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Appendix C CPSC-Supplied Animal Studies Of the four studies submitted to the National Research Council for evaluation, three were initially intended to answer the question "What is a safe level of lead in paint?" The fourth study carried out by Barltrop under a contract from the Center for Disease Control was intended to study the relative absorption of various lead compounds.* In evaluating these studies, this Committee sought to determine whether or not the animals studied represented a proper model for comparison to a young child. The two crucial points considered were age and diet. A summary of the study designs and results are given in Tables 1 and II. Supporting data for statements made in this appendix relative to diet and age are given in Appendix B. AGE Age is an important factor in both the susceptibility of the brain to the effects of lead and the intestinal absorption rate of lead. Young animals, particularly suckling animals, are more susceptible to nervous system injury than juvenile or adult animals.5,13,25,26 In addition, the intestinal absorption rate of lead is significantly higher in suckling animals (see Appendix B). The starting age of the rats used in the Midwest studyl6 ranged from 30-34 days, and in the St. Mary's study6 from 30-32 days. In rats, the "growth spurt" of the brain occurs during the first 24 days post- partum. In humans, the "growth spurt" continues well into the third or fourth year postpartum. In rats, the intestinal absorption rate of lead drops significantly at the time of weaning (approximately 22 days) and reaches adult values at about 30 days. Thus, the rats in both studies were too old for comparison to human infants and young children. This committee could find no data relative to the rate of brain growth in the baboon. In rhesus monkeys, 70 percent of the adult brain weight is reached at the time of birth. The baboons used in the South- west study'" ranged in age from 18.2-31.0 months, and in the NYU study, from 3-23 months. The fact that all animals were weaned suggests that they were essentially beyond the vulnerable period. Extrapolation of the data on brain growth in rhesus monkeys also suggests this. Diet - The intestinal absorption of lead is influenced both by dietary composition and dietary deficiencies. In particular, a diet containing lipids or milk increases the absorption of lead. Several dietary deficiencies, including deficiencies of iron, calcium and copper, * The fact that Barltrop's study (St. Mary's study) did not meet the criteria established by this committee should not be interpreted as a criticism of study design, since this study was not intended to determine a "safe level" of lead in paint. 29

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also increase the absorption of lead. The average child's diet contains both fats and milk. In addition, a significant percentage of children in the U.S.A. have been found to have dietary deficiencies of both calcium 1 Q R and iron. '*° None of the animals in the CPSC-supplied studies received milk in their diets. With two exceptions, the diets did not contain added fats or oils. Two baboons from the New York study were fed lead octoate (100 yg/kg/day and 500 yg/kg/day) in olive oil. After approximately 100 days, blood lead concentration ranged from 60 to 80 yg/dl in these animals. The St. Mary's study showed that lead compounds dissolved in vegetable oils were absorbed better than the same compounds not mixed with oil. All animals received diets formulated to provide optimum nutrition for the particular species of animal used. In addition, the baboons from the New York study had dietary supplements of fruit and mul^tivitamins twice a day and Imferon (iron) injections to prevent anemia. We are forced to conclude that the nutritional status and dietary components of the study animals did not simulate the conditions found in the young child at risk for lead poisoning. Method of Lead Administration - Neither of the baboon studies used old paint. The paint was pulverized to simulate the weathering found in old paints. Nevertheless, there is no assurance that this method closely approximates the weathered old paint films available to a child. The Midwest rat study may be condidered a replication of earlier studies by Gage and Litchfield.32,33 -phe results confirm the earlier work and further document the higher availability of lead in older paint formulations. Both the St. Mary's study and the New York study had adequate controls for measuring the dose of lead administered. Barltrop (St. Mary's study) combined the lead dose with feed and baked it into a hard stick form to prevent scattering. The diet was weighed before and after feeding to determine the amount actually consumed. The New York group fed the lead dose in a gelatin capsule so that the consumption of the entire dose was easy to determine. In the Midwest study lead was mixed in the loose diet and in the Southwest study lead was administered in a Fig Newton. Measures of Internal Dose and Effect - All studies provided blood lead values for the control period and at various intervals during the study period. The control blood lead levels (mean approximately 10 yg Pb/dl) for all animals were significantly lower than those found in the average child living in an urban area (range of means 17-32 yg/dl).^0,59 Tissue lead concentrations were provided as follows: Brain (SW and MW), bone (SW, NYU, MW), kidney (all studies), liver (SW, NYU and MW). The Southwest study provided the greatest number of measures for metabolic change. These included ALA-D, FEP, erythrocyte porphyrinogen synthetase, plasma acetylcholinesterase, blood choline concentration, corticosteroid acetyltransferase and choline acetyltransferase. Both New York and Midwest provided measures of ALA-D, FEP and hematocrit. Most results 30

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showed values indicating no significant change after lead administration. Unfortunately, since the animals did not adequately simulate the physiologic state or dietary conditions of young children, we feel that these results cannot be used to determine that similar doses of lead are safe for young preschool children, especially children less than three years of age. Significant Findings - We feel that several significant findings resulted from these studies. They are as follows: 1. The presence of lipids in the diet increases the absorption of lead (New York and St. Mary's - see Table III). 2. Lead octoate is absorbed more readily than lead chromate (St. Mary's). 3. A dose of 100 yg Pb/kg/day (as 0.28 percent Pb paint) is sufficient to increase blood lead levels by approximately 12 yg Pb/dl (from 10 yg Pb/dl to 22.3 yg Pb/dl) in juvenile baboons (New York). 4. ALA-D activity is immediately depressed in all baboons when blood lead levels reach 50 yg Pb/dl (New York). 5. Plasma acetylcholinesterase is significantly decreased in baboons fed lead napthenate or lead octoate at 200 yg/kg/day (Southwest). 6. Younger baboons show a greater uptake of lead in bone than older baboons (New York). 7. The chemical form and particle size influence the absorption of lead (Midwest, St. Mary's and New York). 8. Comparable doses of lead compounds incorporated into a paint matrix are less well absorbed than the simple salts (New York). 9. Absorption and retention are related to the dose fed (St. Mary's) 10. Considerable variation in effects occurs in animals fed the same dose, thus indicating that even inbred laboratory animals have varying degrees of susceptibility for lead (all studies). Additional Studies - The studies of Gage and Litchfield32,33 are often quoted as evidence that negligible risk is associated with the ingestion of lead in modern paint formulations. Their studies did show that lead in paint is about 1/3 - 1/4 'as well absorbed as inorganic lead salts. Thus, the New York study on lead octoate is corroborated and the two studies form the basis for estimating that the paint matrix reduces absorption by a factor of 3-4. The studies of Gage and Litch- field were carried out on rats weighing between 105 - 120 g which indicates that the animals were more than 30 days old. Thus, the neuro- logic development and intestinal absorption rates were not comparable to those of a young child. Based on the studies of Chisolm and Harrison in which a mean fecal lead output of 44 mg/day was found in children 31

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with severe lead poisoning, Gage and Litchfield concluded that an intake of approximately 50 mg/day would represent a dangerous level. What the authors failed to realize was that this mean fecal Pb output was found in symptomatic children, most of whom had encephalopathy, and that although the mean fecal lead output was 44 mg Pb/day, the median output was 27 mg/day (range 5.04-104.0 mg Pb/day). In addition, the asymptomatic group of children described by Chisolm and Harrison ' all had ? 60 yg Pb/dl in whole blood with positive roentgenographic evidence of lead storage in the bones and a median fecal lead output of 1.ll mg Pb/day. Thus, Gage and Litchfield's estimate of a dangerous level of lead intake was based on a fecal lead output 40 times greater than that found in children with positive evidence of long-term lead exposure and blood lead levels in a range associated with the appearance of neurologic damage. In summary, this Committee was unable to recommend a "safe level" of lead in paint on the basis of the four studies provided by the CPSC. None of the studies were carried out on animals whose age and dietary components simulated the conditions of a young child. These studies do show that lead salts used as driers in paint are less well absorbed than the same salts not incorporated in a paint film. 32

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Table I Experimental Design (Cont'd) NYU I HK1 | S1 . HUMS MSI. I.K.MI COMIWMI 4/011 HATI.KIAI. I'll), M1MIU.K OK ANIMM.r./KKOUP IHIKATION (T) uf/ki'/il.iy Z 1 i i.l No . T i•») (vk.) 0 - 4 6 0 Kll. 40" 13 t f PAINT CHIPS ' (•in) N.ipllu'nate 50.0 4 6 ^ 1OO.O " 46 •AiNi' currs 200.0 " 46 "itoVi" O.OJ2 Load 500.0 " 4 4 PAIMT 1_C.II1.PS - PAINT Cllll'S >fd 1 Wk 11.5 0.5 "" 4 6 Octoatc Oclnato 1.1 O.'ofl 20 13 0.10^".. tcto.ite 12 O.I Icud 10 500 . 1,000 n Chip Slz. 50.0 " 46 u M |2 7.9 0.53 20 13 < 50 y ' " " 100.0 " 46 100 " 8 23.1 2.05 20 13 200.0 " 46 10 500.0 4 4 " " 12 Chronate :hroi.iatc "25 6.9 0.42 ' 20 13 50*0 -~lpOO M Chip Siz 200 " 2 11 19.4 1.95 20 13 < 50 p 500 " 26 136.1 12.43 20 13 100 0.06 2 All dok^s contained 100 0.28 2 0.07 5Z Lead 100 «.'••'• 2 6 100 2.C 2 6 Diet Frd for 48 hrc Lead Arcta'e Lead Acrtatc 2p,«te»t cont.ol 100 b 4 4 100 7 4 100 26 200 24 500 25 10.000 2 • 4 20 Intravenous 2 6 Lead Octo.llc »cnd Ottoalc in <'..in "oil Klxrd in torn Oil 100 40". ?tc»3" 2 5 Acetntc 500 40.7 '2 5 Aldynatv Naptlirnntc Octoare Tallatc ?'•i? UU?.rl_wi th oil Acetate Oxide Suicide iM.,i . 180 u Old Paint 511.9 66. VI. " 20 13 UPS Carbon.ite Metal 180 - 250 \i rOOTVOTLS: • Paint Chip Size < 500 u 119.9 11.92Z 20 13 h chips 500.1000 ,i used by MJdwcbt IpOO Jf/kf/dnyfor ~ cautes. 0.12 (ui.ighr/wc.c'it) 2 vecku InKKod of i iOZ females 100 H./'M Al i v . Data nut considered. £ Kailnnal Bureau of Blood S»aii,l Ing Sr«iui.nc c wi'rk" ' Wrc.V Standard! Doae of Lead ) 2 ui ,rr 0 2x2x? Doae 1 ? i ', nili..r At 4. 8 nnj 11 verk*. nrvoriil Anlirali. •.'••JrhM.l li^foro 11.5 !•» All. Pi x x > 'jQ3 i;: l.ni 3x 2x 1 . 1> ]alrJ ."'.-hri. In tiof «hn| !,)• hr P 50 li>. Alt. Da CIH;P« for urfm. ii.Hoc i Inn. >1i t w,.iKl,id befoir 100 or. All. lla ind nflcr. 200 ug All.lu 500 m Dally A t. da. NIXKOrSY orCKorST HtCHOI'SY Ni;cnni'SY 34

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Table II Results from CPSC Supplied Data ABSORPTION COEFFICIENTS Southwest NYU Midwest St. Kary's level of lead is increased results 1 BLOOD PARA.MK1KKS 7:F Blood U..lcl Control 10.8 * 0.039 i.g 2 50 ,. g/kg/day napthenate caus significant increase to 11,9 t 0.046 UK Z. Greatest level 15.1 * 0.045 ug Z was caused by 500 ^g/kg/day Controls varied around 10 ug %. Experimcntal data too limited to make adequate evaluation. Reported "steady state" data fur appropriate age (4-8 months) animals fed paint chips 9 months at dose levels 12 ug/kg/dayand 100 ug/kg/day caused biood levels < 20 ug Z. Animals fed 100 ug/kg/dayin the series 0.06Z. 0.28Z. 0.50%-nd 2.02 lead in paint. The "steady state" data was normal for the least lead in paint. The greatest concentration caused an average blood ele- vation of 19.1 ug Z. However, 0.28* lead caused a blood lead elevation of 21.8 ..g Z. 3-aminolevulinic acid denydratase (.ALAD) No significant difference be- tween average values In all groups studied. "Steady state" values reported. Insufficient data to evaluate trends and rates of develop- ment. Authors report Immedi- ate depression in all animals where blood-lead levels reached a steady state concentration of 50 ug Z or more. /Proposed the measurement as pre dictive determinant to lead exposure/ Free »rythrocyte rfqrphvjrin (FE?) No significant difference be- tween average values in all groups studied. selected to show only surable response for "in- tion period." ose-response relationships du No es ablished. Did compare 3 different materi- als of varying lead avail- ability. Did not compare by plotting data from studies in 197) and IW. /Propose FEP as the critical biological effec^7 Erjfthrocyte porphyrinogen s^nthetase lEPS) Random change. Not determined Plasma acetylcho11nesterase Si&iiif icantly decreased in anl- Not determined mate fed napthenate and octoate at 200 ,.g/kg/day Blood choline concentration No significant difference between arterial and venous levels. HematocrIt Not determined Other hftmaXologic measurements Not determined Not determined Measured; data not correlatol t response to paint lead content Measured; data not correlated t response to paint lead content Not determined All data lost for sample weeks 4 and 8. Four deter- minations in all groups ex- cept the NBS Group were dropped for week 13 data. for lead concentration In paint less than 2.05Z was no different from control. All others were significantly higher. Control values vary around 9 ug Z. Lead Octoate ab- sorbed more than lead chrurn- ate. Smaller particle size allowed greater uptake. Octoate 500-lOOOu 19.3pg Z < 50 u 27.2 Chromate 500-lOOOu 14.5 Lead Ace- tate 38.3 Enzyme activity nut signlfi- Not determined cantly different from control^ for all lead concentrations in the paints containing octo- ate and chromate. Significantly depressed by old paints containing carbonate. Earliest response in 8th week for paint containing 66X lead. No significant difference Not determined Not determined Not determined Not determined Not determined Not determined Not determined So significant difference be- Not determined tween controls and experimental animals, except for animals fed carbonate (NBS) paint. Difference ocrurred at week 13. Not determined Not determined I Erythrocyte count, reticulocyte None determined cJunt. Ivukiu•ytr ouinl. dlffvr- rntlal leukocyte count, KHC OH- mot li f ragiiitv, and tferum pro- tej.ns. No differences obaeryedg 35

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Table II Results (ContM) 1 I *XL* — 1 Mldwcot OTHER TISSUE l)h I tRMINATlONS St. Mary'a Content Slight elevation. Does not show dose-response relation- ship. CorticostercjUl Acetyltransferase No significant difference. Cho1ine Acety11ransterase Some alterations not signifi- cantly correlated to dose. 3one "Leaa Content Not determined No significant difference be- Not determined Sot determined Not determined ounger animals have greater up- take. Preponderance of evi- dence indicates doses from 100 to 500 ug lead/kg/day as lead ii paint at a concentration of 0.5% lead does not cause signi- flcant Increase in tissue bur- den. No significant Increase in tween controls and experimental tissue burden. aninals. Liver Lead Content (Co "hirlied dlTtcrcntc between controls and experimental animals. io siu,.i ' icju sue burden. Increase In ll.-.- t detected in all groups at , Band 13 weeks; exception week 13 for animal fed NBS carbonate paint (0.2 ug/g t issue). »t determined ot determinod .evated at 4 weeks in animal fe old carbonate paint. Lead leve significantly elevated at 8 and 13 weeks. Not detected in all groups at 4 and 8 weeks. Exception at 8 weeks on NBS-carbonate paint (1.4 ug/g tissue). At 13 weeks detected lead in all groups not in a consistent dos response relationship. )ol de. Lect ,_'d in all groups at 8 and 13 weeks; except »t 13 weeks animals fed both car- bonate paints had detectable lead concentration. ot determined ot determined ot determined No paint data Control mean total lead .51 ug Octoate 500-lOOOu 2.38 ug < 50 u 4.30 Mg Chromate 300-1000 u 2.18 ug < 50 u 3.35 uS No point data. a Table III Comparison of Lead Accumulation in Tissues of Weanling Rats.- Lead acetate Lead acetate in oil Dietary Kidney Blood UR lead/ 100 ml Bone Total lead iig Concentra 1 1 on Total lead jig 0.02Z 11.28 56.31 5.87 11.52 51.81 6.08 0.02Z 20.25 97.5 9.03 22.75 93.3 11.53 a Data from Barltrop. 36