of average observed IQ deficits appears to be approximately 5 points at mean PbB levels of 50-70 pg/dl and about 4 points at mean PbB levels of 30-50 pg/dl (CD, p. 13-35). Although such IQ deficits are relatively small on average, such shifts in the mean can make a substantial difference in the percentage of children with IQ's in the extremes of the population distribution (i.e., below 80 and above 125) and may impact the intellectual development, school achievement, and social development of the affected children sufficiently so as to be regarded as adverse" (CD, p. 13-36). Figure D-2 in Appendix D illustrates how an apparently small shift (4 points) in IQ in the mean of a normal distribution may result in important differences in the tails of the distribution. i TEH 0413551 DUP050454861 A recent study and follow-up of U.S. children from families of low socio economic status appear to confirm previous conclusions that PbB levels above 30 pg/dl may be associated with IQ decrements (Schroeder et al., 1985). An initial assessment at 1-6 years of age showed a significant effect of blood lead in the range 6-59 pg/dl on IQ after controlling for social covariates, such as SES, home environment, and maternal IQ. Five years later, when all PbB levels dropped below 30 pg/dl, lead effects on IQ were no longer signi ficant. Furthermore, the correlation between maternal and child IQ, which had been suppressed initially in children with PbB levels above 30 pg/dl, returned to expected levels when decreases in PbB levels occurred, while concomitant variables remained stable over the 5-year period. In European children estimated to have PbB levels between 15 and 30 pg/dl, small deficits in IQ and attentiveness have been observed, although no consistent statistically significant associations have been found (Smith et al., 1983; Harvey et al., 1983, 1984; Yule et al., 1984; Hunter et al., 1984; Winneke et al., 1983, 1984). The criteria document concluded from these studies that "the possibility of small neuropsychologic deficits being associated with lead exposure in apparently asymptomatic children at the exposure levels studied (i.e., 15-30 pg/dl) cannot be completely ruled out, given the overall pattern of results obtained with the crosssectional study designs employed by Winneke and the British investigators. Small, 1-2 point differences in IQ seen in some of their studies between control and lead exposure groups might In fact be due to lead effects masked by much larger effects of socioeconomic factors, home environment, or parental IQ" (CD, p. 12-98). In replicating their previous study, Schroeder and Hawk (1986) found a highly significant linear decrease in IQ with increasing blood lead level across the range of 6 to 47 pg/dl in low SES black children, 1-6 years of TEH 0413552 DUP050454862 VII-25 age. This confirmatory finding is particularly compelling because the potentially confounding factor of socioeconomic status was effectively controlled by selecting a very homogeneous group of children, and the results indicate that IQ effects may be detected without evident threshold even at these low PbB levels, at least in this population of children. The recent study by Silva (1986) reported no significant effects on IQ among higher SES children in New Zealand, whose mean PbB level at age 11 years was 11 pg/dl. Although various behavioral measures were significantly related to PbB, these findings on older children are difficult to relate to the other childhood studies cited here. [Results of encoding experts' probability judgments on leadinduced IQ decrements are summarized in Section 7.C.2. In general, the results indicate that according to most of the experts encoded, risks of small but measurable IQ deficits exist at PbB level's as low as 15 or 25 pg/dl. Some experts felt there were risks of small IQ decrements at a PbB level of 5 pg/dl.] In addition to IQ decrements, PbB levels in the 30-50 yg/dl range may be associated with deficits in auditory and language processing, motor coordination, appropriate social behavior, and the ability to focus attention (de la Burde and Choate, 1972, 1975; Needleman et al., 1979; Winneke et al., 1983). The degree to which lead's effects on neuropsychological performance at these levels persist into later life remains to be established. One study followed the academic performance of a subset of the children initially evaluated by Needleman et al. (1979) and found that grade retention was clearly associated with past dentine lead levels, while the relationship between other outcomes and past dentine levels were either marginally (e.g., IQ scores, classroom behavior) or statistically non-significant (e.g., teacher ratings) (Bellinger et al., 1984). , TEH 0413553 V DUP050454863 VI1-26 Altered electrical activity in the brain has also been associated with PbB levels in children (along with IQ decrements; Burchfiel et al., 1980) in the range of 30-50 pg/dl, with no evident threshold down to 15 jjg/dl or somewhat lower (Benignus et al., 1981; Otto et al., 1981, 1982, 1985). The functional significance of many of the electrophysiological changes observed below 30 pg/dl (i.e., slow wave potentials, synchronized EEG amplitudes, visual evoked potentials) has not been established, although some changes persisted for at least two years (Otto et al., 1982), but inconsistent or unexpected findings across studies require clarification. (Winneke et al., 1984; Otto, 1985; Robinson et al., 1985). The effects on hearing or nerve conduction in the auditory pathway that have been related to lead exposure in children may be indicative of subtle, but potentially important neurological impairment. Slowed nerve conduction in the auditory pathway (i.e., increased latencies of brainstem auditory evoked potentials [BAEP]) were directly related to increased PbB levels in children (6-12 years old across the range of 6 to 59 pg/dl) (Otto et al., 1985). Attempts to replicate these findings in an independent group of children 3 to 7 years old found that the latency of one BAEP wave, as well as hearing threshold, increased linearly with the maximal Pb8 levels found in the children's medical records, from 6 to 56 pg/dl (Otto, 1985; Robinson et al., 1985). Latencies of three other BAEP waves, however, exhibited a curvilinear relationship to lead exposure history, suggesting a possible biphasic effect of lead on nerve conduction velocity in the auditory pathway with facilitation at PbB levels below 25 pg/dl and slowing at PbB levels above 25 pg/dl (Otto, 1985; Robinson et al., 1985). In contrast, Otto et al. (1985) observed a linear relationship between PbB levels and BAEP across the entire range of exposure. Also, in contrast to their earlier TEH 0413554 DUP050454864 VII-27 findings a significant increase was found in hearing threshold with increasing lead exposure history, suggesting that lead exposure may impair hearing and the peripheral segment of the auditory pathway (Otto, 1985; Robinson et al., 1985). Given that a hearing loss occurring in early childhood that remains undetected may result in speech and learning impairments as the child develops, the implications of this finding as well as the findings of altered nerve conduction In the auditory pathway should be pursued as part of understanding lead's putative role in subtle performance deficiencies among pre-school and school-age children. The preliminary nature of these auditory function results must be emphasized, however, and until comprehensive longitudinal, audiometric, electrophysiological, and speech measurements in children are done, it will be difficult to resolve this issue. In summary, there have been Inconclusive findings and contrasting interpretations regarding lead's effects on specific neurobehavioral indicators and functions (e.g., verbal performance, emotional reactivity, perceptual-motor integration, short-term memory, attention, electrical activity In the brain) and the mechanisms involved. The overall evidence, however, indicates that lead is associated with neurological impairment in some children with PbB levels between 30 and 50 pg/dl and that effects on certain behavioral and electrophysiological measures which may have some small, but potentially important and persistent effects on neurological function, support a continuous dose-effect gradient down to exposure levels as low as 15-30 pg/dl PbB, or perhaps, somewhat lower (CD, p. 12-37). The impacts of lead on heme synthesis and related systems are summarized in Table 7-7. Because heme synthesis is a continuous process, most of these effects are reversible upon removal or reduction of lead from the organism or cellular systems involved. However, given: a) that there may be long-term 1 TEH 0413555 ~ DUP050454865 Table 7-7. SUMMARY OF LEAD'S EFFECTS ON HEME BIOSYNTHESIS AND RELATED SYSTEMS IN CHILDREN A CO r^H o> A CO * r* i-- CTO 0 r-- 4-3 ** 0 03 fi. F `F XP oe o _ 03 O VO 21 a *0 oe h* <oo 01 00 *-- 03 0> -CO c 0c 0 0 F" its **(-- o JX L0 O 00 ro 04 t - CTi i Z F-- r-> "0 A a -c C <C f-- wo <0 a- (0 03 40 0) o OO c 4-3 c L. p 1-- 03 03 03 03 P C. .a c e 03 C 40 0) 03 P fi- *0 r- V) 0 0) <C <0 o OS X3> A CM CO 01 LO -- 00 CM 0 CO A p- 04 r-* CM f%- A 0 A X 0 i-- ^ 'C -- M 0A P -- 0 P p-- cd 0 o N PP - p 0 *r- 0 0 3! C F* O W1 F" F- C r" *f - 0 L- |Ap-- 0 l a 0 B <0 O QC A S O F eu <F" a- * r. CL T 0 **00 A VO 0 PS f--* A VO r-* 0 p- -- > 0 0 p^ > A *c 4c0. * p-- X fmm (0 P 40 0 -0 p eP 0 -0 0 0 c wo o p- g 0 P WO p-- 0 E >r* 0 O 40 X o cc nr 3 X VII-28 | c A 0 OX CO 00 *-- CO 0 *F* 0 /-- to **" A A A 0 *-- r** p-- 0 0 re I-- p p 0- 0 !-- >1- >0 0 P -rc. c_ 0p wo X c 0 00 X f-- o o Li. - 13 A O C CO 0 CM 00 A CO 0 00 c 0 r* rs. 0 r-- 0C A F- C - > 0 O 0 A u CO c CO 0 WT F-- r-- 0 0 >A X VO * o 4JN * 0 0 r-- 0 F-- 0 X 40 P * P p- f-- 0 e X3 -- 0 0 O *0 wo C U -- a 0 F" 0 ac S Z 0 A o `40 o X c 0 XJ <c A 0 r-- A fmm 0 P 0 c 0 wo o ec A CO 0 A I-* 0 P 0 W! P P 0 CC q) X F-- LO 0 "O P 00 XC P0 r- X3 N 0P L p-- 0O ZX 0 a *rs X ^0 NCOf * 00 fmm fmm A A Af- X *0 pH l"* 0 0P f- 0 P A 0 F" Aa - t- 3 0 0 ca 0 P c 0 0V0 0 r**H wo go 0 0 a-- im is a > r-H 3 0 wo C--X A WO 0 Q. Cl 0 X3 C 0 1-- F-- 0 WO p 0 X Z 0* CO -0 CO *-- 00 0a-- A0 0 I- p 00 &. r-- O FCJ 0 WO XJ p 0 0X 3 0 S FP 00 n-- ^ mJ ,, -0 o o 2 X 03 u A z 1 Lf> 1 >> a_ * >0 OP 1 F- <> -J *A <p o 4- <0 o 03 C w> o r- a. 4-3 p t-- <( oX 03 f-- F*"* p X r-- P C0 LU *--* o H --W 3ea f*--o n. ^ 0) a o H. v| 00 C oo > oc o s r* X L. P <o O 40 WO X 0 fmm -- wo W) o o 0 - 0 F c wo X P c -F- 0 p CO <F JZ- c > s a. p >t 0 10 4-3 LU >> wo *0 P WO c > o F" a. 0 -a LU c eS o r O 0 f-- P *- JZ 0 c c wo p 0 O n- <0 *0 -0 o t - W3 r-- 0 0 F** P0 O -0 3U c. P r* s **- < A- 4C SP -0 e 3 <C 0 CL 40 Cl CS 0 L. C0l >WO 0s SC E i--i r- O W0 P 40 F- X &P 0 Po A- P > 0 X r-- PX *i- 0 3L 0 0 g. OE O WO 0O 0 <- WO 0 W> 0 P F 0 L- WO WO 0 0 *^ P X "O P p" C r-- >0 0 P WO c 0 00U O *- O C P S A<F" L OC 0X 0 F- 0 vo o wo A <C I Po <u s -a 0 0 N *r- X F-- P P r-- P5 3 L. 0 0U T5 C 0 3 C- 0 PP O t- 0 CPC oco *F *F" *F"" P wo fm0m 0 W) 3X S E *r- wo 3 WO O WO re U o t. < CLP CM wo rs F-- OS 0 F>0 A f-- a 0 A* XP f--O> 0 Wf *" O0 SX 0o X W! 0 c rs H- Q. C O *5f r* N P0 O -- 0 "O 0 cz A E w> wo F-- p- W> r-- 0O XX P0 Cp w>o ,S0S^ W) 0 O0f- S3 5uo LT3 O X0 O -P O *0 P 06 O>0 0* > h-p- oi P LOC0 OC P *- 0 CP 0 U fiSC 0 C- 3 1-- P3 0 F-- g-xj 4-- ec0 H-4 0 u P c 0 E XJ CL CO O 0 F-- 00 VO v > 0 -F- 0 X WO "O t0 0X0 EP 3 0 c wo x >* wo VJ *^- P F* F* 0 F-- WO u 0 c *= u O S -11-0 0 PX o fl Ur* t- O o 0 - fiP33 r- 0 0 <C oO CO CM o Pi *-4 CM ! oo CO 1 o <w TA 5 A A Lf> CM F-- 0 W0> SX a VJ ae-* <4PU00*i-- Tp0cnLL3.j TJ 0 0 3^0 <p io e wo ^ Pw C <0 VO fi- 0 XJ 0 f- P u i- i- Xf X C i-- O a>r- *- x p wo o o ju o t- P O <E2 ifl Pu c 00 0 0.03 - WO p pwo *o P 0) Cic a3 ccn 0 T- f P p 0 c cWl r-- 0) 00 Q. I*- re V) (/) L p 1C A X c u0 ca- O XJ wv e 0 >> vo x *-- 03 -a 0x)j 03 O PP g uo O Sl it. rB P VO g e03 0 f- *0 * 0 0 -o > 0) c L- P *i-- 0W3O jD V3 *03j o > O 03 1- 0 > pWi c c 5O 00 *F- o x t. F- O wo 4-3 <e o C L 0p VO * m- 0 *-- > - o , CLX C 0fi- W0O *F- t~ XJ VO JO 03 F-- P > 03 e. > O 03 0 C VO r-- JS ao 03 WO wo 0 C 0 VO 03 X re 0 H U J3 <0o Wr <fr O X LU H DU P050454866 VII-29 functional consequences of even transitory changes in developing tissues in children; b) heme's pervasive role in many organ systems and physiological processes; and c) the sensitivity of heme production to lead, lead's inter ference in the heme synthetic pathway must be carefully considered. As discussed in Appendix D, lead interferes with heme synthesis at several points in its metabolic pathway: 1) Activity of the enzyme ALA-D, which catalyzes the conversion of ALA to porphobilinogen, is inhibited in red blood cells at PbB levels below 10-15 pg/dl with no clear threshold. ALA-D activity in soft tissues such as liver, brain, and kidney, appears to be inhibited to the same degree at similar PbB levels; 2) Accumulations of ALA, which result from inhibited ALA-0 activity, have been noted *in plasma and urine at PbB levels of 40 pg/dl, and possibly as low as 18.pg/dl. Increases in non-utilized ALA likely occur in brain, kidney, and other tissues at roughly the same PbB levels associated with ALA accumulations in plasma; (3) Lead impairs the transmitochondrial transport of iron and instead of producing heme, the mitochondria accumulate its precursor, protoporphyrin which, lacking iron, is incapable of performing its essential respiratory function. As a result of lead intoxication in newly forming erythrocytes, protoporphyrin (referred to as erythrocyte protoporphyrin or EP) takes the place of heme in the specific pocket of the hemoglobin molecule. As the red blood cells remain in the circulation, zinc is rapidly chelated at the center of the molecule in the site normally occupied by iron (Piomelli et al., 1982). The resulting zinc protoporphyrin (ZPP) is tightly bound in the available heme pocket for the life of the erythrocyte, normally 120-130 days (Lamola et al., 1975). The PbB threshold for elevated EP in children is approximately 15 pg/dl in children with significant elevations greater than one and two TEH 0413557 DUP050454867 standard deviations above normal EP mean levels occurring in 50` of children studied at PbB levels of between 25-30 and 35 pg/dl, respectively (Roels et al., 1976; Piomelli et al., 1982). The health significance of EP or ZPP accumulation is that it indicates that heme or hemoprotein synthesis in many tissues has been impaired as a result of lead's entry into mitochondria (CO, p. 12-46). Previously, EP elevations at PbB levels around 30 pg/dl were considered to be of concern based on functional disruptions in hemoglobin synthesis at 40 pg/dl and neurobehavioral effects above 50 pg/dl (EPA, 1977). In setting the current lead NAAQS in 1978, 30 pg/dl was adopted as a maximum safe PbB for an individual child, allowing some margin of safety relative to levels associated with inhibition of hemoglobin synthesis or neuro psychological deficits. This PbB level was equivalent to the Centers for Disease Control's (CDC) previous criteria level for undue lead exposure e for young children. Recent data, however, have provided more information on the extensive impact of lead on the body heme pool and associated disruptions of many physiological processes (see Figure 7-1). With increasing lead exposure, impairment of heme and hemoprotein synthesis intensifies in different organ systems resulting in reductions in oxygen transport, changes in cellular energetics, neurotransmitter function, and in biotransformation of drugs and other foreign agents, and impairments in the biosynthesis of important substances such as 1,25-dihydroxyvitamin D (1.25-0H2-D). Inspection of Figure 7-1 reveals effects that can be viewed as intrinsically adverse as well as those that reduce the body's ability to cope with other forms of toxic stress, e.g., reduced hepatic detoxification of certain drugs and other xenobiotics (as a result of lead-induced impairment of hepatic enzyme systems), and possibly impairment of the Immune system (CD, p. 13-30). TEH 0413558 DUP050454868 vii-3i Figure 7-1. Multi-organ impact of reductions of heme body pool by lead. Impairment of heme synthesis by lead results in disruption of wide variety of important physiological orocesses in many organs and tissues. Particularly well documented are erythropoietic, neural, renal-endocrine, and hepatic effects indicated above by solid arrows (--Plausible further consequences of heme synthesis interference by lead which remain to be more conclu sively established are indicated by dashed arrows (-- ). Source: Criteria Document (Figure 13-4). TEH 0413559 DUP050454869 Of the functional consequences associated with heme reductions and lead's interaction with those processes, perhaps the best quantitative data are available on the negative correlation between PbB levels (beginning at 12 ug/dl) and circulating levels of the vitamin 0 hormone, 1,25(0H)2 0 (Rosen et al., 1980). Highly significant and profound depressions in circulating l,25(0H)g D levels were found in children whose PbB levels ranged from 33 to 120 pg/dl, with the most striking decreases above 62 pg/dl. The criteria document concludes that it appears likely that lead-induced reductions in heme underlie this association, and that impaired production of 1,25(0H)2 D can have profound and pervasive effects on tissues and cells of diverse type and function throughout the body (CO, p. 12-49): (1) Altered levels of 1,25(QH)2 D may afffect calcium homeostasis and thus calcium-dependent processes essential tp several enzyme systems, the transport of and response to various hormonal and electrical stimuli, and cyclic nucleotide metabolism. In addition, lead may directly affect the role of 1,25(0H)2 0 in cell differentiation/maturation, immunoregulation, pancreatic function (e.g., insulin secretion), and mediation of tumorigenesis (See Appendix D.l(c); CD, pp. 12-40 to 12-42); (2) The effect of lead on 1,25(0H)2 0 is a particularly robust one, with PbB levels of 30-50 pg/dl resulting in decreases in the hormone that are comparable to decreases observed In children with severe kidney injury lacking two-thirds of-normal, renal function, as well as in those with various genetic disorders such as vitamin D-dependent rickets and hypoparathyroidism (Rosen et al., 1980; Rosen and Chesney, 1983; Chesney et al., 1983). At higher levels, lead's interference with heme synthesis and other red blood cell functions (e.g., inhibition of Py-5-N activity which affects TEH 0413560 DUP050454870 VII-33 membrane stability) may result in anemia based on available literature. [Section 7-C.2 summarizes results of the encoding of experts for their probability judgments with respect to lead-induced hemoglobin reductions. These results according to several experts suggest risks of hemoglobin deficits at a lower PbB level than is generally accepted as being associated with anemia, i.e., 40 pg/dl). Although anemia is a serious clinical manifestation, the inhibition of heme synthesis at lower blood lead levels has much wider implications for a multitude of organs and systems, as described above, especially in the developing child. The CD concludes thatt "Given the available evidence indicative of significant effects on neurological functioning and other important physiological processes as PbB levels increase above 15-20 pg/dl and approach or exceed 30-40 pg/dl, the rationale for continuing to view 30 pg/dl as a "maximum safe" PbB level is called into question and substantial impetus is provided for revising the criteria level downward, i.e., to some PbB below 30 pg/dl. At this time, it is difficult to identify specifically what blood-Pb criteria level would be appropriate in view of the existing medical information. Clearly, 30 pg/dl can no longer be seen as affording any margin of safety before PbB levels are reached that are associated with unacceptable risk of notable adverse health effects occurring in some children. This is based on at least two grounds: (1) PbB levels in the 30-40 pg/dl range are now known to "mask" for some children markedly elevated chelatable body lead burdens that are comparable to* lead burdens seen in other children displaying overt signs and symptoms of lead intoxication; and (2) PbB levels in the 30-40 pg/dl range are also associated with the onset of deleterious effects in several organ systems which are either individually or collectively seen as being adverse. "At levels below 30 pg/dl, many of the different smaller effects reported as being associated with lead exposure might be argued as separately not being of clear medical significance, although each is indicative of interference by lead with normal physiological processes. On the other hand, the collective impact of all of the observed effects (representing potentially impaired functioning and depleted reserve capacities of many different tissues and organs) may, at some point distinctly below 30 pg/dl, be seen as representing an adverse pattern of effects worthy of avoidance with some added margin of safety. The onset of signs of detectable heme synthesis impairment in many different organ systems at PbB levels starting around 10-15 pg/dl, along with indications of increasing degrees of pyrimidine metabolism interference and signs of altered nervous system activity, could be viewed as such a point. Or, alternatively, the collective impact of such effects TEH 0413561 DUP050454871 VI1-34 might be argued as becoming sufficiently adverse to warrant avoidance (with a margin of safety) only when the various effects come to represent marked deviations from normal as PbB levels exceed 20-25 yg/dl and begin to approach the more clearly adverse 30 yg/dl level. Lastly, other arguments have been advanced to the effect that any deviation from normal biochemical levels or physiological functioning in any organ system should be viewed as adverse health effects to be avoided, even at PbB levels below 10 yg/dl." (CD, p. 13-40) Table 7-8 presents the staff's assessment of the data in the CD that are most useful in determining-a safe PbB for protection of the sensitive populations. The table focuses on those effects associated with PbB levels at and below 40 yg/dl. The clearly adverse effects at higher exposures are listed in Table 7-5. Based on the above discussion, the staff concludes that: 1) multi-organ effects resulting from impairments in heme synthesis and vitamin D metabolism are likely between 25-30 yg/dl, and potentially significant effects on these processes may be possible at the lower PbB 'levels indicated, but the evidence and risks are difficult to determine at present; 2) the risks associated with altered brainwave activity and possibly reduced auditory function at PbB levels < 30 yg/dl are also difficult to determine with available information; 3} similarly, there is incomplete information on the medical significance of elevations In EP that are first detected above 15 pg/dl, and the dose-response relationship between lead and hemoglobin decrements; and 4) there is considerable uncertainty and controversy regarding the nature and degree of lead's impact on neuropsycho logical function although the weight of the evidence suggests a small but significant association between lead, IQ, and disturbances in sensory/ attention processes at levels between 30 and 50 yg/dl and possibly lower. It is expected that more conclusive information will result from ongoing research. TEH 0413562 DUP050454872 Pb8 40 yg/dl 30 yg/dl 25 yg/dl 20 yg/dl 15 yg/dl 5-10 yg/dl VII-35 Taole 7-3. STAFF ASSESSMENT OF :<SY HEALTH EFFECTS OF USAO Observed Effects Reduced hemoglobin synthesis; anemia in some children1 Possible IQ (1-4 point avg.! and benavioral deficits2 Significant reductions in vitamin 0 hormone synthesis3 * Possible slowed nerve conduction velocities1 Suocle alterations in brain electraphysiology5 ImDlications Strong evidence far significant ana persistent affects an hema tological, neurological, immunological and detoxifica tion systems. Significantly elevated EP Possible IQ (1-4 point avg.) and attentional deficits7 Significant reductions in vitamin 0 hormone synthesis3 Possible slowed NCVs Subtle alterations in brain electraphysiology5 Significant Py-5-M activity inhibition3 Likely multi-organ effects resulting from heme and vitamin 0 impairment. Some risk of benavidral/sansary dtsturoance and effect on cognitive function or academic capacity. Significantly elevated EPS . Possible 10 (1-2 point avg.) and atjantional deficits3 Reducad vitamin 0 hormone synthesis Subtle alteration; In brain electraphysiology, auditory function-0 Likely multi-organ effects resulting from heme and vitamin 0 impairment. Some risk af behavioral/sensory disturbance and effect on cognitive function or academic capacity. Elevated S? Possible IQ (1-2 point avg) and attentional deficits9 * Reduced vitamin 0 hormone synthesis3 Suotle alteration? in brain electrophysiology, auditory function-0 Some risk of multi-organ effects resulting from heme ana vitamin 3 impairment. Some risk of benavio ral /sensory disturbance ano affect on cognitive function or acaoemic capacity. Lowest level of elevated EP Possible IQ and attanttonal deficits9 Reduced vitamin 3 hormone synthesis Suocle alteration; in brain electrophysiology, auditory function-0 Reduced ALA-0 activity11 Small risk of multi-organ impair ments resulting from heme ano vita min 3 impairment. Some risk of behavioral/sensory disturbance ano effect an cognitive function or academic capacity. Reduced ALA-D activity,11 Py-5-fl synthesis3 * Significant functional effects unlikely. 7 Experimental alterations in neurochemistry and cellular energy metabolism*2 Effects detectable at law in vitro levels or experimental dosages; corresponding human PbS.levels and functional significance difficult to determine lBetts et ar., T973; Rosen et al., 1974; Adenbojo, 1974; Pueschel et al., 1972 2oe ia 3Ufda and'Choate, V37Z, 197S; Peri no and Ernhart, 1374; Ernhart at al., 1987; Ernhart, T983; Tfeedleman et al., 1979; Meedleman, 1934; Schraeder at al., 1985; Schroeder and Hawk, 1986 3Rosen at al., 1980; Manaffey et al., 1982; Rosen and Chesney, 1983 ^Seppalainen at al., 1979, X983; Seppalafnan and Hernberg 1980, 1982; Feldman et aT., 1977 SQtto et al., 1981, 1982, 198S; Otto, 1985; Robinson et al., 1985; Seningnus et al., 1981; Burehfiel at al., 1980 6Piome111 et al., 1977; 1982; Roels et al., 1976; Hammond et al., 1984; Rablnowitz et al., 1985 7Needleman et al., 1979, 1982; Needlem'an, 1982; Schroeder et al., 1985; Schroeder and Hawk, 1986 8Valentine and Paglla, 1980; Angle and Mclncfre, 1978; Angle et al., 1982 ^Harvey et al1983, 1984; Yule et al., 1984; Hunter at al., 1983; Wlnneke et al., 1983, 1984; Schroeder and Hawk, 1986 lOtto et al., 1982, 1985; Otto, 1985; Robinson et al., 1985; Wlnneke et al., 1984 ^Hernberg and Nikfcanen, 1970; dranick et al., 1973; Roels at al., 1975b; Wada et al,, 1978 IZBull et al., 1975, 1979; Holtzman and Shen Hsu, 1976; McCauley et al., T979; Holtrman et al., 1978; Silbergeld and Adler, 1978; Silbergeld at al., 1979, 1982; Purdy et al., 1981; Litman and Correia, 1983 TEH 0413563 DUP050454873 VII-36 The staff believes that the collective impact of all of these changes along with other lead-induced effects at low PbB levels should be considered sufficiently Important to warrant avoidance. In evaluating the above health effects Information in the context of deciding on an appropriate maximum acceptable Pb8 level, it is important to note that as part of its lead poisoning screening program, the CDC have revised its definition of lead toxicity for individual children from 30 pg/dl to 25 pg/dl PbB, accompanied by an elevated EP level (_> 35 pg/dl) (CDC, 1985). Detecting these levels identifies a child as requiring immediate medical and environmental intervention. The revisions were based on the recent evidence of neurobehavioral, hematological, and vitamin D metabolism effects of lead cited above, and on evidence that a blood lead concentration between 30 and 50 pg/dl may underestimate the body burden of lead in a child. CDC argued that 30 pg/dl provides little or no margin of safety, and that the biologic threshold for lead toxicity as indicated by increasing EP levels, is below 20 pg/dl (CDC, 1985). However, CDC acknowledges that practical considerations must be taken into account in setting this level. An intervention level of 25 pg/dl therefore represents an accommodation based on a pragmatic decision on the limits of effectively implementing the existing screening program and on the level of risk that is tolerable in that context. The Clean Air Act requires that the air standard be precautionary in nature and that the level should not be based on economic or technological considerations. While the lead NAAQS and CDC's program share the common goal of reducing children's lead exposure, there is an important distinction. The screening program is a form of secondary prevention and is necessary to prevent lead toxicity among susceptible children, but is based in TEH 0415)564 DUP050454874 VI1-37 part, on practical, technological, and cost considerations. In contrast, the lead NAAQS is a form of primary prevention to control lead emissions at the source, before opportunities for human uptake and undue risks arise, and Is not to be based on cost. The staff concludes on the basis of the above considerations that the COC intervention level is not directly an appropriate surrogate for the lead NAAQS and that a PbB level of 25 pg/dl contains little or no margin of safety from potentially adverse effects on heme synthesis, vitamin 0 metabolism, and possibly neurological and behavioral functions. Conversely, it is felt that the risks of adverse effects are minimal for an individual child at a PbB level below 15 pg/dl. In'order to avoid potentially significant risks among young children and to protect as many children as possible wjio can be protected by a lead NAAQS.with an adequate margin of safety, the staff concludes that the maximum acceptable individual PbB level should be chosen from the range between 15 and 20 pg/dl. 2. Summary of Probability Encoding on Lead-Induced Health Effects The scientific information describing dose-response relationships for lead, as with most environmental pollutants, is generally limited and incomplete. There is a large variation in people's susceptibility to air pollution-induced health effects, and scientific evidence is rarely conclusive in establishing a causal relationship for health effects resulting from pollutant exposure, especially if these effects involve a latency period or other contributing factors. Given the precautionary nature of the Clean Air Act and the need to protect public health with an adequate margin of safety, it is important to characterize, as explicitly as possible, the range and implications of uncertainties in the data base as part of the ambient standard review. One way to address uncertainties in the scientific TEH 0413565 DUP050454875 knowledge about a particular health effect is to obtain probability distributions based on expert judgments. Obtaining, or encoding these judgments involves interviewing experts to assess their judgments concerning the probability that a certain fraction of the sensitive population would suffer a particular adverse health effect at a given exposure level. Probability judgments can be used to describe an individual's assessment of the likelihood of an event based on the current state of information, which includes both his or her judgments or interpretations of existing studies and theories and the quantitative data available. Because different experts will have different judgments, it is also important not to merge these judgments into a single average, but rather to present to the decision makers the range of risks based on the range of judgments, and thereby also, identify the range and form of disagreement among experts. Probability distributions representing the judgments of experts on two health effects were formally assessed directly using the technique of probability encoding. Detailed results of the encoded judgments and their application to compute health risks in children living near representative lead point sources are provided in Wallsten and Whitfield (1986). The report also describes the methods used in eliciting the judgments. The methodology employed to calculate population exposures associated with different air lead scenarios used in the health risk assessment is summarized elsewhere (Johnson and Paul, 1986). It is important to note that the population exposure results are preliminary and are undergoing further evaluation. Of the numerous health effects of lead, reductions in hemoglobin levels and IQ decrements were chosen for probability encoding. It must be emphasized that although there is considerable uncertainty regarding TEH 0413566 DUP050454876 VII-39 the dose-response functions for these two effects, particularly at low lead levels, these endpoints are not the most sensitive indicators of lead toxicity, nor are they necessarily the most critical in terms of public health. Because this exercise was EPA's first application of formal risk assessment procedures in reviewing a NAAQS, it was important to select health endpoints: a) that could be readily quantifiable in common measurement units {in contrast to classroom behavior, for example); b) that could be readily understood in terms of their medical significance (in contrast to changes in ALA or nerve conduction velocity, for example); and c) for which exist a sufficient number of qualified experts who span the range of respected opinion and interpretation (unlike for example, lead-induced changes in vitamin D metabolism for which few experts can be identified). Since only a finite number of PbB levels can be presented for encoding, it is necessary to interpolate between levels in order to use the judgments in risk assessments. Such interpolations were made by fitting suitable probability distributions to the encoded values for both hemoglobin and IQ effects (see Wallsten and Whitfield, 1986, for a detailed description). The present discussion utilizes the functions fit to each individual's probabilistic judgments to present a summary of the quantitative results for both hemoglobin and IQ. The functions provide an accurate represen tation of the underlying encoded values, both because goodness of fit was excellent and because each expert endorsed the output of the respective functions as representing his or her judgments. 2. Encoding Judgments on Lead-Induced Hemoglobin Decrements Of five experts selected, probability judgments of four were encoded with respect to the frequency of lead-induced hemoglobin levels below TEH 0413567 DUP050454877 either 9.5 or 11.0 grains per deciliter (g/dl) in homogeneously exposed populations of young children. The fifth expert (Expert B) felt un comfortable with the notion of judgmental probability encoding and declined to have his judgments encoded. The experts were given the option of considering separately the population of children in the age groups 0-3 and 4-6 years, because of the age-related differences in iron deficiency. It is generally agreed that for children a hemoglobin level of about 12 g/dl is normal and about 9 g/dl is anemic. Thus, of the two levels specified, a hemoglobin concentration of 9.5 g/dl would be much more likely to be considered as an adverse health effect. Although both hemoglobin levels are sufficiently low to warrant concern, there would likely be extensive debate over whether a hemoglobin level of 11 g/dl would necessitate preventative measures in terms of a lead air quality standard. In the interests of brevity and of focusing in on the more critical effects, results are summarized here only for the judgments regarding 0-3 year olds (the more sensitive age group), and for the dose-response function for hemoglobin levels less than or equal to 9.5 g/dl (See Figure 7-2). [Expert C, believes that a single dose-response function, applies to children in the 0-6 year age range; with his concurrence, his judgments were reproduced In both the 0-3 and 4-6 year age groups.] The following discussion regarding Figure 7-2 is extracted directly from Viallsten and Whitfield (1986): The graphs are analogous to the usual dose-response functions found in the literature, except, of course, they are based on probabilistic judgments rather than on direct data. The dark, central curve in each panel shows the median judged dose-response curve for each expert. In other words, for a given panel, according to that expert, at each blood lead level there is a 0.50 probability that the true response rate is above the indicated value and a 0.50 probability that the true response rate is be! ow i t. TEH 0413568 DUP050454878 VII-41 Figure 7-2. Probabilistic judgments of Experts C, D, and regarding the dose-response function for hemoglobin levels <,9.5 g/dl in children ages 0-3 years (from Wallsten and Whitfield). TEH 0413569 DUP050454879 The two lighter lines on either side of the median curve contain the central 50% credible interval. Thus, according to the expert in a particular panel, at each blood lead level there is a 0.25 probability that the true response rate is below the lower light curve, a 0.50 probability that it is between the two light curves, and a 0.25 probability that it is above the upper one. In a similar manner, the dashed curve contains the 90% credible interval. The more tightly packed are a family of functions in a panel, the less uncertainty does an expert indicate in his judgments. Thus, Figure 7-2 gives a rather complete representation of each expert's probabilistic judgments. Figure 7-3 is less complete, but provides a convenient means of comparing judgments across experts. The axes are the same as in Figure 7-2. The vertical bars at each lead level represent each expert's central 90% credible interval for response rate, and the symbol within each bar Indicates the median judgment at that lead level. It must be borne in mind that these judgments are with' respect to lead- induced response rates over and above any base response rate due to iron deficiency and other factors. Thus, levels of uncertainty, as. well as differences or similarities of opinion reflected here, are focused solely on the effects of lead on hemoglobin. Note first that expert A did not feel that there was a measurable lead-induced hemoglobin effect at PbB levels below 45-55 pg/dl, and therefore judgments at 9.5 g/dl are not shown for him; indeed, his median judgment for the percentage of children age 0-3 years with hemoglobin levels below 11 g/dl at PbB = 45 pg/dl is 3%, and this rises to a most likely rate of 17% at PbB = 75 pg/dl. There is overlap in the judgments of experts C, D, and E, although not to the degree as for their judgments regarding hemoglobin levels below 11.0 g/dl which are not displayed here. For example, these experts judged with a probability of 0.9 that the following fraction of children 0-3 years old which would have hemoglobin levels below 9.5 g/dl with PbB of 35 pg/dl were within the following ranges: 3-8% (Expert C); 4-13% (Expert D); 3-41% (Expert E). At a PbB of 25 pg/dl, the corresponding TEH 0413570 DUP050454880 DUP050454881 Figure 7-3. (ip /6 g*6 > qn) ^HiiqDqojd nr o ~r cos 1 o tO "OT + T o C--^ - uJ --J -a co<)d hOl rO m i'-ca S' ! -o -j - o "2 a> > <0 _j TaJ 03 i 11 TJ O O CD - UJ 'v. - a CD in r o <N Comparison o f judgments o f Experts C, 0 , and E regarding the p ro b a b ility o f hemoglo in children ages 0-3 years a t d iffe re n t blood-lead le v e ls . The v e rtic a l bars at eac represent each expert's 90% c re d ib le in te rv a l fo r response rate and the symbols in d i judgment at th a t blood-lead level (from Wallsten and W h itfie ld ). ... T - in to -o *** -o C D - Ul H*** ------- ------ - ------ ; h -o <- UJ TJ -a CD -o in _ >-- O_ CsD ITS VI1-44 range of the fraction of children affected with a probability of 0.9 are: 3-6% (Expert C); 1-4% (Expert 0); 2-29% (Expert E). For a PbB of 15 pg/dl, these 0.9 credible intervals are: 2-5% (Expert C); 1-2% (Expert 0); 1-23% (Expert E). For a PbB of 5 pg/dl, the following range of fractions of children 0-3 years would have hemoglobin levels below 9.5 g/dl with 0.9 probability: 1-3% (Expert C); 0 (Expert 0); 0-10% (Expert E). Considering the median judgments (i.e., the response rate for which there is a 0.5 probability that the actual rate is either above or below the indicated value), C and E agree in estimating the most likely response rate at 5 pg/dl to be 2%, while D is most certain that the response rate is 0. Expert C's median response rate judgment increases relatively slowly with increased PbB, while that of expert 0 increases relatively quickly. As a result, at PbB * 55 pg/dl, D and E agree that the most likely response rate is 20%, while C considers it to be 7%. p Of these 3 experts, expert E expresses considerable uncertainty in his judgment about the dose-response function, while experts C and 0 express much less. Note also that the judgment of expert D suggests a slight threshold between PbB levels 25 and 35 pg/dl, but that the judgments of the other two do not suggest a threshold for hemoglobin levels below 9.5 g/dl in 0-3 year olds. The corresponding judgments for lead-induced hemoglobin levels at or below 11.0 g/dl, and for children 4-6 years old, are not displayed here. Expert A judged that blood lead below 45 pg/dl would not cause hemoglobin levels to drop as low as 11.0 g/dl. As with 9.5 g/dl, the Judgments of experts C, 0, and E for 11.0 g/dl tend to overlap, but the degree of similarity displayed is greater than at the low hemoglobin level. None of these 3 experts' judgments suggest a threshold above which blood lead would result in a hemoglobin level below 11.0 g/dl. According TEH 0413572 DUP050454882 VII-45 to their median judgments, the best estimate of response rate for 0-3 year olds, hemoglobin _< 11.0 g/dl, is between 4% and 9% at PbB = 5 pg/dl, rising to between 26% and 33% at PbB = 55 gg/dl. The judgments for children 4-6 years of age followed the same patterns as for children 0-3 years, with all the experts judging smaller probabilities of effects in the older group. Detailed results can be found in Wallsten and Whitfield (1986). b) Encoding Judgments About Lead-Induced IQ Decrements It should be noted again that IQ was chosen not because it is the only, nor necessarily the best, measure of cognitive ability, nor is it being considered as a surrogate for other suspected lead-related central nervous system and behavioral effects that have been explored (e.g., brain wave activity, sensory motor, perceptual and attentional deficits, negative classroom behaviors). Rather, IQ decrement emerged as most appropriate to consider because of its acknowledged functional significance, its easy specification, and the amount of data (albeit controversial) on its relationship to lead exposure. The probability judgments of six experts were encoded with respect to the outcomes of a hypothetical, ideal experiment in which a very large number of subjects were randomly assigned at conception to various exposure groups and were exposed to (or sheltered from) lead until their seventh birthdays. Although each child's lead uptake would not be constant due to changes with age, physiology and behavior, the hypothetical experimental conditions were specified such that at their third birthdays, all children in each group have the same measured PbB level. Environmental lead levels necessary to yield a given PbB level at age 3 in a particular child were specified as remaining constant through the seventh birthday, at which time the WISC-R IQ test was administered. The very large numbers of TEH 0413573 DUP050454883 VII-46 subjects per group eliminated any concern about sampling error, and the random assignment of subjects to conditions eliminated any concern about complex analyses of covariance. Each group was assumed to differ only in terms of exposure to lead. Probabilistic judgments were encoded regarding: (a) the mean IQ decrement for each exposure group (5, 15, 25, 35, 45, and 55 pg/dl on their 3rd birthday) relative to a lead-free control group; (b) the mean IQ of the control group; and (c) the within-group IQ standard deviation. Judgments about control group mean IQ values and within-group standard deviations were necessary to derive probabilistic estimates about the lead-induced increase in percent of children at each lead level whose IQ scores are below a specified IQ value of interest. Detailed results, ' including the encoded judgments, mathematical functions fit to those judgments, goodness of fit measures, and derived subjective probabilities about dose-response functions, are given in Mallsten and Whitfield (1986). For brevity, summaries of results for IQ decrements only are presented here. The experts were given the option of considering possible interactive effects of socio-economic status and lead on IQ (based on findings from several studies discussed in the CD and this staff paper) by considering low SES children living in households with incomes in the lowest 15 percentile separate from the remainder of the population. All the experts, except F, believe that at the doses under consideration, lead interacts with variables that contribute to SES level. Therefore, all except Expert F provided separate judgments for the two SES levels. Figure 7-4 summarizes the judgments of all six experts regarding mean IQ decrements for the low SES group. The following discussion regarding the figure is extracted directly from Wallsten and Whitfield (1986). TEH 0413574 DUP050454884 VII-47 Figure 7-4. Probabilistic judgments of experts regarding mean IQ decrements for low SES group. Blood lead is on the abscessa and mean IQ decrement (mean control group IQ minus mean exposed group IQ) is on the ordinate of each panel (from Wallsten and Whitfield-, 1986). TFH Ml 3575 DUP050454885 VII-48 Each person's judgments are shown in a separate panel. Blood lead is on the abscissa and mean IQ decrement (mean control group IQ minus mean exposed group IQ) is on the ordinate. The dark, central curve in each panel shows the median judged IQ decrement for each lead level. In other words, for a given panel, according to that expert there is a 0.50 probability that the actual mean IQ decrement would be greater than the indicated value, and a 0.50 probability that it would be less. The successively lighter pairs of curves that bracket the median curve represent central 50%, 90%, and 95% credible intervals. Figure 7-5 allows a comparison of judgments across the experts. The axes are the same as in Figure 7-4 . The vertical bars at each lead level represent each expert's central 90% credible interval, and the symbols are his or her median judgments. Expert F consistently judged the IQ effects of lead to be less than did the other experts, and evidenced considerably less uncertainty about the magnitude of these effects than did the others. F was certain that there is no IQ effect of lead up to at least 15 pg/dl. At 25 pg/dl, the median judged IQ decrement is about a 0.5 point, and this increases to a median judged IQ decrement of just under 2 points at 65 jjg/dl. Accord ing to F, at 25 pg/dl, the IQ decrement" exceeds approximately 1 point with probability 0.05, while at 65 pg/dl, it exceeds 5 points with the same probability. There are overriding similarities in the judgments of the other experts, although there are also small, consistent differences among them. Thus, only G, H, and J give any credibility to there being IQ effects as low as 5 pg/dl, while I does so at 15 pg/dl, and K does at 25 pg/dl. The judgments of H and J are consistently very close, as are those of G, I, and K, which as a group are somewhat lower than those of and H and 0. Considering the five sets of judgments, the median judged IQ decrement at 5 pg/dl ranges from 0 to 2.5 points. The median judged IQ decrement at 55 pg/dl is from about 7 to 11 points. According to the judgments of G, H, and J, with probability 0.05, the IQ decrement exceeds 3 to 5.5 points at 5 pg/dl, while according to all 5 experts, it exceeds 11 to 17 points at 55 pg/dl with the same probability. Considering intermediate PbB levels. Expert F judged a probability of 0.5 that the mean IQ decrement at a PbB level of 35 pg/dl in low SES children would be 0.5 points. Corresponding median judged IQ decrements at 35 pg/dl for theother experts are: 1.5 (Expert G); 8.4 (Expert H); 3.6 (Expert I); 7.0 (Expert J); 4.0 (Expert K). The median judged IQ decrements at 25 pg/dl for low SES children are: 0.25 (Expert F); 2.7 (Expert G); 4.9(Expert H); 2.3 (Expert I); 4.8 (Expert 0); 2.9 (Expert K). At a PbB levelof 15 pg/dl, the median judged IQ decrements TEH 0413576 DUP050454886 VI1-49 fc tuo 4-3 to <- CO in co T" 0>3 03 CP--l o JS 0) -M -C -o K TS*33 ----03 (fa. 3= Ui H d3O. t**-J+fS> c > 3: cn &03 XJ 05 <UV/>)i 4c->- <Co lCOO 3! 03 03 05 tino --<-- i-- rp ^ r- 05 I-- h------ - -O- < . - -- -- o-- - -- -t |* hT ( *>* f in > _0J3 05 3. m *D O pi *D O _o 05 * m 8 ( --o H -----------------<3-H 05 m *Ow- 'O0L1 ^3 i S 4J ** O C O - 03 c-- ^ (Q r-- U S. 03 03 4J > .*0 C 01 03 i-- O' u ' *-- v> C - 0) 3 -P f- <U W t E 03 -D . cCn x0J ro-- pp JC ^ L U <U <B (0 (IS 03 03 JZ VS 4C-3 -<P0 P O' t0-3 M03 C44 Q- U 03 X CL E 03 0c3 -03 vi a Vo<Ou0I pp00>---33 *i"3 *pteo* V5 -O X033 4ESJ *0fI-3i g 03 X033XO3 P a o Pos hQ tO I-------<-------1 o Oc JoOZ*-"Ocp-- I--OH *> m Vp-) 03 v tiJ(QPO- in nr* -r. ~T oi (D K) o 9E- . -s9 O A3 >, CJ -O t/1 12 < tr^ni. 3CT1 DUP050454887 VII-50 for low SES children are according to these experts: 0 (Expert F); 1.4 (Expert G); 3.5 (Expert H); 0.7 (Expert I); 3.5 (Expert J); 1.3 (Expert K). As with hemoglobin, credible intervals were calculated for each expert's judgments. For example, the 0.9 credible interval is a set of mean IQ decrement values such that there is a 0.9 probability of the true value falling within it. The 0.9 credible intervals concerning mean IQ decrements for the low SES children for different PbB levels are as follows: 45 pg/dl: 0.45-2.07 (Expert F); 3.5-9.3 (Expert G); 6.4-13,9 (Expert H); 3.3-9.1 (Expert I); 6.3-11.4 (Expert J); 4.4-8.4 (Expert K). 35 pg/dl: 0.23-1.05 (Expert F); 2.1-7.3 (Expert G); 4.6-12.7 (Expert H); 2.2- 6.5 (Expert I); 4.4-9.3 (Expert J); 2-5.5 (Expert K}. 25 pg/dl: 0.11-0.52 (Expert F); 1.1-6.3 (Expert G); 2.6-9.0 (Expert H); 1.2- 4.6' (Expert I); 2.3-7.2 (Expert 0); 1.1-4.7 (Expert K). 15 pg/dl: 0 (Expert F); 0.6-3.5 (Expert G); 1.8-6.7 (Expert H); 0.3-1.7 (Expert I); 1.5-5.4 (Expert J); 0.5-1.8 (Expert K). 5 pg/dl: 0 (Expert F); 0.2-1.8 (Expert G); 1.2-4.5 (Expert H); 0 (Expert I); 0.9-3.9 (Expert J); 0 (Expert K). Judgments about mean IQ decrement for the high SES group are not dis played here, although all the experts, except F, felt that the risks of lead effects on IQ would be smaller in the high SES children. Also, as with the low SES population, F consistently judged the IQ effect to be less than did the other experts. From 25 pg/dl on, the judgments of the others overlap, with, as before, those of H and 0 being very similar and somewhat greater than those of G, K, and I, which themselves are similar. Only H gave any credibility to the existence of an IQ effect at 5 ug/dl, G, I, and J did so at 15 pg/dl, and F and K concur at 25 pg/dl (Wallsten and Whitfield, 1986). TEH 0413578 DUP050454888 VI1-51 Considering all the experts simultaneously, the median judged IQ decrement at 15 pg/dl in the high SES group ranges from 0 to 2.4 points; at 55 pg/dl, it ranges from 1.4 to 7.9 points. According to G, H, I, and J, with probability 0.05 it exceeds 1 to 7 points at 15 pg/dl, while according to all the experts it exceeds 4 to 11.5 points at 55 pg/dl with probability 0.05. c) Discussion Considering the scientific debate that has prevailed about the IQ effects of lead, the degree of consensus reflected in the present results l is notable. This is particularly so, since the experts were selected so as to span the credible range of opinion. As occurred with the hemoglobin results, encoding subjective probabilities from the scientific experts about specific, well-defined scientific outcomes eliminated or minimized dis agreements about definitions, policy, and other matters. The remaining differences, evidenced in the preceding results, are mainly due to differing interpretations of, and extrapolations from, the scientific evidence. As discussed previously, the health endpoints that were assessed using probability encoding should not be considered'the individual effects most crucial to a determination of the appropriate maximum acceptable PbB level. Judgments of some of the experts suggest that effects on IQ and hemo globin could occur at and below 15 ug/dl. It should be noted, however, that in general the judgments tend to support that the range of 15-20 yg/dl, discussed previously, is appropriate for a decision on the maximum acceptable individual PbB level. In fact, several of the experts assigned fairly high probabilities that potentially important hemoglobin and IQ decrements could occur in children with PbB levels starting at 25 pg/dl. | TEH 0413579 DUP050454889 3. Predicting Blood Lead Levels under-Alternative Air Lead Levels Three approaches are examined here that can be used to estimate the impact of alternative air lead levels on PbB levels among children. The first is to combine the estimates of daily lead uptake from all routes of exposure under specified air lead concentrations with the derived lead uptake-to-blood lead relationships, as presented in Section V.A. The second approach is to directly apply mathematical relationships between air lead and blood lead derived from population studies and appropriate statistical analyses that account for children's exposure to atmospheric lead through pathways other than inhalation such as Ingestion of dust and soil (Section V.B.2). Finally,' a hybrid of the first two approaches is provided in the criteria document in which mathematical relationships derived from population studies are applied,to estimates of lead concentration in Individual media (Section. V.B.l). These three modeling approaches are discussed below and the results are presented (in Table 7-14) for consideration in the possible use of one, two, or all three approaches (with any necessary modifications using improved data) in assessing the protection provided by alternative lead NAAQS. All three models estimate PbB levels in terms of population mean levels. For purposes of setting a lead NAAQS, It is necessary to determine the blood lead distribution corresponding to a given mean PbB for the population of children such that a specified percentage of children are protected from exceeding a maximum acceptable PbB level. In determining such a distribution, it is important to recognize that there is significant behavioral and biological variability within any population, and it is those individuals with the potentially greatest adverse response to any given lead exposure that are of greatest concern in establishing a primary TEH 0413580 DUP050454890 lead NAAQS. A method to consider the most susceptible segment of the population of children is discussed here. As noted for other metals in tissues of human populations, the distribution of PbB levels for any relatively homogeneous population closely follows a lognormal distribution (CD, Section 11.3.4). A lognormal distribution is completely specified by its geometric mean and geometric standard deviation. It is possible, therefore, to use a geometric standard deviation of a population's blood lead distribution to calculate the mean population blood lead level that would place a given percentage of the population below an acceptable maximum PbB for an individual child. Several epidemi ological studies have indicated that the log values of measured individual PbB levels in a uniformly exposed papulation are normally distributed with a variation, including analytical variation, ranging between 1.3- and 1.4, when expressed as a geometric standard deviation (GSD) (Tepper and levin, 1975; Azar et al., 1975; BilTick et al., 1979). The NHANES II study, which provides the best available data in terms of quality control and sample size, yields estimates of GSOs in the range of 1.34 to 1.39, uncorrected for analytical variation, for various homogeneous subgroups of young children with comparable race, sex, age, income, and place of residence (i.e., degree of urbanization) (CD, p. 11-29 to 11-30). The distribution of PbB levels in U.S. children is a broad one because there is a distribution of exposures those children face, a distribution of behavior patterns that affect the uptake of that exposure, and a distribution of biological absorption and excretion rates. The GSDs for separate homogeneous populations Identified in the NHANES II survey may not therefore be appropriate to use in targeting a protection level for a certain percentage of the non-homogeneous population of U.S. children (Schwartz, 1985b). This is indicated by the fact that f TEH 0413581 DUP050454891 VI1-54 the GSD for all black children living in central cities was 1.46 and for all children sampled in NHANES II, the GSD was 1.47, not adjusted for age, income, or degree of urbanization (DHHS, 1984). Furthermore, in calculating a GSD that would be used to predict the effect of changes in exposure under alternative lead NAAQS on the percent of children exceeding some cutoff PbB level, the appropriate GSO removes a portion of the total variation in blood lead due to differences in air lead exposure without removing the variance due to other factors such as baseline exposure and biological differences (CD, p. 11-7) so that the distribution of Pb8 levels at an air lead zero can be estimated. With regard to the above GSDs cited in the CD, by adjusting the Pb8 distribution for demographic variables, much of the variance in baseline exposure, behavior patterns, or biological factors, and not solely the variation due to air lead levels may be removed. For example, NHANES II blacks have consistently higher PbB levels regardless of income, residence location, parent's educational level, or dietary consumption, and this difference should remain as a real factor that contributes to the GSD (Schwartz, 1985c). Similarly, location is another factor that represents more than just differences in air lead exposure given that food lead levels, baseline soil and dust lead levels, water lead levels, and other factors can vary from city to city. In fact, regression analyses of NHANES II data indicate that there is a variation in mean PbB levels among cities, and that correcting for demographic proxies (e.g., income, race, degree of urbanization) for air lead exposure leaves a residual variation in site means due to variations in non-air exposure (Schwartz, 1985c). In regression analyses, Schwartz (1985c) attempted to directly remove the variance in NHANES II PbB levels due to air lead exposure by adjusting every individual's PbB level to what it would be at zero air lead, while ! TEH 0413582 DUP050454892 VII-55 allowing for variations in background non-air lead exposure. The estimated GSD from this analysis, 1.428, is shown to be higher than those calculated for the homogeneous sub-groups primarily because of the natural variation in baseline exposure among sites with similar demographic characteristics, rather than the variation in demographic characteristics between sites. Schwartz (1985d) reapplied the same techniques to calculate the GSD for children's Pb8 levels measured in NHANES II after excluding from the analysis those individuals that would not be expected to be substantially affected by changes in the lead NAAQS. Such children would be those likely to have higher than average pica activity and those exposed to excessively High concentrations of lead in dusts, particularly from lead in paint. A blood lead cutoff of 40 pg/dl was chosen as the lowest reasonable number .above which air lead changes would not be important. [Logistic regressions of NHANES II data indicated that gasoline lead was a statistically significant predictor of PbB levels above 35 pg/dl.] After excluding all children with Pb8 levels over 40 pg/dl and adjusting the distribution to zero atmospheric lead, Schwartz (1985d) calculated a GSD of 1.419. [These results are consistent with a study, conducted by Shier and Hall (1977) and analyzed by Urban (1976), of children 6 years old and and younger randomly selected in Pittsburgh during 1974 and 1975; as in the Schwartz analysis of NHANES data, the GSD (1.37) for the general population in Pittsburgh did not change after excluding children from homes with lead-based paint (Pope, 1986b).] Thus, for the NHANES II population of children a GSD without attribution of any source of lead exposure except gasoline lead and industrial air lead emissions may be taken as a rounded-off value of approximately 1.42 (CD, p. 11-31). The staff recommends that a value of 1.42 be considered the most appropriate GSD for purposes of calculating the percent of children above a cutoff PbB TEH 0413583 DUP050454893 V--13 the epidemiological studies should be noted. a) Measurements of lead in the environment were generally limited and taken from samples separated in time and space from actual population exposures (as indexed by blood lead). Consequently, reported air lead concentrations in outdoor air (measured at centralized, stationary monitors), for example, have different relationships to the true personal airborne lead exposure of the target population in different studies; b) In order for the relationships between blood lead and environmental lead to have general predictive value for other populations, steady state or near steady state conditions must have prevailed wherein the amount of lead inhaled and ingested per unit time was reasonably constant long enough for virtual equilibration to occur between lead in air, food, dust, etc., and blood lead (Hammond et al., 1981). As discussed below, in situations where lead concentrations in different media are only moderately correlated, environmental exposure cannot simply be characterized by the lead concentration in one medium, like air or dust. (Brunekreef, 1984); c) The blood/air lead relationships generally are limited in that at most two or three, but frequently, only one environmental source of lead is measured in each study. Because of the simultaneous presence of lead in multiple media, such relationships underestimate or otherwise confound air lead's effect on total exposure unless lead intake from the other sources remains approximately constant and lead concentrations in different media are well correlated. In situations where the latter condition does not hold, environmental exposure cannot be simply characterized by the lead levels in air (for example, near point sources where the accumulation of lead in soil is related more to historical, rather than present, emissions, especially when control measures are being or have been taken). These difficulties can be partly overcome but unfortunately, longitudinal assessments TEH 0413507 DUP050454894 of simultaneous exposure to all media have not been made and only limited information exists from studies measuring lead isotope ratios in blood and in the environment, a method which has emerged as a valuable tool to apportion lead exposure among different sources (Facchetti and Geiss, 1982; Yaffe et al., 1983; Tera et al., 1985). d) As with the uptake/biokinetic approach, the importance of specific sources of exposure varies widely from one individual to the next, and reliance on a blood/air relationship from an "average" case may be inap propriate to predict different individual risks but can provide reasonable estimates of possible population-wide impacts. e) Again, similar to the uptake/biokinetic approach, environmental and blood lead sampling, analytical techniques, and quality control (if any) differ among studies and may explain part of the variability of the results; and f) Possible confounding variables that influence PbB levels but which are not related to air lead measurements (e.g., lead in paint, canned food and plumbing, socioeconomic status, parental care, housing and 'play conditions, calcium intake) cannot always be disentangled. Control for confounders can be achieved by comparing populations that differ only in their exposure to airborne-derived lead. However, identifying such groups has been difficult. Another possibility is to perform a multivariate statistical analysis in which adjustments are made for some or all of the confounders before calculating the blood lead/air lead relationship. This requires Information on the value of each confounder for each individual, which is also very difficult to estimate. In the case of lead, several confounders tend to work in the same direction as air lead. For example, elevated exposure and unfavorable social conditions often are both concentrated in central cities. Consequently, when statistical adjustment is incomplete. TEH 0413508 DUP050454895 the relationship between air lead and blood lead will likely be inflated. The situation is complicated when more than one exposure variable besides air lead is entered into the analysis. Adjustment for a confounding variable may result in all of the shared variance between confounder and exposure variable attributed to the confounder; this can inevitably lead to underestimation of the "true" impact of the exposure variable {Rutter, 1983). Thus, adjusting for environmental exposures such as soil or dust lead, which are determined to a large extent by air lead levels, can result In an underestimation of the total Impact of airborne-derived lead on blood lead (Brunekreef, 1984). 1. Blood/Air Lead Relationship Using Disaggregate Model The CO concludes that experimental inhalation studies (see Table 5-2) and epidemiological studies on adults (Azar et al., 1975) exposed to relatively low air lead levels (<3.Q pg/m3j' produce linear inhalation blood lead/air lead slopes of 1.64 and in the range of 1.08-2.57 respectively (CD, Tables 11-38, 11-40), Inhalation slopes for children were estimated in the CD from the population studies of Angle and Mclntire (1.92 + .60), Roels et al, (2.46 j^0.58), and Yankel et al. (1.53 _+ 0.064), yielding an unweighted median slope of 1.92 (CD, p. 11-105). These studies were chosen for analysis and emphasis in the CO because they were judged to address several key factors sufficiently well to establish meaningful relationships. These factors include a well-defined study population, a good measure of individual exposure, measurement of blood lead with adequate quality control, a statistical analysis model that is biologically plausible and consistent with the data, and control or measurement of important covariates (CD, p. 11-63). In addition, they were selected so that, with the exception of some children in the Yankel et al. study, attention can be restricted "to those individuals without known excessive occupational or personal exposures" (CD, p. 11-65). TEH 0413509 DUP050454896 V-16 It should be emphasized, however, that most of the children in these studies lived in the vicinity of lead point sources (i.e., smelters). The relationship between blood lead and direct inhalation of airborne lead provides information useful for changes in air lead on a time scale of only several months (CD, p. 11-186). Over time, suspended lead is deposited and incorporated into soil, dust, and water, and enters the food chain. Since prior and current atmospheric fallout directly modify the daily burden of Ingested lead, larger changes in blood lead would be predicted if the associated changes in the surface deposition of lead were accounted for, rather than simply inhaled air lead (Angle et al., 1984). To account for the simultaneous presence of lead in multiple environmental media, the CD has analyzed the separate relationships between children's blood lead and dietar7, soil, and dust lead. These analyses are summarized in the tables Included in Appendix C and are described in detail in Chapter 11.4 of the CD. A set of the most reliable relationships derived from these analyses are applied in a further analysis presented in the CD (CD, Table 13-6) and reproduced in this paper (Table 7-12) as a way to characterize average total lead exposure among U.S. children under alternative air lead levels. A similar disaggregate model was developed by Angle and Mclntire (1979) and Angle et al. (1984) in forming an Integrated lead exposure function from measurements of lead in air, soil, and house dust and relating that to PbB levels of children living in various areas of Omaha. 2. Blood/Air Lead Relationship Using Aggregate Model In the disaggregate modeling approach, "inhalation" lead slopes are derived by statistically adjusting blood lead/air lead slopes by whatever indirect air exposure variables (e.g., house dust lead) that were measured in the individual epidemiological studies, and then combining separate TEH 0413510 DUP050454897 slopes available for other exposure media (e.g., dust, food, water) to arrive at an integrated lead exposure function. With the exception of Angle and Mclntire (1979), the community studies from which inhalation slopes have been derived have not simultaneously measured lead in more than two or three media and consequently, the integrated lead exposure function is necessarily based on data from multiple studies involving different populations, exposure conditions, measurement techniques, etc. An alternative method of calculating the effect of changes in air lead on children's blood lead is to analyze Individual community studies in which reliable "unadjusted" blood lead/air lead relationships can be derived such that the impact of both direct (inhaled) and indirect (via dust, soil, etc.) contributions of air lead are combined, or aggregated, in one variable (i.e., air lead). To only use an "adjusted" blood lead/air lead slope (i.e., inhalation slope) would result in an underestimation of the impact of atmospheric lead on children's total exposure since air lead levels, in general, are significantly correlated with other important exposure variables such as hand and household dust lead (Brunekreef, 1984). The population studies with identifiable air monitoring methods and reliable blood lead data are summarized in Table 5-3. As is the case for the data in each of the experimental studies, different statistical analyses of these studies have resulted in a range of possible values for the blood lead/air lead relationship (0). Unadjusted (i.e., aggregate) relationships are presented in addition to adjusted (i.e., disaggregate) relationships derived from regression analyses, the latter which refer to the blood lead/air lead relationships due to direct inhalation exposure. In Table 5-4, the calculated 0 values listed in Table 5-3 for each study are presented according to the blood lead levels, ages, and type of location of the investigated children. Relatively wide ranges of 0 values are TEH 0413511 DUP050454898 S| cT 3A 9 3 jS 9 *0 % 9 V-18 | H H H - M 9 tr o Hi 33 Hi ^ 39 CM ?M O Hs. r*. CT CT OO 0f J3 n i *n foli (eU s -- 44 * "3 Qi f- L. U *3 +0 . ; 91 <rt C3 *- *3 J* *= *2 - e C- <9 *o jr m3 <c t ho-. o X 35 <A O g --. p" 00 l/> O' M 0) vt o CCT. 9C --> o<-^ 41 Jj> O. - V 393 a. tf T- V* S- -- W -- CT*-- -- 0) 3 oeoo SC as w<j -I e * > O u* *- 3 V 40 ' > i S <a9* T3 <9 .g3 >1/10 0 3E 40 fl 3 *3-* O T- - a. 41 CD 3 <0 j O > > > HA e -a a. e* vi v o jq -o5 s53 o i-- ai ns i3 HH #H 40 o. W O- M VI 1^ in Id |/H- 9 3W Q. S --5 VI - - s a v> U 9 li S AllflH Uh h 9 CTttJ OL o n. o w* <C <f> l 3v tflr --w a 30Hi c c t U (A Hi CT <Q *-H 41 i-- fc. - "3 -- C 9 fll- CM CM u <h a. ai 30 30 9*-- O S 4i CT CT S) I 9 9 ( Q. hc e o c . u j* h > e o o. e e e :41 41 41* 0) w** h- a a U lO bo LO uo < HO 3 SO W 0) 41 M VI U 13 <9 0 O <9 %O b- O e> > +tc t_JS 43 4J> H. C40OO3M h SA3 tfl ^h V A 0 g 3 Ch W 4^ 10 h 6 3 (A V) M 0*0W VI -9 <0 <9 3 U -no V (9Q) 41 T3 3 S6<9-- h O <9 9 *h c t a.a. MAoo <1 I I Z0 .. V) VI 13 0 Hco --* ro c u m </> co c q h w - ut <CU-IS>J|lH9HHI HCT CO'OVA '-HO Hi Hi O Hi Uh O oC < a *ovo -TJ O * h * HC>H*H.U4HH V. VI ve o >)J9 O c. >, VI -h . <9 <9 U U > CT h- H- .* 30 CLThCTCNT<h ht wI C3hh IAI hI Sh Oh O U i9 Hi vo 0 <^o^y 4 31*0 C -v *eH U 36 JS Vi 45 C _ 4J 3 a. O CT O O h e o j s u w-- g o -s-cii *t -O 9 4-- - *o i <- e j z W 4- <9 ea U OVI CT U"<M O. <9 o CL X -h VI - > 3 <9 so or IS. 3 CT C O . a < *- o - (9 W e40 40 VI <9 - a i fly Cb o CT 40 e * vi - VI s CTO < U JS COO CT VI Hi a." i o. c 33 OU i- CO CS w. VI CO VI CT Hi i tH- Jtf O. H C *J 3 H- C. 3 CO O CT 4tLr*t Hi 9O. V12 U o- e 33 O tU t3 M O tSi V -- pN rt W O-J T3 hO Hi CM < I l I Hi W 3 9V<P<09 O-iToI o C-J -H H-J cn CT rs. CO CM tn CM CM o 3 t A. OONHlfl 41 (A CHOi ^H* VO m Hi CM >CT Hi 10 9* Hi o e o 33i *J r a i ct e >_ vo u <r c m _ I * lO o CM O O Wr~ 6s s " i e m^ .x j * S -C VO T J* 'CT CM -* +4 i o SH-i VI oHi CMt c<TIt7 LNfJ OC o hi h 4 c m a --* co n 9H 4 'l-^AJC<UV} CM II | l| 6* e c c c trt i/i to *o S vc.l U> I>.> >* a va in m 9* on h *-*^ t co *gc-- 3e j m < * JCITJ (Hi . 3 * V c m 30 atf . o -C9O1 v> * r--* VO 0? f. o or* CC Hi VO fCsT, 10 41 > CT OC f- > CT O Hi >M I H H S h 9 VI H t_ O <0 41 30 CT Hi f* S3 nv i h O C>T CM h-9 f*"! <9 C (Q H* *J ** O <9 v e L. 33--n S (9 a eo 3 49 CT o o O Cr eu h O 0^ii <9 U CH> CT 9Im^ 5^2 P^. CM c t eo Hi Hi H. *a*B Ji JCH VA CM t I I <9* CM h * SO V Hi Hi ^ VO s si 2A S< Hi CT 9T "CT v > * W 0 Hi WVA --VO U3 J*=i CM Hi I C t is lA nr CM CM Ow c. e 4-i co i to 4-- CTV CM g Hi VCT VI II U 11 * S C >V 10 S- 0 00 0 4- Ut- g *0 ^ ** ^CM *? CO Ph CO V OS III H CM Hi Hi CT VI * * 4 CS Jk-- U *H S NCT NCTNCT *h> OL. ( M3 3 * -O O CT O 40 xCL Ue -*' CAT CCTT C S- > CM 2--H. g o " *H VI U. 19 VI 0 i- t>i U-- >9 UJ w 4 H Ul C tit. W Hi Hi >i CT e 40 CMP-*h h . NNH > li c t c t -H e Hi Hi H H V> *0 V0i 0 Hi CT V> P*. Urn -*H Ol 3H H. JS C0H 3 * ( iJ >l> H PM <9 CT * T O --10 v H* C U P*. 9 40 O CT J VH CM t-- in co r* 5T O a: iu H DUP050454899 T able b - 3 . SUMMARY Of EPIUEMIOLOCICAL STUOIES ON LEAD-EXPOSED CHILDREN (CONTINUED) 3_ o T> M <rjsi*jr:--jor>^. 0 33*i9> se osure, e of number u th ln y u05 Vr9 <V9. *--CL s* * a3>5 C -af~ <0 l. *U<J9 vo- 1--O +c- .1 <= +J V19I -V39) 4005 9a V) 9<u Crt T *>-t =a3t tetoo -- a** Co VuV 1V/>1 J0*5 9<at_ut ae3Ua SC --* 3 0. 05 * O JoS x45 oa. eo s L. <9 (O. (EA. VO. VU V0195 -e0tJ5 2 w afc WVO0O 3(SA 9 0cE5 3 OCo 9S3 *v<4y fc- v C J x: o. 19CU<WVLVU5 VoCO*<--V3O)>Vv(O0A*" #<s*U- VOSOU*x0>oA-.) eiesag j = <o/o9.^o* ar .9 x: o j (CA 9V> <rt VI* f -*x**r- <i?m9.--Ov>jvCl^oHaQ>* --Iv>Qi1 i--/o V OW> <9 4.* C<9 V <fc. -- (cagQj IOel//1l 5s4K_1 *O1ieI-//1I bU0. a935i 9 Q3. 0U5 C3 0b5. C3 f* 0OU9 S30C51'<--3-3'C34C>> 0U3 O2N0 9oo -9; C<On Cos 9-CjrO-- a> s cc0A5n <u0 V> --sus--rv* (A 90i-14 7 St 4 COO srro** " J ^ ni- 35 u Ob. 05 .1C9 O>W JbB. i9 E V>vOl3sui Vae*3e>ca -- <i0 so fumO> c*3--I*t5*H >OS* EE wUi 3 >t> e <>0 > *UO4.i 19 C0O5 <UtoU LaO->* *--O>J1 J-U39 --* C(1 V.I C9*5j 3eV3OI 9v60U<5 0i >** t. ao --<9 * aB aoci--ohi aUi ^u Osflol oVeeI g1c9* x--~ 31* 0* 05 -fs 03 * aVs O33B 4- <3*A3 .000b3iCX.155. - /--<9* 4J aa at V- 19 e >I M9- 9 42 *"* O c A05 *3a9t *5 to s J*SV 94Q V) 41 -a 01 u -->01 C<09951 9 -- +0to1* aa.i S at --^M41l JXC &- aUt 44-5 9ezs--4g<Agu (9 01 - gat > 9V)^*- 4a>. a tSe/Sui t/> *-- 0) /0 3 <J C. 605 V O 3 93 v) 49 9 V O V b. t vu9ati v> `jre--> sa >5 t. U a C *jQ- --VI 9 -- xe *--a>aiifi*U*ua431 49). o. c oo s -r- --p** a ' g7 v vt & 01 S I-- : C f"> ; *Of to a>> VI*--- 9at*-- 4J S Qe a(a eto <baa3>0.. 9--v5 9 ~4~5 ^ >-* VI 4-> b. 05 --* r* S 3 c 3 v) r9 6 4J V Ui 9 9 b. V* 3 <9 O CO V) DUP050454900 TEH 0413513 Table 5 -4 . BLOOD LEAD/AIR LEAD SLOPES1 IN CHILDREN FUR DIFFERENT AGES AND EXPOSURES V- 20 10~3 oj L e03) cn r*-- cr> re +4 *-4 o j cao* x: 0o3 t/i < r* 3* c. IS mO % re M 44 c4-> 03 i-- Q roe a. 5- <51t* to 1C oj zs eo 4roore4* CO CaOi o> 4a>. 0033 t-X 03 C 3 C. CO rme 00 o> 3, -o </) (O fc. 03 <0 I OJ TJ O --O 0 <0a3? <yv ai l T> <M V r-* o\ CO1-O *3 <C0 0J L0--3 03 4*4f 43 OC < ufi- C >-4 o j 2: cC3la. <0tf---0cre re (Q CO re ifllOO VC t-4 * CM O I CM VJ 03 -- * OO CSC CO 0S *` 4 L VO <*- CO r<>7.i *}* pos>, CO -4 01 re -O V VO Cl P CO O rH 03 0% 03 vi i- L. -- 0) r-- 03 r-- C <C QOC fO 44 C3CO 4043 03 4OC- r<~/l-<O0 O O03 CO* o a cn --*w | cn VO <C0O U"> M iO a to 0u3 oO OJ 44 * r-- e cn <co2o^po--*i c WO VO cf <Ti <" OHHsr o+ cn o! *t*o*>*. tO CM 04 VV 44 4-> 03 OJ c. 0J 03 3to*oo' >cn-s eo Pr-S.. W(*. 0* 1* oCSi CoO CcOn <Q * 03 4- 44 03 03 03 <- <C/S -XtO-J JO^J O a C N03 --"s CreflCOP SL.I0S1 > H, CO CM L& nCsO i COI o r-coo O Or CoO* H ocPi---ni* .*T053 *23 i<n"s 44 *nTcs3 03 ^o COicn -- ns *r- ns q o ss ai CM <ofn m CM A VO r-* ar\ 4043 03 <41 44 03 in pa^>. aO0c3 ou <*- ^r 03 CO cns cn 6--^ 03 O Cappws. L03ecoi w*J *-H c03 * ZS CO ro Sca. ps. G* cn ioi to VO CM O4* Cl o m CM A oC- va>*i f0>l3j 44 JZ --3 at- ou -uC tn -- 03 42 c. 4- 3: O IS 4- <o/> eo *0 CL**- 03 X 44 44 OJ x03: 44 iA r-- zf-s5 0y3l JnZs o fl) c ns JZ *rcr 44 uZS 44 sz -a 40re43 44 03 O 03 L3 L \n 03 0J3UOX*r*I> XI 44 44 O x4ft4?: -fcOr 44 " 03 *-- 1/1 03 03 >O recre? 0W3 O vi ns 03 nCs XaI*o co -tr/-t vos? 4re4 -roe 03 re 03 (A r- 03 L3. O</) ax. 03 rere? 40rc4e3 0t-3 `T0Z3 *tr-- 44 <3i 44 re vn 03 *r- 3 03 5 L. T5 o cL. W1 res *^3 re u03 . Lm *rre" <re e -a re 03 os IX L OJ CL roe? o 03 c l re ` ^-*03 O CL-O T? ^ -- re re 44 <4- 03 C i-- o -- re 3 S OJ T? -- U O T- C- c o o o 03 i-- V IS -Q UI r-- ^4-- cv c o ,Cr- 0g3 L. 44 re O 03 03 a.4- XS 13 S r0 4 1/14. U C Ol C Z5 *f- p- aor ZS O t/ 0) o o c x: L- re O 44 -o 0J v> 44 2 S f--03 L> -- f* 44 44 re(ft c 0? u CL 0J -C c 0c3n is i- re >)!-- 03 03 -X <_ -- 03 f-- XI 2 VI c. 03 03 O i-- L. CL a a> t * 04 L re O V) S 4J re o rer a -- re L Cl 0) iA 44 03 c 03 L-CL.cn 44 *r* TP *4r4" C re O a. 40>1 c 03 > CL & C 0J 44 vi iL** 4043 Vft 0J 13 r0e3r 4re4 L- -O a. re 0J trt 03 > 43 *- x^s Cl 03 vi Cre- ure 03 c CL >j 4S3 i--re ZJ a>O t- oaj . r0e?) Z? *ur- on -C O 44 0 03 03 cre. "<13 44 r--to i--re zs 44 re? KJi O r0e)roen C *-- r* re > a. 1 VI w r" <U t/i 03 *-- c u 03 CL o im. *r cn 44 srCeC7> re<3A? ree 003 co) X433 O -- <u >S =>V3I > b oo o5 X Ui H- DUP050454901 V-21 observed for industrial and urban areas at low and high Pb8 levels and for all ages of children. The apparent trend towards smaller slopes with Increasing PbB levels is consistent with findings within some studies (Angle and Mclntire, 1979; Roels et al., 1980) and other observations of curvilinear blood lead/exposure relationships {Azar et al., 1975; Moore et al., 1977; Gross, 1981; DeSilva, 1981; Sherlock et al., 1982; Hammond et al., 1981). As discussed, the CD determined that the disaggregate inhalation slopes derived from the studies by Angle and Mclntlre, Roels et al., and Yankel et al. are the most reliable given their overall quality. It is Important to note several additional studies and analyses that may provide equally relevant and useful information for purposes of estimating an aggregate blood lead/air lead slope. Tables 5-3 and 5-4 identify surveys besides those of Angle and Mclntire and Roels et al. which studied children (0-10 yrs) whose blood lead levels were below 25 pg/dl. These studies (Brunekreef et al., 1983; Zielhuis et al. 1979; Brunekree'f et al., 1981) reported well-defined study populations, employed available quality control procedures for blood.lead analysis, and measured or controlled for important covariates (see Table 5-3). Several specific comments should be made regarding these studies: 1. The series of studies reported by Zielhuis et al. (1979) and 8runekreef et al. (1981) included many environmental measurements (lead in ambient and indoor air, lead in dustfall indoors and outdoors, soil, streetdust, floordust, tapwater, and dustiness of homes) and regression analyses to determine the impact of different variables on PbB levels (i.e., the above environmental indices as well as distance from the smelter, parental education, age of the child, mouthing activity, cleanliness of the child). Venous blood lead samples were analyzed by standard techniques and although information on interlaboratory comparisons Is not given in the i \ TEH 0413515 DUP050454902 V-22 original study, quality control participation is reported by one of the investigators in a subsequent review (Brunekreef, 1984). Air lead was measured at two sites in 1976, and presumably in 1977, 0.2 and 0.4 km from the smelter. The levels in Table 5-3 were taken from Brunekreef (1984) and represent those measured at 0.4 km from the smelter. Air lead was measured at 6 sites continuously for 2 months in 1978. Brunekreef (1984) estimates 8 (4.0) for 1976 by assuming a difference of 2.0 ug/m^ in average air lead exposure levels between the 2-3 year old children with the highest and lowest PbB levels. After adjustment for parental education, the blood lead difference of about 8 ug/dl decreased to 7.2 ug/dl, resulting In a slightly lower e estimate (3.6). For 1977, a difference of 1.0 ug/m^ was assumed for air lead exposure levels between exposed and control children aged 2-3 years who had PbB levels of 18.2 and 14.6 ug/dl, respectively, again resulting in a of 3.6. In 1978, only children living between 0.4 and 1.0 km of the smelter were sampled and air levels did not correlate with blood lead within this population. Thus, no direct estimate of 8 can be derived, although soil lead and indoor and outdoor dust lead, and therefore, accumulated lead deposition, accounted for a significant fraction of the variance in PbB levels (Brunekreef et al., 1981). Based on the above criteria used to determine key studies in the CO (p. 11-63), it appears that these series of studies near Arnheim and the subsequent analyses In Brunekreef (1984) are of sufficient quality to provide reliable aggregate slopes between blood lead and air lead. 2. The more recent study by Brunekreef et al. (1983) on Dutch city and suburban children measured venous blood (which was analyzed as part of the European Community laboratory quality control program) and many environmental and social variables and potential confounders (lead In drinking water, soil, street and playground dust, hand dust, indoor dust, TEH 0413516 DUP050454903 V-23 mouthing behavior, dietary intakes, parental education and occupation, age of home, etc). The very high ft value (8.5) derived by Brunekreef (1984) even after adjustment in a multiple regression analysis for six of the confounders, may be related to an underestimation of ambient air lead levels due to the fact that low volume British Smoke air monitors were employed. In contrast to the hi-vol samplers used in most other studies. The extent of inflation in the estimated slope as a result of any underestimated air lead level is uncertain. Brunekreef (1984) notes however that even if this bias is accounted for, the difference in urban and suburban air lead levels was probably not larger than 0.2 yg/m^. The contrast in lead deposition between the areas was significant (i.e., 643 vs. 220 yg/m^/day), indicating that ongoing lead pollution accounted for a good deal of the differences in PbB levels, although variations in historical emissions can not be entirely ruled out. The relatively low PbB levels in this study (* 8-13 ug/dl) could be another partial explanation of the high & estimates-, given that other studies used to derive 6 included children with PbB levels on average closer to, and above, 30 ug/dl, at which point the blood lead/lead intake relationship is estimated to be non-linear and levels off; below 30 yg/dl, this relationship appears to be approximately linear (CD, p. 11-104). Despite the uncertainties in the air monitoring data, this study appears to have been carefully designed and conducted and though the precise value of the blood lead/air lead relationship is not certain, the estimated ft value appears to be significantly higher than the mean inhalation slope derived from other studies of comparable quality and relevance. In addition to these studies, the available statistical aggregate analyses on the criteria document's three "key inhalation slope" studies fEH 0413517 DUP050454904 V-24 on children require brief discussion. 3. The three inhalation 8 values {0.6, 1.92, and 4.40) attributed to regression analyses performed by Angle and Mclntire (1979) (CO, Table 11-39) all included adjustments for soil and house dust lead. An unadjusted regression analysis found a 8 of 1.4 for 6-18 year olds (Angle and Mclntire, 1979). Unadjusted coefficients of 0.66 (all children), -2.63 (1-5 yr olds) and 2.10 (6-18 year olds) were obtained by Brunekreef (1984). The surprising 8 for the 1-5 year olds could be due to the fact that this age group was only sampled during one year, whereas sampling of older children was performed over 6 years. 8runekreef`s reanalysis illustrates two points: 1) any slope derived for all children in the study (1-18 yrs) likely is deflated by including the discrepant results of the 1-5 year olds; and 2) by adjusting for factors that covary with air lead (soil and house dust lead) in the analysis, the slope for air lead decreased three-fold from 2.10 to 0.69 in the 6-18 year olds. 4. The inhalation 8 value of 2.46 from Roels et al. (1976) was estimated in the CD by adjusting for dust lead levels measured on the children's hands. An unadjusted regression analysis by the authors of the combined data (1976 through 1980) yielded a 8 value of 5.3 (Roels et al., 1980). Brunekreef (1984) segregated the data and compared groups with large differences in exposure (i.e., <1 km from smelter vs. urban/rural; 8 5.9) groups with small differences in exposure at high exposure levels (i.e., <1 km vs. 2.5 km from smelter; 8 * 4.6) and groups with small differences in exposures at low levels (i.e., 2.5 km from smelter/urban vs. urban/rural; 8 a 13.7), The high estimate at the lower exposure level is influenced by two extreme values; removing them leaves a slope of approximately 9.8. As in the Brunekreef et al. (1983) study, the use of low-volume samplers may have underestimated air lead exposures, and overestimated the 8 value, especially DUP050454905 V-25 for those children near the smelter where large particles predominate. The slope may be underestimated for young children, however, since this study only sampled children older than 10 years of age. Given these different factors and analyses, it is difficult to estimate a "true" aggregate slope from Roels et al. {1976, 1980), It is clear that a range of possible slopes for this study has been calculated that are dependent on exposure levels and adjustments for dust lead, and which are all greater than the slope for inhaled air lead alone (2.46) cited in the criteria document. 5. Similarly, analyses of the Yankel et al. (1977) data adjusted for soil lead, cleanliness, dust, education, and/or pica have yielded Inhalation S estimates ranging between 1.01 and 1.53 at an air lead level of 1.0 pg/m3 (Yankel et al., 1977; Snee, 1982; Walter et al., 1980; CD, Table 11-39). Brunekreef (1984) estimated 5 values between 2.4 and 3.3 depending on age after comparing the highest and lowest exposed children's unadjusted PbB levels based on the 1974 data. The remaining slopes listed in Table 5-4 are based on data from children whose PbB levels, as some In Yankel et al. (1977), exceeded 25 pg/dl. As discussed in the CO, the relationship between lead uptake and Pb8 levels above about 30 pg/dl appears to be non-linear (CD, p. 10-31; Marcus, 1985). Because PbB levels above 25-30 pg/dl are above the maximum PbB level of health-related concern (see Section VII.C), however, these slopes are less relevant to the present review. In summary, the above analyses using the aggregate approach assume the same source for most lead in air, soil, and housedust, and that adjustment of PbB levels for soil or dust lead that yields an Inhalation slope that under estimates the "true" impact of atmospheric lead on Pb8 levels. A range of values can be estimated from a) additional, and apparently relevant, studies TEH 0413519 DUP050454906 V-25 not used to derive Inhalation slopes in the CO (i.e., Zielhuis et al., 1979; Brunekreef et al., 1981, 1983} and b) aggregate analyses that include both direct (inhalation) and indirect (via soil, dust, etc.) air lead contributions in the key "inhalation slope" studies cited in the criteria document. Although far from conclusive, these studies and analyses suggest a range of possible blood lead/air lead aggregate slopes in the range of 2 to 10 for young, moderately exposed children with the most reliable slopes falling between 3 and 5 (CD, p. 11-104). Because the blood/air lead relationships were derived from studies which measured air lead concentrations averaged over periods ranging between one month and one year (See Table 5-3), and because long-term averages (e.g., annual) may not reflect short-term (e.g., monthly) peaks, it is possible that applying these slopes to estimate the impacts of different air lead levels would yield overestimates of PbB levels -if the air lead standard considered is a one-month average (See Section VII.A). Any overestimation, however, is likely to be small given the long-term pattern of lead accumulation in the environmental media to which children are predominantly exposed (i.e., soil, dust, food) and the resulting modulation by the environment of potential short-term peak exposure levels. Therefore, it can be assumed that these slopes are applicable in estimating PbB levels associated with different monthly, as well as calendar quarterly, average air lead levels. It is important to add, as discussed in Appendix A, that some of the absorbed lead that accumulates in the skeleton deposits in the spongy trabecular bones (e.g., rib, vertebrae) where it may be resorbed into the blood stream. Because blood/air lead slopes are derived from epidemiological studies in which exposure to air lead was assessed over days, weeks, or' ( I j TEH 0413520 DUP050454907 V-27 months, an additional factor must be allowed for possible re-entry of lead into the blood transferred from bone or other long-term storage (Chamberlain, 1983). Based on isotopic ratio and radiolabel tracer studies on adults, Chamberlain et al, (1978) estimated this factor to be 1.3, although it is likely to be higher in children because of the rapid growth and high rate of turnover in their skeletal systems. Applying this factor to the blood lead/air lead aggregate slope range discussed above (3-5) yields a range of about 4 to 6. Use of these slopes to predict blood levels associated with alternative air lead levels is discussed in Section VII.C.3 along with the two other modeling approaches introduced in this section. TEH 0413521 DUP05 0454908 VI. CRITICAL ELEMENTS IN THE REVIEW OF THE PRIMARY STANDARD A. Mechanisms of Toxicity The toxicological impact of environmental lead can either be the cumulative product of continuous low-level exposure, or of single or repeated acute exposures. Adverse effects are due essentially to the mobile fraction of absorbed lead within the body. Thus, a major determinant of toxicity is the distribution of lead among binding proteins and compartments that contain susceptible enzyme systems or other target sites (Raghavan et al., 1981; Silbergeld, 1983). The effects of lead on subcellular structures and processes result in biochemical derangements common to and affecting, many tissues and organ systems. These biochemical alterations can be linked to the diverse types of lead-based functional disruptions of organ systems that operate in a coordinated, interdependent way. o The major molecular basis underlying lead's toxicity in various human tissues is believed to be its ability as a metallic cation to bind with specific biochemical ligands, such as sulfhydryl, amino, and carboxyl groups, present in biomolecular substances crucial to normal physiological functions (Moore et al., 1980). This binding interferes with physiological processes through the following mechanisms; 1. Inhibition of enzyme activity Lead inhibits at least two enzymes in the heme biosynthetic pathway, delta-ami no!evulinate dehydrase (ALA-D) and ferrochelatase (Chisolm, 1981), as well as enzymes and cofactors involved in maintaining the structural integrity of red blood cells and protecting them against oxidation -- Na+, K+-activated adenosine triphosphatase (Na+, K+ - ATPase), pyrimidine s' -nucleotidase (Py-5-N), superoxide dismutase, and glutathione (Hasan et al., 1967; Secchi et al., 1973; Raghavan et al., 1981; Angle et al., 1975; TEH 0413522 DU P 050454909 VI-2 Paglia et al., 1975; Valentine et al., 1976; Levander et al., 1980; Gelman et al., 1978). The synthesis of tetrahydrobiopterin (a cofactor in brain neurochemistry; see below) and the activity of brain adenyl cyclase (associated with neurochemical receptors) are also inhibited by lead in vitro and in vivo at low concentrations (Purdy et al., 1981; Sauerhoff and Michaelson, 1973; Nathanson and Bloom, 1975). It is important to note that although catalytic activity of these susceptible enzymes may be diminished across a wide range of lead exposure down to very low levels, sometimes- without an observable threshold, the physiological or functional consequences of such inhibitions depend on the reserve capacity of the enzymes, the health and nutritional status of the individual, and subsequent exposures to lead and other environmental stress factors. These issues as well as dose-response relationships are addressed in Section VII .C. and Appendix 0. 2. - Altered cellular energy metabolism and ion transport Energy metabolism occupies a central position in all biologic processes and substantial interference with one or more steps in cellular energetics can have immediate and severe effects on the usual functioning of a cell, tissue, or organ. Mitochondrial structure and a variety of its functions in energy metabolism are very sensitive to lead, particularly in rapidly developing tissues in the young (Holtzman and Shen Hsu, 1976; Bull et al., 1979; Holtzman et al., 1978). Effects including uncoupled oxidative phosphorylation (Goyer and Moore, 1974), inhibited substrate oxidation (Bull et al., 1975), and changes in mitochondrial membrane permeability and transport of ions, especially calcium (Ca++), sodium (Na+), and potassium (K+) (Holtzman et al. 1977; Bull, 1980; Van Rossum et al., 1985) occur at levels of lead as low as 15 micromolar in intact cellular systems. Because of the pervasive role calcium plays in regulating cellular TEH 0413523 DUP050454910 function, a wide range of linkages between lead's impact on Ca++ and energy metabolism, and altered functional activity and developmental delays in the kidney, liver, brain and smooth muscle have been proposed (Bull et al., 1975, 1979; Bull, 1980; McCauley et al., 1979; Silbergeld, 1983; Pounds et al., 1982) and are discussed below. 3. Competition with ions for essential binding sites and altered neurochemistry Lead absorption, distribution, and retention is known to vary depending on dietary intake of calcium, iron, copper, and zinc, as well as other nutrients (e.g., protein, fat, vitamin 0) (Mahaffey and Michaelson, 1980). In addition, increased susceptibility to the toxic effects of lead on heme synthesis and on neurological function has been associated with deficiencies in calcium, iron, copper, and zinc (Mahaffey-Six and Goyer, 1970, 1972; Klauder and Petering, 1977; Cerklewski and Forbes, 1976). These metabolic interactions can be expected among elements that share common chemical properties and compete for common metabolic binding sites, such as the mucosal proteins responsible for absorption and transport across the intestinal wall, and on specific intracellular enzymes. Lead-induced alteration of cellular calcium homeostasis, at lead con centrations as low as 50 micromolar, either by direct competition at receptor binding sites (Barton et al., 1978; Ong and Lee, 1980; Habermann et al., 1983) or indirectly by reducing energy production and impairing mitochondrial and cell membrane transport "pumps" (Pounds et al., 1982a) could disturb multiple cell functions of different tissues that depend upon calcium as a messenger of hormonal and electrical stimuli or as a modulator of cyclic nucleotide metabolism (Rasmussen and Waisman, 1983; Rosen, 1983). For example, low levels of lead inhibit the calcium-mediated regulation of pyruvate kinase activity essential to hepatic glycolysis (Pounds et al., TEH 0413524 DUP050454911 VI-4 1982b), and some calcium-dependent neurotransmission that regulates the propagation of nerve impulses in the brain {Silbergeld et al., 1977; Silbergeld and Adler, 1978), as well as peripheral neuromuscular junctions (Cooper et al., 1984). Besides competition with calcium at synaptic binding sites, other mechanisms by which lead at low doses may alter the functioning of neurotrans mitter pathways (see CD, Table 12-7) include: 1) inhibition in the brain of the enzymes (Na,K)-ATPase which helps maintain the ion distribution about the cellular membrane required for neuronal activity (Vallee and Ulmer, 1972), and adenyl cyclase, which regulates cyclic AMP metabolism and synaptic transmission (Nathanson and Bloom, 1975); 2) inhibition of sodium-dependent neurotransmitter uptake (Silbergeld and Goldberg, 1975); 3) impairment of cerebellar and cerebral energy metabolism (Holtzman et al., 1978; Bull et al., 1979); 4) inhibition of tetrahydrobiopterin, which helps, control the synthesis of the neurotransmitters dopamine and norepinephrine (Purdy et al., 1981); and 5) inhibition of heme synthesis resulting in a) an accumulation of ALA in the brain that disrupts the synthesis and function of the neurotransmitter GABA (Sassa et al., 1979; Silbergeld and Lamon, 1980), and b) reduced heme levels in the liver that appear to indirectly alter associated activity in the brain of the amino acid, tryptophan, and the transmitter to which it contributes, serotonin (Litman and Correia, 1983). In addition to the above mechanisms, lead may exert its toxicity by its ability to rapidly cleave messenger RNA (at concentrations in solution as low as 0.001 millimoles) and disrupt protein synthesis (Farkas, 1975; Brown et al., 1983). It is uncertain whether a common underlying mechanism is involved in the diverse functional impairments produced by lead. It does appear however, that lead affects biological systems directly rather than through metabolic TEH 0413525 D UP 050454912 VI-5 transformation, and that there may be no biological threshold for its effects at subcellular or cellular sites of action. External exposure levels or internal circulating levels (blood lead concentrations) of lead sufficient to achieve subcellular or cellular concentrations associated with the bio chemical changes described above remain to be defined. B. Effects of Concern Lead may produce physiological, and ultimately, pathological effects in a variety of tissues and organ systems across a broad range of exposure levels. Evidence for such effects is drawn from in vitro, animal toxicological, and human clinical and epidemiological studies. Based on these data, summarized in the CD (Chapter 12), effects in the following areas are of primary interest: 1) heme biosynthesis and related functions 2) neurobehavioral function 3) cardiovascular function 4) kidney function 5) reproduction and development 6) possible carcinogenesis/mutagenesis 7) immunological function 8) liver, gastrointestinal, and endocrine function The major implications of the available literature related to each of these effect areas are discussed in Appendix D and summarized in Section VII.C. as they relate to assessing the risks associated with alternative lead NAAQS. C. Sensitive Population Groups Two populations, pre-school age children (<_ 6 years old) and pregnant women, are defined in the CD as particularly sensitive to lead. Several factors predispose young children to lead-related risks: 1) normal mouthing ! TEH 0413526 DUP050454913 behavior (e.g., finger licking and immature dietary habits) which can transfer lead-contaminated soil and dust from their hands into the gastro intestinal (GI) tract; 2) greater lead intake into the respiratory and GI tracts on a body weight basis; 3) greater lead absorption and retention rates; 4) greater prevalence of nutritional deficiencies which enhance lead GI absorption rates and toxicological effects; 5) relatively greater proportion of their lead body burden in soft tissues and other labile pools rather than in slow exchange pools (e.g., dense bone matrix) as compared to adults; 6) a less developed blood-brain barrier that can allow greater entry of lead into the brain; and 7) an inherently greater physiological sensitivity of developing tissues and organs, as indicated by lower thresholds, and greater severity of lead-induced effects in the hematological and neurological systems. In addition, dietary and metabolic imbalance's, and periods of physiological stress, not unusual in young children, can cause variations in the level of toxicologically active lead through bone-lead mobilization and changes in lead absorption rates (Chisolm and Harrison, 1956; Rosen and Markowitz, 1980; Araki and Ushio, 1982). Physiological sensitivity to lead may be at a maximum during fetal development when the central nervous system is undergoing its most pronounced growth. Persistent effects on neurological function have been observed following in utero lead exposure in experimental animals and have been suggested by some preliminary results from human longitudinal studies. The pregnant woman is considered sensitive insofar as she is the exposure vehicle for her unborn child, since lead is transferred across the placenta. However, there is some evidence that indicates a greater risk of maternal TEH 0413527 DUP050454914 delivery complications at relatively low PbB levels as well (Appendix 0.5). There were about 23.3 million pre-schoolage children in the U.S. in 1982 (U.S. Bureau of the Census, 1982); some 14.2 million lived in urban areas and based on available estimates, approximately 240,000 live near point sources where lead exposure is generally higher (the latter figure may be an overestimate due to recent plant closures) (CD, Table 13-10; Battye, 1985c). The CD estimates that about 4.4 million children between ages 3 and 5 years are particularly sensitive to lead because of iron deficiency (CD, p. 13-47). The total number of women of child-bearing age (between 15 and 44 years) is estimated to be about 54 million, with about 33 million living in urban areas (CD, Table 13-10); of these, approximately 7 percent are pregnant at any given time (CD, p. 13-47). Levels of risk are not uniform throughout these populations but are likely to be distributed according to individual exposure conditions, behavioral patterns, and physiological sensitivity to lead. As discussed in Section IV.F., for present purposes, exposures to and blood lead levels of children exposed to high levels of lead in paint will not be estimated in this assessment. Pope (1986a) estimates that in 1980, between approximately 6.2 and 13,6 million U.S. children under the age of 7 lived in homes containing >0.7 mg/cm^ lead in painted surfaces, a level considered by the Centers for Disease Control to be hazardous to young children. Lead-based painted housing with peeling paint, holes in walls, or broken or cracked plaster are considered to be particularly hazardous to children because of the relatively easy accessibility of paint chips or lead-contaminated dust. The estimated number of U.S. children residing in lead-based painted homes in 1980 with such deteriorating conditions ranges from 235,000 to 842,000 (Pope, 1986a). TEH 0413528 DUPO 50454915 VII. FACTORS TO BE CONSIDERED IN SELECTING A PRIMARY STANDARD FOR LEAD This section, drawing upon the previous evaluation of scientific information from the criteria document, outlines the key factors that should be considered by the Administrator in designating appropriate criteria for averaging time and sampling frequency and in establishing the level of the lead primary standard. Preliminary staff conclusions and recommendations regarding the most appropriate policy options in each of these areas are presented. A. Averaging Time To be protective of human health, the averaging period for the lead standard should be chosen such that variations of exposure that could result in adverse effects do not occur unless the standard is exceeded. Stated another way, its purpose is to prevent extremely high peak concen trations from being averaged out by extended periods of low concentrations if those high peaks represent a health hazard. The current averaging time for the lead primary NAAQS is a calendar quarter (3 months). When the lead standard was proposed in 1977, the averaging time for the primary lead NAAQS was specified as a calendar month which is somewhat shorter than the approximately 60 days before steady state PbB levels in adults adjust to changes in air lead concentration (Rabinowitz et al., 1973; Griffin et a!., 1975).' A month averaging time was considered appropriate because of the greater risk of exposure of young children (42 FR 63076). Subsequently, EPA promulgated the current NAAQS with a calendar quarter averaging time based on the conclusion that an air lead level of 1.5 pg/m3 as a ceiling would be safe for indefinite exposure of young children and that the slightly greater possibility of elevated air lead levels within the quarterly period was not significant for health (43 FR 46246). The risk of shorter term exposures to air lead concentrations elevated above a quarterly-averaged | TEH 0413529 DUP050454916 vi i-2 standard that might go undetected were considered in the 1978 standard decision to be minimized because 1) based on the ambient air quality data available at that time, the possibilities for significant, sustained excursions were considered small, and 2) it was determined that direct inhalation of air lead is a relatively small component of total airborne lead exposure (43 FR 46245). More recent data on short-term air lead levels are considered below. The following assessment of additional health and exposure information available since 1978 and other evidence suggests that a monthly averaging time may be'more appropriate than a calendar quarter. Whether a quarterly average standard can provide adequate protection at a level that minimizes the risks associated with even short-term exposures is also discussed. 1. Equilibration Period for Blood Lead in Children Duggan (1983), based on limited lead balance data in infants, has preliminarily estimated a considerably shorter half-life of blood lead in children (< 1 week) than in adults (18-28 days; Griffin et al., 1975; Rabinowitz et al., 1976; Chamberlain et al., 1978), Few direct measurements have been made on the equilibration period for blood lead in children, although the higher metabolic rates in children would be expected to produce a more rapid turnover rate of red blood cells, along with lead, in their blood compared to adults (Chamberlain et al., 1978). A population of poor, urban children with pretreatment PbB concentrations greater than 50 pg/dl received chelation therapy and were then followed prospectively for the next 2 to 2 1/2 years (Chisolm et al., 1985), Following therapy, blood lead levels increased within one month to varying degrees, depending on the housing conditions the children returned to, and stabilized after three months. Individual records showed that PbB levels increased usually in 3 months by approximately 10 pg/dl in children who moved from lead-free or renovated housing to old housing with some TEH 0413530 DUP050454917 v ii-3 lead-paint hazards and that PbB levels decreased in a similar fashion in those who moved in the opposite way. The authors conclude that such observations suggest that PbB is "quite sensitive to changes in exposures to lead" (Chisolm, 1985), although these results may not be directly applicable to the substantially different exposure conditions associated with .lead in ambient air. A more rapid equilibration rate for blood lead in children is indicated by regression analyses of NHANES 11 data in which individual children's PbB levels were most closely correlated with the previous month's gasoline lead consumption compared to the current month and second previous month's gasoline lead use (the third previous month's gasoline lead coefficients were not significant) (Schwartz, 1985a). A one month lagged gasoline lead also best fit blood lead in regression analyses of New York and Chicago screening data (Schwartz, 1985a) and of cord blood lead in Boston (Rabinowitz et a!., 1984b). In addition, for the prevalence of children then reported (1976-1980) to have lead toxicity (PbB > 30 pg/dl) in CDC quarterly screening reports and in NHANES II, a greater portion of the variance was explained by one month lagged gasoline lead, compared to concurrent or previous gasoline lead use (Schwartz 1985a). Perhaps a more important consideration is the time it takes for the very small fraction of "active" lead to be transported in plasma and extracellular fluid to the various target body organs and tissues. It appears that lead levels in plasma rise with levels in whole blood in adults (Everson and Patterson, 1980; DeSilva, 1981; Cavalleri et al., 1978) and that lead is removed from plasma with a half-life of less than one hour; indeed, ingested lead appears within urine in less than an hour (Chamberlain et al., 1978). These findings suggest that the rate by which lead is transferred to soft tissues via the plasma is fast enough that excess lead entering the bloodstream I TEH 0413531 DUP050454918 vn-4 would be rapidly transported via plasma to tissues. In addition, as illustrated in Figure 10-2 of the CD (p. 10-18; Manton and Cook, 1984), the relationship between plasma lead and blood lead is curvilinear upwards suggesting that transient shifts in blood lead would result in plasma values greater than that predicted on the basis of equilibrated percentages at lower PbB values. This curvilinearity becomes manifest in adult subjects at 50-60 pg/dl (DeSilva, 1981; Manton and Cook, 1984), but may well apply at relatively lower PbB levels in children. Further support comes from data on experimental animals whose levels of lead in brain, kidney, and femur followed more of a direct proportionality with the level of dosing than with blood lead, which may relate to the fact that plasma lead rises proportionally faster than whole blood lead (Azar et al., 1973; Grant et al., 1980). Based on the above data, it appears that increased lead exposure may produce increases in steady state PbB levels in children sooner than the 60 days observed in adults, and that such changes may not reflect those occurring in the levels of toxicologically active, or mobile, lead throughout the body, particularly if exposure is in the form of intermittent pulses. Based on the analyses of NHANES II and gasoline lead data, children's PbB levels and the number of children with elevated lead levels appear to be responsive to monthly changes in air lead emissions. 2. Health Impacts Associated with Short-term Peaks in Lead Concentrations Most animal and human studies of lead toxicity use measures of lead exposure which reflect accumulations over time (such as blood and tooth lead), and thus do not readily allow effects of different exposure patterns to be distinguished. It is generally accepted, however, that acute exposures to very high lead levels can result in immediate changes in TEH 0413532 DUP050454919 blood lead and overt toxicity. PbB levels and ALA-D activity in workers experiencing occupational lead exposure for the first time were significantly altered after only a few days of exposure, and concentrations of urinary lead and urinary ALA changed significantly after about two weeks (Tola et al., 1973). Hemoglobin and hematocrit levels were significantly lower in the workers at the end of the observation period (about 3 months). Similar results were seen under controlled conditions in which single experimental lead exposures were followed by a rapid (<2 weeks) alteration in the heme production cycle, as indicated by significantly elevated EP in adult men and women (Stuik, 1974; Cools et al., 1976). The sensitivity of these biochemical parameters to short-term changes in lead exposure is consistent with the fact that lead is rapidly transported via blood plasma into target tissues such as bone marrow. However, in light of the extremely high exposure levels in these studies (e.g., air lead in the work areas studied by Tola et al. were up to 2-4 mg/m^ and the average PbB level rose from approximately 12 yg/dl to 40 pg/dl in 3 weeks), it is difficult to relate these findings directly to children exposed to ambient concentrations of lead, primarily through indirect pathways such as soil and dust. Although the health significance of short-term exposures to lower levels of lead that are relevant to ambient air conditions is difficult to determine for children at present, there does appear to be some cause for concern. This concern is based on the following findings: 1) based on limited occupational and experimental studies, short-term exposures (< 2 weeks) to high levels of lead result in significant changes in heme biosynthesis; effects on other physiological processes associated with similar short-term exposures and effects of short-term exposures more typical of ambient conditions remain to be studied; 2) lead accumulates in.the body and is only slowly removed, therefore repeated exposures to small amounts over many months may produce TEH 0413533 DUP050454920 VlI-6 elevated PbB levels (COC, 1985); 3) the mean-life of lead in blood is approxi mately 30 days and the toxicologically active fraction of blood lead appears to respond quickly to changes in exposure; and 4) limited epidemiological evidence indicates that children's blood lead levels respond to month to month variations in air lead emissions. In summary, it appears that a monthly standard would be more protective of children's health than the current quarterly standard, especially around point sources where emissions may be more sporadic. Not only would a monthly standard when compared to a quarterly standard set at the same level reduce short-term increases in children's lead exposure, it would also reduce average long-term air lead levels and deposition, since controls would be necessary to meet the standard in months with increased emissions, and would thereby reduce the number of children with long-term elevated blood lead levels. Although a monthly lead standard appears to be the most appropriate averaging time, if the implementation of a monthly standard is impractical due to monitoring limitations (see Section 7.B), a quarterly averaged standard could provide equivalent health protection by adjusting the level to reduce the probability of short-term (e.g., monthly) air lead concentrations above whatever target level is considered adequate. In evaluating the adequacy of the current quarterly average standard, it is necessary to consider the extent of short-term peaks in air lead levels that can be anticipated as a result of the implementation of such a standard. Recent data on monthly and quarterly air lead averaged concentrations are considered below. Air quality analyses were performed on all available SAROAD data (10,711 monitor-quarters) collected from stationary source, microscale (for mobile source emissions), and neighborhood scale monitors between 1980 and 1984 (Battye, 1984). Table 7-1 presents the results of comparing maximum monthly average lead concentrations to quarterly average lead TEH 0413534 DUP050454921 TABLE 7-1. MONTHLY-TO-QUARTERLY AVERAGE CONCENTRATION RATIOS FOR DIFFERENT SITES TEH 0413535 It It II II uIiiiuitrIti nii ii *ooo W JuZ aj m*~c to- -- W _o <0 X! t - JcZn r* O YO C WOt- VII-7 -ft o CM CM CM * ** ^ 3 n at ^ co un- vj d a>< -- i-- *-- r-- CW p<-o *QoJ Wt4O O W W -> io- <O0. Sco co CM CM o CM co f3> 03 33 w j_C*>- t<u3-0 4o--0->. aO. Ow oC 3 /-- Lft < - CO CM CM OS CO VO. VO ^ *S3 i-- ^ CM CM CM w oo* U> '-ft CO r" CO CM CM cos * * CO t CM l C VO CQ CM VC * 4 p-- p~ p-- CM CM K1II1I?irIt1Ir! iiti iiii t11IIiiK1tIiil! J*a4JrSowre3----3--5J_- 4O5LCUC->.0LL iit*XiIxit1111I1111I1I -oLf*) uc s<c0: *ro" ~<u p- 4-J at YC0l -44ProWc3cO---"J>. Osr.< 4w-> rtp*n* aCa_.. JoScaJL. +c<La4J. -uLac0M). Lo<LCcD.iL 4o0cQJ.. a Lft as at 42-LT-3O5> 0o03o0. DU PO50454922 VII-8 concentrations at different types of monitoring sites. These ratios are largely independent of average lead concentration (Battye, 1984) and suggest, for example, that in order to protect against a maximum monthly average concentration of 1.5 pg/m3 around point sources, a quarterly average concentration of approximately 1.1 pg/m3 (using a mean ratio of 1.4) would be required. If the more conservative 90 percentile value of 1.82 is used, a quarterly average concentration would have to be adjusted to approximately 0.82 pg/m3. Without such adjustments, a quarterly average of 1.5 pg/m3 around point sources would allow monthly maximum averages as high as 2.1 pg/m3 using the mean ratio, and 2.7 pg/m3 assuming the 90 percentile ratio. The magnitude and potential health significance of such excursions in air lead levels over a given quarterly average standard, especially if repeated, suggests that in addition to the^reasons previously outlined, a monthly standard would be more protective. If a quarterly standard is retained, it would have to be adjusted so as to preclude excessive excursions above the monthly target level. A quarterly standard adjusted in an appropriate manner could provide health protection roughly equivalent to that of a monthly standard around point sources. At non-point source sites where lead concentrations are less variable, an adjusted quarterly standard would be somewhat over protective. B. Form of the Standard and Sampling Frequency 1. Alternative Forms of the Standard Any ambient standard is defined not only by its averaging time and level, but by the characteristic way attainment with that standard is determined, i.e., its form. Compliance with the current lead NAAQS is deterministic--the maximum arithmetic mean average over a calendar quarter is not to exceed 1.5 pg/m3. The staff recommends that the primary lead NAAQS TEH 0413536 DUP050454923 VII-9 be stated in a statistical form rather than the current 'deterministic form. A statistical form can offer a more stable target for control programs and, with reasonably complete data, is less sensitive to meteorological conditions than is the deterministic form. In general, monthly or quarterly mean concentrations of lead will vary from one month or quarter to the next, even if emissions remain constant, due to the random nature of meteorological conditions that affect the dispersion of lead particles in the atmosphere. Under a deterministic form, compliance with the standard, and consequently emission control, requirements, can theoretically be determined on the basis of a single "atypical" month or quarter. The general limitations of the deterministic form are discussed more fully elsewhere (Biller and Feagans, 1981). Recognition of these limitations has most recently led EPA to propose statistical forms for the particulate matter standards. Conceptually, a statistical standard could be expressed in many different forms. There are several approaches in determining the form of the standard that would directly recognize the statistical variability associated with the estimated maximum monthly or quarterly average concentrations. In general, two different types of standards have been forwarded. The first is the "parametric" approach, in which the underlying distribution of air quality data would be explicitly taken into account in determining compliance with the standard or in setting targets for control programs. Hypothetically, if correct assumptions regarding these distributions could be made, potential errors in the classification of areas as either attaining or not attaining the standard could be reduced. An alternative method that has been cited as a way of accounting for the variability in air quality estimates Involves the development of a tolerance interval so that a site would not be.classified as attain- TEH 0413537 DUP050454924 VII-10 merit unless the measured concentration is below the standard level by more than this tolerance interval. Conversely, non-attainment would not be considered unless the maximum monthly or quarterly average concentration was above the standard by an amount greater than the tolerance interval. Within this tolerance interval, attainment status would be "too close to call" -- additional data would be needed before a definite attainment determination could be made. Although standard forms that explicitly account for the vari ability in air quality measurements by way of tolerance intervals have certain advantages, only preliminary analyses have been undertaken to date (Hayes et a!., 1985). This initial work clearly indicates that considerably more analyses of the statistical properties of air quality data, the implications of these standard forms on attainment policy, and the difficulties in implementation must be undertaken before the Agency can move ahead and specify an appropriate tolerance interval. While EPA plans to further consider this approach and its associated issues in future NAAQS revisions, further consideration of a standard using a tolerance interval would be premature at this time. For this review three different statistical approaches have been examined. [Each one is equally appropriate for both monthly and quarterly averaging periods.] The alternatives include an expected maximum calendar month (quarter), expected maximum month (quarter), and expected highest 3 months (quarters) standard. The computational scheme for an expected maximum calendar month (quarter) standard is to compute the average over the past 3 years for each calendar month (quarter) {i.e., average all the Januarys, Februarys, etc. or all first quarters, all second quarters, etc,). For an expected maximum month (quarter) standard, the maximum monthly (quarterly) TEH 0413538 DUP05 0454925 YII-11 average would be identified for each calendar year within the 3-year period and the average of these maximum months or quarters would be computed. Computationally, the expected highest 3 months (quarters) average is equivalent to the expected maximum month (quarter) average, unless a single year contains two or more of the highest 3 months (quarters). In essence, each of the alternatives involve a different averaging convention using three years of data. Other forms, such as an expected exceedance rate (requiring that the expected number of monthly averages greater than x ug/m3 should be less than I in three years, for example, were discounted in part because limited data points would be available upon which to base the computations (36 in three years for a monthly average). The following hypothetical data set will be used in Table 7-2 as an illustrative comparison of each of the alternative forms of a quarterly average standard. In this instance", the critical value would be used to determine attainment or non-attainment, by comparing it against a given standard level. Hypothetical Data Set For Example Calculations in Table 7-2 Quarterly Lead Average (ug/m3) Year 1 234 1981 1982 1983 1.18 2.98 0.76 2.55 3.21 5.44 3.34 1.94 1.29 2.77 2.68 3.67 As expected. Table 7-2 indicates that the deterministic approach of using the maximum quarterly average in a single year results in the highest critical value because it is determined by a single high quarter. The three alternative forms produce somewhat lower values as a result of averaging over a three year period. The difference between the expected maximum quarter TEH 0413539 DUP050454926 TABLE 7-2. COMPARISON OF ALTERNATIVE FORMS USING HYPOTHETICAL DATA3 TEH 0413540 c 3 O C. 03 4-3 <C 3 O' s r* <0e 4-3 (-- -- 3 a. in 44 4>443> S 03 t- *043 C o j <o 0a> *-- c > p- C "0O i-- o O CO C r- 3<D r-- > r-- fO rO CO u oi 4J-- p-- -) f-- O CO e o> CL ^d" LO T033 cn3n C- 4-> c_ < U CD <0 403- > 4-3 4- 3 03 in "O K O f- in 0C- JZ Its a; 0c 1--3 3 r--0 W f0 <tJ > (0A3 -C jc <0o >, CD r-- -C fmt--m 4-3 C 03 44fl. <D i-- CL CD <o in c +3 r-- -p-- V) W (DC -f-> 20 0 4-3TOOO VI1-12 01 03 +J C r0 3 3 4-> ,r-- O 3 re > U0 *9 <e fZ -C CD fmm 't-- <p- 03 >i XT i--03 CD C +4 4-3 03 J3 a 4r---> r-- rO 0c V) 4-> 9 0<10 40- +J O O 03 *00*03 0icCn\ OU 33L- L 4- > O *0LU o *u in U f-- 3 <n x: 3g 01 in 03 0u 0 4-3 m 03 4-3 9 f -a > <z X 5 03 O <0 rG t3r 4-3 -C CD tO-m T3 . in r- C ro 4OO-P3 03 f>mm c *p-- r0 J= 03 * in O0 ai a) 03 >* O 4-3 4-3 03 cn in c 03 Cl X 03 O 4-3 ra c L. 03 4-> fC 0c0 &. JZ 4-3 tuo 03 J4OZ-3J <C 03 u 03 > S0Z3 4-3 a>fm> 4-- <0 >1 O 0 r-- C 4- t- i-- -r- 1 nS --* --0CD)(Uo <u oU V) 1s e; t 4 c cn -- i--O 3 O ^ g crur fO ** 301. CO P^s 00 cn E 301. 00 sf S 3CD . cn p-- * 0O3T id u 03 > <0 r-->> C. 03 4-> c. OJ re t3 3O J<ZD crpc-- OOO 03 9 CL 0 X toc 1-- im. *r 4-> 2s 03 >> 4-3 03 r-- 9 wl CL O *3 O O JE SS O O *r-- in 0fmm 40-> c03n *-- oj f-- 3 - 03 V5 03 > C. 4n3s * 03 1/1* c fc* 0 3 - >*r- 40J3 40 9 O r t- t4-- c_ <e C03 40-4) 9 cr 4O-3 03 in >0 0<39. 4-> in 03 OJ x: 4J C03D cr-p~inU- ns -i M-- 03 O re 4-J aj - l +j > Cr- ffl W ( 03 9 03 f-- 03 (e 03 crx0:1 4-3 O a>-C3 -r- 9 <C CX 0Q,XS B 03 OO 03 O O 0> > ra 03 x: tn 4-j r- 03 >s 0031 1 cn (O c 03 B 03 x: 9 > 4J S !" CX f >-tm.V4-Z-> 2 03 *f - 0) 4fm->m ^ in 03 ro L X 9 cr f0O3 4-3 S >> c03n 9 U ns (Q L <- -O 03 X c> nj 03 Sr-- m 3 ** V. 0) U XS 03 m00 -c O O L 4-5 t- ( J= O Id 03 03 a. 99- 4-3 in m 03 L. xC:D r0o1 *T-- >J 4T CO CO t_ 03 03 JS > 4-> O 4- in O 03 CD 03 <0 CD C id 03 C- > 03 <9 > 0J >> f-- 03 U 4-3 03 9 4-> a. c- (0 0O 9cr u <n4-> in c E 1-- !-- C t- s a 03 L- e t- 9 S 4043 u. 44 03 *t- L- C. 4-> X n3 03 nj 03 ns 9 > 9 "O S ar *r- 4-1 -9 ts t- c S 03 O 9 CD fO 4043 *r9o (. S n3 O O C 03 r L L 0) 03 +4 X 03 O. CLr- tofmmm ns > o. X 5 0< s: os UJ s 3 r~ X ro S 0O3 t. 44 O 404J 03 O. <<0- 0X 3 uj - 4-5 in J0Z3 CD jz m 9 t- <u 4043 44 L. O (O 03 9 CL O' X UJ * c; <CoD o. o9o o r- >a> L. C_ C o "4uO0-oJ3 OJ <0 <a *4<-o05 ns s4oz4 o Cl *3 i; DUP050454927 VI1-13 and the expected highest 3 quarters results from the first and second highest quarters falling in the same year. The expected maximum calendar quarter produces the lowest value. As a further comparison of the alternative forms, modelled data for a secondary lead smelter were examined for each of the 3-year periods of meteorological data ending in the years 1975, 1976, 1977, and 1978 (See Table 7-3). Similarly, Table 7-4 compares the modelled data for a lead battery plant for each of the 3-year periods of meteorological data ending in the years 1967, 1968, 1969, 1970 and 1971. In both cases, emissions were assumed to be constant. As in the above example, the rank order of the alternative forms in terms of stringency is the maximum quarterly (monthly) average; expected highest 3 quarters (months); expected maximum quarter (months), and; expected maximum calendar quarter (months), but the difference inthe average critical values is small. This comparison illustrates how the maximum quarterly (monthly) average, the deterministic approach, can vary sharply from one year to the next. The alternative forms tend to smooth these fluctuations out. In selecting the most appropriate form for the standard, the focus should be on identifying the form that best reflects the overall health objective and produces a reasonably stable target for control strategy development. Based on these initial analyses of the three alternatives forms considered, the expected highest 3 months (quarters) appears to best satisfy these objectives. This form permits averaging to smooth out year to year fluctuations due to meteorological conditions and to ensure that an "atypical" value does not dominate, yet provides some control over the second and/or third high months (quarters) should they occur within the same calendar year. 2. Sampling Frequency In reaching a decision on the standard,the averaging period (monthly TEH 0413541 DUP050454928 Table 7-3. Comparison of Critical values3 of Modelled Quarterly and Monthly Averages Around a Secondary Lead Smelter Quarterly Max. Quarterly Avg.*5 Exp. Max. Cal. Qtr. Exp. Max. Qtr. Exp. Highest 3 Qtrs. Monthly Max. Monthly Avg.*3 Exp. Max. Cal. Month Exp. Max. Month Exp. Highest 3 Months Source:Hunt, 1985. Predicted Critical Value in 1975 1976 1977 1978 4.42 3.72 3.62 3.64 3.49 4.04 3.88 3.50 3.49 4.04 3.92 3.54 3.80 4.04 3.92 3.61 5.07 3.95. 4.38 4.66 4.62 4.86 4.55 4.50 4.82 4.73 4.82 4.81 4.36 4.12 4.55 4.71 Average Critical Value 3.85 3.73 3.75 3.84 4.72 4.28 4.55 4.71 Relative Reduction in Average Critical Value 0 -3% -3% 0 0 -10% - 4% 0 Table 7-4. Comparison of Critical Values3 of Modelled Quarterly and Monthly Averages Around a Lead Battery Plant Quarterly Predicted Critical Value in 1967 1968 1969 1970 1971 Max. Quarterly Avg.*5 0.64 0.64 0.85 0.84 0.61 Exp. Max. Cal. Qtr. 0.63 0.64 0.71 0.72 0.70 Exp, Max. Qtr. 0.67 0,64 0.71 0.72 0.70 Exp. Highest 3 Qtrs. 0.70 0.64 0.71 0.72 0.71 Monthly Relative Reduction Average Critical Value in Average Critical Value 0.72 0 0.68 -6% 0.69 -4% 0.70 -3% Max. Monthly Avg.*5 0.89 0.85 1.08 1.05 0.96 Exp. Max. Cal. Month 0.91 0.90 0.85 0.90 0.81 Exp. Max. Month 0.91 0.90 0.92 0.90 0.96 Exp. Highest 3 Months 0.94 0.93 0.95 0.93 0.97 Source: Hunt, 1985. 0.97 0.87 0.92 0.94 0 -11% -5% -3% a) The critical value would be used to determine attainment/non-attainment by comparing against a given standard level. For max. quarterly avg. it is the highest quarter in the specified calendar year. For the alternative statistical forms, it is the computed value for each 3-year period ending in the specified calendar year. b) Max, quarterly or monthly average is comparable to a deterministic form of the standard. TEH 0413542 DUP050454929 vs. adjusted quarterly), form (deterministic vs. statistical), and frequency with which ambient air lead samples are collected should be considered. Given the normal operation of the current one-in-six day lead sampling schedule, with normal 75% data capture, it is clear that the number of samples collected in the course of a month (3) would not provide a statistically valid estimate of the actual air quality for the period (Thrall et a!., 1984). Consequently, it is recognized as will be discussed below that should a monthly average lead NAAQS be chosen, it would be necessary to increase ambient air lead sampling to more frequently than one-in-six days, especially during periods and in areas of relatively high air lead concentrations. Recent analyses also suggest that the precision associated with one-in-six day sampling for a quarterly average (deterministic form) lead standard may be unacceptable (Hunt, 1986). Hunt examined the precision associated with alternative sampling frequencies (every sixth day, every third day, every other day, and every day) with 75% and 100% data capture for monthly and quarterly averaging periods and for both deterministic (using one year of information) and statistical (using three years of information) forms of the lead standard. Precision estimates were calculated for 95% confidence intervals for the following categories of monitoring sites: 1) source-oriented sites with maximum annual quarterly averages less than the current standard of 1.5 yg/m3, 2) source-oriented sites with maximum annual quarterly averages greater than the current standard, and 3) National Air Monitoring Stations (NAMS) urban maximum concentration sites. Using the criterion that the true monthly or quarterly arithmetic mean for a specific time period (e.g., a given month (quarter) or the average of 3 highest months (quarters) in a specific three year period) should lie within TEH 0413543 DUP050454930 VII-16 + 10% of the sample arithmetic mean, the initial results from this analysis suggest the following: 1) The standard with the best precision and requiring the least frequent sampling would be a statistical quarterly average; 2) The required sampling frequency with data capture ranging from 75 to 100% could vary according to site type. For NAMS maximum urban concentration sites, the required sampling frequency would be one-in-three days. For source-oriented sites with maximum quarterly averages less than the current standard, every other day sampling would be needed. For source oriented sites with maximum quarterly averages greater than the current standard, the sampling frequency would have to increase to every day. If a monthly average is selected, the statistical form again would be more desirable than the deterministic in terms of precision and sampling frequency. The sampling frequency for a monthly statistical standard would have to increase compared to a statistical quarterly average. For NAMS maximum urban concentration sites, the sampling frequency would have to increase to once every other day with 100% data capture. For source-oriented sites with maximum quarterly averages less than the current standard, every day sampling would be needed with approximately 75% data capture. Sampling frequency would have to be increased to every day with 75-100% data capture for source-oriented sites with maximum quarterly averages greater than the current standard. The analysis also suggests that if the data collected are to be used to predict future events (i.e., a given month or a 3-year average is considered typical of all future months or 3-year periods), then the sampling frequencies presented above would have to be increased and in some instances a precision of +_ 10% could not be achieved even with every-?day sampling with 100% data TEH 0413544 DUP050454931 VII-17 capture. While this analysis clearly suggests that more frequent sampling may be required, it is premised on the assumption that the coefficients of variation estimated from past data will resemble future conditions when ambient lead levels are lower and the variability in lead data may decrease. Thus, these results should be viewed as conservative and future sampling requirements could probably be less intensive. As an alternative to increased sampling frequency using the hi-volume sampler, the States could seek approval for a modification to the Federal Reference Method for lead and replace the specified high-volume air sampler with a similar, "low-volume" sampler that operates with a sample flow rate approximately l/10th that of the high-volume sampler. The low volume sampler is operated continuously for a period of one month to yield monthly integrated ambient lead samples, which are analyzed conventionally. In approving such a modification for the State of Connecticut, the Agency noted that while there, was acceptable agreement between lead samples collected by the low-volume and high-volume samplers at a colocated urban site in Connecticut, it was not clear that such agreement would necessarily be found in all areas of the country. Therefore, additional testing would be necessary before the low-volume sampler could be approved for use in other areas, especially in areas of relatively high lead concentrations and/or where coarse mode particles are predominant, or for universal use as an equivalent method. It was also noted that the level and degree of documentation of the design, construction, operation, and quality assurance procedures of the modified sampler, while adequate for use of the sampler within Connecticut, are not sufficient to readily allow use or adoption of the sampler by other States {Purdue, 1984; McElroy, 1984). TEH 0413545 DUP050454932 REVIEW OF THE NATIONAL AMBIENT AIR QUALITY STANDARDS FOR LEAD: ASSESSMENT OF SCIENTIFIC AND TECHNICAL INFORMATION OAQPS DRAFT STAFF PAPER Strategies and Air Standards Division Office of Air Quality Planning and Standards U.S. Environmental Protection Agency Research Triangle Park, N.C. 27711 February, 1986 TEH 0413468 DUP050454933 TA8LE OF CONTENTS List of Figures Page ............................................................................................... v List of Tables............................................................. ..................................... vi I. Purpose . .................................................................................... .... I-l II. Background................................................................................... .... XI-1 III. Approach...................................................................................................... III-l IV. Lead Exposure: Multimedia Considerations .................................... . iv-l A. Airborne Lead. . .................................................................... IV-3 B. Lead in Soil . ................ ................. IV-6 C. Lead in Oust . ............................................................. .... IV-8 0. Lead in the Diet.................................... .. ....................................... IV-IO E. Lead in Mater........................ ... ................................... .... IV--12 - F. Lead in Paint......................................... ............................ ' . . . IV-13 V. Estimating LeadExposure andBlood Lead Levels........ V-l A. Integrated Lead Uptake/BiokineticModel .................................. V-2 B. Statistical Relationships between Blood Lead and Airborne Lead ................................................................................... V-10 VI. Critical Elements in theReview of thePrimary Standard . . . VI-1 A. Mechanisms of Toxicity.................................................................. VI-1 8. Effects of Concern ........... ....................... .... VI-5 C. Sensitive Population Groups............................................................ Vl-5 VII. Factors to be Considered in Selecting a Primary Standard for Lead...................................................................................................... VII-l A. Averaging Time............................................................... ... VII-l B. Form of the Standard and SamplingFrequency.......................... VII-8 C. Level of the Standard .................................... ........ VII-18 D. Summary of Staff Conclusions andRecommendations .................. VII-84 TEH 0413469 DUP050454934 iv VIII. Critical Elements in the Review of the Secondary Standard. . A. Terrestrial Ecosystems .................... . ........................................ B. Aquatic Ecosystems ................ ....................... . ............................ Page VIII-1 VIII-1 VIII-13 C. Staff Conclusions and Recommendations. ... .................... . Appendix A. Lead Metabolism and Physiological Measurement................ VIII-17 A-l Appendix B. Estimates of Lead Uptake ..... ................................... Appendix C. Lead Uptake and Blood Lead Concentration ....... Appendix D. Health Effects of Lead . . ............... ......... Appendix E. Long-Term Accumulation of Lead in Soil in Rural . . . Areas References b -1 C-l D-l E-l TEH 0413470 DUP050454935 Number 4-1 4-2 5-1 7-1 7-2 7-3 7-4 7-5 7-6 C-l C-2 0-1 D-2 E-l V LIST OF FIGURES Title Principal Pathways of Human Exposure to Lead .................... IV-2 Trends in Maximum Quarterly Lead Concentration for Various Monitor Types . ................................................................IV-5 Summary of Relationships 8etween Lead Uptake and Blood Lead . ........................ ... ................................................... ... V-8 Multi-Organ Impact of Reductions of Heme Body Pool by Lead................ .............................................................................. VII-31 Probabilistic Judgments of Experts C, D, and E Regarding the Dose-Response Function for Hemoglobin Levels 9.5 g/dl in Children Ages 0-3 Years................................ .... VII-41 Comparison of Judgments of Experts C, 0, and E Regarding the Probability of Hemoglobin Levels 9.5 g/dl in Children Ages 0-3 Years at Different Blood Levels ....................................................VII-43 Probabilistic Judgments of Experts Regarding Mean IQ Decrements far Low SES G'roup ............................................ .... . VII-47 Comparison of Judgments Across Experts Regarding Mean IQ Decrements for Low SES Group .......... VII-49 Distribution of Children's Blood Lead Levels as a Function of Population Mean Blood Lead Under Different Air Lead Concentrations ................................................................ VII-58 Relationship. Between Daily lead Uptake and Blood Lead in Adult Men ................................................... ............................... C-3 Schematic Models of Lead Metabolism in Adult Men. C-5 Lead Effects on Heme Biosynthesis.................... ... . 0-2 Cumulative Frequency Distribution of Verbal IQ Scores in Subjects with. Low or High Levels of Lead........................ D-30 Predicted Particle Dry Deposition Velocity for Wild Grass Canopies....................................................................... .... . E-3 j TEH 0413471 DUP050454936 vi LIST OF TABLES Number 4-1 4-2 5-1 5-2 5-3 5-4 7-1 7-2 7-3 7-4 7-5 7-6 7-7 7-8 7-9 7-10 7-11 Title Typical Lead Concentrations in Various Exposure Media . . . . Frequency Distributions of Maximum Quarterly Lead Concentrations by Type of Site ........................................................ Model Balance Schemes for Average Lead Intake and Uptake in Children Under Alternative Air Lead Levels ............................ Summary of Experimental Lead Inhalation Studies ........................ Summary of Epidemiological Studies on Lead-Exposed Children . Blood Lead/Air Lead Slopes in Children for Different Ages and Exposures........................................... ................... .... Monthly-to-Quarterly Average Concentration Ratios for Different Sites ............ ........................................ Comparison of Alternative Forms Using Hypothetical Data . . . Comparison of Design Values of Modelled Quarterly and Monthly Averages Around a Secondary Lead Smelter .................... Comparison of Design Values of Modelled Quarterly and Monthly Averages Around a Lead Battery Plant ............................ Summary of Lowest Observed Effect Levels for Key LeadInduced Health Effects in Children .................... ....... Summary of Lead's Effects on the Nervous System .................... ... Summary of Lead's Effects on Heme Biosynthesis and Related Systems in Children ..... .................................... . . Staff Assessment of Key Health Effects of Lead .................... . Population Mean Blood Lead Levels Required to Prevent 99.5% of Children from Exceeding Specified Blood Lead Levels . . . Average Blood Lead Levels for Children Under Different Air Lead Levels Estimated Using Integrated Lead Uptake/ Biokinetic Model ... ....................................................................... Air Lead Levels Required to Protect 99.5% of Children from Exceeding Alternative Maximum Acceptable Blood Lead Levels, According to Aggregate Epidemiological Model ............................ Page IV-2 IV-5 V-4 V-12 V-18 V-20 VI1-7 VII-12 VII-14 VI1--14 VII-19 ' VII-21 VII-28 VII-35 VII-59 VII-60 VII-68 | TEH 0413472 DUP050454937 vii Number Title Pa^e 7-12 7-13 7- 14 8- 1 8-2 8-3 B-l B-2 C-l C-2 C-3 C-4 C-5 E-l E-2, -3 E-4 -5 Contributions from Various Media to Blood Lead Levels of U.S, Children (CO Disaggregate Model) VII-71 Maximum Individual Blood Lead Levels for 99.5% of Children Under Different Air Lead Levels, Based on Mean PbB Predictions from CD Disaggregate Model . ........................ ... ............................... .... VII-72 Summary of Estimated Blood Lead Levels Under Different Air Lead Levels Using Three Modeling Approaches a) Using GSD of 1.42 . . . ................................................................VII-73 b) Using GSD Between 1.34-1.39 ........................................................ VII-78 Lead-Induced Effects in Hydroponically Grown Vascular Plants , VIII-5 Experimental Evidence of Lead-Induced Effects Relating to Soil Microbial Activity . ...................................................... . . VI11-8 Effects of Waterborne Lead in Aquatic Vertebrates (Fish) . . . VI11-15 Summary of Environmental Lead Measurements from Various Locations ...... ................................ ........... 8-9 Generalized Relationships Between Lead'Concentrations in Air and in Dusts and Soil ....................................................................8-13 Impact of Different Levels of Lead Uptake on Blood Lead as Predicted by 2 Compartmental Models ............................................ C-8 Predicted Equilibrated Blood Lead Levels Over Time Among Children with Constant Lead Uptakes ............................ C-10 Studies Relating Blood Lead Levels to Dietary Intakes .... C-12 Estimates of the Contribution of Soil Lead to Blood Lead . . . C-13 Estimates of the Contribution of Housedust to Blood Lead in Children ......... .................... .......... C-13 Estimation of Particle Size Distribution Weighted Dry Deposition Velocity . . i ..................................... E-3 Estimation of Long-Term Accumulation of Lead in Soil in Rural Areas Based on Dry Deposition Flux Under Different Air Lead Levels................ ... ............................... ... E-5, -6 Estimated Soil Lead Concentration in Rural Areas Based on Model-Predicted Dry Deposition Flux and Estimated Average Wet Deposition Flux........................................................................................... -11 Annual Consumption of Lead in Gasoline Additives in the United States from 1929-1983. .................... .... E-13 TEH 0413473 DUP050454938 REVIEW OF THE NATIONAL AMBIENT AIR QUALITY STANDARDS FOR LEAD: ASSESSMENT OF SCIENTIFIC AND TECHNICAL INFORMATION OAQPS STAFF PAPER I. PURPOSE This paper evaluates and interprets the most relevant scientific and technical information reviewed in the draft EPA document "Air Quality Criteria for Lead" (EPA, 1984) in order to better specify the critical elements that EPA staff believes should be considered in the possible revision of the primary and secondary National Ambient Air Quality Standards (NAAQS) for lead. This assessment is intended to help bridge the gap between the scientific review contained in the criteria document and the judgments required of the Administrator in setting ambient standards for lead. As such, particular emphasis is placed on identifying those conclusions and uncertainties in the available scientific literature that the staff" believes should be considered in selecting the averaging times, forms, and levels for the primary and secondary standards. While the paper should be of use to all parties interested in the standards review, it is written for those decision makers, scientists, and staff who have some familiarity with the technical discussions contained in the criteria document (hereafter referenced as "CD"). II. BACKGROUND Since 1970 the Clean Air Act, as amended, has provided authority and guidance for the listing of certain ambient air pollutants that may endanger public health or welfare and the setting and revising of NAAQS for those pollutants. Primary standards must be based on health effects TEH 0413474 DUP050454939 criteria and provide an adequate margin of safety to ensure protection of public health. As several recent judicial decisions have made clear, the economic and technological feasibility of attaining primary standards are not to be considered in setting them, although such factors may be considered to a degree in the development of state plans to implement the standards (D.C. Cir., 1980, 1981). Further guidance provided in.the legislative history of the Act indicates that the standards should be set at "the maximum permissible ambient air level . . . which will protect the health of any [sensitive] group of the population." Also, margins of safety are to be provided such that the standards will afford "a reasonable degree of protection . . . against hazards which research has not yet identified" (Committee on Public Works, 1974). In the final analysis, the EPA Administrator must make a policy decision in setting the primary standard, based on his judgment regarding the implications of all the health effects evidence and on the requirement that an adequate margin of safety be provided. Secondary ambient air quality standards must be adequate to protect the public welfare from any known or anticipated adverse effects associated with the presence of a listed ambient air pollutant. Welfare effects, which are defined in Section 302(h) of the Act, include effects on vegetation, visibility, water, crops, man-made materials, animals, economic values and personal comfor-t and well-being. In specifying a level or levels for secondary standards the Administrator must determine at which point the effects become "adverse" and base his judgment on the welfare effects criteria. The current primary standard for lead (to protect public health) is 1.5 micrograms per cubic meter (ug/m^), maximum arithmetic mean ! TEH 0413475 DUP050454940 in-i averaged over a calendar quarter. The current secondary standard for lead (to protect public welfare) is identical to the primary standard. For both primary and secondary standards, lead and its compounds are measured as elemental lead and currently are collected using a high volume air sampler. In addition to the lead NAAQS, several other federal regulations have been adopted in order to control human exposures to lead. These include EPA's schedule for the phased reduction of the allowable lead content in gasoline and the national drinking water standard for lead, as well as the Department of Housing and Urban Development's goals to eliminate lead-based paint hazards in federally-funded housing, the Food and Drug Administration's regulations on the lead content'of foods and ceramic products, the Consumer Product Safety Commission's limit on lead content in paints, toys, and furniture, and the Occupational Safety and Health Administration's standards for occupational exposure to lead. In addition, the Canters for Disease Control have established criteria for health classification of children screened by lead poisoning prevention programs. III. APPROACH The approach used in this paper is to assess and integrate information derived from the criteria review in the context of those critical ele ments that the staff believes should be considered in the review of the primary and secondary standards. Particular attention is drawn to those judgments that must be based on the careful interpretation of incomplete or uncertain evidence. In such instances, the paper states the staff's evaluation of the evidence as it relates to a specific judgment, sets forth appropriate alternatives that should be considered, and recommends a course of action. TEH 0413476 DUP050454941 it i-2 The principal focus of this paper is on the effects of inorganic lead either airborne or deposited from the air onto dusts, soils, vegetation, food, and water. The impact that lead from non-atmospheric sources, such as paint and solder, has on human exposure is also considered. The effects of organic lead vapors which are not commonly found in the atmosphere (see Section IV.A) will not be addressed. Section IV presents relevant features of human exposure to atmospheric and non-atmospheric sources of lead through various pathways. Section V presents different approaches to estimate the impact of alternative air lead levels on lead body burdens as indicated by blood lead levels. Section VI addresses other essential elements with regard to the primary standards; these include the following: ,, 1) identification of possible mechanisms of toxicity; 2) description of health effects and their relation to exposure levels; and 3) identification of the most sensitive population groups; Drawing from the analyses of the criteria document information contained in Sections IV, V, and VI, and the associated appendices. Section VII identifies and assesses the factors the staff believes should be considered in selecting an averaging time, form, and level of the primary standard. Selecting an appropriate standard level includes a determination of an acceptable blood lead level and the impact a given air standard would have on the distribution of blood lead levels in the population of concern. Staff conclusions regarding alternative policy options in each of these areas are also presented. Section VIII contains an examination of information in the criteria document the staff believes is most relevant with respect to the secondary standard. This discussion includes: TEH 0413477 DUP050454942 Ill -3 1) identification of the levels at which lead-induced changes in terrestrial and aquatic ecosystems have been demonstrated; 2) assessment of the available data base (laboratory and field studies) to identify quantitative relationships necessary for the prediction of environmental impact; and 3) staff recommendations concerning a secondary standard. TEH 0413478 DUP050454943 IV-g and major roadways (i.e., microscale) reported the majority of concentrations over 1.6 pg/m3, Only one population-oriented or neighborhood site had a quarterly average greater than 1.5 pg/m3 between 1980 and 1983, whereas 14% and 16% of quarterly averages in source-oriented and microscale site-years, respectively, exceeded this value. Trends in maximum quarterly averages between 1980 and 1983 are illustrated in Figure 4-2. Because of recent changes in lead monitor siting guidelines, the lead monitor network currently is being expanded and changed. In order to avoid biases relating to changes in the monitoring network, the trends analysis included only sites where valid data were available for three of the four years studied (Battye, 1985a). It should be noted, therefore, that these trends data, with the exception of those for "all" monitoring sites which v ... include currently unclassified site-types, are based on a limited number of available monitoring sites that remained in service since 1980 (e.g., 27 stationary source sites, 9 neighborhood scale sites). Despite the new siting guidelines implemented in 1982 that added sites closer to traffic emissions, microscale readings have been declining, corresponding to the phasedown of the lead content in gasoline and reductions in leaded gasoline usage due to the gradual phase-out of older cars burning leaded gasoline. Similarly, annual and maximum quarterly average lead levels near point sources have also decreased since 1980, partly due to increased controls by lead-emitting sources in compliance with state implementation plans as well as to decreased industrial production at lead-emitting facilities (Silvasi, 1985). B. Lead in Soil The natural occurrence of lead in the earth's crust averages 5-50 pg lead/g soil [one pg/g is equivalent to one part per million or 1 ppm] lead in various soils (Shacklette et al., 1971; McKeague and Wolynetz, 1980). Much of the lead in the atmosphere deposits on terrestrial surfaces TEH 0413479 DUP050454944 IV-5 Table 4-2. FREQUENCY DISTRIBUTIONS OF MAXIMUM QUARTERLY LEAD CONCENTRATIONS BY TYPE OF SITE* Site type/time frame 1980 through 1983 All monitors0 Stationary source Microscale roadside** Middle scale Neighborhood scale 1983 only All monitors0 Stationary source Microscale roadside*1 Middle scale Neighborhood scale Percent of site years in concentration ranqes*5 <0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0 Mean Total siteyears Total number of sites 69 22 62 16 17 40 39 42 61 32 5 8 27 18 5 2 2 0.53 1189 3 11 0.95 159 13 3 0.99 30 0 0 0.53 33 0 2 0,51 62 414 56 18 15 29 71 19 53 24 16 47 53 33 72 28 5 9 32 13 0 1 3 0.51 360 2 11 0.88 45 S 0 0.83 19 0 0 0.50 15 0 0 0.40 29 360 45 19 15 29 aData are from the SAROAD system and represent the numbers of site-years for which the maximum quarterly concentrations fall within the designated concentration ranges. To be included, a site-year must have four valid quarters of data. Concentration ranges are In units of ug/m^. ^Includes sites previously classified into categories (e.g., urban) that do not meet any of the current definitions. ^Microscale sites are within 5-15 meters from a major roadway and 2-7 meters above the ground. Source:8attye, 1984 rO UCJc !trO' --I. Si Figure 4-2. Trends in maximum quarterly lead concentration for various monitor types." Source: Battye,1984 ^EH 0413480 > DUP050454945 photoreaction (Huntzicker et al., 1975) and are readily adsorbed onto atmospheric particles (Edwards et al., 1975), their presence in the atmosphere is transitory. Therefore, any health hazards associated with organic lead exposure are most likely to occur in an occupational setting and will not be assessed here. In contrast to automobile exhaust, atmospheric lead emissions from industrial plants processing lead and its products contribute little to the overall pollution load across large, regional areas although fallout from these sources can be severe on a local scale. The high concentration levels which are found around lead smelters in particular result mainly from fugitive emissions predominately made up of large (>7 pm) lead particles resulting from materials handling, furnace upsets, and furnace charging and tapping operations {Landrigan et al., 1975; Oennett et al., 1977; GCA, 1984). Beyond.the immediate area {0.25-1 km) of lead stationary sources, process emissions from stacks, predominately as lead sulfates and oxides with a size range between 1 and 10 pm, become the major source of lead in soils and air (Dorn et al., 1976; Roels et al,, 1980; Davidson and Osborn, 1984). 2. Ambient Concentrations As indicated in the CD (Section 7.2.1), lead levels in urban areas and near point sources have been markedly reduced since 1977 by the use of unleaded gasoline in new cars equipped with catalytic converters, the lead-in-gasoline phasedown program, and steady reductions in emissions from all types of industrial and commercial sources in compliance with the 1978 lead NAAQS. Recent (1980-1983) air quality data for 414 stationary source sites, micro-scale roadside sites, middle scale roadside sites, neighborhood scale roadside sites, and other non-classified sites are summarized in Table 4-2 (Battye, 1985a), The monitoring sites located near stationary sources TEH 0413481 DUP050454946 IV-3 A. Airborne Lead 1. Physical, Chemical and Spatial Characteristics In general, about 50% of automotive lead emissions deposits within a few hundred meters of major roadways (Daines et al., 1970; Huntzicker et al., 1975; Ingalls and Garbe, 1982} while the remaining particles are small enough to remain airborne and travel hundreds or thousands of kilometers. This likely accounts for the surface contamination of polar glaciers, oceans, and other remote locations around the globe (Murozomi et al., 1969; Duce et al., 1975; Davidson et al., 1981b,c, 1982; Settle and Patterson, 1982). In general, U.S. urban and rural airborne lead particles have a mass median aerodynamic diameter* (MMAD) consistently between 0.3 and 0.7 micrometers (pm) with most of the mass associated with submicron particles, although a distinct peak is seen in the upper end of many of the particle size distributions between 5 and 10 pm (Davidson and Osborn, 1984). Inorganic lead is emitted from automobiles as lead halides, hydroxides, and oxides and reacts with atmospheric ammonia and acid sulfates to form principally lead sulfate (e.g., [NH^ SO^'PbSO^.) with minor amounts of lead carbonates and halides remaining (Habibi, 1970; Ter Haar and Bayard, 1971; Dzubay and Stevens, 1973; Biggins and Harrison, 1978, 1979). Small amounts of lead additives used in gasoline (tetraethyl- and tetramethyl-lead) may. escape to the atmosphere by evaporation from fuel systems or storage facilities. Relatively low concentrations of these organic lead compounds have been typically found in atmospheric samples (1 - 6% of total lead) except in special situations such as gasoline stations or garages (Skogerboe, 1975; Harrison et al., 1979). Because these organic lead compounds decompose by *MMAD is used as an indicator of particle size of a lognormally distributed aerosol such that half the mass lies on either side of the MMAD. TEH 0413482 DUP050454947 Figure 4-1. Principal pathways of human exposure to lead. Heavy arrows are those pathways discussed in greatest detail. From CD, Figure 7-1. Table 4-1. Typical Lead Concentrations In Various Exposure Media Medium Ambient Air (ug/m^)b Indoor Air {ng/m^)d Soil (ppm) Street Oust (ppm)*1 House Oust (ppm)d Typical Foods (pom) Water (ug/1,) Paint Rural Area 0.01 - 0.3 0,003 - 0.2 Urban Area 0.03 - 4.4 0.01 - 0.4 5-30 30 - 4500 80 - 130 (90) 50 - 500 (300) 100 - 5,000 (1500) 50 - 3,000 (1000) 0.002 - 0.98 <! - 180 ug/1 <1 - >5 mg/cm^ Same Same Same Near Point Source(s)a References 0.2 - 10.2 Tyler, 1984; Yarn, 1984 0.07 - 3.1 Yocum, 1382; Cohen and Cohen, 1980; Rabinowitz et al.. 1984b ISO - 15,000 -CO, Table 7-11; Mi el he et al.; 1983; See Tables B-l and 8-2 (25,000) Nriagu, 1978; CO, Table 7-26 70 - 100,000 (10,000) U.S. EPA, 1977; Landrigan et al., 1975; Morse et al., 1979; Anqle and Mclntire (1979) Same CO, Table 70-1 Same Sharrett et al,, 1982; EPA, 1985a Same 81 nick and Gray, 1978 aWfth1n 2-5 kra of sources Including primary and secondary lead smelters, battery plants. Represents quarterly averages monitored between July 1982 and July 1984. cRange of Indoar/outdoor ratios used (0.3 - 0.8) from Yocum, 1982 except near point sources where large particles pre dominate and infiltration into homes is low, ratio appears to be closer to 0.3 (Cohen and Cohen, 1980). ^Values In parentheses represent estimates provided in CO (Tables 7-24 and 7-26) as typical averages. Sinee there may be several layers of lead-based paint on a given surface, absolute concentration of lead is less useful than ntg/cm^. Surveys by HUD in Pittsburgh' showed that more than 70S of pre-1940 dwelling units and 20% of post1960 units had at least one surface with more than 1.5 mg/cm^ lead paint (NAS, 1980). TEH 0413483 DUP050454948 IV. LEAD EXPOSURE: MULTIMEDIA CONSIDERATIONS In order to assess the risks associated with alternate lead NAAQS, it is necessary to understand the influence exerted by atmospheric lead on the total lead exposure of the population^) of concern through the various exposure pathways. Relevant data on these pathways and the relationships between air lead and lead in other media are summarized in this section. Section V presents methodologies to estimate blood lead levels associated with alternative air lead levels. The sources and pathways of human lead exposure are diagrammed in Figure 4-1 and typical levels of lead in different media to which U.S. populations are exposed are presented in Table 4-1. Up to the current time, between 85-90% of airborne lead in the U.S. originated from gasoline combustion, with the remainder from stationary industrial processes such as primary and secondary lead smelting, battery plants, lead alkyl production, irori and steel production," ore pulverizing, copper smelting, and combustion of oil, coal, and waste oil. Atmospheric emissions can influence human exposure through direct inhalation of lead-containing particles and through ingestion of lead which deposits onto soil, dusts, vegetation, and other environmental surfaces. This deposition can occur by either or both of two mechanisms: 1) continuous dry deposition due to various mechanisms which may include gravitational settling or wind-related deposition; and 2) episodic wet depostion due to either washout of coarse mode particles (>2.5 micrometers in diameter) which are found mainly near emission sources, or the "rainout" (incloud precipitation scavenging) of smaller particles which are more widely dispersed. Human exposure to lead can also be traced to lead in paint pigments and solder in canned foods and plumbing. TEH 0413484 DUP050454949 IV--7 where it is retained in organic complexes near the soil surface (CD, p. 7-28), The ability of soil to immobilize lead largely depends on soil pH and organic content (i.e., fulvic and humic substances). Many U.S. soils appear to have a large capacity to'bind lead with only a small fraction dissolved in soil moisture where it is available for plant uptake {see Section VIII). The environmental impact of lead on the biota of terrestrial and aquatic ecosystems is discussed in Section VIII. The upper layer of roadside soils may contain atmospheric lead from 30 to 2000 ppm in excess of natural levels within 25 meters of the roadbed beyond which concentrations decline abruptly in relation to traffic density and vehicle speed (Page and Ganje, 1970; Quarles et al, 1974; Wheeler and Rolfe, 1979; Pierson and Brachaczek, 1976), In contrast, soil lead concentrations around various lead point sources generally decrease exponentially within a 3-10 km radius from 100-60,000 ppm down to background levels {CD, Appendix 7-C). However, elevated soil lead levels have even been found at distances exceeding 20-25 km from some smelters (Wixson, 1978). Limited data indicate that lead in soil near primary and secondary lead smelters occurs as lead oxides, sulfide, sulfate, and elemental lead (Olson and Skogerboe, 1975; Corrin and Natusch, 1977). Urban soils are contaminated by lead from a combination of automotive and point source deposition as well as from paint chips from indoor and outdoor surfaces. Elevated soil lead concentrations (as high as 2000 ppm) have been found within 10 feet of wood frame houses painted with lead-based paint (Ter Haar and Aronow, 1974). Accumulations of lead in soils (and dusts) around brick or stone structures have also been found, and can be partially attributed to washoff lead collected on roofs, ledges, and exterior walls (Wheeler and Rolfe, 1979), and possibly to an aerodynamic effect of ! TEH 0413485 DUP050454950 IV-8 the structures on deposition of Pb from nearby sources. Vegetable garden soil samples collected in a 30-mile radius of downtown Baltimore had lead levels up to 10,900 ppm with a median value of 100 ppm (Mielke et a!., 1983). Much of this lead was attributed to automotive exhaust and industrial emissions because of the near absence of lead painted houses and the clustered pattern of lead levels around downtown. Soil lead concentrations in a sample of city parks have also been reported to be quite high, ranging from 200 to 3300 ppm (Chow et al., 1975; Zimdahl and Hassett, 1977). The contribution that lead in soil can make to total lead exposure under alternative air lead levels is addressed in the modeling approaches presented in Section V. C. Lead in Dust Oust is a normal component of the home (i.e., "house dust") as well as the outdoor environment where it can be found on sidewalks, playgrounds, driveways, and other hard surfaces. Anthropogenic materials deposited on these outdoor surfaces will be referred to as "street dusts". In addition, the very top layer of soils (including leaf litter) to which people, particlarly children, come in direct contact, are considered in the criteria document to be "soil dusts". Both house dust and street/soil dust contain lead from atmospheric deposition, "natural" soil, and paint chips. As with roadside soil, significant correlations between lead concentrations in street dust and the proximity and density of traffic have been found (Rolfe et al., 1977; Lau and Wong, 1982). As summarized by Nriagu (1978), street dusts from different U.S. cities contained between 300 and 18,000 ppm lead. A survey of street dusts in 77 midwestern cities showed an average lead content of 1,636 ppm in residential neighborhoods and 2,413 ppm in commercial and industrial areas (NAS, 1980). Limited chemical analyses of roadside soils and dusts from TEH 0413486 DUP050454951 IV-9 U.S. cities found lead predominately as sulfate, along with minor amounts of oxide and halide salts (Olson and Skogerboe, 1975; Corrin and Natusch, 1977). Gutter debris in Dearborn, Michigan contained mostly large lead particles ranging between 40 and 1000 pm (Pierson and Brachaczek, 1976). Airborne lead deposited on streets, sidewalks and driveways is subject to further distribution by wind and water. Windblown particles associated with dust are apt to be redeposited within the urban environment because of the complex wind currents caused by buildings and street canyons. There is somewhat conflicting evidence on the persistence of lead in street dust. Laxen and Harrison (1977) found that only a light rainfall (2 to 3 mm) is sufficient to remove 90% of the lead from the road surface, mainly to surrounding soil and to waterways. A survey of rainwashed areas in the U.K, and Mew Zealand concluded, however, that the acidity of rain (pH between 4 and 5) was insufficient to completely dissolve and transport lead particles, and that residue near streets pose a health hazard to children who are prone to ingest street dusts (Day et al., 1979). The rate of removal of lead from dusts is also dependent on the frequency and efficiency of street cleaning operations. In the absence of empirical data regarding this mechanism, it is reasonable to assume that lead concentrations in urban street, curb, and sidewalk dust will rise between precipitation and street cleaning episodes, and drop thereafter. Lead levels in house dust can be expected to vary considerably 'depending on house cleaning practices, the presence and condition of lead-based painted surfaces, the presence of cigarette smoke, the amount of dust and soil blown into or carried into the house on clothing and shoes, (especially on those occupationally exposed to lead), indoor sources of lead other than paint (e.g., soldering), the permeability of the home to outdoor air (which can It e m o 413t DUP050454952 IV-10 vary with season), and the outdoor concentrations of air lead. Surveys of a diverse set of homes indicate a wide range of house dust lead levels between 18 and 16,000 ppm (EPA, 1977; Harrison, 1979; Angle and Mclntire, 1979) and as high as 100,000 ppm within 2 km of smelter (Landrigan et a!., 1975). It is well established that children who play in dust and soil, especially in urban areas and on sites polluted by long-term fallout from industrial emissions, ingest lead in these media through normal mouthing behavior. Significant correlations have been found between blood lead levels and lead in soil, household and street dusts, and on children's hands (Lepow et al., 1975; Sayre et al., 1974; Angle and Mclntire, 1982; Quah et al., 1982; Brunekreef et al., 1983). In order to assess the impact of atmospheric lead on children's total exposure, it is necessary to estimate the contributions of different air lead levels to outdoor and indoor soil/dust lead levels as well as the amount of dirt a child may ingest, both inadvertantly and deliberately. These issues are addressed in the modeling approaches presented in Section V. 0. Lead in the Diet The ingestion of food appears to be a major component of most individuals' total lead uptake, although the exact amount is a function of the size and type of diet. The occurrence of lead in the diet may be a result of a) natural sources of lead; b) deposition of airborne lead particles onto vegetation, soils, and water; and c) the harvesting, processing, transportation, packaging, preparation, and storage of food during which lead can be introduced at every stage either by atmospheric deposition or through metallic contamination, particularly from solder. As would be expected from the differences in the handling of various | TEH 0413488 DUP050454953 IV-11 foods, lead contents vary considerably, ranging from 0.002 to 1.65 ppm (average is 0.65 ppm) (CO, Table 70-1). Lead in unprocessed foods such as fresh fruits and vegetables comes from atmospheric deposition on vegetation surfaces and uptake from soil moisture through roots (Schuck and Locke, 1970; Motto et al., 1970). The, potential for lead uptake through the roots is determined primarily by the soil's organic content and pH; at normal soil pH levels (4.5 to 8) and with sufficient organic content, lead is bound to organic complexes in preference to other metals that are plant nutrients, e.g., zinc, calcium, manganese, magnesium {CD, p. 6-32). With changes in soil properties such as reduced organic content and lower pH, a greater fraction of total soil lead may become mobilized and its potential for uptake by plant roots enhanced (CD, p. 6-38). Several studies have shown that lead on the surface of leaves (and bark) is closely related to traffic density and distance from the highway, (or more specifically to air lead concentration and particle size distribu tion), and that not all of the lead particles deposited on plant surfaces can be washed off (Motto et al., 1970; Schuck and Locke, 1970; Lagerwerff et al., 1973; Pilegaard, 1978; Garty and Fuchs, 1982; Tanaka and Ichikuni, 1982). Leafy aboveground vegetables whose edible portions are exposed to atmospheric lead (e.g., spinach, lettuce) tend to have the highest lead levels (Spittler and Feder, 1978) while for many crops, the edible internal portions (e.g., corn and wheat kernel's) may have considerably less lead than the outer exposed parts such as stems, leaves, and husks (Ter Haar, 1970), depending on food processing methods. Belowground crops such as potatoes and onions are only partially protected from atmospheric deposition since their roots accumulate lead from the soil as well as indirectly via translocation from the leaves (CD, p. 7-34). Meat products that enter our j TEH 0413489 DUP050454954 IV-12 food chain may also be affected by atmospheric as well as from lead via the deposition and accumulation of lead on forage subsequently eaten by livestock (Graham and Kalman, 1974; Crump and Barlow, 1982). Recent studies on lead content of various foods, both before and after processing, packaging, and preparation, and on food consumption patterns in the U.S., provide information on dietary lead intakes for different populations (Beloian and McDowell, 1981; Wolnik et al., 1983; National Food Processors Associations, 1982; Pennington, 1983; U.S. FDA, 1983, 1984). Based on these data, the CD has apportioned lead in "typical" child and adult diets to the following sources: natural soil lead, atmospheric lead, lead in solder, and lead whose origin cannot be determined at present. These estimates and their associated uncertainties are discussed in terms of their application to estimating lead exposure in Section V. . Lead in Water Lead is a natural, usually minor, constituent of surface and ground waters. Atmospheric lead can enter the aquatic system through direct fallout or in surface runoff as suspended particles or adsorbed to soil particles. Under most conditions (pH, temperature, alkalinity), lead forms insoluble salts and precipitates to sediments, which probably accounts for the low lead content of U.S. source water supplies; the average concentration ranging between 3 and 4 micrograms Pb per liter water (pg/1) (NAS, 1980). In contrast, lead levels in household drinking water can be much higher due to plumbing corrosion and subsequent leaching of lead, ranging between 10 and 30 pg/1 on average. The combination of corrosive (i.e., soft or acidic) water and lead pipes or lead soldered joints in distribution systems create localized zones of high lead concentrations (Worth et al., 1981) as high as 380 jjg/1. In general, levels are highest in samples of hot and/or stagnant "first draw" water. TEH 0413490 DUP050454955 IV--13 Drinking water is a major source of lead exposure among many infants while they are dependent on baby formulas during their first year. EPA's Office of Drinking Water is currently reviewing the degree of protection afforded by the existing lead standard of 50 (jg/1 against health risks in this sensitive population. The CD's estimates of the contributions that natural, atmospheric and solder lead make to young children's total lead exposure via drinking water and total diet are addressed in the modeling approaches presented in Section V. F. Lead in Paint Ingestion of lead-containing paint is considered to be the most frequent cause of severe lead intoxication among children (Chisolm, 1971; CDC, 1985). Significant correlations have been found between the quantity and condition of lead painted surfaces in homes and blood and fecal lead levels in inner city children (Urban, 1976; Hammond et al., 1982). Signifi cant differences in blood lead levels have been found in relation to housing condition among children as young as nine months with highest levels in children living in deteriorating pre-World War II housing, intermediate levels in well-maintained and rehabilitated older housing, and lowest levels in children in public housing and newer units free of lead paint (Clark et al., 1984). Other recent investigations indicate that In addition to peeling lead-based paints, intact lead-based paint contributes to elevated blood lead levels in children (Gilbert et al., 1979; Galke et al., 1975). Despite numerous reports extending back to the turn of the century linking childhood lead poisoning and ingestion of paint dust and flakes, it was not until 1971 that the Lead-8ased Paint Poisoning Prevention Act was passed. Under the Act, which has since been amended, the Department of Housing and Urban Development has regulatory and research responsibilities TEH 0413491 DUP050454956 IV-14 for eliminating the hazards of lead-based paint poisoning in federally funded housing. In 1977, the Consumer Product Safety Commission banned as hazardous, household paint (including toy and furniture paint) containing more than 0.06% lead. Prior to 1940, some interior paints contained more than 50% (500,000 ppm) lead. Use of lead pigment paints declined slowly between 1940 and the lata 1960`s after which it declined at a rapid rate (NAS, 1972). Pope (1986a) estimates that in 1980, the interior and/or exterior surfaces of between 21.5 and 47.3 million households in the U.S., mostly built before 1960, contained greater than 0.7 mg/cm^ lead in painted surfaces, a level considered hazardous to young children by the Centers for Disease Control* (CDC). Between 6.2 and 13.6 million children under the age of 7 are estimated to have resided in lead-based'painted housing in 1980 (Pope, 1986a). Even if coated with low level-leaded paint, the underlying layers of lead-based paint in older homes represent a large reservoir of lead exposure in children, particularly If there is peeling paint, broken or cracked plaster, or holes in the walls. The number of lead-based painted homes with these deteriorating conditions (i.e., "unsound") in 1980 is estimated to have been between 800,000 to 2.9 million with approximately 235,000 to 842,000 children under age 7 living in such homes (Pope, 1986a). Lead-based paint continues to be the major source of high-dose lead exposure and symptomatic lead poisoning for children in the U.S. (Chisolm, 1971; CDC, 1985), and it appears that exposure to lead-based paint will continue to be a problem for decades to come. Between 1973 and 1980, only 10% of remaining pre-1940 housing units and 5% of remaining housing units built in the 1940's had been removed from our nation's housing stock by demolition, disaster, or by other means such as conversion to commercial space (Bureau of the Census, 1983). Less than half of these units were TEH 0413492 DUP050454957 IV-15 located in central city areas where lead poisoning is most prevalent. In addition, poor urban families -often have no choice but to live in poorly maintained older housing because the vast majority of new housing units created from 1973 to 1980 is located outside of central city areas, and acute shortages of modern and lead-free, low income rental units exist in many cities (Farfel, 1985), Although exposure to peeling and intact lead-based paints are implicated as major sources of elevated blood lead levels in children, it is important to note that no si-ngle source of lead in the environment accounts for elevated blood lead levels in all children. For example, in fiscal year 1981, the U.S. Centers for Disease Control screened 535,730 children and found 21,897 with lead toxicity. Among the children identified, 15,472 dwellings were inspected and 10,666 or approximately 67- percent were found to have lead paint hazards (CD, Table 11-65). Conversely, approximately one third of the homes of affected children Inspected did not have identified lead paint hazards, [however, failure to demonstrate a linkage between lead paint and elevated blood lead does not mean that no exposure to lead paint exists.] Even for those children for whom a potential lead hazard has been identified, contributions from other lead sources are difficult to determine. Furthermore, it is apparent that the precise contribution that paint makes to'total exposure to lead is likely to be highly variable. For example, fec'al lead excretions of 1,000 pg/day were independently found in children exposed to flaking paint in old housing at times when they had blood lead concentrations between 60 and 80 pg/dl (Chisolm and 8arltrop, 1979). In children with lead encephalopathy and average blood lead concentrations of 333 pg/dl, fecal lead excretions ranging from 5,000 to 104,000 yg Pb/day were reported (Chisolm and Harrison, 1956). TEH 0413493 ' DUP050454958 IV --115 Most importantly, high exposures to lead in those children living in older housing with flaking or intact paint will not be significantly influenced by any changes in atmospheric lead emissions. Children with pica for paint chips or others living in lead-based painted homes who are excessively exposed to lead contaminated dust through normal hand to mouth activity cannot be expected to be protected by any lead NAAQS no matter how stringent. For this reason and because exposure to paint lead is so highly variable, the staff will make no attempt here to quantitatively estimate exposures of children who are excessively exposed to lead-based paint under various air lead levels in Section V, as is done for other exposure media. It is clear that any exposures and blood lead levels predicted for children under various air lead levels using the approaches in Section V will be significantly higher for children with high paint lead exposure. As will be discussed further in Section VII, preventing excessive exposure to existing sources of lead in and around housing is a problem that must be specifically addressed by an appropriate combination of legislation, housing code inspection and enforcement, financial incentives, parental education, and other social welfare programs. TEH 0413494 DUP050454959 V. ESTIMATING LEAD EXPOSURES AND BLOOD LEAD LEVELS In order to assess the health risks associated with alternative air lead levels, it is necessary to estimate the blood lead (PbB) levels that would be distributed in the population(s) of concern under various air lead concentrations. [The amount of lead measured in whole blood is an index of the rapidly diffusible fraction of the total body burden of absorbed lead and is generally used as the dosage, or index of exposure, in investigating the various human health effects associated with lead.] Three approaches are examined that can be used to estimate or predict the impact of inhaled and ingested lead aerosols and compounds on the body burden of lead as indexed by blood lead. These approaches are presented for consideration for possibly using one, two, or all three (with any necessary modifications using improved data) in assessing the protection afforded by alternative lead NAAQS. The first approach is to use measured rates of "uptake" of lead through different pathways (e.g., inhalation, ingestion) from experimental studies together with available mathematical models from lead balance studies to project either total body burde'n or the amount of lead in any of the presumed "physiological" kinetic compartments (e.g., blood, soft tissue, bone) at any time (Hammond et al., 1981). This "uptake/biokinetic" modeling approach attempts to account for the following: a) the amount of lead in the body at any one time is the product of dynamic Interactions of partially offsetting processes of absorption, distribution, storage, mobilization, and excretion; b) these processes vary with the route and rate of exposure, a person's age, nutritional and health status, and baseline exposure; and c) uptake from all sources by all absorption routes can be modeled, thus providing an estimate of the relative importance of atmospheric lead exposure, either directly or indirectly, to total body burden. f TEH 0413495 DUP050454960 The level of lead in one tissue (e.g., blood) and its relationship to levels of lead in other tissues responds to many external and internal factors. A discussion of lead's absorption, excretion, retention, and distribution within a child's body under different exposure and physiological conditions is provided in Appendix A. Any application of this model's outputs, should however, recognize the limitations of the data and the significant variability among populations in their behavioral, exposure, and physiological characteristics. The second modeling approach is to estimate separate empirical relationships between average levels of lead in air, food, water, dust, soil and in blood, which are available from experimental exposure and observational, or epidemio logical, studies of different populations (i.e., "disaggregate" approach) (CD, Section 11.4). The third is referred to as the "aggregate" approach whereby a relationship between blood lead and air lead is derived that reflects both direct inhalation exposure and indirect exposures via secondary deposition processes. The validity of these latter two approaches, which rely primarily on epidemiological data, requires that the input of lead from all sources must have been reasonably constant long enough for virtual equilibration to occur between blood lead and environmental lead levels (Hammond et al., 1981). The nature of the relationships detected between lead concentrations in blood and various environmental media, and the merits and limitations in using empirical relationships to represent lead exposure through multiple pathways, will be discussed in Section V.B. A. Integrated Lead Uptake/Biokinetic Model There have been several studies measuring the intake, uptake, and metabolism of lead in volunteers, from which balance schemes have been constructed (Kehoe, 1961; Chamberlain et al., 1978, Rabinowitz et al., j TEH 0413496 DUP050454961 V-3 1976, 1977). These balance schemes are derived from limited data obtained under experimental conditions and their application thus far has been restricted to adult males. It is also possible to construct balance schemes by making estimates about lead intakes and various metabolic factors. This approach suffers from the fact that the data and assumptions employed are based on the results of many separate pieces of research, and therefore important variables may be omitted. However, provided the data exist, balance schemes can be constructed for different groups with different exposures to lead to assess the importance of specific exposure factors under variable conditions (e.g., alternative lead NAAQS, phaseout of lead in soldered cans and in gasoline). The staff has attempted to devise model balance schemes for U.S. children, aged 2 years, under alternative air lead levels. Because this analysis assumes that the various air lead levels are maintained constantly, averaging time (considered in Section VII) will not affect the uptake estimates. As discussed in Section VI.C, pre-school age children (6 years old) and pregnant women (as exposure vehicles for the fetus) are specified in the CD as particularly sensitive to lead. Of this group, children between 2 and 3 years old experience, in general, the highest blood lead levels (Mahaffey et al., 1982; Billick et al., 1979), most likely due to their greater hand-to-mouth activity as well as to various metabolic processes (Harley and Kneip, 1985). In order to predict the maximum impacts on young children, uptake estimates are calculated for 2 year olds and PbB levels will be estimated for those children and presented in Section VII. The results summarized in Table 5-1 give a broad outline of the actual and relative magnitudes of average intakes and uptakes of lead by different pathways and from different sources. It is important to recognize the limitations of this exercise, which involves TEH 0413497 DUP050454962 Table 5 -1 . MODEL BALANCE SCHEMES FOR AVERAGE LEAD INTAKE AND UPTAKE IN 2 YEAR OLD CHILDREN UNDER CONSTANT AIR LEAD LEVELS1 +> U13 C' 3 oo a. tn cm co finv <r> m i i cm OOM < vc i o --* i h in\ xir i in i-< CO O if) <0 Cm vo CO c m o vo 1 woo <U to CO 1 1 CO 1 c r*- c m SWH ! <VJ 03 o O O 1 CM CM* l * Lf> * pH h - O V-4 pH CO d- m1 CM* i CM CO M CO O p-- CO m m* CO c m o m r*^ c m m r*w CM HCO t1 ii r '-O O O *3* r- o m m m o VO vo in m o tn co pH *0" <0CO 1 CO 4 o CM f--l CO 0* lO 1 <3* CO <0* CM 1 CM CO * CM CO O i-- 5f CO CO VO LCOCO CO O f"-* LO CO VO CM CO VO VO I 1 111 i^OO pH * O * r-w o --i c m *et co o co co --* vo un CM 1 O') f-- CO 13 4-> u c t1-- 3 o a. to CO ^ 3. lO o CM r* L. a c 03 CS3 H ph CM t--io o in 1 1 VO 1 VO r--t *3* CO vn r-v i co * 1 *--1 i * in O O CM <tcwo * CM r-H VO O <0* 1 CM O O in \ 1 CO \ if) r--t <0" CO tn r-- 1 r-- * 1 rH t in o a c m <5^ 0--0 H CO $ If) 1 co* ^ c m t CM CO CM CO O r-- ^ CO pH co in i d* CO O' CM 1 co f 1 CM CM CO O r-- '=*' CO O O CO CO CM O O CO P** CM co r> 1 1 fi i O tn in o in in r--t 44 moo CO CO CO o CO CO r-t r^. m O r- f-H * p H Kt CM in ^ sf 1 1--4 I 11 CO 1 O O CO r-- o m in m CO o r--1 CM CM o CM CO P-^ CO VO CM * r--t CM r-- 1 <r* o *-H Ju0O3 CO a> 4^ o c 3 oO CO O- 00 cn 3. m cm CM 1-- tC o c. 1) c 03 PH l-1 VO *3*4 oo If) 1 i m i CM CO Hf IO ^ I r-t' o o4 1 CM o i in co CO CM 1--H i-H O CM * pH O 1 m 1 1 1 CO vo CM 00 in^ i o 4 o \ CM O i <* *m * pH d* CO pH 4 CO mi CM 1 co CM CO pH in o ?# 4 CM o If) m m in in i pH t t1 o ( O r--t If) o vo in m pH r--t r*H i--H CO VO 1 4 co oo c\i Ifi) ooI a a CM csjroo -- pH _ vo OUOH CM a CM CM CM VO CM CM CM I I I I I 1-1 CO tn to tf> 00 o * UO 00 CO O 00 CO CM I in t/1 >5 >. C p-s /0 ^ 3 -T3CO -- V) -V. S -V. 3 05 CO -VTO -O C C <- a s -r- 3 3 3.*--' 1-- CO '--' O w* 3. C SCO Si -o --' o E g 0) <U *p" o 5- L W L 3. CO rp- .p- CL <4- ^ 3. L. L. Q- 3 U 'w o 03 vn o 03 a o > i wji (0-CXI<0<-OJ3lO 4J S +* 1- TM *J r~ 111 3-0 r- O <U - C3 4-> tQ 13 o r- C_ 4-> J= JUt -- -3 (0t-C4->r04M(0 03 *p- O +J -- CU C- CL O C tn r-- >> O L VI ? d)H O <Q OO e CUr-- -o *DO<U(U3*OCJCM -PTJEEl-- lOTUJ ai 3 C *- f- O 03 0 3. O wl-l- > rHCMco^finvor^ >> i fd n -o o tn JH 3. ns +J cu to 4-> 03 E > to *o O 03 L. in *p-- L. 03 03 3. 4-i *p- JC U c l -a E <= 3 4i-- tn 4-> O *D 3 4-> 13 to o 3 JX C- 13 in fO c* O r-- 4H O "O o tvs "a C CL L. U 13 *- 3 13 -3 i-- <G 13 *r- C -3 U -p- 3 -O r-- OJ E O nj 03 r- o x: *<- 03 CJ tn Q. 13 4-3 p-- L. *p- VT> 4H Q. >) 3 L. F O 13 V- >> C-- 4-3 03 o E -a O L- <o to JZ J-> c tn to c 3.4-- 40 3 -3 4-> 13 p--* --h rO tf1m3 a <o j c u -o a ea 4 O --i pH pH p --% >5p--< p-- <o >V4H >v --N P--T3 to 3 <o ^ xs *o '*' *^. *--- c 3. 3. 3- r-- 3. ,w'p--T55 wp 13 C *0 ^ 13 4H 4J O 4H to tn t-- *p- 13 3. to a; p* 4-> r-- p-- ' SL a a. "O 03 C L_ t-- T5 > r- s o F *r- <o to o tn o O S3 +j L. L. Wp *0 L 4-- tO 4^ 03 *f- P 4J4JO a) -a U in in sz to JC 3 3 4- to 13 to OO'P o 4-> *-- 4H 13 3 CL J-> t. S 4-> r- 4-> 3 13 O C L. 03 O 13 3 *o -- o *- 0 5 0 to -a to 4^ cs *p- E o 03 cnMh< ti * c m in VO p"^ CO pH pH pH pH p H pH pH XS C 5 C f--3 g 4- 13 tO 4H CL 3 >! XJ to to *o 03 p- 31 p-- VP to 4H 4-3 O3 J-- pH o c: a U 0) V> e: <U > 5 VJ JO o 3 *f-- O > V) Xc r-- CD 4-J T3 c C r-- r CU o a. u CL <a. 3<L -<o0 c l aj f-- O r~~ XJ0O33 J/COa pUO- L3. -- 03 <0 -a u u r- c 03 CL O u >> (O H L <o (A C 3J C*r C O r- 4- C C r-- > > 3 r) -mmrm- amr.-. P-- to c c O 03 OJ L. L. t? "3 C t-- p- JC JC V) U V c oo P L P 4-> c l in in S l - t3 tn 4- 4tn rfacs rH CM CO sog> CO i-- o X il H DUP050454963 3. 4 . 63 5. 6. 7. 8. 4-> co ir- u CM 3 CO 3 i--l O L_ VO 1 i to 1 cc Ui a. 3 O to tn d* to c m i i--l 1 to t to h QM * d- CM CO pH Q CO S a> =3. UJ Of O 0*3 CM CO a\ h I VO -* a> I d* CO I o c to to *d* to tO CM I CO 02 d* f l lO a ts pH CVO^*CJHO --i o Q C UJ >- CM 4-3 02 eo d* to i--. vo* CM o pH *y u. to 1 1 vo 1 p -- O3 <3u o CM 0 CO 0 ^* 1 lO *sf tO 1 3 * 1 to to UJ to pH O CM *d* i-H CO o co <e V-5 tH CO to < ad* CO * ad CM 1 * CM CO CM wOnd CO r o Or--. pH to VO O pH P*"* * r-* P-. pH p H pH pH pH 1 lO 1 ii r- 1 a o r-- ao o O pH tO CM r*H pH O tO pH p H pH O pH CO CO to r-- 'JO i *d* co pH < lO 1 d* CO d" CM 1 0 CvJ Men O h <d* O O a to CM P^. *d- p H CM p H pH pH pH 1 1 1 tt CM a o c m pH * Otnd- -d- CM r*-. r- r-- r*"-. c m d- i 0 CM pH CO LO 1 d* 000 d CM 1 CM co CM CO pH d" CO O r- o COLO to o ^* d* ^* to p H pH pH d* pH I | | 1 tor*- p*-. O O pH * * to CO O PH ON CO CM r-. d* l to * CO CO o> CO p-ot X Ui h- CO Z CO <C --1 UJ UJ > ^ UJ <C --1 *-- Z Q 02 i--i E 3 O --1 C -L> LU Qi C --l .-- <C cj> U4 ' O J-- a: c UJ f-- 2> in <^ an o o 00 UJ o 00 UJ o c < CO --: LU o 21 to CM p--* Id pH c_ a) c 0) a> eo P* lw O3 Cu. O 00 3 O rO L02 C (12 H 1 to ra_>t _o fO h- o pH O pH to 1 l to p H LO CO to 1 CO 1 CM d d* *1 to 1 1 to a pH CM *d" H pH 0 CVI CO d" MOh 1 t VO I o co d* vo to i tft I CO I to * i-- o c m '^rino CO CM0 d- 1 1 i r pH * o ad* t CM to to 1 <d" df0 pH l to p4 CM V> p--. >>.<= ns 3 "O 3 -- to E cn v *-- e c c L. S ^ -p 3 p~" 3 XL"-- <-- --- O --' CL C Eco JC "O'-- O E B ^ ai ty OIL *p" L+J o L =L CT in <d *p- *p- Q-t-- ----- XL l l ad c o ai w o 02 -a O > <U E -X < "O o 1- O J) 0) ra 4-3 t- td 4-3 r- 02 3 (-.4-^0. O flJ*r C3 C_ 4-3 Id 02 o p L 4-3 JC -X P 4p" C 4- fljj id 02 p- O H*r OJ <u Q- 03 C (flp >, O l- in 2 h O <0 oo 0-p- ~0 o o 0) OJ 3 02 3 -v. 4H *a S Eh dd H 05 3 C pp O O 0 3. O PH 1-- 1-- S=- __J !-- --' p H CM pH * CO LO 1 ^J* ^ e CNJ 1 Cvl CM p H ^d* CO ad* co CM CO CO to I c m i co CM O r-1 CO co d* to I 53" CO "d* CM* 1\j CO* CM CO O pH ^ CO >, i <d t/) -a o 'H'. 6 trt p-- -4-2 n3 XL rt3 *WF 4-3 02 >1 <d 4-3 E cu O 02 L. V5 p* L- <32 02 XL 4-3 *p JC O *-- Ou 4H a E= O 3 4-3 02 3 *r- fd o 3 -X 01 a 02 <A <d Cp o r-- 4-3 o -0 C CL o c. O 02 p 3 a 02 p c i-- L. .p e <d p-* 02 e O <d 02 p - o x: t- p 02 _J (0 o iA CL 02 4-> p 5- r- Lft 4-3 CL >5 3 a E O 02 a >> a 4-3 cu o s *a o ro <d JX a 4-3 C VI #d 40 C CL**- d 3 j 3 4J 02 r- '"^s re 0J p o ro JO (J s* a o pH pH pH o to CM CM O pH p H' pH pH 1 1 1 11 PH to pH pH LO CM CM CM to vo to o VO CO pH to O'O o to LO to to CM pH r^. CO III 1 CM CO O O CM pH * to o o co NCONONCOCVJ o r- 0 to to r-. to H N LO ON CM PH 1 1 111 PH O to pH pH to * CM CM CM O tO LO LO tO to H >jP> PH d >j4-> > > *-- ^ ns 3 fd cn Ol^. TJ CT>T3 w c XL XL XL -p* XL ^ aP*-. --F> 10 Sfl - 02 C "^ 02 4-> 4J O 4-> <d 00 L-r fmm a; a. ro to - +j -- - t- Q- p- 02 C > -p- O a p d d O U) O O 02 +J Lj2 C_ VN p- t- V-. 4- *****-. 02 m- 4-3 4-> 4-> 02 03 w vj j : ro 3 3 M- id 02 d *r-- O 4-3 p - 4-3 02 C CL 4-> t- 3 JJ -r- +J 3 02 O C O 3-Oh - !- 13 E O res u d 4-5 C `P- E 02 02 w m h - c _i a* -J c m co oH-tn to r- co H pH p H H pH pH pH 1 CM * CM CM CM d* I vo r*CM d0d" i fmm 0 ON c rc c 3 E O t. 4-- 02 (0 4-3 CL 0 p- >> ta <d 02 ^ -- XL p-- eo +j +j O3 l-- pH 02 JC 3 c C/1 3 Oca c- ai vo y*n>>oss t<,u t- 3 CQ >-I-- OV) Xc i-- o j 40 a c C P- M- ' Q.a 3 o CL (- CL 3 C S c. c- <od p- o W ga o 02 c ra t- O afi uL- 3 t* 02 toVI r-- O U 02 p- C 02 CL O u. >, Id 4-3 c. Id V5 C CJ o `1- 4-3 3 C -- > > O r-- p- <d C c O 02 02 C L. C P-* p<d -- p- jr j c vl u u c o oo P H H 4- E= <_ t. n as <u tn 4- 4- to 02 02 <a p H CM CO DUP050454964 V-6 many uncertainties and assumptions due to a lack of sufficient data. These limitations along with details of the available data and calculations are provided in Appendix B. The children considered in the model do not include the whole U.S. population; they comprise groups with different exposures to lead, some of them extrema, in order to illustrate the variations in lead exposure and absorption in different situations. Section V.A.2 presents methodologies to relate estimates of average lead uptake under alternative air lead levels to blood lead levels. Although this approach predicts hypothetical outcomes and the absolute numbers should not be used uncritically, the model does strive to use the available data, with all its limitations, to the fullest extent possible and to provide a useful tool in eventually distinguishing the health impacts of alternative lead NAAQS. 1. Estimates of Lead Uptake The method employed to estimate the degree to which each environmental source of lead contributes to a child's total daily lead uptake is based on the maximum ambient air lead level allowable for each level considered, probable exposure conditions with respect to other exposure media such as food and dust, and average biological absorption rates for each exposure route. The method consists of a four-step process: 1) definition of ambient concentrations of lead for major exposure sources (i.e., air, food, soil, dust); 2) determination of daily lead intake according to. the relationship: II - C1 * [Pb]1 where I, is the daily lead intake from source i, C-j is the ingestion or inhalation (i.e., consumption) per day of each lead source i and [Pb]i is the concentration of lead in each source i-j; TEH 0413500 DUP050454965 V-7 3) calculation of the amount of lead absorbed from each exposure source i: VV Ai where U-j is lead uptake for each exposure source i, I-j is the daily lead intake from each source i, and A-j is the percent absorption of lead, via the appropriate exposure route for the particular source; and 4) calculation of the total lead uptake from all sources, U^: . Uy - E (I* * AiJ Certain assumptions are required to calculate the average daily intake and uptake of lead for children living in the two general areas specified -- urban/rural and near (within 2-5 km) one or more point sources. The assumptions and estimates used in the calculations presented in Table 5-1 are discussed in Appendix B. 2. Uptake and Blood Lead Concentration To estimate children's blood lead (PbB) levels under different exposure scenarios, several different kinds of studies can be used to derive a relationship between absorbed lead (or lead uptake) and blood lead. Available studies include population surveys in which the blood lead concentration of individuals or groups is correlated with measured lead concentrations in air, food, water, soil, or dust; experiments in which volunteers are exposed to controlled air lead concentrations and their PbB levels measured; and lead balance studies of individuals with measured lead intakes. The most relevant of these studies are discussed in Appendix C along with descriptions of the analyses used to derive uptake/PbB relationships. Data on children from population surveys are discussed in Section V.B. Because of significant metabolic differences, experimental data on adults are used for comparative purposes only. Figure 5-1 compares the relationships derived from the Ryu et al. (1983) dietary intake study on infants, the Chamberlain and Heard (1981) TEH 0413501 DUP050454966 Y-8 LU 1 C4 ]iiOo co LO XU1 E "O *-- OC CQ r-- <P4- <C0> OCO'* ->ao C0M- ~> . 3 (lJ -C/5 J<U. OCi -I^ XSI- 03 N oc *0 v-- in tO *<.ux.? t3O cCrOi z<cU W'-'-O XrIj " cy a) c ^ r~ 4-> O. ra "o "O 03 rt*t) c oo *rP* ^ !0--3 r-- CO r-- J3 4)*D i. -o 0C3 * *\ C 01 o +j raja C_3 CC E fO CU > <0 o j <0 OJ -C > a) a; r-- o s- ^ s- s~ 3 f0 Cu CO O 4-1 OJZ U s--^ C- u 3s *r>J2 c -a < <u t-- Cl) 2 <c -- " s<U + > T3 +-> r-- LtJ 3 r-- r >5-a 05--crz- -3a P- C U) o fQ. -0a3 s r* CO X! o -p -a *3 "Tp* i-- oc: 05 *4 -C O a C W G) CO <y 3 s- -p a) <c a re CO a; S S- 03 "O P tfl JO >> <0 QJ QJ +J r-- -P ZaD. JD cn >S3- C0OJ CM CO -na3ai aup r- I 3 LO o co co un O CM CM (IP/Brt) p^ai poo[.g un I un Os-) *Zrc--3n U. DUP050454967 V-9 analysis of the adult epidemiological data, and the metabolic lead balance/ compartmental models of Rabinowitz et al. (1976) and Harley and Kneip (1985). Despite the diverse nature of the populations, study designs, and methodologies, there is a fair degree of consistency in the relationships. Each study found that a linear function provided as good a fit, if not better, than other non-linear forms at the relatively low exposure levels investigated. Some experimental and epidemiological evidence suggests however, that the relationship between lead concentrations in tissue and cumulative lead intake is only approximately linear at low levels of intake, and that successive increments in intake or exposure result in progressively smaller contributions to blood lead concentrations (Azar et al., 1975; Moore, 1977; Gross, 1981; DaSilva 1981; Sherlock et al., 1982). This curvilinear relationship may be due to increased renal clearance with higher blood lead (Gross,; 1981), distributional non-linearities due to differences in lead binding sites in different tissues (Hammond et al., 1981), and/or to a sizeable pool of mobile lead in bone maintained more or less independently of uptake (Rabinowitz et al., 1977; Chamberlain, 1983). It appears however, that none of the mechanisms introduce significant non-linearities at blood lead levels below 30 pg/dl (Marcus, 1984, 1985; Chamberlain, 1983) and that a linear mathematical model is valid for .relatively low to moderate lead exposures (CD, p. 10-31, Appdx. 11A-2). As discussed in Appendix A, above 30-40 pg/dl, blood lead may be an inadequate index for tissue lead burdens in many children (Piomelli et al., 1984) and linear models are likely to lose their predictive power. For this reason, the relationships depicted in Figure 5-1 are truncated at 30 pg/dl. To estimate PbB levels above 30 pg/dl, which is now above the PbB level of health-related concern for children (see Section VII.C), would require use of non-linear models which are discussed in the criteria document (CD, Appendix II.B). TEH 0413503 DUP050454968 V-10 The compartmental biokinetic model of lead metabolism developed by Mallon (1983) and Kneip et al. (1983) and revised for children by Harley and Kneip (1985) relied on a broad array of experimental and observational measurements of mammalian metabolism and growth patterns, and has been successfully validated using available human experimental and autopsy data. As is the case for any mathematical model, there are inherent limitations and un certainties associated with it. Because this model is based on the most comprehensive data available and has been developed specifically to predict organ lead concentrations over time in young children with continuous lead uptake, it appears that the outputs of the Harley and Kneip (1985) biokinetic model may be the most appropriate to predict PbB levels in children using the integrated lead uptake estimates presented in Table 5-1 and Appendix B. PbB levels calculated from the conjunction of the integrated lead uptake and biokinetic models are presented in Section VII.C.3 (along with estimates using other modeling approaches that are discussed later) in order to estimate potential health impacts among children under alternative air lead levels. B. Statistical Relationships between Blood Lead and Airborne Lead This section addresses two other methods of determining the contribution of air lead to total exposure and the potential health impacts associated with alternative air lead levels. The previous section examined the relationships between blood lead in children and estimated levels of lead uptake from the air, housedust, outdoor soil and dust, and diet. The approaches presented here will be to develop a direct relationship between air lead and blood lead in children and to 1) consider how air lead alone can serve as an index for lead exposure through other media affected by atmospheric lead deposition as well (i.e,, "aggregate" modeling approach). TEH 0413504 DUP050454969 v-n and to 2) evaluate how these other environmental media can be taken into account separately (i.e., "disaggregate" modeling approach). Various experimental and community studies provide quantitative relation ships between air lead and blood lead. Experimental studies, summarized in Table 5-2, include those in which adult volunteers have been exposed to con trolled levels of laboratory generated lead aerosols, in some cases with isotopic lead tracer. Data from the most relevant studies have been re-analyzed in the CD to yield blood lead-air lead "slopes" (g), where g measures the change in blood lead that is expected for a unit change in air lead. Because intake of air lead through the diet and dust was probably minimal for"the adult subjects in these experiments, these studies may underestimate the dose response that would be seen among children to environmental changes in air lead (Angle et a!., 1985). * Epidemiological (i.e., community) studies provide correlations between air lead and blood lead in different populations of children and adults under varying conditions of lead, from current or previous atmospheric fall out and other sources, and may yield estimates of dose response that are biological ly more relevant. Two modeling approaches using the best available epidemio logical data can be applied to estimate quantitatively the relationship between air lead and blood lead in children: 1) a disaggregate model in which total exposure to air lead is assessed by separately analyzing the relationship between blood lead and inhaled air lead versus the associated changes in blood lead as a result of exposure to lead that has deposited onto soil, dust, food, and water; and 2) an aggregate model in which blood lead/air lead relationships are analyzed such that integrated environmental lead exposure is represented by a single variable, i.e., air lead. Before discussing these approaches, several important factors in interpreting TEH 0413505 DUP050454970 Table 5-2. SUMMARY OF EXPERIMENTAL LEAD INHALATION STUDIES V-12 m^ r- ir> c mi cni ma * n CuMo tCnsl O *"H a aSj CO T-r. O if X Ui ns M <aXU. S- CT3 !+O (A C * K- UO t4J1 O1A u **- a x s. JSQ O OO iUA 3 XS +J W i---oa <0 +J *f<Ulj9l S3S* rJ<S*0 JfI9A=lU<C0 #)&Q. CO .flau vx <u voi x > <u ro O r- > E ci in oj in "u* O 0 4) VI 3 I <Od -*49--O) Ua>s J*4USJ1 < I*0 i*OC-T ou DUP050454971