Document a189jddppYZXx3RrvzQ5v7bEM

HUMAN HEALTH CONSEQUENCES DUE TO LEAD EXPOSURE FROM AUTOMOTIVE EMISSIONS This third, dull lead, with warning all as blunt * "Who chooseth me must give and hazard all he hath."- The Merchant of Venice II, VI, 8-9 Shakespeare (1596/7) Kathryn Mahaffey Terri Damstra Warren T. Piver Herbert S. Posner Hans L. Falk (Chairman) June 8, 1976 s/s L CONTENTS Contents Recommendation and Conclusion 1, Environmental Transport and Transformation of Automotive Emitted Lead 1.0 Rate of lead Particulate Emission into the .fl^osphere by Motor Vehicles Moving Through a Geographical Area 1.1 Lead Content of Gasolines 1.2 Driving Speed or Mode of Driving 1.2.1 Leaded Fuels 1.2.2 Unleaded Fuels t- 1.3 Design Feature, Operating Conditions and Age of Both the Engine and the Exhaust System 2.0 Rate of Removal of Lead Particulate Emissions 2.1 Rate of Removal of Aerosol-Size Lead Particulate Emissions 2.2 Rate of Removal of Lead Particulate Emissions which Settle Out at Short Distances from the End of the Tailpipe 2.2.1 Chemical Reactions Involving Lead Particle Emissions 2.2.2 Runoff in Water ; 2.2.3 Deposition on Soils and Plants and Uptake by Plants 3.0 Rate of Accumulation of Particulate Lead Emissions 2. Sentinals of Potential Lead Hazard 1.0 "Normal", "Reference" and "Discrimination Values" 2.0 Whole Blood, Erythrocyte, Plasma and Serum Concentrations of Lead 2.1 Whole Blood 2.2 Erythrocytes 2.3 Plasma and Serum \ DUP040013729 3.0 Enzyme Activity and Product Accumulation 2- * 3.1 General Principles 3.2 Clinical Sequelae of Lead Toxicity for: Lead Pose. Blood Concentration or Body Burden Comparison; and for Enzyme Activity or Intermediate or Product Accumulation Comparison 3.2.1 Adults 3.2.2 Children 3, Relationship Between Exposure to Lead and Health Effects in Hymans 1.0 Introduction 1.1 Variability of Response to Lead Exposure 'm 1.2 Metabolic Effects of Varying Levels of Lead Exposure 2.0 Lead Exposure in Adults 2.1 Usual Exposure 2.2 Ingestion of Lead at Elevated Levels in Adults 2.3 Inhalation of Lead in Adults 3.0 Lead Exposure in Children 3.1 Lead Retention in Children 3.2 Estimates of Lead Exposure for Normal Children 3.3 Estimates of Lead Exposure in Lead Poisoned Children 4.0 Other Parameters Affecting Lead Toxicity 4.1 Form of Lead 4.2 Presence of Other Components in the Diet 4.3 Metabolic Condition of the Subject /"o ) DUP040013730 -3- 4.0 Lead Toxicity 1.0 Neurotoxicity of Lead 1.1 Effects of Lead on the Central and Peripheral Nervous System 1.1.1 Encephalopathy 1,1..2 Neurological Diseases 1.1.3 Peripheral Neuropathy 1.2 Neurological and Behavioral Toxicity of Chronic Lead Exposure in Children 1.3 Behavioral Toxicity of Chronic Lead Exposure in Animal Species '0i 2.0 Effects of Lead on Reproduction 3.0 Effects of Lead on Chromosomes 3.1 Carcinogenicity of Lead Compounds 4.0 Effects of Lead on the immune System 5.0 Experimental Tolerance to Lead 5.0 Emission Control Devices and Fuel Lead Additives Replacements: Characteristics and Fate of Exhaust Emissions 1.0 Exhaust Emissions from the Catalytic Muffler 1.1 Sulfur Exhaust Emissions from Catalytic Mufflers 1.2 Release Rate of Catalyst Components to the Environment 2.0 Exhaust Emissions from Catalytic Mufflers from the use of Fuels with Higher Aromatic Content 3.0 Exhaust Emissions from the Fuel Additive Methyl Cyclopentadienyl Manganese Tricaroonyl: HMT 4.0 Alternative Fuels SJ2 i DUP040013731 Recoirmgndation and Conclusion Lead has been recognized as a toxic element and at high dosage levels its toxicity is most significant for the central and peripheral nervous System. The prevalence of non-industrial lead toxicity is particularly apparent in children of young age. In our deliberations the committee has looked at available data regarding lead emission from automobile exhausts to learn about the physical and chemical dimensions of the particulates containing lead. It was learned that not all lead leaves the auto with the exhaust and that the particulate matter has different physical properties depending on age or performance, gf engine or exhaust systems. This information was valuable regarding the fate of the parti culate matter in air. (See Chapter 1, Sections 1.0 to 1.3). For lead no sink has been discovered that would remove lead from potential human contact even though much of the particulate matter is of a size that would fall out rapidly and of chemical composition which makes the lead less water soluble than when it was emitted. Lead in dust can be ingested and absorbed particularly by young children foilwing mouthing of objects or can be swallowed with food if not carefully washed off. Once in the soil it is not readily taken up by most food plants. (See Chapter 1, Sections 2.0 to 2.2.3). Regarding intake of lead by humans, greater emphasis is put on that portion Ingested compared to that Inhaled. Many factors are involved in the absorption of the lead from the gastro-intestinal tract and the degree of absorption is natch lower than from the lung for adults. For children the percentage reduction of ingested and Inhaled lead does not differ greatly on the basis of data currently available. Although adequate data are available on the absorption in the adult, this does not apply necessarily to young children where data are sparse, but the absorption I 2- of lead appears to be higher. It may not be very important to distinguish absorption via the gastrointestinal or the respiratory tract when in either case lead could have originated from auto exhaust. (See Cnapter 3), The biochemical interactions of lead in mammalian species have been well studied to serve as explanations of observed effects and also to be of use in monitoring health effects and exposure to lead. (See Chapter 2). From these studies it became apparent that blood lead determinations are not as useful as previously assumed, at levels of relatively low increases. Blood and urine determinations of some of the biochemical changes together with blood lead determinations supply a much better picture or people's past or present exposure and ill-health. Biochemical lesions can be Observed where blood lead levels were considered as "normal" for that moment. Many disagreements are based on the correlation of past lead exposure with bipod lead levels and neurologic symptoms. Other shortcomings in correlation of mental retardation or hyperactivity in children with blood lead levels become obvious on reviewing the literature while correlations with anemia ot increased susceptibility to infections have been established by animal studies- (See Chapter a). The Committee agrees with Sir A. Bradford Hill (1): "All scientific work is incomplete whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us freedom to ignore the knowledge we already have or to postpone the action that it appears to demand at a given time". Our recommendation, therefore, is to phase out lead in gasoline by reducing its content as has been proposed by the U.S. EPA and by many other developed countries, or to hold the maximum allowable concentration at a lower level as has been in effect in most European countries for some time (2), J --r-- t DU P040013733 1 "Wp. 'rr',Tv'T!V^*r-' */ 3- Evsn If current levels of lead exposure for children or future generations are too low at the time of writing to have a clear cut adverse effect on them, it may Only be a matter-of time until a critical level could be reached for some,.and disease would result because the lack of a sink for lead allows its buildup in the immediate environment of children, (See Chapter 1, Section 3.0). If lead is allowed to remain in gasoline even at lower levels, it would be imperative to prevent its spread into the environment by filtration of other devices. Replacement of lead by other fuel additives or by engineering modifications to the engine or exhaust system should have reduced adverse health effects as its primary consideration in the evaluation for performance vis-a-vis lead. (See Chapter 5). DUP040013734 ' emendation and Conclusion References: 4- - 1. Hill, A, 3. The environment and disease: Association or causation. Presidential Address. Proc. Roy. Soc. Med. (1965) 58: 899--, 2. Groups d'etude international du plomb et du zinc, les effecs de Vaddition de plcmb a 1'essence, examen de la situation actuelle. 12/73/1 7/18/1973, 1-40. DUP040013735 1-1- 1. e n v ir o n men t al t r a n s po r t a n d t r an s f o r ma t io n o f a u t o mo t iv e e mit t e d l e a d This portion of the report is concerned with the fate of participate lead compounds emitted to the atmosphere from the combustion of leaded gasoline in spark-ignition engines. As this term will be used here, the fate of particulate lead has the following description. It is concerned with not only how these emissions are initially partitioned between air, water, and solid phases when discharged from the tailpipe, but also how this partitioning varies with time due to the physical-chemical properties of these emissions and to environmental transport and transformation processes which act upon^them. Because there are many properties and processes which influence the fate of exhaust emitted lead particulate matter, use will be made of a mass balance as a simple method of keeping track of what properties and processes influence how these particulate lead emissions are partitioned. For a given geographical area, this mass balance can be written as: Rate of Lead Particulate Emission into Atmosphere by Motor Vehicles Moving Through Geographical Area Rate of Lead Removal from Geographical Area by Physical and Chemical Processes Rate of Accumulation of Lead Within this Geographic Area In essence, this approach of cataloging the properties and processes which influence the partitioning of lead particulate emissions is similar to that used by Huntzicker, et al. (1975) in their material balance study of automotive- emitted lead in the Los Angeles Basin. I.0 Rate of Lead Particulate Emission into the Atmosphere by Motor Vehicles Moving Through a Geographical Area" " Particulate emissions from mobile sources amount to about a million tons/year, whereas CO is emitted at a rate of about 66 million tons/year. DUP040013736 1-2hydrocarbons at a rate of 12 mill ion tons/year, and nitrogen oxides at a rate of 6 million tons/year (PHS Publication - 1963). Particulate emissions from mobile sources are composed of both organic and inorganic substances such as lead, carbon, halogens, iron, oxides of metals, and oil mist. When leaded fuel is used in spark-ignited engines, lead compounds can make up a substantial percentage by weight of the particulate emission. Hirschler and his coworkers {1957, 1964) estimated that lead compounds comprised 58 to 78S by weight of particles less than 5 microns in size (fine), and comprised between 34 to 60S by weighty of particles greater than 5 microns in size {coarse particles). The factors which effect both the rate of particulate lead emissions and the physical-chemical properties of these emissions are; fuel lead additive content; the driving speed or mode of driving; and the design and operational features, maintenance, and age of both the engine and the exhaust system. The important physical-chemical properties of these particulate emissions are: total amount emitted, shape> and size distribution of the j particles; chemical composition of these particles as a function of particle size; and the location of the lead compounds in a cross-sectional slice of the particle. The particle size is an important characteristic. The most commonly used index of particle size which is reported in experimental studies is the mass median equivalent diameter (MMED), This property is determined from the log-normal size distribution of particles such that half the mass Ties on either side of the WED {PHS Publication - 1970), Therefore, this is an average particle size determined on the basis of total mass. Returning to the material balance equation, the physical-chemical DUP040013737 -- / / / properties of emitted lead containing particulate emissions have a profound influence on both the rate of removal and the rate of accumulation within a geographical area. 1.1 Lead Content of Gasolines The average lead contents of gasolines sold at gas stations, on a national basis have been determined by dangers, et al. (1975), these average contents are: 600 ug/ml (2.3 gm Pb/gal) for premium grades; 494 ug/ml (1.86 gm Pb/gal) for regular grades; and 134 ug/ml (0.5 gm Pb/gal) for low-lead grades. In many of the experimental studies on characterization of lead particulate emissions a special type of test fuel; Indolene, is used. Two types of Indolene fuel are used, Indolene HO 0 which contains no lead, and Indolene HO 30 which contains 3 ml tetraethyl lead (TEL)/gal. 1.2 Driving Speed or Mode of Driving A summary of data on how both constant driving speed and the 7-mode Federal Test Cycle (Federal Register - 1966, 1968, 1970) effect the physicalchemical characteristics of lead particulate emissions has been given by Springer (1973). Since this review, several additional studies on the characterization of lead particulate emissions have been reported by Moran, et al, (1971), Habibi (1973), Ter Haar (1972), and Boyer and Laitinen (1975). This summary is given in Table 1, Before presenting this data summary, it is necessary to include several comments about these experimental programs and their results. Measurements of particulate emissions have been made with engines mounted on dynamometers, and with engines driven on chassis dynamometers. Experiments have been performed for constant vehicle speeds, accelerating engines, decelerating )i d DUP040013738 / 1-4engines, and for engines operating under definite driving cycles. It has been demonstrated that at a constant speed or cruise condition, lower emission rates are observed than when an engine is accelerating or decelerating. However, ^ as the cruise speed increases, the rate of emissions increases but the MMED of the particulate emissions decreases. During acceleration from a constant speed condition, the emission rate and the MMED of the particles increases because the rapid change in speed tends to dislodge the layer of exhaust emission deposits which has been built up along the length of the exhaust system when the engine "il? was operating at a constant speed. For this reason, the emission rate measured in gm/mile (McKee and McMahon - I960, Hirschler and Gilbert - 1964) increases rapidly during acceleration. Continued high rates of speed may initially discharge greater quantities of lead than is being burned. Eventually the rate drops to a stable level. After this type of driving, the exhaust system will begin to build up another deposit layer. Emission rates for an initially cold engine are much higher than for an engine which has been stopped after it has warmed up and then restarted again (hot start versus cold start). In addition, Ninomiya, et al. (1970) demonstrated that several test cycles were necessary for the emission rate to drop to a stable level. For these reasons, the 7-mode Federal Test Cycle and the Federal Mileage Accumulation Schedule (Federal Register - 1968) were developed. By using these two procedures, deposits of exhaust materials are stabilized and the measurement of emission rates would more nearly reflect actual types of driving patterns and situations. Even.with these recognitions and standardi zations, individual drivers and Individual engines will produce their own DUP040013739 J 1 -5- unique sets of results for emission rates and particulate characteristics. This needs to be remembered when using these results to simulate the characteristics of particulate exhaust emissions for the present U.S, motor vehicle fleet. Before leaving the subject of how driving speed affects particulate lead emissions, several additional observations are important to mention. During normal driving operations about 1/3 Of the total lead used in combustion remains in the vehicle (Hirschler and Gilbert - 1964}, Part of the lead is deposited on the surfaces" of the engine-exhaust system and part ends up in the lubricating oil due to leakage around the piston rings. In summary, therefore, the following general comments about how driving speed or mode of driving effect the physical-chemical characteristics of particulate emissions can be made: 1.2.1 Leaded Fuels 1. Lead particulate emission rate increases as constant vehicle speed {cruise} Increases, 2. At slower constant vehicle speeds, the majority of lead particulate emissions are greater than 5 microns MHED; at higher constant vehicle speeds, the majority of lead particulate emissions are less than 0.5 micron MHED. 3. As the lead content of gasoline increases, the weight concentration of particles and the emission rate Increases for all types of driving modes. 4. For the 7-mode Federal Test Cycle lead emissions increase as fuel lead content increases. It should be remembered that this test <r.ij DUP040013740. \ ' 1 -6- procedure includes constant vehicle speed operation, acceleration, and deceleration types of driving. Therefore, the emission rate for the 7-mode Federal Test Cycle is an average rate for all of these different types of driving operations, it is well demonstrated that acceleration-deceleration produce higher emission rates than cruise conditions, hut it would be difficult to compare these two types of driving on an absolute basis. 5; The major chemical form of lead in particulate emissions for all types of driving conditions is the mixed halide, PbBrCi. Other minor* constituents are PbCIg.PbCIBr, (PbO)2PbBr2, PbO*PbSO^, PbS04, Pj3(P04)2*PbClBr, and PbClBr-NH^Cl. Fe^ is also a major constituent of large particulate emissions. In addition unspecified carbon compounds are also part of these emissions. 6, The analytical identification of (PbO)2PbBr, PbSO^, and Pb3(P04)2 and Pb(QH)Br has been challenged by Heidel and Desborough (1975), 7. Morphologically particulate emissions are made up of a carbon core which holds adsorbed to it polynuclear aromatics (4-6 membered rings Boyer and Laitinen - 1975). This core is surrounded by the lead compounds and double salts which have condensed from the vapor phase (Sampson and Springer - 1973 and Linton et al. - 1976). 1.2.2 Unleaded Fuels 1. Particulate emission rates are generally lower than for leaded fuels for comparable driving conditions, 2. Chemically, these particles are mostly carbon with adsorbed multi ring polycondensed aromatics which are formed during the combustion process, i | DUP040013741 Uv. 1-7 3. The .emission rate increases as the aromatic content of the fuel increases. 1.3 Design Features, Operating Conditions and Age of Both the Engine and the Exhaust System Variations in air/fuel ratio and spark timing have very little effect on the emission rate and the characteristics of particulate emissions (Sampson and Springer - 1973, Ganley and Springer - 1974), In Table 1, however, it is adequately demonstrated how cold start versus hot start conditions plus the number of driving cycles influences the rate of exhaust particulate emissions (Ninomiya, et al. - 1970). The design, operating conditions, and age of the engine-exhaust system have been shown to have an important influence on the characteristics of particulate lead emissions. The axial temperature along the length of the exhaust system is a function of the driving speed (Edwards -1973). Sampson and Springer (1973) and Ganley and Springer (1974) have demonstrated how axial temperature and exhaust gas temperature influences emission rate and weight concentration of particulate emissions. For a cruise condition of 55 mph, and Indolene HO 30 leaded fuel, there was a rapid Increase in particulate weight concentration for an exhaust gas temperature drop between 640 - 470 F. This weight increase was attributed to the condensation of 7ead salt vapors onto a carbon particle core. X-ray diffraction identified this material as a mixture, of PbCl2 end PbBrCl. The particulate weight concentrated remained constant from a temperature range of 470 - 250^. Below 250F, the weight increased again, presumably due to condensation of high molecular weight organic compounds which boil in this temperature range, from the exhaust gases. DUP040013742 / 1 -8Organic chemicals which boil in this temperature range have significant vapor pressures. Therefore, after a short period of exposure to the environ ment outside the exhaust system, the particle would be composed of its carbon/ polynuclear aromatic core, surrounded by a lead salt shell. Earlier, Hirschler and his coworkers (1957, 1964), and more recently Habibi (1970, 1973) have examined How tne age of the engine-exhaust system affect both the rate and physical-chemical characteristics of particulate emissions from the combustion of leaded fuels In spark-ignited engines. Habibi's results are for the 7-mode Federal-Test Cycle. %hese results are summarized as follows: 1. Lead particulate emissions are deposited along the length of the exhaust system. In addition, burned lead can be found deposited on engine parts and retained in the oil. 2. During high speed or high .pad driving conditions (such as acceleration) these deposits can be reentrained by the high velocity exhaust gases, 3. There is a general increase In lead emissions with mileage accumu lation, The effect of accumulated mileage on emission rates and MMED of emitted particles is shown in Table 1 (Habibi - 1970, 1973), In essence, average particle size on a mass basis increases as the age of the exhaust system (mileage accumulation) increases. 4. Chemically, the very large particles (>2Q0u) are 60-65" lead, 30-35% Fe203 and 2-3S soot. Again these results of Habibi are summarized in Table 1. DUP040013743- 2.0 Rate of Removal of Lead Particulate Emissions 1-9- From the foregoing discussion of factors which influence the rate and character of lead particulate emissions, the following observation can be made: A. For city-type driving, which involves low-speed cruise, acceleration, deceleration and idle driving conditions, the production and emission of particles with MMEO's greater than 5 microns is favored. Because of their mass and size, they will settle out from the atmosphere at a short distance from the tailpipe. Chemically, these particles will be composed mainly of PbBrCl which is preferentially deposited on the outer shell of the particle. \ B. For turnpike driving which will be more of a higher constant speed type of driving, the rate of particulate lead emissions will be higher than for lower speeds, but the MMED particle size will be 1-2 microns, and chemically the lead salt will be PbBrCl which is deposited on the particle surface. 1 Therefore, city-type driving produces more rapidly settling material and turnpike driving produces more aerosol-size material. The MMED of the particles increases with age of the engine-exhaust system for 7-mode driving cycles and the larger size particles contain a higher percentage pf lead salts than do the smaller size (aerosol size) material. These properties have a very great influence on how lead particulate emissions will be partitioned between air, water, and solid phases both as function of time and as a function of the processes which describe the transport and transformation of these particles. S DUP040013744 1 -10- 2.1 Rate of Removal of Aerosol-Size lead Particulate Emissions Aerosol-size lead particulate emissions have an WED less than 0.5 microns. It has been adequately demonstrated that this material can be transported in the atmosphere for great distances (Huntzicker, et al, - 1975). In 1958, the average annual concentration of lead in air ranged from 1 to 4 ug Pb/m (NAS-1972). In non-urban areas near cities, the average air concentration hats been measured at 0.21 yg Pb/m% and for rural areas, the average air concentration has been measured as 0.10 ug Pb/m (McMullen, et al. - 1970). CoTucci, et al, (1959) found an annual average air lead concentration of 8.9 ug/m near a busy New York City highway and 11.3 ug Pb/m near a busy Los Angeles highway. In the Los Angeles study, 18 g Pb/m3 was the maximum value measured. Hablbi (1970, 1973) and Hirschler and Gilbert (1964) have determined that aerosol-size lead particulate emissions (particles less than 0.5 WED) are composed of the double salt, 2 PbBrCl'NH^Cl, and carbonaceous material. Because of the sampling procedure used by Habibl (1973), it has been suggested by Ganley and Springer (1974) that this salt forms in the atmosphere after leaving the tailpipe. Plerrard (1969) has studied the photochemical decomposltion of lead halides from automobile exhaust. Both lead chloride and lead bromide darken when exposed to light (Norris - 1895, Renz - 1921), presumably releasing free halogen. The release rates for bromine and chlorine from the photolysis of PbBrCl have been determined as 1.6x10 umole/{cmc) -(sec)milliwatt of radiant energy for bromine atoms) and 1.0x10" nmole/(ca^) (sec)`milliwatt for Cl atoms. Bromine and chlorine atoms react with Og to produce the free radicals Cl00* and BrOQ-. These two radicals can ;.= 1-11participate In those atmospheric reactions which perpetuate smog forming reactions as follows: Cl* + 02 + M i==? C100* + M Cl00* + NO -------- CIO* + NO- CIO* + NO-------- * Cl* + NO- 2ClQ*--> Cl * + C100* Cl* + ClOO* 2C1* + M Cl, h\> - CV2 Cl2 + M 2C1* Other constituents of automobile exhaust emissions include olefins, aldehydes, and ketones. The presence of an active halogen could result in the rapid addition of this atom to these chemical species. The lead portion of this dismembered PbBrCl salt presumably reacts with 02 to produce PbO. This would be the predominant reaction, but reaction with organic constituents present in polluted air cannot be ruled out. Aerosol physics and the growth and removal of aerosol-size particles by atmospheric processes has been studied by Heisler, et al. (1972) and summarized by Seinfeld (1975). Chemical reactions, condensation and evaporation, coagulation, and sedimentation are all important atmospheric processes which not only determine how rapidly the particle will be removed from the atmosphere, but also can be used to identify the source of that particle by the chemical element balance proposed by Friedlander (1973). *i ii DUP040013746 1-12- In attempting to quantitate the amount of lead removed by cor./ective transport, use can be made of the correlation between airborne lead and carbon monoxide (Colucci, et al. - 1969). Huntzicker, et al. (1975) have refined this concept. On the basis of simultaneous measurements of lead and CO with corrections for other sources of these two pollutants, they have determined a dimensionless weight ratio of Pb/CO, of 6.2+ 1.6 x 10-4 . For the Los Angeles Basin, they estimate that approximately 21% of the lead emitted by automobiles is removed by convective transport of aerosol size and vapor phase organic lead compounds. The measurement of vapor phase organic lead compounds has bean reported by Purdue, et al. (1973) and by Snyder (1967). Since ther are losses to the atmosphere of gasoline by vaporization, it is conceivable that a portion of this ; measured organic lead could be tetraethyl lead. This could be confirmed by a technique using high-temperature electron capture GC developed by Green (1968). In the atmosphere, TEL could react with 03 or OH radicals and ultimately be oxidized ; to PbO, but there is no verification of this mechanism. 2.2 Rate of Removal of Lead Particulate Emissions Which Settle out at Short I Distances from the End of the Tailpipe ---- - -- I The major focus of this discussion will be on lead particles which have an aerodynamic equivalent diameter of greater than 5 microns. Because of their size and shape, they will settle from the atmosphere at very short distances from the end of the tailpipe. These particles will be deposited or. all solid surfaces, such as roadways, gutters, sidewalks, buildings soil, plants, etc. In short, large lead particulate emissions will settle out on any surface or any living thing within the immediate proximity of the roadway. Because urban children often play in the immediate vicinity of city streets and roadways, it is important" to understand what iactors influence the rate of removal of these particulate lead t i h rJ 1 l *1 I 1 // DUP040013747 1 -13emissions which are deposited on surfaces, plants, and people located near roadways. Creason, et al. (1971) set up an experimental program to determine if automobile emissions were a source of atmospheric contamination by lead,.and if these emissions were of respirable size or were deposited on the soil near the roadway. Dustfall and suspended particulate pollutants were collected at four sites in metropolitan Cincinnati, Ohio, for a three-month period from OulySeptember, 1968. The collection points were located at 25 feet and 100 feet from the road, and the sites were chosen to represent various urbanization and industrial patterns. For the three-month period, tdtfal dustfall rates ranged from 4.7-13.3 g/m2 -mcith at the 25 foot locations and from 3.4-18.6 g/m2 * month for the TOO foot locations. Dustfall rates for lead at the 25 foot sites ranged from 17-48 mg Pb/m7 month, and ranged from 8-T7 mg Pb/m2 -month at the 100 foot sites. The concentration Of lead at the 25 foot sites for the three months averaged 3743 ug/g and 2942 ug/g at the 100 foot site. Unfortunately, there was no correlation of these mass fluxes and concentrations with traffic volume. Angle et al. (1974) measured dustfall rates, air concentrations, soil concentrations, boot tray concentrations (surface between top of shoe sole platform and the body of the shoe), milk, house-dust, and water concentrations of lead for urban locations in Omaha, Nebraska. The air concentration of lead ranged from 0.63 to 0.29 ug Pb/m3; dustfall rate for lead was 33 mg/m2`month in the urban area and 3 mg/m2*month in the suburbs; soil lead concentrations ranged from 444-123 ug/g; boot tray lead concentrations ranged from 1000-283 ug/g; lead concentration in house-dust ranged from 572-147 ug/g; lead concentration in milk averaged less than 0.04 ug Pb/ml; and lead concentration in water was less than 0,01 ug/g. These exterior fallout values of le.d concentration and mass fluxes provided a significant correlation with measured blood lead levels for a group of urban and surburban children, all well past the age of the pica problem. | ; ` ..... DUP040013748 .' "  ~v~.. V X4 LZ.i_ -> X. X, 1 -14- 2.2.1 Chemical Reactions Involving lead Particle Emissions "' ` " ';"r \ Olson and Skogerboe (1975) collected samples from the top centimeter of soil at sites Within 2 meters of heavily traveled streets and highways in Fort Collins and Denver, Colorado, Chicago, and a highway leading to a lead smelter in the New Lead Belt of Missouri,. From the work of Habibi (197C, 1973), the major chemical form of large particulate emissions from spark-ignited engines has been determined to be PbBrCl, The major chemical form of lead found in soil and city street dust collected from curb and/or parking lot areas was PbSOa. Olson and Skogerboe (1975) reasoned that PbBrCl was converted to Pb.SO.4, presumably \ by reaction with SO2. There was no kinetic rate information given for this con version process. PbSOa has a solubility in cold water of approximately 0.004 gm/lOCce. This is a water solubility which is about two orders of magni tude lower than for PbCl2 or PbBrg. There was no information on the solubility of PbBrCl. In addition, Olson and Skogerboe (1575)found traces of PbOg and PbO in the Fort Collins samples. In the Denver, Chicago, and Fort Collins samples, however, the predominant chemical form of lead was PbSOa- 2.2.2 Runoff in Water Lead particulate emissions deposited on urban streets, curbs, and sidewalks will be washed away by precipitation and street cleaning operations. This run-off goes into storm sewers which empty into receiving waters. Assuming that lead in street dust is in the form of PbSO^, the water insolubility of PbSOa will cause It to precipitate and become part of river, stream, and ocean sediments. It should be remembered that the rate of removal of lead particulate emissions by this mechanism is a strong function of the amount, severity, and form cf precipi tation, and the frequency and efficiency of urban street cleaning operations. Whereas the weather is not predictable, urban traffic density patterns have been ... !1 k \ I DUP040013749 ***> -' 1-15well established. Therefore, it is not inconceivable that lead concentrations in urban street, curb, and sidewalk dust will rise between precipitation and street cleaning episodes, and drop sharply following either of these incidents, ' Once transported to sediments, remobilization, availability and uptake by aquatic organisms and the implications of the presence of lead in water and food supplies have been the subjects of much research. This is rather an extensive literature and one of the major forums for the presentation of this type of information on the geochemistry of lead has been the Trace Substances in Environmental Health Meeting held annually in Columbia, Missouri, since 1966. The NAS Report on Lead (1972) also contains an extensive summary of this literature. This example of the chemical transformation of lead particulate emissions which settle in dust and dirt to PbSO^, its subsequent transport into the aquatic environment and deposition in sediments, and its subsequent transport into aquatic organisms, is the major public health concern associated with the widespread release of trace metals such as lead to the environment. Metals may change valence and associated ligands, but the metal itself is still present. There are natural background levels of lead in the environment, however, what is being measured in the studies reported here are levels of lead compounds which are substantially above background levels. Because lead is believed to be a nonessential toxic element, this continual build-up is viewed with great concern. 2,2.3 Deposition on Soils and Plants and Uptake by Plants The deposition of lead particulate emissions on Soil, the concentrations of lead as a function of distance from the highway, and the levels taken up by plants also have received extensive experimental consideration. Swaine (1955) estimated the average lead content in the earth's crust of 16 ppm with a range of 26 to 200 ppm. Bowen (1966) estimated an average world-wide lead content in soils of 10 ppm, again with a range of 2 to 200 ppm. Lead particulate emissions deposited DUP040013750 1 -16on soil can be subjected to the following transport phenomena: chemical reaction, absorption, adsorption, solubilization, leaching, runoff, microbially mediated chemical transformation, uptake by plants, reentrainment by wind, removal by Children playing in dirt, removal on shoes of people walking through the area, and other physical transport mechanisms. Schuck and Locke (1970) as a result of studies with consumer crops suggested that particulate emissions from the combustions of leaded gasolines by motor vehicles produced a topical dust coating of which 50% could be washed off with water. In addition, lead was not taken up by these plants via their root system. Ter Haar (1970) concluded from the analysis of plants grown at different distances from highways that the main source of lead in crops was derived from the natural pool already available to the plant in the soil. V'ith regard to absorption by plants of particulate lead emissions, a number o' other studies (Oedolph, et al. - 1970; Motto, et al. - 1970; Motto - 1970) do not reach any definitive conclusions. The suggestion, however, that particulate lead emission are simply deposited as a washable layer on plants is the general opinion of these authors. Unpublished results for soils amended with radio-labeled Pb(N03)2 (Battelle-Northwest - 1972) have shown that this soluble form of lead is not readily taken up by either barley or soybeans* Simultaneously, an analysis Of the effect on soil microbial populations was undertaken for soils amended with 1,10, and 100 pg Pb/gm dry weight of soil. These studies were designed to examine the mechanisms by which microbially mediated processes make metals more available for transport across root membranes and translocation within the plant. The natural lead concentration of the soil before amendment was 5 ug/g. Therefore, these additions represented substantial increases in the total quantities of lead in the soil. DUP040013751 / 1-17- The soil was classified as a Ritzville soil. At the three levels of lead amend ments used, there were no observed effects on microbial numbers or respiratory activity. In addition, there was very little reduction in crop yields as soil amendments of lead increased. In effect, these studies confirm the observations that the plants normally exclude all but a very small amount of lead by a mechanism operating at the soil-root interface. For further discussion on the uptake of lead by plants, the reader is referred to the MAS Publication entitled Airborne lead in Perspective (1972). Beyond the recognition that lead particulate emissions car. be reentrained during high wind meteorological conditions, not much more can be said about this removal mechanism. Runoff has been discussed earlier. Observations by lepcw, et al, (1975) of the "mouthing" behavior of ten children who had been playing In an area where the average soil lead concentra tion was 11,000 ug/g, and the average lead concentration on the hands was 2400 ug/g, established that this was a significant mechanism for children to remove by ingestion, lead deposited on the soil. Similarly, Yos'.el, et al. (1974) observed that the ingestion of housedust containing large concentrations of lead which was on the bands of children, was a source of a substantial Intake of lead by children, 3.0 Rate of Accumulation Of Particulate lead Emissions The final component in this pseudo-mass balance approach to how particulate lead emissions partition themselves between air, water, and solid phases of the environment, is a term describing the rate of accumulation of lead within a geographical area. It Is apparent that both the time-scale and the location of the measurement site become very important factors for determining what the rate of accumulation will be. It follows from this, that at sites within a geographical area that the time dependent concentration would be either cyclic i A DUP040013752 1 -18or remain relatively constant. Measurement sites near a roadway will exhibit a cyclic type of behavior, whereas sites further from the road, but not near houses or buildings on which lead paints have been used, will exhibit a more nearly constant lead concentration as a function of time. The cyclic behavior of lead concentrations measured near the roadway is due to the inability of the paved surfaces to sorb lead particulate fallout. Precipitation, turbulent winds created by traffic, and street cleaning can cause the concentration of lead near a roadway to fall sharply. Even though the lead concentration fluctuates at sites near the road, it will always have 4 value greater than the concentration of lead determined at sites away from the road. Concentration gradients for a perpendicular direction from a roadway and average concentrations of lead at locations in urban and rural areas have been determined by many authors. These concentrations and concentration gradients are point values which have been determined for a specific time, and may or may not represent the time dependent characteristics of lead concentrations for a particular geographic area. In order to understand the difference between the instantaneous value of the concentration and fluctuating nature of the lead concentrations, use is being made of the methods used to analyze the situation Occurring in turbulent diffusion. The instantaneous concentration of lead is composed of a fluctuating concentration and a time-smoothed concentration. Oaines, et al. (1970) present data on atmospheric lead levels as a function of traffic volume and distance for the roadway, Oedolph, et al. (1970) have determined soil concentrations for lead as a function of distance from a roadway carrying an average vehicle load of 29,000 vehicle/day. They derive an expression for mapping soil lead concentrations at different location sites DUP040013753 1-19from the roadway. Kinard, et al. (1976) have measured lead concentration patterns in soil for an urban setting in Columbia, $, C. A city block with variable vehicle loads on the streets in this area was used in this study. Hemphill, et al. (1974) determined lead concentration gradients in soil for a perpendicular direction from a roadway in Missouri which was used to haul lead ore to a smelter. Ter Haar and Aronow (1974) present concentration profiles for lead in soil for the perpendicular distance both from a road to a house painted with lead paint, and from a road to a brick house. As the house painted with lead-based paint was approached, the soil concentration dropped then rose to approximately twice the concentration of lead measured at or near the roadway. For the brick house, the lead concentration of lead measured at or near the roadway. For the brick house, the lead concentration declined until a position half way between the road and the street was reached. The concentration then increased as the brick house was approached, but did not reach the average concentration measured near the road. Pay, et al. (1975) measured concentrations of lead in street dust at different locations in London. The concentrations of lead in dust ranged from 800-15CO ppm. In Summary, at or near the roadway, the lead concentrations in dust and dirt ranged from 700-4000 ppm. The upper value of 4000 ppm was from the study of Creason, et al. (1971). At a distance of 50 to IDO feet from the road, measured soil concentrations in different urban and rural settings gave values which ranged from 60-3200 ppm. In interpreting these results, care should be exercised since the type of buildings and the types of exterior finishes applied to these buildings are important considerations. In the air,.lead concentrations ranged from 2.5-12 vg Pb/n3r near the roadway to 1-2 ug Pb/m3 at distances 100-500 feet from the roadway. Near the roadway, both air and soil concentrations of lead were strong functions of traffic volume or traffic load. DUP040013754 tKf- ay*:'V v. t .'r'.+c.':v .t >s4/_v-m^y. 1 -20- Even though the measurements on concentrations of lead in dust and dirt are made at specific times, the data of Creason, et al. (1971) do show definite changes in lead concentrations as a function of time. Therefore-, these results and others cited, strongly suggest that there is a definite pattern of accumula tion of lead in the environment from automobile exhaust and, that the measured concentrations are not just isolated measurements without significance. It should be remembered that this is a time-smoothed accumulation of automotive emitted lead or a residual concentration of lead remaining after the action of those rate processes which tend to remove lead particulate emissions from a given area, have been subtracted from the exhaust emission rate process for lead particulate matter which puts this material into this same area. Therefore, on a short-term basis, i.e. in between rainstorms, there will be positive accumulations of lead at locations near roadways. For urban children playing in areas near roadways, this short-term or fluctuating accumulation of lead In dust and dirt can present a significant exposure situation. On the basis of literature information reviewed, in urban environments the majority of lead emissions produced by city type of driving are large particles which settle out at short distances from the end of the tailpipe. The basic chemical form of this particulate emission is PbCIBr which is converted to PbSO^. DUP040013755 TABLE t PHYSICAL-CHEMICAL CHARACTERISTICS OF PARTICULATE EMISSIONS FOR DIFFERENT ENGINES DIFFERENT FUEL LEAD CONTENT, AND DIFFERENT MODES OF DRIVING cOu pu P 4C-l Voc c p C/I OP OCo5L .<404 3 XX u U<0 *i4. xojSp-r aq. .4o* o 4oC* sL4 ^U oc P 'J b .ai o ra H CC co La3u (oCEO/IL oC uo acs a. o p a*-- a> c UJ *o :&-> ^ <L> S yZt<MDjC JgaSUCsl Wxcn- p<ao vai >c.aw.co ocns*xo* .c*- x* u. 3B 4- c m vi <r P *1.0 C .tt 1>0*31S*4c041i4d ouu. /^g 2 TJ f-z J*PZJJ>3iOOC<QO. .Ocn *2j.nVjucio * 4- :<*>* Pcr> w >, > a43. JS C x~ o 40 43 rx a <y c m i- ^ r-* e E W PVI P 44 /0 C e u. -a > c u o O 3E <0 44 P -jx *- my * 3: 44 s ** P GPP c a- m 3t + * &>> au xu: j*ej c p > a> o44 a> PS. WI* 2 ~L *0 P 44 H- P OGC P O o 44 44 44 JO 3: PGVIU P V <0 >> 3W^U UCc o P >$ 44 U < 'L P 44 O0 <9 .-0 44 gj 0.0. <9 c' C .4 3 i?44 UP*-^. G rOoOl QJtQ3- 4S(4f.l rr~v 4OC4 j o. u c p > It * 44 o C oI" 4 in O yj r- 44 s Cp P 44 P 44 G 44 '5 o tv U r >i . 3 .O CU O *rJQ 44 O W UN oo Po. e in m Q f-lOonftcjoconwocri f-r^d d o dd od f-- *0 in c m CM CO CO r-- dd p ,P 3 P :3 a pa. *P "O "P3 pcp . 3oZ *Po N) 4 P x*3> PC =3 PPPPPPPPPPPP 3 3 3 3 3 .3 J- 3 3 3 3 3 UUUOUUPOu- u. U- S- L i. 3 L. T i- L L u u yo x; r rx r o o o o a.a. aaaaaaaaaa E H E S 6 E .6 odoooooooooo coincoincoincotncovocom p 44 r-- p r-- P f 4 t * W f-- 43 44 J3 P 0 0 3 0 r* U17 fi Of E V> > > V> E >> /> -o P V TO CO > U *0 CO u co a CO JC .IX* f ^ r-- 1 O 1 u 10 0 > aioo> <l > > u- > 0* n is* N in in uo in m in 01 crt 0 a> gi 01 ^ ^ .. rx* I- XX. x-- (A 19 4> (A i- U 44 vVaL *0^ 4 o P U m 44 ^U. >> VI -Q P F-4> 0400 O m U J= 1 H- ^ 5T r>- PP %o as o vO 40 40 ai .fc P .rx* P X-- > X- O VI < EO 3 .0 O .*.44 ,x *X V - r-- U. * tfl U> <0 P *0 OCX. 0p so T-x l/l 10 44 vt U -u 44 *PP rP- .10 44 U<Q. p u in 44 Lu o>, -p v> P r-- 44 O 44 O 5 m x j x: p 1 1-- fx. X Pp B 10 a> a> 10 40 40 O ai U P 0 P*-- 3> * VI <EO 3m OX* *-44 1 VIxO W 4" tflO 0 O OO > "O CL x O PO S O co CO -o xpo> ou % if VI p V) X Sx B 40 U O Pz -- 1 0 4 hot 4 cold 4 hot 3 ml TEL/gal. Indolene 0.20 0.12 0.22 0.11 Pb = 131 by wt C = 4751 by wt. DUP040013756 c $ a* cn </> ^ CL CJ CM C I0 O 4-4- h~ a o * tl to .n <u a* ty * co tn c 0 uo^v 01 fO V r---v'4- o* r-* d *3 5 > TJ CU *F-- 4- u cu Q. tn 4-> O v* F* E EO O Oo O O r. LO f -- 4 tof> c> in-- ,r^ to r-- co -?* Cv G <2j n <s> N d 5KO rv Ed X5 O *~ >o u CO at u*> o- ::<<,<q4xr o'v*t^vua3* 44 C a & C3 JO cl u. n o* ^u * o *> a .13 ." = O rO-- V-QO ,--2B 4-> CVJ l/VCO <n o w u <x >, t O 0 CO J3 CM v> u 0 a. CM C *Q tn C CM A Q. O. r- w VI O V 0*4- CO 03 U tn (A tn *rip* tn g *f- -- *j g c, qj 4^ O m r- T3 O 3 fi* uf fsw *n U o in c 1- 44 >0 U <9 V* r* h -- O CM V 5 3l c m #o 4> u *j a k. Cl O. ' 5- -:0V e -o <0 > >,W J3 V> <9 Z 4 O C O. JO JQ CO CU O CL 25 O* O *0 f * >-- r1 E E :E *H *-- OOONO o *o *o o c m o co o tn o o O i r- '4 t to to > r-- r C^ CO rt--n tO * r * CM CM A F-- CO J* C& 0 <2/ 0 o f>. cn "ad c <0 >> e2 JO C V <9 os: s v o "O I (U c r> w b +4 d j- ex w "3 S CX 0 0*0 *c (A (A (B I-- c S #-- r-- 4-00 tn T3 .* a* s i*55 a* CO <0 a* * * -* 4^ XJ C0 X S- r-- o 3 4- tn to o V 1-22> O a to co CM ICC CO o oo o oo tn -- oi UM o-- o ooo Q o <y 0 '3 o> -J T3 UJ 0> *- o <0 r-- <y E CO &. a* <U 0* f-- o tn v) tn ( > <p> o tn U co O< 3 33 tn <U J- 5L V u OJ --- r o 4-> CO u gg f-- r-- U tO 4* .40 U. U >>C*> O W-.HK J= > O^-C 4* _ cx Q> CX eg v) r- O E E T3 *Or-->8 0*.f^ O 44 r-- F-i* tO U tn tn o O 0 3 tO U O CM *0* to 1 Ub. <C ' N 6 41.0 co do to ns O 01 er* t- <U O> COM tn *X E 3 CO tn O to **4- O -r-o\ v> o i- r- tn o <0 0* O 3* T5 CL CM O 4> tO 3l O tn c a; a *-- U (4 > T3 O CJ ' -l cr. a c *T" '3 > *3 stn o CO t > a u r^CM CO a* 3 U- TS <y T3 40 OJ --4 J- tn C Q* Of-- V4 U 5^ TO 44 OJ 44 C7> <o C "F-- 3> E *** fi- L. cn a a -- u o tn CO CO i 04 to O) tn cvi * <3 3 OJ T3 4 V to tn O CO CO O --* o o .* dl 0 <o t. CO IO * PQOU) d Co g dr- *-- CO . C zc o h + <u o u j O ,2C LU C >3= -.ZC o'10 c crv c Ol .F-- --ir0r* o uj o rSic--g,iO >uP)0'cX#id<-o Mm J 4)-J X Ui O UJ *r- oo r-- tEn rO r-^ <3 Ci o cTO H- *ts c c-T3 iA a* g > 44 U U L. <0 O u. 44 rJ0 0* fcT3 *3 fl> Q f-- *J fa O 4t C4 <0 !>. 1. lr.^ -c o cx tn h CM CM tO U*> S-44 T3 3 3 O a* xj *4 <0 CO>-' oo 3*- T3 U Uorn o*-* u o> to o o>^-* r-*CO 44 a> o u. > cu JC o o PS* an :cs DUP040013757 / :* CHAPTER 1 '*23- REFERENCES Angle, C. R,.HeIntire, M. S and Colucci, A, V. (1974), Lead, in'air, dustfall, soil, het-sedust, i. and water; correlation with blood lead of urban and suburban school children n 0. D. Hemphill, (ed.), Trace Substances in Environmental Health. Vol. 8: 23-29, University of Missouri, Battel!e Pacific Northwest Laboratories. {1972). Cortract Ho, 211B00844 for NIEHS. Fate of Heavy Metals and Heavy Metal Complexes in Soils and Plants. Quarterly Progress Report - October 1- December 31, 1972, Bowen, (1966). Trace Elements in Biochemistry, Academic Press, New York. Boyer, K. W. and laitinen, H. A. (1975), Automobile exhaust particulates. Properties of environmental significance. Environ, Sci. & Technol. 9(5): 457-469. Colucci, J. M., Begeman, C. R., and Kumler, K. (1969). Lead concentration in Detroit, Hew York, and Los Angeles air. J. Air Poll. Cont. Assoc. 19: 255-264. Creason, J, P,, McHutly, 0., Heiderscheit, L. T., Swanson, D. H., and Buechley, R. W. (1971). Roadside gradients In atmospheric concentrations of cadmium, lead, and zinc. In D. D, Hemphill, (ed.), Trace Substances in Environmental Health. Vol, 5: 129-142, University of Missouri. Daines, R, H., Motto, M., and Chilko, D. M, (1970). Atmospheric lead: Its relationship to traffic volume and proximity to highways. Environ. Sci, Technol, 4(4): 318-322. Day, J- P., Hart, M,, and Robinson, M, S. (1975), Lead in urban street dust. Nature 253: 343-345. Dedolph, R., Ter Haar, G. L., Holtzman, R., and Lucas, H. Jr, (1970), Sources of lead in perennial rye grass and radishes. Environ. Sci. Tech. 4(3): 217-223. Edwards, J. B. (1973); The chemistry of spark-ignition engine combustion and emission formation. In G. S. Springer and D. J. Patterson, (eds.). Engine Emissions: Pollutant Formation and Measurement. Plenum Press, New York. Federal Register. (1966). Control of air pollution from new motor vehicles and new motor vehicle engines. 31, Part II (March): 5170-5178. Federal Register. (1968). Control of air pollution from new motor vehicles and new motor vehicle engines, 33, Part II (June): 8304-8324, Federal Register. (1970), Control of air pollution from new motor vehicles and new motor vehicle engines. 35, Part II (November): 17288-17313. Fried!ander, S. K. (1973), Chemical element balances and identification of air pollution sources. Environ. Sci. S Technol. 7(3): 235-240; 5`s`o DUP040013758 r~ r *?f,.' ?& B'-'r'"* ft ' +* ;* v\.r.. " - ,*' ' * 1 *\ 1-24- Ganley, J. T. and Springer, G. S. (1974), Physical and chemical characteristics Of particulates in spark Ignition engine exhaust. Environ. Sci. & Technol. 8(4): Green, L. 2, (1S68). Characterization of lead alkyls in petroleum products using high-temperature electron-capture GC, Facts and Methods 8(4): 4-7, (Publication of Hewlett-Packard Corp.), Habibi, K, (1970). Characterization of particulate lead in vehicle exhaustexperimental techniques. Environ. Scl. & Technol. 4(3): 239-248. Habibi, K. (1973), Characterization of particulate matter in vehicle exhaust. Environ, Sci, & Technol. 7(3): 223-234. Heidel, R. H, and Desborough, G. A. (1975). Limitations on analysis of small particles with an electron probe: pollution studies. Environ. Poll. 8: 185-191. Keisler, S. L., Friedlander, S. K., and Husar, R. 8. (1972). The relationship of smog aerosol size and chemical element distributions to source characteristics. Report from W, M, Keck Laboratories of Environmental Health Engineering, California Institute of Technology, Pasadena, California, Hemphill, 0. 0. (ed.). (1966), Trace Substances in Environmental Health. Vol. I-IX, University of Missouri, Columbia, Missouri, Hemphill, D. 0., Marienfeld, C. 0,, Reddy, R, S., and Pierce, j. 0, (1974). Roadside lead contamination in the Missouri lead belt. Arch. Environ. Hlth. 28: 190-194, Hirschler, 0. A., Gilbert, L. F., Lamb, F. W,, and Hiebylski, L, H. {1957}. Particulate lead compounds In automobile exhaust gas. I & EC 49: 1131-1142. Hirschler, D. A, and Gilbert, L. F. (1954), Mature of lead in automotive exhaust gas. Arch. Environ. Hlth. C{2): 297-313. Huntzicker, J. 8., Friedlander, S. K., and Davidson, C. I, (1975). Material balance for automotive-emitted lead in Los Angeles Basin, Environ, Sci, & Technol, 9(5): 448-457. Jungers, R. H., Lee, R. E. Jr., and Lehmden, 0. J. (1975). The ERA National Fuels Surveillance Network. I. Trace constituents in gasoline and commercial gasoline fuel additives. Environ. Hlth, Perspec. 10: 143-150. Kihard, 8, T., Tisdale, J., ana Alexander, E. (1976). Assessment of lead distribution patterns in urban and rural environments, J. Environ, Sci. Hlth. -- Environ. Scl. Eng. All(2): 153-164, Sff AiSfr-m-v* J DUP040013759 Lepow, H. L., Brucknan, L., Gillette, M., Markowitz, S., Rofaino, R., and Kapish, J (1975). Investigations into sources of lead in the environment of urban children. Environ. Research 10: 415-426. Linton, R. W., Loh, A., Natusch, 0, F. S. Evans, C. A,, and Williams, P. (1976). Surface predominance of trace elements in airborne particles. Science 191: 852. McKee, H. C. and McMahon, W. A. dr. (1960). Automobile exhaust particulates -- source and variation. J. Air Poll. Control Assoc. 10(6): 456-^62. McMullen, T, B., Faoro, R. B., and Morgan, G. B. (1970). ProMle of pollutant fractions in non-urban suspended particulate matter. J. Air Pc 11. Control. Assoc. 20: 369-372. Moran, J. B. and Manary, 0. J. (1970). Effects of fuel additives on the chemical and physical characteristics of particulate emissions in automotive exhaust. Interim Rept. to NAPCA submitted by the Dow Chemical Company, Midland, Michigan, duly. Moran, J, B., Manary, 0. d.. Fay, R. R., and Baldwin, M. d. (1971). Development of particulate emission control techniques for spark-ignition engines. Final Technol. Rept, to EPA, EHS 70-101, Dow Chemical Company, Midland, Michigan. Motto, H. L. (1970). Relationship of automotive lead particulates to certain consumer crops. Environ. Sci. & Technol. 4(4): 332-338. Motto, H. L., Baines, R. H., Chilko, 0. M., and Motto, C. K, (1970). Lead in soils and plants: Its relationship to traffic volume and proximity to highways. Environ. Sci. & Technol. 4(3): 231-237. National Academy of Sciences (NAS). (1972). Lead: Airborne Lead in Perspective. Committee on Biologic Effects of Atmospheric Pollutants, Division of Medical Science, NRC, NAS, Washington, D. C. Ninomiya, J, S,, Bergman, W., and Simpson, B. H, (1970). Automotive particulate emissions. Presented at the 2nd International Clean Air Congress. International Union of Air Pollution Prevention Association, Washington, 0. C. Report available from Automotive Emissions Office, Ford Motor Company, Dearborn, Michigan. Norris, R. S. (1895), Amer. Chem. J. 17: 189-191. Olson, K. W. and Kogerboe, R. K. (1975). Identification of soil lead compounds from automotive sources. Environ, Sci. & Technol. 9(3): 227-230. 5*5^ i DUP0400137601 Pierrard, J. M. (1969). Photochemical decomposition of lead halides from automobile exhaust. Environ. Sci. Techno!. 3(1): 48-51. Public Health Service (PHS). (1968). The Sources of Air Pollution and Their Control. PHS-Pub.-1548 (revised). USDHEW, Division of Air Pollution, Washington P. C. Public Health Service (PHS). (1970). Control Techniques for Particulate Air Pollutants. Pub. No. AP-51. USDHEW, PHS, NAPCA, Washington, D. C. Purdue, L. J., Enrione, R. Thompson, R. j., and Bonfield, B. A. (1973). Determination of organic and total lead in the atmosphere by AA spectrometry. Anal. Chem. 45: 527-530. Renz, C. (1921). Photochemistry of lead compounds: Z, Anorg. All gem. Chem. 116: 62-'O. i Sampson, R. E. and Springer, G. S. (1973). Effects of exhaust gas temperature and fuel composition on particulate emission from spark-ignition engines. Environ. Sci. & Techno!. 7(1): 55-60. Schuck, E, A. and Locke! J. K. (1970). Relationship of automotive lead particulates to certain consumer crops. Environ. Sci. & Techno!. 4(4): 324-330. Seinfeld, J. (1975). Air Pollution: Physical and Chemical Fundamentals. McGraw-Hill Book Company, New York. Snyder, L, J. (1967). Determination of trace amounts of organic lead in air. Composite sample method. Anal. Chem. 39: 591-595. J Springer, G. S. (1973). Particulate emissions from spark-ignited engines. In G. 5. Springer and D. J. Patterson, (eds.). Engine Emissions: Pollutant Formation and Measurement. Plenum Press, New York, Swaine, 0, J. (1955). The trace element content of soils. Commonwealth Bur. Soil Sci, Techno!. Consn. No. 48, Herald Printing Works, Conley Street, York, England. Ter Haar, G. 1. (1970). Air as a source of lead in edible crops. Environ, Sci. & Techno!. 4(3): 226-229. Ter Haar, G. (1972). The sources and pathways of lead in the environment.' International Symposium on the Environmental Health Aspects of Lead. Amsterdam. October. % T* ^V7 i. ij . ! >k. 1-27- Ter Haar, 6. L. and Aronow, R. (1974). New information on lead in dirt and dust as related to the childhood lead problem, Environ. Kith. Perspect. 7: 83-89. Ter Haar, G. L. and Bayard, M. A. (1971)* Composition of airborne lead particles. Nature 232: 553-554. ^ Ter Haar, G, l., Lenane, 0. 1., Hu, 0. N,, and Brandt, M. (1972). Composition, size, and control of automotive exhaust particulates. J. Air Poll. Control Assoc. 22(1): 39-46. Vostal, J, J., Tav.es, E., Soyce, J. W., and Chainey, E. (1974). Lead analysis of house-dust: A methods for detection of another source of lead exposure in inner city children. Environ. Hlth. Perspec. 7: 91-97. * ir'- syv DUP040013762. 2. SENTINALS OF POTENTIAL LEAD HAZARD 1,0 '`Normal11, "Reference'* and "Discrimination Values* ; The term "normal blood level" and other "normal" values for body fluids or tissue*- with regard to lead hazard are frequently used. It is important that they not be abused in the context stated or implied. For this reason, a brief consideration of the use of the above terms in general appears to be in order, followed by the degree of its applicability to lead hazard, "Normal value" is varyingly useful depending upon the degree of cor relation of the values within and outside of the "formal range" with the clinical conditions involved. In some cases the correlation is good while in others it it ,iot as good because Of the following factors: transient, wide fluctuations in the values unassociated with clinical changes; insufficient specificity of the test for the parameter being tested and poor correlation between the value in the tested fluid and the degree of involvement of receptor sites either structurally, quantitatively or over time. In addition, and equally as important, the term "normal" suffers in its use from three logical fallacies: ambiguity in context (i.e. it connotes healthy in the clinical sense; Gaussian in the statistical sense; and either ideal, conventional or habitual in the popular sense); the circular reasoning involved (i.e, a "normal" population is one Which is, overall, free of a condition while the presence of differences from this group defines, overall, the presence of the condition); and emotional connotations attached (i.e. what is "normal" is acceptable while that which is "not normal", "abnormal", is harmful and should be corrected). For these reasons, while it would be surprising if "normal" were to be eliminated from use completely in the near I 2-2- future, an attempt Is being made to foster the application of other terms introduced (1), "Reference value" and "reference interval" are coming into greater use > in Europe and North America, For example, 97" and 100F (36.2 ar.d 37.8C) can be "reference values" for individuals or groups while this degree Of variation would he indicative Of an abnormal condition in others. Several "reference values" may be present for a test taking into consideration: the vitae of a reference population; external and internal conditions of specimen collection; the analytical method used with its associated precision and accuracy; and the statistical tests used. The terms "discrimination value", "decisive value" and "critical value" are more specific. These are "the best dividing Tines between the 'normal' and the 'diseased' or between 'those who -need not be investigated further' and 'those who do"' (2), Sunderman (1) listed the factors for its determination: a clear definition of the disease; clear demarcation of the stage to be speci fied by the test; ability to detect a high proportion of "true positives"; ability to accurately eliminate other conditions (a low rate of "false positives"); knowledge of prevalence of the disease; and consideration of the risk to the patient of a positive or negative misdiagnosis. It is often not possible to get this degree of specificity with a single test. However, two or more tests can many times be used together to define the group of individuals that are "diseased'' or that "need to be investigated further." Sjgww*-- w . DUP040013764 . 2.0 Whole Blood, Erythrocyte, Plasma and Serum Concentrations of lead 2-3* "normal values" for the concentrations of lead, mainly in whole blood, have been reported extensively. Obviously, all have not been determined with the same degree of precision and accuracy and much reference is made to variations between laboratories and on the same sample because of the trace concentrations often present and the ease of contamination at one point or another in collection or assay. Independent of the extraneous factors, however, it is more reasonable that a variety of "reference values" and "reference intervals" exist among groups of.the infants, children and adults of both sexes, and in the varying populations and occupational groups assayed. It has even been sometimes stated, quite candidly, that the higher values in lead exposed groups are "normat" for the group. In specifying only "normal values" as above, there is either the impli cation that the amounts present are of a nonhazardous nature or that there is an acceptable degree of hazard considering the circumstances. The ambiguity is that, for a particular individual or group, the value obtained may be outside of its "reference interval" and, under these conditions, the lead might be either safe or biologically hazardous at the present, or in the future because of accumulation or developmental aspects. These possibilities are not suggested by indicating a result as a "normal value" within the "normal range." "Reference values" and "discrimination values", where possible, would be more useful. Waldron (3) recognized the above thoughts for lead hazard as follows. "A more valid approach would be for each center to establish its own reference values taking into account such factors as diurnal and seasonal variations (4-7) and then to match results against those for the appropriate reference DUP040013765 2-4- . population* The results could then be expressed either In terms of standard deviations from,the mean or as an age-race-sex specific percentile such as Elveback has described (8). Used in this way, blood lead estimations would alert the physician or environmental hygienist to an unrecognized source of contamination while at the same time serving as valuable corroborative evidence of excessive exposure in suspected cases of poisoning.'* i 2.1 Whole Blood Whole blood lead (Pb-B) concentration has probably been the most widely used test to detect human exposure to lead hazard* However, its diagnostic value at the border of the upper "normal" and the lower concentration levels for suspected exposure, is controversial. For example, easy contamination and poor quality of analysis In some laboratories have given spurious and widely divergent results (9-12). It has been found that whole blood lead is more a measure of very recent exposure (13-15) than of total burden, most of which is in both some of the hard and soft tissues. The lead in body stores, it is known, can be mobilized by chelating agents (16,17), and there is some data, by a variety of dietary and physiological factors (18,19). Dietary sources (food and beverage) and water, as well as paint, dust and dirt contamination (the latter group by hand to mouth or direct mouth transfer mainly by children) could cause transient fluctuations (20-24). The hematocrit is greater in children than adults, it can vary for a variety of clinical reasons and it is also decreased as a symptom of lead poisoning. On these bases, some have attempted correction of whole blood lead values for the hematocrit since the lead is mainly on and within the erythrocytes. The correction has been controversial (25-30). Finally, some hematologic effects occur in children and adults at blood lead concentrations below 40 ug/ioo ml (16,25,31-33). Between 50 and 80 wg/100 ml, chelatable lead ret DUP040013766 2-5- in children (34) and urinary excretion of two catecholamine metabolites in mice and in children and the brain concentrations of the compounds in mice (35), are affected. Also some clinical effects (3,36,37) have been reported in children and adults in this dose range. Goldwater and Hoover (38) reported the "normal" concentrations of lead in blood and urine (150 ml of urine from a 24-hour collection) in over 800 specimens each from 16 countries, including New Guinea (aborigine population) and the United States. The subjects were mainly hospital employees or clinic patients, of both sexes, and were screened to eliminate cases of unusual exposure to lead. Chemically clean glass or polyethylene bottles were used for the samples which were mailed to a central laboratory in the United States for analysis by one of the standard dithlzone methods. They defined "normal", for the study, as "the amount found in persons who have had no evident occupational, medicinal, or other unusual sources of exposure." Tnere is no implication of safety or hazard in the definition. The "normal" range found was about 5-40 ug/100 ml* and the values included those of 45, 50, 53, 60, and 100 (New York City) ug/100 ml with, in all likelihood, additional values in the latter range. The distribution was skewed, as seen from the Tow median (18 ug/100 ml) and mean (17 ug/100 ml) values. In about 95S* of the tests the values were 40 ug/100 ml* or less. There seem to be three minor, but Important errors in the Goldwater and Hoover (33) report. The derived, corrected values are given above and the justifications here. (1) From the data, it appears that the normal range of blood lead values is 5-40 rather than 15-40 ug/100 ml. (2) To be consistent with the paragraph directly above in their report and with the two values given in their Summary and Conclusions section, it appears that 95% of the blood lead values rather than 98% was meant. And then (3) the mean + two standard deviations would give about 40 ug/100 ml rather than 50 ug/100 ml as the value that includes 95% of the bicod lead values; three standard deviations would yield 99% of all values up to 50 ug/100 ml. The interpretation of (3) is coherent with the paragraph above in their report where 95% of the urine lead values are included in two standard deviations (about 65 ug/100 mlK However, because the distributions are skewed, it can only be surmised that the corrected values are what was meant. err rt DUP040013767 2-6They referred to a comprehensive review of the world literature by G.J. Stopps, presented at a meeting (39) also referred to by Stopps (40), and reproduced partly elsewhere (41), which yielded similar and slightly higher values between 1941 and 1965 and some higher values, as well, between 1931 and 1940 (figure 2.1). McLaughlin and Stopps (42) have now determined the blood and urine concentrations of lead, respectively, in 420 and 3,819 .1. DuPont de Nemours & Co, employees, who were not working with lead products, at 23 locations in the United States and analyzed the data for nonsmokers vs smokers. The mean whole blood concentrations were: nonsmoker?., 19.1 ug/100 ml; cigarette smokers, 19.9 yg/lQP ml; other smokers, 17,3 ug/100 ml. These values were not significantly different. However,, lead in the urine of ncosmokers was significantly slightly less than in the two other groups; 27.1 vs 28.6 and 29.0 ug/IGO ml, respectively. They quoted several other studies that found a difference or no difference and, for two of these, gave the mean blood concentrations reported: nonsmokers, IS and IS.3 ug/100 ml; smokers, 21 and 16.4 ug/100 ml. Butt, et al. (43) reported a mean blood value for lead in 47 'presumably normal" hospital employees of 17.7 + 0.8 (S.E.) ug/100 ml. They did not give the range and the standard error appears to be unusually small, Robinson, et al, (44) reported data for children of ages 5 hours to 13 years, where there was "normal temperature,..no history of pica, previous lead poisoning, or symptoms suggestive of lead poisoning". These were for 9 newborns: range, 7-28 ug/100 ml; for 28 infants including the newborns and up to 6 months old: range, 5-31 ug/100 ml and median, 15 ug/100 ml; for 75 children from 6 months old to 13 years: range, 2-54 ug/100 ml and median, 27 ug/100 ml with 90S,of the values from 15-40 ug/100 ml. The difference between the values for the newborn to 6 months and 6 months to 13 year groups was statistically highly significant. However, there was not a significant difference between groups from 6 months to 4 years and 4 years to 13 years, and thus, the 6 months to 13 year values were pooled for statistical analysis. All values were plotted on a scattergram. DUP040013768 . % V* 2.2 Erythrocytes 2-7- Usually 90S or more of the blood lead travels with the erythrocytes (25,45) and the lead appears to be taken up rather quickly from plasma to erythrocytes (46,47); there appear to be easily and more difficulty released compartments for lead (18,47), one of which is associated with the membrane and the other Inside the cell (48); inhibition of both heme (14) and globin (30) synthesis with their associated enzyme inhibitions and product accumulations occur (31), Na/K ATPase inhibition, K+ loss and some degree of shrinkage and crenation (30) and fragility of the membrane (44,49) occur; and a decrease in the number of circulating erythrocytes (anemia) is often a symptom'of lead toxicity (50). The effects within erythrocytes and the spillover of accumulated products into the plasma and urine are objective factors and have been quantified. Some of these are seen at lower levels of lead exposure. They are reported further below. While the erythrocytes are considered by some to be mainly an inactive transport and storage site for lead, and while there is considerable evidence against at least the worst and most of the moderate of the following situations, several possibilities are either known to some degree or are still speculative. The following possibilities are not, by any means, implausible and should con tinue to be sought at the lower and moderate levels of blood lead concentrations. (1) Some of the erythrocyte lead is easily releasable with chelating a*, ts and may also be easily released to the plasma under a variety of dietary or physiological conditions, to be potentially available in the plasma for reaction with susceptible tissues; (2) direct'effects on the erythrocytes may pose, in itself, some form of hazard; (3) effects on susceptible tissues, secondary to the erythrocyte responses may occur; and (4) some of the responses of erythro cytes may mimic types of events occurring at other sites. I * DUP040013769 2.3 Plasma and Serum 2-3- As noted above* most of the lead in blood is associated with the erythro cytes. In case? of increased total lead in blood or frank toxicity, what is the reported distribution of lead between the cells and the plasma or serum? Among the earlier reports, Aub, et al. (51) reported that 802 of the lead in the blood of severely toxic rabbits was in the plasma. Teisinger (52) reported a more equal distribution between cells and plasma in human lead poisoning* but in a later report (53) stated that most of the lead was in the erythrocytes. Smith, et al. (54) reported the concentration of lead in serum in association with the development or disappearance of toxic symptoms in humans. After analyzing the extensive report by Smith, et al. more recent investigations on this issue will be reviewed. Several factors must be noted at the outset in the Smith, et al. report: (1) In their extensive Tables* data for 45 of what appears to be 103 patients is presented in two or more Tables, (2) Lead exposure in 58 individuals (562) was by the administration of a lead colloid, intravenously, for cancer chemo therapy. . The other exposures were industrial, paint, unknown and X-ray exposure in one case (this type of exposure 1$ unclear). The number of individual patients and their types of exposures are sorted in Table 2 i. Factors such as a potential altered distribution after i.v. treatment as compa**ed to the inhalation and/or ingestion exposures, and the potential of an effect of the malignancy in those receiving lead colloid is considered here. (3) It is clear that Smith, et al. (54) were well aware that they wished to "minimize any changes in equilibrium of the serum and cell lead" from their description of the technique for defibrination and separation of serum from the clot, and its DUPG40013770 ' -'ik jnws<vt . 2 -9justification. Bambach, et al. {45) presented data a few years later that the serum and plasma yield similar results for lead concentration under a variety of preparatory conditions. (4) The concentrations of lead have been converted from mg/1.0 ml to ug/100 ml; 10 ug/100 ml was about the limit of detection. (5) The report is complex, the symptomology subjective in many cases and the interpretation of some parts open to differing opinions. However, there are important comparisons to be made with recent data. This report escaped quotation by many others partly, it is suspected, because few have measured plasma or serum lead concentrations in recent years, probably because these are generally considered to be quite low. Some of the data are summarized in Tables 2,2 and 2.3. In Table 2,2 it is shown that there was no detectable lead in the serum of individuals of the authors' Tables 4, 5, and 11, representing respectively, "normals", individuals hospitalized for reasons not related to lead and patients mainly 4 months (2 months in one case) after a toxic episode. However, for the two groups of individuals of their Tables 9 and 10, who were either in acute toxicity or in an active phase of chronic toxicity, lead occurred in the serum. When the clinical symptoms were clearly present (their Table 9), the serum concentrations were 20-150 ug/100 ml, mean = 58 ug/100 ml; with weak or temporarily absent clinical symptoms (their Table 10), the serum concentrations were 10-40 ug/100 mV, mean = 20 ug/100 ml. The concentrations of lead in the cells + fibrin and in whole blood for the patients of their Tables 9, 10, and 11 were higher, as expected, than for the nonexposed individuals of their Tables 4 and 5. Part of the data of their Table 12 is abstracted in Table 2.3 here. The concentrations occurring in serum from day 0 to as much as 150 days later is .1 <CL if DUP040013771 2-10recorded along with the patients health status, relative to lead toxicity. Although there isn't a good quantitative relationship, the directions of change i for serum lead concentration and the patient's clinical state are generally correlated. There are little or no differences in mean serum concentrations when the lead colloid 1.v., industrial, and unknown exposures are compared. Thus, for the clearly symptomatic patients, the concentrations were, respectively, 57, 69, and 48 ug/100 ml; for patients with weak or temporarily absent symptoms, these were 20, 18, and 20 ug/100 ml , respectively* There is a weak correlation between the serum and the cells + *ibrin concentrations in the clearly sympto- \ matic patients (their Table 9) but no correlation when there was Tittle dr no clinical symptoms (their Table 10). Bessman and Layne (55) administered edathami1 calcium disodium (CsNagEDTA) to two adults and three children and assayed either the whole blood or RBC lead concentration along with the plasma concentration for each, before and 2, 4, and 8 hours after treatment. The data are shown in Table 2.4, Prior to treat ment, the blood or RBC lead was above normal in two cases, patients b and c, and the plasma concentration in c was quite high, 63 ug/100 ml. The treatment had variable effects on RBC lead, but increased the plasma concentration in each case, to a startling extent in patient c. No statement was made with regard to the clinical outcomes of the individuals. Robinson, et al. (44) reported plasma lead concentrations for 82 "normal" children: in 53, lead could not be detected; in 22 it was <_9 ug/100 ml; and in 7 it was > 9 ug/100 ml and hemolysis had occurred to sane extent in apparently all of these. . j d 2-11 Butt, et al, (43) reported serum lead concentrations in three groups of individuals in the Los Angeles area. In 122 blood donors, the mean serum concentration * 3.9 ug/100 m ; for 96 hospitalized patients, the mean = 2.7 ug/IQQ ml; and for 48 ''normal" employees, the mean = 2.8 ug/100 ml. Age, sex. auto driving, and length of time in the Los Angeles area did not appear to have an effect on the mean serum lead values. McKoberts (49) published an interesting report on individuals working in an automobile battery factory prior to and following knowledge of this operation by the Factory Inspectorate. McRoberts became the appointed factory doctor. In the report he first reviewed, rn depth, the basis for the belief that an Increased plasma or serum concentration of lead might be associated with toxicity. Plasma, RBC, and whole blood lead concentrations were among the data collected for 18 individuals. Thirteen remained well, though son had an increased concentration of lead in the blood, and the other 5 had some forms of symptpmology. The Tables in the report considered the 18 individuals separately. Of the 13 individuals that remained well: plasma lead concentration on 29 blood samples was 1-10 ug/100 ml (plasma concentrations were not determined on hemolyzed samples); whole blood lead on 43 samples ranged from 33-173 ug/100 ml though values of 18 and 250 ug/100 ml were also obtained; and 5 of these 13 individuals had a transient anemia (hemoglobin < 13.0 g/100 mi, the lowest of the low hemoglobin values were 11.8, 11,9, and 12.3 g/100 ml). The first of five workers with the "symptoms" showed a slight tremor, occasional "stipple" cells, and a hemoglobin of 11.7 g/100 ml. He had only J1 DUP040013773 been working in the plant for two weeks and there was no known previous occupational exposure to lead. The initial whole blood lead'concentration was 510 ug/100 ml. It was 790 ug/100 ml two weeks later, and then following suspension from work, the concentration was still high, after another month, at 535 ug/100 ml. The individual was hospitalized, though he was asymptomatic on examination by several physicians, at which time three weeks later, the plasma concentration = 16 ug/100 ml; whole blood - 313 ug/100 ml; and hemo globin had risen to 14,0 g/100 ml by this time. The next day at 9 a.m., a sample showed plasma = 71 ug/100 ml; whole blood = Zj 5 ug/l66 ml. A small, test dose of calcium disodium EOTA was given i.v. between noon and 2 p.m. The 4:30 p.m. blood sample showed plasira * 59 ug/100 ml; whole blood 297 ug/100 ml At 7:25 p.m. the individual had epileptic-type convulsions, frothing at the mouth, followed by cyanotic coma and temporary cardiac and respiratory arrest. Acidosis was present on blood analysis after resuscitation. At 9:30 a.m. the next day the lead concentrations were; plasma 3 6 ug/100 ml; whole blood = 283 ug/100 ml; and the next day these were: plasma = 3 ug/100 ml; whole blood = 241 ug/100 ml. About a month later, discharged from the hospital, these were: ] plasma 10 ug/100 ml; whole blood, 141 ug/100 ml. The second individual with "symptoms" developed anemia after three months with the firm. In the first four weeks of work suspension he complained of tiredness and intermittent, vague pains in the muscles of his arms and legs, though clinical examination didn't reveal abnormalities. Hematologic morphology improved with time. Hemoglobin was between 10.8 and 12.0 g/100 ml for about a month and then rose to 13.0 g/100 ml in another 1 1/2 months. Plasma lead concentration was from 3-8 ug/100 ml over a five-week period, but with 22, 17, 16, and 12 ug/100 ml concentrations interspersed, and only the 17 and 16 ug samples 2-13seemed consecutive. Whole blood lead concentration varied from 66-120 ug/100 ml in 14 samples, with a possible plateau between 106 and 120 ug/100 ml within a ten-day period. The third individual worked for seven days before suspension because of a hemoglobin of 11.2 g/100 ml. The anemia did not Impro.e over a month, even with oral iron therapy. No other symptoms than this degree of anemia are mentioned. Plasma lead was 10, 15, and 4 yg/100 ml on three samples, and the respective whole blood lead concentrations were 117* 66, and 22 yg/100 ml, The fourth worker had been absent from work for a whil| because of "Influenza", At the time of examination he complained of malaise, weakness* and general aches and pains. Two blood samples over a month's time, respectively, showed normal hemoglobin values of T5.2 and 14.9 g/100 ml; plasma lead con centrations of 16 and 5 ug/100 ml; and whole bleed lead concentrations of 85 and 67 ug/100 ml. The last worker complained of tiredness and irritability. His hemoglobin varied from 10.9 - 13.8 g/100 ml on seven samples over a four-month span, and in a seemingly cyclic pattern. Four of the blood samples In six (672) from this individual hemolyzed to some extent. This was a high proportion since for only 3 of the 13 asymptomatic individuals, hemolysis occurred in 3 out of 5 {60%), 2 out of 5 (40%), and 3 out of 8 {37*) of the cases and there were few other instances of hemolysis. Plasma lead concentrations wt e 6 and 12 ug/ 100 ml, about three weeks apart, and respective whole blood . ,,d concentrations were 415 and 480 ug/100 ml. Other whole blood lead concentrations for this individual were 88, 381, 435, and 480 ug/100 ml. ii i ? 2 i j f .5 - k\ \ DUP040013775 2-14McRoberts concluded that 10 ug/100 ml appeared to be an approximate dividing line between the presence and absence of symptoms, but that there was little correlation between concentration on a specific day and symptoms at that time. Rosen, et al. (26) reported plasma lead concentrations and hematocrits for 165 children including: 13 newborns; 14 and 17 children in two "normal" whole blood lead range groups of 20-29 and 30-39 yg/lPO ml respectively; 8-24 children in succeeding 10 ug/100 ml lead concentration ranges up to 40b*1 90-99 ug/100 ml; TO in tbs 100-136 ug/100 ml range; and 17 children with sickle cell disease and with whole blood lead concentrations,of 18-136 ug/100 ml. The plasma lead concentrations found in each case were somewhere between 1 and 7 yg/ TOO ml, with mean concentrations of 3.Q-3.3 ug/100 ml. The mean hematocrit values were; SOS for the newborns; 362 for the two "normal" whole blood lead groups; 342 in the 49-49 and 50-59 ug/100 ml groups; 33, 31, 29, 28, and 26$, successively, for the remaining groups; and 20% in the children with sickle cell disease. Thus, Rosen et al. demonstrated a remarkable constancy of plasma lead con centrations over a wide range of whole olood lead concentration and hematocrit values. Elsewhere, Rosen and Trinidad (18) discuss experiments with Ca and CaNa2EOTA that decrease RSC concentrations of lead, and other factors (48,56-58) that also appear to affect this site of lead storage and, in some cases, also lead in bone stores, Chisholm (27) in an editorial to the Rosen, et al. (26) report, wisely points out that "whether plasma lead concentration is measureably higher in symptomatic (our underline) cases remains obscure", and indeed, Rosen, et al. do not state the clinical status of their children at any of the lead concentrations. It is not unusual, however, to see asymptomatic children in the presence of relatively high blood lead concentrations, but one might expect there to he some symptoms in this large number of children. fC f DUP040013776  WWW 2-15- Angle and Mclntire (25) found plasma lead concentration in the range of 4.5-7.2 ug/100 ml in 40 teenagers, ages 14-18. ; 3.0 Enzyme Activity and Product Accumulation ' 3.1 General Principles The use of biochemical analyses (some physiological and other function tests will also be mentioned), to aid in the diagnosis of illness is at least as old as the terms "physiological chemistry" and the field of clinical chemistry. Thus, the intermediates and end products of clinically important biochemical sequences, the activities of enzymes involved, incorporation of precursor molecules, concentrations of compounds along shunt sequences and the presence or concentrations of otherwise abnormal products have been used successfully to assess the degree and paths of tissue and organ pathology. In more recent years, we have wished to precede the state of illness in a variety of ways, including: the detection of abnormally sensitive individuals and a description of the causes of sensitivity; the identification of populations at risk; assessment of lesser degrees of abnormal tissue and organ function to preclude treatment and to prevent Irreversible deficits; and the identifi cation of detrimental combinations of exposure, neither of which is as hazardous by itself. As we learn more about what can be assayed and as the tests become care sensitive to smaller changes, not only do we learn about clinically relevant events but we enter the range of clinically, and perhaps even preclinically. Insignificant changes. There are new both inappropriate sentinals and sentinals where a considerable difference of opinion can occur. DUP040013777 :V, \ tft 2-16When we consider these differences of opinion we must recognize two types: the first is whether or not a change is actually of importance to the state of health; the other, whether or not this degree of change is to be accepted after balancing the benefits, risks, and actual detriments. The latter, however, is not the issue here. The question is rather, are the effects observed actually of preclinical or clinical significance? Even here, two more subdivisions occur: has the change actually affected a clinically important sequence, or has the safety margin been reduced? And whether or not we will accept a reduction of safety margin is dependent upon a combination of the extent of margin that remains along with the nature of the risk, and an individual's psychological willingness to accept or not accept it. And to place the psychological aspect at the bottom of the system analysis is not, at all, to denigrate it, because it can enter in subtle ways at other stages, and also because we have learned considerably about how the mind and body interact in clinically important ways. 3.2 Clinical Sequelae of lead Toxicity for: Lead Dose, Blood Concentration or Body Burden Comparison; and for Enzyme Activity or Intermediate or Product Accumulation comparison. The diagnosis of toxicity due to lead absorption has not been easy. It is made partly on the basis of subjective and objective symptoms, a variety of signs and a variety of blood or urine tests for lead, enzyme activities, and intermediate or endproduct accumulation, and if possible, by evidence of unusual exposure, individuals may be asymptomatic or symptomatic and be in a variety of states of hazard. Goyer and Rhyne (59) point out that "the onset of lead toxicity, even acute toxicity, is not a sharply defined event. Rather, it C7/ 1 DUP040013778 -*=? 2 -17involves a continuum of change from normalcy to ill health (6C)", and that "symptoms of toxicity or cellular effects of lead correlate with tissue content of diffusable or mobile lead,...This concept explains at least in part why one individual with a relatively small exposure to lead and body burden of lead may have clinical symptoms of lead toxicity whereas a lead industry worker with large body stores of lead, largely in the form of fixed or nondiffusable lead in bone, may not have symptoms." An individual who is in an asymptomatic phase can have an exacerbation^, of symptoms. Trigger mechanisms for this have been sought and may include normal physiological events, dietary influences, and chelation effects. Though these may act through the mobilization of stored lead, other mechanisms may also be operative. 3.2.1 Adults: Smith, et al. (54) ranked the symptoms and signs of lead toxicity in adults as shown In Table 2,5 with the caveat "It should be remembered that all of these symptoms will never be found in any single case and frequently a patient is presented for observation or treatment whose past history to lead exposure would cause one to expect symptoms conforming to Groups II or III when only those of Group I can be demonstrated." Lane, et al. (61) gave the i . . listing as shown in Table 2.6, and Dagg, et al, (62), a shorter list of symptoms in descending order of their frequency as presenting symptoms (Table 2.7). A-v 3.2.2 Children; The symptoms and signs in children are somewhat different than in the adult. For example, peripheral neuropathy is more common in adults than *6' in children while encephalopathy is much more common in children (59). Irrita bility, vomiting, abdominal pain, ataxia, anorexia, behavioral changes, speech disturbance, seizures, intercurrent fever, and dehydration can be seen in S DUP040013779 Ss, . "> \ children (16), Symptoms in children in descending order of frequency, as listed by Sachs, et al. (63), are shown in Table 2.8. \ 4 S' " -X r?^ DUP040013780 . - / 2-19^ TABLE 2.1 SORTING OF INDIVIDUALS AND THEIR TYPES OF LEAD EXPOSURE No. of unre Smith et a'l, peated indi No. of individuals for each exposure (54) Table viduals in i.v. lead Indus- Unknown Paint X-ray No. the Table colloid trial No, of repeated indi viduals in the Table 9 41 20 12 8 1 - 10 24 14 4 4 1 r 11 11 ID 5 3 2 -8 12 19 14 4 1 - - 19 13 9 5 1 3 -- 7 Total 103 58 24 18 2 i V\ v. \X DUP040013781 2-20- TA8LE 2.2 LEAD CONCENTRATIONS IN SERUM, CELLS + FIBRIN AND WHOLE BLOOD OF FIVE CATEGORIES OF NORMAL AND LEAD-EXPOSED INDIVIDUALS Smith et al (54) Table No, No.; Types cf Individuals Concentration ( uq/100 ml) Serum Cells + Whole Fibrin Blood 4 38; "normals" Nil 10-110 10-50 5 47; hospitalized (nonlead) Nil 20-130 10-60 9 41; acute and active phase of chronic toxicity with clarrly pre sent clinical symptoms 20-150 50-730 (mean 53) 50-41Q 10 35; same *s Table 9 10-40 30-370* 20-180* but with weak or tem (mean 20) porary absence of clinical symptoms 11 17; 4 months or more Nil after an acute or active phase of chronic toxicity 140-640** 70-220* *Qne of the 35 patients had concentrations of: 20 ug/TOO ml (serum), 2,290 ug/100 ml (cells + fibrin) and 830 ug/100 ml (whole blood) **An additional individual, the same as in the above footnote, and 2 months after the `oxic episode had concentrations of: nil (serum), 1,1)0 ug/100 ml (cells + fibrin) and 640 ug/100 ml (whole blood). cx DUP040013782 2-21 TABLE 2.3 THE RELATIONSHIP BETWEEN CHANGE OF LEAD CONCENTRATION IN SERUM AND CHANGE OF CLINICAL STATUS . Patient and Sequence of Serum Concentrations (ug/100 ml) Sequence of Clinical Conditions a* 20,60 b 30,20,nil c nil,20 d nil,40,50,nil e nil,30,20 f nil ,20,30,50,90,30,nil g 10,50,nil h 10,50,40,30,nil,nil,30,nil i nil,50,20,nil j nil,40,20 k 10,20 1 10,nil.nil m 30,20,nil n 30,50,nil,nil 0 nil,30 P nil,20,20,50,50 q 30,nil,nil,nil Poor, died Poor, improved, we11 Fair, symptoms after acidification therapy Good, fair, fair, well l Fair, poor, died Good, fair, worse, bad, bad. improved, well Good, fair, well Good, poor, improved, better, well, fair, poor, well Good, poor, improved, well Good, fair, fair Fair, fair Fair, good, well Fair, good, good Fair, poor, improved, well Poor, died Fair, fair, poor, poor, worse Fair, fair, good, well *In the report (54) the patients are identified by initials, sex and type of lead exposure. j I 4T7 6> DUP040013783 2-22- Patient a* b c d ;N TABLE 2.4 EFFECT OF CaNa9EDTA ON PLASMA, RBC AND WHOLE BLOOD LEAD CONCENTRATIONS Before Blood Treatment Hr after treatment Age Fraction 0 24 8 Adult Adult 3 year 4 year 5 year RBC Plasma Whole Blood Plasma RBC Plasma RBC Plasma Whole Blood Plasma IS 2 61 0 275 63 12 0 7 2 23 - 17 70 - 27 186 68 123 i 80 109 139 12 10 22 17 3 19 100 48 34 55 12 12 *In the report (55), the Individuals are identified by initials. C7? A /I DUP040013784 2-23 TABLE 2.5 CLINICAL SYMPTOMS AND SIGNS OF LEAD POISONING (54) cay* > i * * : Lvvv3 -vf v *; ? ;; -* itvJ'V' .V'-.- *. y ' *.: . - * ? "* ;.\a, rtv,;. v. *. . as *.*. M* Oer.erii .i;::, vr. b-ciu'.v'J . tu.iy isc*n. *, r.eritae!* Cieseral i-oHi-3 yf laalaij.- **? Fb.-fet Jr*! Jit* Arth-jltU S'. {Ut icv3;ti'>o K-YTCf.'d tvnilr Kyr-..:.;nii-iu to As `ail Slight pyrosis -' .* ; A ; '.*. r.f .. . .:.i ..i w a v . . . 4r*j . .V^-'r*- v Isaai'tss i Art til Jn\:. i\sv C- ' *. s'.r.-a.i fails ia cl., rc Wrist drop FiVt dec? <* Digestive syileia Psjflittst aiataiUc Metallic taste Coated toague Slight ato.-erda. i Anorexia Slight coaxtipitita Ctritiparion Si:-bt abdvcCaJ ? -Ife Metallic lasts Ci -`.r-i toajris AS'-rrais ' Martel it .s;'.pv.:c.s IV.*-W r. ;J '.iiC'-cU av* ibaejU Ririd :- : - i-.. Kstvow ryst;S: l.-.~iab.:!;:y aria .s J .Eight frcstal -- dry:: - fr ; SliitLi tremorj : FtriMj- T..-rv) s>>n!aa -Sytai*. ! 5::^ht uiv*9 A;**-.;-'; * Iseomeis Jr.; ,*inu ?sin:tatioa 1 C>S`*prics* Jacrraj-d radixci Ftir: Ury frit*.'rias . Increased irritability Nesr;-:: Eye pyounJs ir.ay shotr Vi real d::ur (.; .-e cbokiag at optic dircs Ear: pbi!:V4 . -. Hst'.aciaitionj Coos. FarSiysU Cerebral p.'.isy Ross! ?; tar-tr-'J 2 wtuvtes1 Trie.: v{ nl'.r:zzli* r.zd :iv sveaal j griayt'.s? casUl:; fri-e ItrnW a<j a very i Lead iiid tluclea!-.? tv- .rjbt rise j t-wsea aormailir-ira s;d ! a positive rite Tori; aeorre is A I t or- i-.i stiv C'.i.i :r, urice Ustr.itop.wyhyrnwi* Tleiimtvria Ft. Itiv-r bat flartusCstf lead DUP040013785 TABLE 2.6 CLINICAL SYMPTOMS AND SIGNS OF LEAD POISONING IN ADULTS (61) Mild symptoms and signs: Tiredness, lassitude, constipation, slight abdominal discomfort or pain, anorexia, altered sleep, irritability, anemia, pallor, and less frequently diarrhea and nausea. The presence of a blue line in the gums and of a metallic taste are useful indicators of increased lead absorption. Severe symptoms and signs; Severe intermittent abdominal pain (colic), reduction of muscle power -- for example wrist drop, muscle tenderness, paresthesia, and other symptoms or signs of neuropathy or encephalopathy. 'i*' . .. J DUP040013786 2-25 TABLE 2.7 CLINICAL SYMPTOMS OP LEAD POISONING IN ADULTS IN DESCENDING ORDER OF REQUENCY (62) Abdominal pain Constipation Vomiting Non-abdominal pain Asthenia Paresthesia Psychological symptoms Diarrhea i 3 ia it l! ;! / :: / a 4 .<THO f DUP040013787-' - 2-26- TABLE 2.8 CLINICAL -SYMPTOMS OF LEAD POISONING IjH CHILDREN IN DESCENDING ORDER OF FREQUENCY (63) Drowsiness Irritability Vomiting Gastrointestinal symptoms Ataxia Stupor Fatigue $S23&2lir-** > 2-27 I i / \ :1 ;3 i } Figure 2.1 Lead Concentrations reported for* "nonnal" populations, in five-year Intervals, froft* 1931-1965 (41). & J LJ \ DUP040013789' REFERENCES 2-28- 1* Sunderman, F. W. Jr.: Current concepts of "normal values", "reference values" and "discrimination values" in clinical chemistry. Clin. Chem. 21: 1873-1877 (1975). 2. Murphy, E. A. and Abbey, H.: The normal range -- a common misuse. J. Chron. ^ Dis. 20: 79-88 (1967). 3. Waldron, H. A.: The blood lead threshold. Arch. Environ. Hlth. 29: 271-273 (1974). 4. Vigliani, E. C.: Recenti studi sul saturnismo in Italia. Med. Lav. 41: 105-123 (1950). 5. Suzutani, T. and Taira, H.: Biochemical behavior of lead: 1, Lead content in blood of rabbit administered with lead. Wakayama Med. Rep. 7: 29-36 (1962). ' i' 6. Hoschek, R.; Bleispiegelwerte m Blut bei gesunden Arbeitern einer Bleifabrik. Med. Welt. 2687-2690 (1961). 7. Blanksma, L. A., Sachs, H. K., Hurray, E, F., and McConnell, M. J.j Incidence of high blood lead levels in Chicago children. Pediatrics 44: 661-667 (1969). 8. Elveback, L.: The population of healthy persons as a source of reference information. Hum. Pathol. 4: 9-16 (1973). 9. Donovan, 0. T., Vaught, V. M., and Rakow, A. B.: Laboratories which conduct lead analyses on biological specimens. Arch. Environ. Hlth. 23: 111-113 (1971). 10. Berlin, A., del Castilho, P., and Smeets, J,: European intercomparison programme. In Proceedings of the International Symposium, Environmental Health Aspects of Lead. Commission of the European Communities, Luxembourg, 1033-1046 (1973). IT. Kepler, J. F., Maxfield, M. E., Moss, W. D., Tfetjen, G. and Linch, A. L.: Interlaboratory evaluation of the reliability of blood lead analyses. Am. Indust. Hyg. Assoc. J. 31: 412-429 (1970). 12. Lauwerys, R., Buchet, J.-P., Roels, H., Berlin, A., and Smeets, J.: Inter- comparison program of lead, mercury and cadmium analysis in*, blood, urine and aqueous solutions. Clin, Chem. 27: 551-557 (1975). 13, Gross, S. B., Tsay, O.-Y. and Middendorf, M.; Kehoe lead balance data in humans: variability, Toxicol. Appl. Pharmacol. 37: (1976). Abstr. No. 162, Society of Toxicology 15th Annual Meeting 3/14-18/1976. 5b'3 DUP040013790 2-29- 14. Chisholm, J. 0. Jr., Barrett, H. B., and Harrison, H. V.: indicators of internal dose of lead in relation to derangement in heme synthesis. Johns Hopkins Med. J, 137: 6-12 (1975). 15. Browder, A. A., Joselow, M, M, and louria, D. B.: The problem of lead poisoning. Medicine 52: 121-139 (1973), y' 16. Increased lead absorption and lead poisoning in young children: A state ment by the Center for Disease Control, J. Pediatrics 87: 824-830 (1975). 17. Jugo, $., Maijkovic, T., and Kostial, K.: The effect of chelating agents on lead excretion in rats in relation to age. Environ. Res. 10: 271-279 (1975), 18. Rosen, J, F. and Trinidad, E. E,: Significance of plasma lead levels in normal and lead-intoxicated children. Environ. HIth. Perspec. Exptl. Issue No. 7: 139-144 (1974), '^ 19. Reigart, J. R. and Whitlock, N. H.: Longitudinal observations of the relationship between free erythrocyte porphyrins and whole blood lead. Pediatrics 57: 54-59 (1976). 20. Waldron, H .: Subclinical lead poisoning: a preventable disease. Preven tive Med. : 135-153 (1975). 21. Elwood, P. C., Morton, M. and St. Leger, A. $.: lead in water and mental retardation. Lancet 1: 590-591 (1976). 22. Lepow, M. L., Bruckman, L., Gillette, M., Robino, R., and Kapish, J.: investigations into sources of lead in the environment of urban children. Environ, Res. 10: 415-426 (1975). 23. Gillette, M., McGrade, B. J., and Lepow, M, L.: The roles of behavior and environment in childhood lead accumulation. Pediatric Res. 10: 303 (1976). 24. Angle, C. R. and Mclntire, M, S,: Environmental controls and the decline of blood lead. Pediatric Res. 10: 345 (1976). 25. Angle, C. R, and Mclntire, M. S,: Red cell lead, whole blood lead, and red cell enzymes. Environ, 'HIth. Perspec. Exptl. Issue No. 7: 133-137 (1974' 26. Rosen, J. F,, Zarate-Salvador, C. and Trinidad, E. E.: Plasma lead levels in normal and lead-intoxicated children, J. Pediatrics 84: 45-48 (1974). 27. Chisholm, J. J. Jr.: Lead in red blood cells and plasma, J. Pediatrics 84: 163-164 (1974). I & J DUP040013791 2-30- 28. Angle, C. R. andMclntire, M. S.: More on the relevance of the concentra tion of lead in plasma vs. that in blood. J. Pediatrics 85; 286-287 (1974). 29. Rosen, J, F., Zarate-Salvador, C., and Trinidad, E. E,: Reply. J. Pediatrics 85: 287-288 (1974). 30. White, 0. M. and Selhi, H. S.: Lead and the red cell. Br. J. Haematol. 30: 133-138 (1975). 31. Zielhuis, R. L.: Dose-response relationships for inorganic lead, 1. Bio chemical and haematological responses. Int. Arch. Occup. Hlth, 35: 1-18 (1975). 32. Zielhuis, R, L,: Dose-response relationships for inorganic lead. 2. Sub jective and functional responses-chronic sequelae-no-response levels. Int. Arch. Occup. Hlth. 35: 19-35 (1975). 33. Mordman, C. H. and Hernberg, S.: Blood lead levels and erythrocyte <5amlnolevulinic acid dehydratase activity of selected population groups in Helsinki. Scand. J. Work Environ. Hlth. 1: 219-232 (1975). 34. Chisholm, J. 0. Jr., Barrett, M. B., and Mel1its, E. D.: Dose-effect and dose-response relationships for lead in children. 0. Pediatrics 87: 1152-1160 (1975). 35. Silbergeld, E. K. and Chisholm, J. J. Or.: Lead poisoning: altered urinary catecholamine metabolites as indicators of intoxication in mice and children. Science 192: 153-155 (1976). 36. SeppSldinen, A. M., Tola, S., Hernberg, S,, and Kock, B.: Subclinical neuropathy at "safe" levels of lead exposure. Arch, Environ. Hlth. 30: 180-183 (1975). 37. Vitale, L. F., Joselow, M, M,, Wedeen, R. P., and Pawlow, M,: Blood lead -- an inadequate measure of occupational exposure. 0. Occup, Med, 17: 155-156 (1975). 38. Goldwater, L. 0, and Hoover, A. W>: An international study of "normal" levels of lead in blood and urine. Arch. Environ. Hlth, 15: 60-63 (1967). 39. Stopps, G. J.: Lead concentration in blood and urine of "normal" populations: A review, read before Symposium on Environmental Lead Contaminations* Washington, D, C., December 13, 1965. 40. Stopps, G. J., Maxfield, M. E,, and McLaughlin, M.: Lead research: Current medical developments. Paper presented at 31st Annual Meeting of the Industrial Hygiene Foundation, Pittsburgh, Pennsylvania, October 18-19, 1966. S% DUP040013792 2-31- 41. Stopps, G. 0.: Symposium on Air Quality Criteria -- Lead. J. Occup. Med. 10: 550-564 (1968). 42. McLaughlin, M. and Stopps, G. J.: Smoking and lead. Arch. Environ. Hlth. 26: 131-136 (1973). 43. Butt, E. M., Nusbaum, R, E., Gilmour, T. C., and Oidio, S. L.: Trace metal levels in human serum and blood. Arch. Environ. Hlth. 8: 60-65 (1S64). 44. Robinson, M. 0., Karpinski, F, ,, and Brieger, H.: The concentration of lead in plasma, whole blood and erythrocytes of infants and children. Pediatrics 21: 793-796 (1958). 45. Bambach, K., Kehoe, R. A., and Logan, M, A.: The plasma-cell partition of blood lead. 0. Pharmacol. Exptl. Therap. 76: 326-337 (1942). 46. Clarkson, T. W. and Kench, 0. E.: Uptake of lead by human erythrocytes in vitro. Biochem. J. 69: 432-439 (1958). 47. Barltrop, D. and Smith, A. M.: Kinetics of lead interaction with human erythrocytes. Postgrad. Med. <3. 51: 770-773 (1975), 48. Rosen, J. F. and Haymovits, A..: Red cell-lead (RBC-Pb): Use of the calcium ionopbora, A23187 to characterize a rapidly exchangeable compartment. Pediatric Res, 9: 286 (1975). 49. McRoberts, W.: Alteration in the fractionated blood lead concentrations in the development of inorganic lead poisoning, and the concept of the role of "lead integration" in lead absorption. J. Soc. Occup. Med. 23: 3-18 (1973). 50. AVbahary, C.: Lead and hemopoiesis. Amer. J. Med. 52: 367-378 (1972). 51. Aub, 0. ., Fairhall, L. T,, Minot, A. S., and Reznikpff, P. Lead Poisoning. > Medicine 4: 1-250 (1925). 52. Teisinger, J.: A rapid micropolarographic method for quantitative determina tion of lead in blood, Z. Ges. Exp. Med. 98: 520-538 (1936), 53. Teisinger, J., Zumanova, R. and Zezula, I.: Effect of edathamil calcium- disodium on the lead content of red blood cells and blood proteins. Arch. Industr. Hlth. 17: 295-301 (1958). 54. Smith, F. L. II, Rathmell, T. K,, and Marcil, G. E,: The early diagnosis of acute and latent piumbism. Amer. J, Clin. Pathol. 8: 471-508 (1938), S'06 DUP040013793 2-32- 55. Bessman, S. P. and Layne, E. C.: Distribution of lead in blood as affected by edathamil calcium-disodium. Amer. J. Dis. Child. 89: 292-294 (1955). 56. Rosen* 0. F. and Hsymovits, A.: Lead intoxication: evidence for a rapidly displaceable red cell-lead (RBC-Pb) compartment. Pediatric Res. 8: 164 ' (1974). 57. Rosen, J. F, and Roginsky, M.: Lead intoxicated children: Plasma levels of 25-hydroxycalciferol (25-HCC). Pediatric Res, 7: 393 (1973), 58. Rosen, 0. F,: Lead-203 (203Pb) and EDTA: interactions with parathyroid hormone (PTH), calcitonin (CT) and 1,25-dlhydroxyvitamin D, (1,25-(OH) 2 D,) in bone organ culture. Pediatric Res. 10: 335 (1976). 59. Goyer, R. A. and Rhyne, B. C.: Pathological effects of lead, Int. Rev. Exptl. Pathol. 12: 1-77 (1973). # 60. Goyer, R. A. and Chisholm, 0, J, Or.: Lead in "Metallic Contaminants and Human Health", D, H. K, Lee (ed.), Academic Press, New York, 57-95 (1972). 61. Lane, R. E., Hunter, D., Malcolm, D., Williams, M. K., Hudson, T. G. F., Browne, R. C., McCall urn, R, I., Thompson, A, R., de Kretser, A. J., Zielhuis, R. L., Cramer, K., Barry, P. S. I., Goldberg, A., Beritic, T,, Yigliani, E. C., Truhaut, R., Kehoe, R, A,, and King, E,: Diagnosis of inorganic lead poisoning: a statement, Brit. Mad. 0, 4: 501 (1968). 62. Dagg, 0. H., Goldberg, A., Lochhead, A., and Smith, J, A,: The relationship of lead poisoning to acute intermittent prophyria. Quart. 0. Med, 34: 163-175 (1965). 63. Sachs, H. K., Blanksma, L, A., Murray, E. F., and O'Connell, M> J.; Ambulatory i treatment of lead poisoning: report of 1,155 cases. Pediatrics 46: 389-396 ,r$ ? \ DUP040013794 3. RELATIONSHIP BETWEEN EXPOSURE TO LEAD AND HEALTH EFFECTS IN HUMANS 3-1 1.0 Introduction In the United States the majority of non-industrial cases of lead intoxi- ^ cation occur in children between the ages of one and six years with the highest incidence between two and three years. Ingestion of lead-containing paint is considered to be the most frequent cause of severe lead intoxication among Children. This may indeed be the etiology of the most severe poisoning cases; however, other sources of lead have assumed increasing importance. Recent clinical and experimental evidence has been gathered which indicate that important adverse health effects occur at levels of lead exposure that produce blood lead concentrations considered harmless in earlier years. A number of cases of lead poisoning also occur in adults.; many of these are either the result of occupational exposure to lead or are connected with consumption of illicit rquor. Contamination of foods with lead from ceramic dinnerware has produced fatal poisoning in children and adults. The World Health Organization has established tolerable levels of intake of lead for adults (1972). These levels include lead from all sources. Currently, no finalized guidelines exist oh permissible level? of lead exposure for children which consider the metabolic differences between children and adults. 1.1 Variability of Response to Lead Exposure Increasing levels of lead exposure generally are reflected by increasing concentrations of lead in whole blood. However, these are not precise relation ships. Wide individual-to-tndividua! variations exist between the concentrations J~P. DUP040013795 3-2of lead in blood and development of specific symptoms of lead toxicity or between concentrations of lead in blood and in other tissues such as kidney or brain (Chisolm, 1971), the factors that precisely determine the partitioning between blood, bone, and such tissues as brain or kidney are not defined, However, as blood lead concentration increases, the frequency and severity of the manifestations of lead intoxication increase, Zielhuis (1975a,b) recently reviewed the concepts of Individual effects and group responses to a given dose of lead. He distinguished between the no-effect level, which is the maximum dose which does not Result in an effect of particular intensity in an individual, with the response of a group as a whole with respect to a particular effect. Quantitative data available on effects produced by a known level of lead intake are individual data. In determining a tolerable level of exposure to lead, it is important to have Information relating duration and level of human exposure to lead with development of certain lead-induced biologic changes. Although large numbers of cases of lead poisoning have been documented in the United States jduring this century, data for use in determining dose-response and dose-effect relationships are scarce. Thus, none of the quantities discussed below are average values representing a large population; such values could differ substantially from the individual response data, 1.2 Metabolic Effects of Varying Levels of Lead Exposure Although blood lead is not always a reliable indicator of the lead con centration in critical tissues such as brain or kidney, blood lead concentration has been used to express the body burden (Zielhuis, 1975a,b; Chisolm,, et al. 1975a). Use-of blood lead to equate body burden has some clear limitations. 25 3-3Spe:ifical1y, blood lead reflects only transport of lead to tissues, and due to equilibrium effects blood lead may re:'..-.in constant while lead in such critical organs as brain and kidney increases. There is considerable debate over the use of blood lead as an indicator of body burden in children, Chisolm, et al (1975b) recently reported that in children, erythrocyte protoporphyrin and urinary 6-ami no!evulinic acid and coproporphyrin correlated well with urine excretion of lead following chelation therapy, while blood lead correlated less well with the chelatable lead. i; . Despite the limitations of blood lead concentration as an indicator of internal dose of Tead, this measurement is utilized frequently because of the availability of blood samples. The Center for Disease Control (1975) recently established guidelines for the clinical evaluation of lead toxicity. Both blood lead levels and erythrocyte protoporphyrin determinations are proposed to assess metabolic effect and the degree of hazard. Determination of urinary excretion of intermediates of heme synthesis, such as 6-aminplevulinic acid requires 24-hour urine samples. It is very difficult to obtain urine collections for this length of time in young children and random urine samples are of little use in these analyses. Tables 1 and 2 are presented In the Center for Disease Cont-ol Report (1975). Class I is "normal" with regard to lead, and it can have two subgroups as in Table 2: la, those children with iron-deficiency anemia, and lb which, "on the basis of present available experience", indicates a "transient or declining blood lead elevation". For lb, the significance for lead poisoning is down graded because of the unaffected erythrocyte protoporphyrin (EP). Erythropoietic protoporphyria is distinguished from these. ! \ | ' N DUP040013797 3-4Class II has two entries in Table 2. In both cases EP is minimally elevated- In one, blood lead is minimally elevated and in the other, lead is increased to the level of Class III. In the latter, however, the signi ficance for lead poisoning is perhaps not as great because of the Class II finding of EP. Class III has two entries. The significance of the one with the lower blood lead level is upgraded from what the lead analysis might suggest because of the moderately high EP value. Class IV is considered to represent a high degree of hazard. It is stated that "significant numbers of children with blood lead levels of 30-39 ug/100 have shown evidence of metabolic impairment as detected by EP testing". The asterisks reflect combinations of lead and EP not generally observed. Relgert and Whitlock (197,6) studied 349 children and reported that "changes in FEP (free erythrocyte porphyrins) are slow and predictable whereas blood lead changes are quite unpredictable. However, when FEP suggests a different clinical category from blood lead, the blood lead is likely to change in the direction predicted by the FEP". Benson, et al, (1976) described biochemical changes in men at weekly intervals, for up to 12 weeks after first starting work at a lead pigment factory. Blood lead began to rise within one week. After the first two weeks, three groups of response could be distinguished with regard to urinary {-aminolevulinic acid and coproporphyrin excretion. In the first, an increase occurred after 3-4 weeks with variable increases afterward; in the second. DUP040013798 ftK**srK3MBiwMnPiOMtWit '-'TTU 3-5there were negligible changes; and in the third, there was an exaggerated response within two weeks of entry. The major finding, they say,, was the very contrasting response shown by some individuals. The following blood lead levels for the biologic effects indicated are found in Zielhuis' publications (1975a,b). ALAD*: no-response level (no inhibition), about 10 ng/100 ml; no-response level for >40% inhibition in adults, 15-20 yg/100 ml and in children, 5-10 yg/100 nil; for >70% inhibition in adults, 25-30 yg/100 ml and in children, 20-25 yg/100 ml^ ALAU: no-response level for AlAU >5 mg/1, 30-40 yg/100 ml; no-response level for ALAU >10 mg/1, 40-50 yg/100 ml. The levels for CPU will be about the same; there are indications that in women these levels may be lower. PPE/FEP: no-response level in adult males, 25-30 yg/100 ml; in adult females and children, 20-25 yg/100 ml. Various other biochemical parameters; in most cases the noresponse level will be at least 50-60 yg/100 ml. Hematologic effects: preliminary evidence is brought forward that, at low blood lead levels, reduction of GSH and Na+-K+-ATPase activity already may occur. However, the slope of the dose-response curve is slight. If Na+-K+-ATPase activity <40 ymole P/hr/mg tyrosine is taken as the specified response, the percentage of responses increases already at PbB - 20-29 yg/100 ml, and for GSH <58 yg/100 ml of RBC, *ALAD = 6-ami no!evulinic acid dehydrase in erythrocytes; ALAU * 6-aminolevulinic acid in urine; CPU = coproporphyrin in urine; PPE = protoporphyrin in erythro cytes; FEP = free erythrocyte prophyrins; GSH = glutathione; PbB - whole blood lead. 5~1 2 DUP040013799- v 3-6at Pb8 = 25-30 ug/100 ml. Anemia (decreased hemoglobin) does not occur in otherwise healthy adults below PbB . 70-80 pg/100 ml, and in socio economically poor children not below PbB * 40-50 yg/100 ml* 2.0 Lead Exposure in Adults 2.1 Usual Exposure Several estimates have been made of common levels of lead exposure. Because gastrointestinal absorption of lead by adult subjects is only about 5-1OX, fecal excretion provides a rough estimate of intake. Kehoe (196.1) reported '& "normal11 mean 24-hour fecal excretions of 230 + 288 ug ($.0.) in a group of 453 subjects and 398 + 310 yg (5.0.) in 102 others. In the former group, the majority of persons had fecal lead excretions of less than 200 ug per day. Blood lead concentrations were not reported. The individuals were active adults, employed under conditions known to result in a negligible degree of exposure te, and adsorption of lead. The latter group was essentially similar. The difference In mean excretions was considered to reflect both local and individual dietary habits and the smaller sample size of the second group (Kehoe, 1961), Tepper reported that the average adult diet contains approxi mately 100 to 140 ug of lead per day (cited in King, 1971). Recent reports on dietary lead content (Kolbye, et a!., 1974) indicate that the lea'' content of the diet of young adults generally averages from 150-250 ug per day. 2.2 Ingestion of lead at Elevated Levels in Adults Kehoe (1961) performed balance studies in four young, adult male volunteers. The period of study varied from several months to nine years. These men ingested lead as lead acetate or lead loride along with their meals during i s~n i * DUP040013800 3-7" . the test period; and the lead was added in quantities of 0.3, 1,0, 2,0, and 3.0 mg per day above no-mal dietary lead intake which was about 300 ug per day. Intake of a total of 0.6 mg of lead per day for one year resulted in a barely detectable increase in the lead content of urine and no demonstrable increase in blood lead concentration. The total 1.3 mg dose of lead per day resulted in a progressive increase in urinary excretion of lead and in the lead content of blood and other tissues. Persons ingesting 2.3 or 3.3 mg per day showed an increase in blood lead concentration which, if continued, would rise above 80 vg/TOO ml, a level that is generally believed to be hazardous. Kehoe (1961) also reported accidental exposure of two young adults who ingested between 5 and 10 mg of lead per day for one month. This level and duration of lead exposure produced symptoms of acute lead intoxication. In the course of the blance studies, absorption of lead from the diet i was found to vary between 5 and 10% for the young, adult male subjects. Similar results were reported by Hursh and Sumo!a (1968) using short-lived radioactive lead. Later workers, using stable isotopes of lead, determined lead absorption by adult males to be 6 to 14% of either lead nitrate or food lead when the lead was ingested with the meal. Under fasting conditions, gastrointestinal lead absorption can be as high as 70% (Rabinowitz, et al. 1974). In 1974, Steak reported the results of lead administration to adult (18-26 yr) volunteers of both sexes. Groups of five subjects received either 20 or 30 yg Pb orally /kg body weight/day for three weeks, except on weekends. X?/ | ' DUP040013801 3-8The lead was given in a glycerin capsule after a meal. The body weights of the individuals were not reported. The following parameters of lead exposure were measured: whole bipod lead, erythrocyte 6-aminolevulinic acid, and hemoglobin. The responses and sequence of changes were as follows: at first, within three days, blood lead increased and erythrocyte 5-aminolevulinic acid dehydrate decreased. In females, erythrocyte protoporphyrin IX started to increase after about two weeks, up to two times pre-exposure values. In males ingesting 20 ug Pb/kg body weight, however, these changes were not observed. Males ingesting 30 ug Pb/kg body wieght/day showed a small increase in erythrocyte protoporphyrin IX. Urinary 5-aminolevulinic acid increased transiently, only in the first week, in males at this dose. Since the body weight of only one individual was given (125 kg), it is not possible to know the total dose of lead to the subjects. If a "reference man" is assumed to be 70 kg, the total dose at 20 ug Pb/kg body weight is j 1.40 mg/day and, for a 54 kg "reference woman", 1.08 mg/day. At these levels i of intake, blood lead concentrations rapidly increased in 17-22 days, from 20.6 to 40.9 ug/100 ml in males and from 12.7 to 30.4 ug/100 ml in females. The blood lead concentrations then tended to become constant. The subjects were treated with EDTA to remove accumulated lead. At the higher dose, 30 ug Pb/kg body weight/day, the mean blood lead concentration rose to 46.2 ug/100 ml. It is not clear if these were the same volunteers of the first study. Blood lead ir. the female subjects reached 41.3 ug/100 ml, which is higher than the 30.4 ug Pb/100 ml produced by administration of lead, at the same dose, in the first experiment. These S~fjT DUP040013802 3-9differences may be due to individual differences if the subjects differed from the first experiment, or to changes in variables such as nutrient content of the diet, which is known to affect the percentage of lead absorbed* These results suggest thct some differences exist between males and females^ regarding tolerance to lead. Females develop a significantly higher level of erythrocyte protoporphyrin IX than males at the same level of lead exposure. This study established that ingestion of approximately 1,0 and 1.5 mg of lead/day, for as short a time as 21 days, will result in significant increases in blood lead concentration and interference with heme synthesis (Stuik, 1974). 2.3 Inhalation of Lead by Adults In adults, approximately 40% of inhaled lead is absorbed across the alveolar membrane or is absorbed by the gastrointestinal tract after being removed by ciliary action from the respiratory tract and swallowed {MAS, 1970). The amount retained will vary with particle size. The 40% figure is based on a ''normal" mixture of particles occurring in urban air. Recently, Chamberlain et al. (1975) investigated the retention of 203Pb by adults following inhala tion, The source was exhaust from a combustion engine in which the fuel contained 203Pb-tetraethyl lead. Thirty-five percent of inhaled lead was retained in the lungs and the lead was cleared from the lungs with a half-life of six hours. About half of the inhaled lead was present in the blood 50 hours after inhalation and about half of the Pb was deposited in bone and in other tissues. From 72 hours on, the amount of Pb in blood declined with a mean biologic half-life of 16 days. The investigators calculated that continuous exposure (24 hours/day) to a concentration of 1 ug Pb/mm of air, for a period of months, would result in an increase of 1 ug Pb/100 ml of whole blood. S-?& DUP040013803 3-10 3.0 Lead Exposure in Children , 3.1 Lead Retention in Children Experiments with children, similar to those performed in adults by Kehoe, have not been conducted. Closely controlled studies that provide ' information about the level of blood lead that accompanies a particular level of lead intake do not exist. Zielhuls' review relating blood lead'concentra tion to hematologic and functional changes discusses mainly adults rather than children. The preponderance of clinical observations suggest that children develop symptoms at lower blood lead concentrations than adults, * * It is also highly probable that children develop a higher blood lead concen tration at equal levels of exposure as compared to adults because of their greater rate of absorption and smaller body size. Absorption of dietary lead by children has been reported (Alexander, et al. 1972) to be substantially higher than in adults. The children in this study were three weeks to eight years of age. A mean value of SOS net absorption and 18S retention of dietary lead occurred. Fomon, et al. (1976) conducted metabolic balance studies in young children from 2 to 25 months of age. Levels of lead Ingestion higher than that usually in the diet were not Investigated. A lead intake of less than 50 ug per day (based on individual balance data) appears to be accompanied by negative lead balance. Interpre tation of the data at these levels is difficult and may be complicated by additional sources of lead than in food, water, and air, e.g. in dust and soil. For children, the actual percentage retention of inhaled lead is not known. Currently, as in the past, when calculations of lead exposure from ! S*>? jL / DUP040013804 3-nair for children are performed, adjustment is made for the smaller respiratory volume of children, but the same percentage retention is used as was determined experimentally for adults. 3.2 Estimates of Lead Exposure for Normal Children Chisolm and Harrison (1956) determined mean fecal lead excretion of children aged 12 to 35 months with no known undue exposure to lead, to be 132 ug per day. The study of Baritrop and Killala (1967) of children 2 to 3 years of age and with no unusual exposure *o lead, reported a mean fecal excretion of 130 ug per day with an upper normal limit of 180 ug. If one assumes that children absorb 40% of ingested lead, a fecal lead excretion of^l30 ug/day represents an average intake of 220 ug of lead per day from all sources. An average intake of dietary lead of SO to 100 ug is suggested by the studies of Mahaffey (1976) and Kolbye, et al. (1974). The Food and Drug Administration, under contract with the Comprehensive Health Care Clinics of Children's Hospital, Washington, D. C., determined dietary lead intake in Self-selected diets of 1 to 4 year-old children (Mahaffey, 1976). The surveys were conducted in 1973-1974 and 1974-1975. In both surveys, the children selected were free of organic disease and were grouped as having a blood lead concentration of <30 or >40 ug Pb/100 ml of whole blood. The groups were matched for age, sex, and other demographic factors. Average dietary lead intake was 105 ug per day in 1973-1974 and somewhat less, 80 ug/day, in 1974-1975. In neither survey was there a significant difference between the dietary lead intake of children with normal or elevated blood lead concentrations. .5' DUP040013805 3-12From available information on ingestion of lead, it appears that many 2 to 3 year-old children will tolerate an oral lead intake of up to 200 ug per day without an elevation of blood lead to >40 ug Pb/100 ml whole blood. Chisolm stated (cited in King, 1971) that as daily ingestion of lead is increased from 300 to 650 ug per day there is increased urinary excretion of 6-aminolevulinic acid, an adverse metabolic effect, i.e,, interference with porphyrin metabolism, the formation of heme. This occurs as the blood lead concentrations rise above 40 ug Pb/100 ml of whole blood. A joint FA0/WH0 Committee (1972) established a provisional tolerable weekly intake of lead for adults of 3 mg but did not suggest a value for infants and young children. A Department of Health, Education, and Welfareappointed ad_ hoc committee (experts in pediatric lead toxicity) recommended (King, 1971) that 300 u9 of inorganic lead per day.be the permissible amount from all sources for one to three-year old children. Mahaffey, et al. (1976b) estimated that young children are exposed to approximately 100 ug of lead per day from air, food, and water, but it is important to note that exposure for a particular child, on any given day, may be from 20 to 500% of this. Although dietary intake of about 200 to 300 ug of lead per day appears to be tolerated by 2 to 3 year-old children, the acceptability of these levels for younger children and for infants of one year or less is not well established. Infants of less than one year are smaller in body size and have higher metabolic rates than 2 to 3 year-olds. These factors produce a proportionately higher exposure to lead from air, water, and food. In addition, calculations of tolerable lead exposure In proportion to body size may not be totally adequate rsv. 'jd' DUP040013806 3-13to establish tolerable lead intakes for infants as there are differences in maturation of the central nervous system, and young infants may absorb higher percentages of dietary lead than do two year-olds. 3.3 Estimates of Lead Exposure in Lead Poisoned Children Chisolm and Harrison (1956) determined the 24-hour fecal excretion of lead by children under six years of age. The children were grouped on the basis of having blood lead concentrations of <60 yg/100 ml of whole blood, or >60 y.g Pb/100 ml with or without symptoms, of lead intoxication such as : anemia resistant to iron therapy, severe constipation, anorexia, hyper irritability, bizarre behavior patterns, interai ttent vomiting, accompanied by mild or severe encephalopathy. Children who were found to be asymptomatic with blood lead concentrations greater than 60 yg/100 ml had roantgencgraphic evidence of lead storage in bone and increased coproporpuyrin excretion in the urine. The children with symptomatic lead poisoning excreted $ to 104 mg of lead per day and the median value was 27 mg per day. Children with evidence of an elevated body burden Of lead but without overt lead toxicity excreted between 116 ug and 9.6 mg per day with a median value of 1.1 mg per day. Those children with blood lead concentrations less than 60 yg/100 ml of whole blood excreted between 12 and 175 yg per day. Chisolm and Harrison (1956) estimated that 5 to 6 months duration of exposures associated with these fecal lead excretions were required to produce these blood lead levels with or without the symptoms. Barltrop and Killala (1967) reported fecal lead content of normal children and children with evidence of clinical lead toxicity from paint ingestion. Lead excretion was reported in mg per single fecal specimen which was collected Coo DUP04Q013807 1 3-14upon admission to the hospital or clinic. Normal children excreted a mean of 130 yg per specimen while the children with clinical lead poisoning excreted between 570 yg and 1.9 mg per specimen. On the basis of these data, it has been concluded that absorption of 1 to 2 mg of lead daily for cive to six months might cause symptomatic poisoning in 1 to 2 year-old children (Lin-Fu, 1972) or might cause an elevation of body burden of lead and a derangement of porphyrin metabolism (King, 1971). Subsequent to these estimates of quantities of 1 end, needed to produce symptomatic lead toxicity in children, three additional investigations on lead exposure in children have been reported (Ter Haar and Aronow, 1974a,b; Hammond, 1974). Ter Haar and Aronow (1974a) reported fecal lead excretion in yg Pb/g dry weight of fecal material/day for 1 to 3 year-olds. Ten control children from suburban Detroit with no known exposure to an excess of lead excreted an average of 4 yg (range 2 to 7) /g dry weight/day, with a daily average of 15 g dry weight of fecal material. These values correspond to an average fecal lead excretion of about 60 yg Pb/day. Blood lead values for the control children were not reported in this publication. Eight children who had been hospitalized with the suspicion of elevated body burdens of lead excreted averages of 4, 7, 18, 19, 20, 40, 49, and 1640 yg/g dry weight/day. For these children an average excretion is not very meaningful as two of them excreted lead in the control range, while one child excreted in excess of 1640 yg/g dry weight/day. The total weight of fecal material excreted by the lead-exposed children was not reported. However, If daily C 0} i i a> \ i i DUP040013808 3-15fecal excretion of 15 grams dry weight is assumed (however, see Hammond, 1974 below), the middle four concentrations correspond to an excretion of 270, 285, 300, and 600 ug Pb/day. Thirty normal children (Ter Haar and Aronow, 1974b) from homes in suburoan /* Detroit where lead poisoning was not a problem excreted a mean of 79 ug Pb/g dry Weight/day with a range of 22 to 174 and a median of 75 ug/g dry weight/day. Children thought to be exposed to lead excreted an average of 1781 yg Pb/g dry weight/day with a range of 8 to 29,030 and a median value of 218 yg/g dry weight/day. Hammond (1974) performed repeated determinations of fecal lead excretion by children having whole blood lead concentrations in. excess of 40 ug/100 ml. He found that fecal lead excretion above "background" levels is highly variable, prpbably due to the fact that the pica habit that produces highly elevated fecal lead concentration is sporadic. He indicated that "by procuring several stool samples, a low lead sample is readily found in almost any child, irrespective of its blood lead concentration". However, the great majority of the children investigated by Hammond having blood concentrations of >40 ug Pb/100 ml whole blood had fecal excretions of >80 ug Pb/g dry weight/day with an average total dry weight of 6 g. The dry weight and lead content of fecal specimens in these studies were highly variable since constipation can occur in children with elevated body burdens of lead. Because of this variability, it is extremely difficult to estimate the quantities of lead ingested by children exposed to large amounts of lead on the basis of a single 24-hour stool specimen. It is not known if the absorption of lead varies with rate Of passage of fecal material through the gastrointestinal tract. Background levels for children not exposed to elevated amounts of lead appear to be more constant. C02 3 I DUP040013809 4.0 Other Parameters Affecting Lead Toxicity ' 4.1 Form of Lead Organic lead compounds such as tetraethyl or tetramethyl lead are highly toxic compared to inorganic lead compounds. Lead values on autopsy following tetraethyl or other organic lead poisoning are sparse. However, the partitioning of lead in the tissues in tetraethyl lead poisoning occurs as one would expect. Tetraethyl lead is lipid soluble and readily diffusible resulting in rapid accumulation in nonossecus tissues, particularly the brain and there is a rapid onset of symptoms; There is little time for lead to '0 accumulate in bone before the symptoms of toxicity occur. This difference in partitioning of lead between persons dying of organic lead intoxication and those with chronic inorganic lead poisoning emphasizes the importance of the concentration of lead in a target organ rather than the total body burden of lead. Data on the relative toxicity of different forms of inorganic lead show a much less clear-cut picture. Several points do stand out: (1) The solubility of the compounds in acidic or basic solutions is not, in itself, predictive of bioavailability, (2) Size is important. The same dose of lead as small particles is associated with greater lead absorption than with large particles. However, when large pieces of lead are ingested, as with lead shot or with a lead curtain weight, these may lodge in the gastrointestinal tract, slowly dissolve, and cause severe lead poisoning. . 3-17Part of the difficulty in interpreting data on bioavailability of different lead compounds is attributed to the variety of assay systems utilized. In long-term studies, the results have been reported from a number of species including ruminants and birds. The gastrointestinal systems of these species are markedly different from that of the human. A considerable .amount of data has been obtained from studies in which the lead compounds were fed for 48 hours (Barltrop and Meek, 1975; Barltrop and Khoo, 1975). Although these studies were well controlled, their short duration provides information on only some aspects of lead absorption. Under circumstances ' i where a difference in absorption may be due to physiological adaptation and not to the physical form of a compound, 48-hour studies are unlikely to detect these changes. For example, studies in animals have shown that iron deficiency enhances lead retention several fold (Mahaffey-Six and Goyer, 1972); however, this effect is not detectable in the short-term assay (Baritrop, personal communication). Barltrop (1974) reported that lead chromate, lead .I sulfide, and lead molybdate produced lower blood, kidney, and femur lead ; concentrations than did lead acetate, while lead oxalate and basic lead carbonate produced higher tissue concentrations of the lead. In these studies, the rats were fed diets containing the various compounds at equivalent lead levels for 48 hours. Elemental lead having a particle size of 180 to 250 u was taken up only one-fifth as well as lead acetate. However, when particle size of the elemental lead was reduced to <180 w, the tissue lead concentrations were approximately twice those with the larger particles. While considering particle size of importance, Barltrop (1974) noted that it is not possible Co DUP040013811 ft 3-18to predict particle size of added lead compounds after incorporation into the diet, or to predict the physical behavior of the particles in the lumen of the gastrointestinal tract. ATIcroft (19511 reported that 200 to 400 mg of lead/kg body weight, ingested in any one day as either the acetate, basic carbonate, or oxide, caused death of calves up to four months old. The apparent absorption of lead in sheep was reported (Blaxter, 1950) to be similar when the lead was given as the acetate, nitrate, or as naturally contaminated hay. However, because both the cattle and sheep are ruminants and have.far different gastro intestinal systems than humans, these results are not necessarily predictive for human absorption of the compounds. Interestingly, Buck (1970) observed that lead in greases and oils is more toxic than elemental load or lead salts. These differences could be due to the nature of the vehicle. Barltrop (1974) reported for rats that increasing the amount of corn oil in the diet increased the absorption of lead. In ten-week studies, Ku et a'l. (1976) found that for both young and mature rats. Ingestion of either lead acetate or a complex of lead with a phospholipid resulted in similar concentrations of lead in the femur, kidney, liver, and brain. Several studies compared the bioavallability of lead as it occurs in natural foods with that of lead acetate. Equal concentrations of tissue lead were obtained in rats (Castles, 1976) and quail (Stone et al., 1976) fed oysters containing high concentrations of lead or an equivalent amount of lead as lead acetate either with or without the oysters. In both of these s 60$ DUP040013812 3-19experlrents the trace metal contents of the diets were found to -he constant in the diets. In humans, Rabinowitz, et a]. (1975) found that blood lead concentration was the same when lead was that of the food or lead nitrate, when the total lead intake remained the same. 4.2 Presence of Other Components in the Diet In general, it is not possible with certainty to separate effects produced by nutritional factors into a component that affects absorption of lead in the gastrointestinal tract from one that alters the metabolic capacity of the animal or human. Garber and Wei (1974) investigated gastrointestinal`absorption of lead in adult mice after oral 2inPb acetate. They found that over a 1000-fold range of dose, the percent absorption of lead did not vary when food was withheld. Food in the gastrointestinal tract reduced the absorption of trace amounts of lead (0.02%) but did not affect the absorption of 2 or 20 mg Pb/kg body weight. The three chelating agents, ethylenediamine tetracetic acid (EDTA), diethylenetriamine pentaacetic acid (DPTA), and nitrilotriacetic acid (NTA), had variable influences. Neither EDTA nor DPTA altered lead absorption while NTA increased its absorption. In longer term studies in rats (7 weeks) Hahaffey and Goyer (1972) did not observe an increase of tissue lead when NTA was fed with the lead. Regarding natural food components, Garber and Wei (1974) reported that lead absorption was increased by the chelating agent sodium citrate and by orange juice, which contains citric acid. Administering sodium citrate with HC1 at a concentration similar to the acidity of the orange juice did not change the absorption of the lead. - Co C ji l I DUP040013813 3-20For some time, milk has been considered to be an antidote for lead in cases of industrial poisoc/'-g. Data in experimental animals appear to be contradictory. Kello and Kostiai (1973) gave six week-old rats a single oral or intraperitoneal dose of 2^2Pb in trace amounts and reported large increases in lead retention when the diet contained several types of milk as compared to rat chow. However, Garber and Wei (1974) gave 210Pb orally with larger amounts of lead as carrier to six week-old mice and found no effect of the milk on absorption. It is not known whether the reported differences in the effect of milk on lead absorption are due to species variability, the dose of lead administered or other experimental variables. There is little doubt that diets supplying adequate amounts of milk can influence susceptibility to lead toxicity by means of providing an adequate supply of calcium and phosphorus. Less than adequate intake of these nutrients are known to increase susceptibility to lead toxicity in humans and experimental animals. Barltrop and Khoo (1975), while they did not test milk, itself, tested several milk components for an effect on lead absorption in rats. They found that the high fat and protein content of milk might be expected to increase lead absorption, but that this effect would be counteracted by the high mineral content of milk. Other foods have been proposed for the prevention of lead poisoning. Sever?! of these contain complex, relatively nondigestible carbohydrates. Carr et al. (1969) reported that in 7-8 week-old rats, when the standard laboratory diet contained 10% alginate, lead absorption was reduced. Kostiai et al. (1971) reported that alginates reduced lead uptake from the gastro intestinal tract of newborn rats. However, in three human volunteers, additions Co? \DUP040013814 3-21of alginate to the diet did not affect lead absorption (Harrison et al., 1969), Koshcheev et .al, (1570) suggested that a generous supply of carrots and cabbage in the aiet of workmen increased lead excretion and reduced urinary coproporphyrin III. The pectin and ascorbic acid contents of these products were considered to be the effective agents. The overall ability of individual dietary components to increase or decrease lead absorption has not been established in humans. Studies to demonstrate these effects should ideally be conducted in humans over a relatively Tong period of time. The effect of foods would have a greater influence over a prolonged time rather than as short-teri' therapeutic .measures. Alternately, animal testing would need to be done in a species such-as the miniature pig, in which the gastrointestinal physiology is similar to that of humans, 4.3 Metabolic Condition of the Subject There is a marked difference in lead absorption between children and adults. Details of the research defining these differences have been described above, Overall, young children absorb 3 to 10 times the amount of lead as do adults. Diets low in several nutrients appear to result in higher body burdens of lead at fixed levels of lead intake. For example, diets deficient in calcium and/or phosphorus result in higher tissue concentrations of lead at equivalent levels of lead intake. These effects of calcium and phosphorus have been reported for a number of animal species. Increased susceptibility to lead toxicity are not a direct function of level of calcium intake. When dietary calcium intake is below the physiological requirement for calcium, increased retention of lead occurs (Mahaffey et al. 1976a). Addition of high levels of calcium does not result in reduced retention of lead as compared I C PS H Vi i! DUP040013815 . 3-22to retention occurring at normal levels of calcium intake (Mahaffey, 1976; Shields and Mitchell, 1941). On the basis of these observations, it is likely that a portion of the increased retention of lead is due to metabolic changes produced by calcium deficiency rather than simply the physical presence of calcium in the gastrointestinal tract. Increased absorption of lead has also been observed in balance studies with human infants receiving diets composed of normal infant foods. Slight reductions in dietary calcium content resulted in increased absorption of the lead present in these normal diets (Fomon et al., 1976). Effects of calcium at higher levels of lead 'm ingestion are not known. Epidemiological studies with young children have shown that children with elevated blood lead concentrations consumed diets that were significantly lower in calcium and phosphorus than those of children with normal levels of blood lead (Mahaffey et al., 1976b). Diets which are low in iron also increase retention of lead, A two- to three-fold increase in tissue lead retention of rats occurred on diets deficient in iron (Mahaffey-Six and Goyer, 1972), The degree of iron deficiency was not extreme as animals from this experiment showed only a modest decrease in hemo globin concentration- Dietary deficiencies of iron consitonly occur in the popu lation grouns in which lead poisoning is most frequent. Levander and co-workers (1975) reported that weight gain and hematocrit were significantly lower in vitamin E-deficient animals fed lead than in animals which were either only vitamin E-deficient or fed lead alone. Tissue lead concentrations are not reported in this publication. Sobel et al. (1938) reported that lead absorption as demonstrated by tissue lead concentrations is greater in rats receiving diets to which vitamin D was added than on rats receiving vitamin D deficient diets. i DUP040013816 3-23 Deficiencies of nutrients do not always produce increased absorption of lead. For example, neither low nor highly elevated Intake of ascorbic acid appreciably influenced tissue retention of lead (Mahaffey and Banks, 1975), Factors other than minerals and vitamins have been found to influence lead absorption. Baritrop and Xhoo (1975) reported that increasing the fat'" content of the diet resulted in a higher absorption of a dose of lead. The protein content of the diet is also a factor in determining susceptibility to teed toxicity. Baernstein and Grant (1942) found that rats fed lead chloride showed lower mortality and a diminished weight loss when *he protein level of the diet was increased from 6 to 13 and 20%. Gontzea and co-workers (1964) observed that doubling the protein content of the diet from 9 to 18% in the rat decreased susceptibility to lead toxicity as judged by lead content of liver, kidney, and blood. Der et al. (1974) observed that rats fed 4% protein diets had higher blood lead concentrations than animals fed 20% protein diets when lead was injected subcutaneously. These data are difficult to interpret because both groups of rats were injected with 100 v9 of lead acetate daily for 40 days. Rats receiving diets containing 4% protein were severely growth-retarded. With equal quantities injected, the dose per unit body weight was markedly different. The pathologic effects of lead are more closely related to the con centration of lead in critical tissues such as brain and kidney than to total body burden of lead. A number of metabolic factors in the subject act to determine the amount of lead absorbed and the partitioning of lead between tissues such as brain and kidney and storage in a relatively nondiffusible matrix such as bone. if fO - --DUP040013817 3-24- mVMk 1 rv PH tP ClUixl liOfTtltll a 29 -S 59 C/fiJv // I das* /// mtviiwlir | *h*J%/w*lY ch'Vf'wJ | jfl&ttted C/u-vr / r JtW9 60-U 50-79 I1U-IS9 r> a i**n ,, l uMe !2 r>t mirh EF < .59 /* EP EF no-isv > job Ph s 29 i la ~ ta EEP + Pb JU-99 lib 4 m fv Pb 50-79 Pb>S0 * * in .* Hi fiv * IV IXP+ tm |m | E>xhwp<>ieiic proup*>sp*t>nji. Combination ol' resulw ko*.n scncraiU uter*ed in practice whenbloovMead.h repeated.the. rr^J:> a* ill cnerjlK indicate cobtarnizution of the fuM >p.vimcfl. (V*n?raUifl of the estimate ef >t of lead MOWjb\m su^e>xcd b\ Mood lead k altered on the had-* w* the F.P multi. Upgrading; of the estimate of rid rf lead int.'\ivjuon Mi'SCrtcJ bv .hloiHi lead i\ altered on the hj'i' of ihf Ef results S svf&mfi** Tnwiya'IwT Tt'vTirnV* DUP040013818 CHAPTER 3 3-2 REFERENCES Alexander, F, W., Clayton, 8. E., and Delves, H. T. The uptake of lead and other contaminants. In Environmental Health Aspects of lead. Commission Of the European Communities and the United States Environmental Protection Agency, Amsterdam, Netherlands (1972), Allcroft, R. lead poisoning in cattle and sheep. Vet. Rec. 65: 583 (1951). y' Baernstein, H. D. and Grant* 3. A. The relation of protein to lead poisoning in tats, 3. Pharmacol, Exptl, Therap, 74: 18 (1942). Barltrop, 0. and Killala, N. H. P. Fecal excretion of lead by children. Lancet 2: 1017 (1967), Barltrop, D. Interim Report to Department of Health, Education, and Welfare. (1974). Barltrop, D. and Khoo, H. E. The influence of nutritional factors on lead absorption. Postgrad. Med, 3. 51: 795 (1975). A Barltrop, D. and Meek, F, Absorption of different lead compounds. Postgrad. Med. 3. 51: 805 (1975). Benson, G. I., George, W. H. S., Litchfield, M. H. and Seaborn, D. 3. Biochemical changes during the initial stages of industrial lead exposure, Brit. 3. Industr. Med, 33: 29 (1976). Blaxter, K, L. Lead as a nutritional hazard to farm livestock. III. Factors influencing the distribution of lead in tissues. 3. Comp. Pathol, and Therap. 60: 177 (1950), Buck, VI. B. Inorganic lead poisoning in cattle, 3. Amer. Vet, Med. Assoc. 156:1468(1970), Carr, T. E. F., Nolan, 3. and Durakovic, A. Effect of alginate on the absorption and excretion of TM3pb in rats fed milk and normal diets. Nature 224: 1115 (1969). Castles, T, R., House, W. B., Wood, 3., Oliver, T, M., Rollheizer, 3. R., Marcus, M. F., Lamb, 3. B. and Sobotka, T. 3. Bioavailability of lead in oysters. Fed. Proc. 35: 211 (1976), Center for Disease Control. Increased lead absorption in young children. A statement. 3, Pediatrics 87: 824 (1975), Chamberlain, A. C., Clough, W. S., Heard, M. 3., Newton, D., Stott, A. N. B., and Wells, A. C. Uptake of lead by inhalation of motor exhaust. Proc, Royal Soc., London, B. 192: 77 (1975). j, d (s / P DUP040013819' 3-26- Chisnlm, J. J. Jr. and Harrison, H. E. The exposure of children to lead. Pedlaries 18: 943 (1956). Chisolm, J. J, Jr. Increased lead absorption; toxicolooieal considerations. Pediatrics 48: 349 (1971), Chisolm, 0. J. Jr. Disturbances in the biosynthesis of heme in 'ead intoxication., J. Pediatrics 64:. 150 (1974). Chisolm, J. J. Jr., Barrett, M. B. and Mellitis, E. D. Dose-effect and doseresponse relationships for lead in children. J. Pediatrics 87: 1152 (1975a). Chisolm, J, J. Jr., Barrett, M. B., and Harrison, H. V. Indicators of internal dose of lead in relation to derangement in heme synthesis. Johns Hopkins Med. J. 137: 6 (1975b). Der, R., Hilderbrand, D., Fahim, Z,, Griffin, W. T., and Fahim, M. S, Combined effect of lead and low protein diet on growth, sexual development and metabolism in male rats. Res. Common. Chem. Pathol. & Pharmacol^. 9: 723 (1974). Fomon, $., Ziegler, E., and Mahaffey, K, R, Unpublished data (1976). Garber, B. T. and Wei, E. Influence of dietary factors on the gastrointestinal absorption of lead. Toxicol. SAppl. Pharmacol . 27: 685. (1974). Gontzea, I., Sutzesco, P., Cocora, D., and Lungu, D. Importance de rapport de proteir.es sur la resistance de I'organisme a 1'intoxication par 1e plomb. Arch. Set. Physiol. 18: 211 (1964). Hansnond, P. B. Sources of lead in children. National Sciences Foundation, RANN, Progress Report (1974). Harrison, G. E., Carr, T. E. F,, Sutton, A. and Humphreys, E. R. Effect of alginate on the absorption of lead in man. Nature 224: 7115 (1969). Hursh, J. B. and Suomela, J. Absorption of Pb from the gastrointestinal tract of man. Acta Radiologica 7: 108 (1968). Kehoe, R. A. The metabolism of lead in man in health and disease. J. Royal Instit. Public HTth. & Hyg. 24: 81 (1961). Kello, D. and Kostial, K. The effect of milk diet on lead metabolism in rats. Environ. Res. 6: 355 (1973). King, B. G. Maximum daily intake of lead without excessive body lead-burden in children. Amer. J. Dis. Child. 122: 337 (1971). Kolbye, A, C., Mahaffey, K. R., Fiorinp, J, A., Corneliussen, P. C. and Jelinek, C, F. Food exposure to lead. Environ. Hlth. Perspec. 7: 65 (1974). (3 DUP040013820 3-27- Koshchcev, A, K,, et al. Use of vegetables in the therapeutic and preventative nutrition of lead workers. Gig. Tr. Prov. Zabol. 14(1): 52 (1970). Kostial, K., Simpnovie, I. and Pi sonic, M. lead absorption from the intestine in newborn rats. Nature (London) 233: 564 (1971). Kii, Y,, Alvarez, H. G., and Mahaffey, K. R, Comparative effects of feeding lead acetate and phospholipid bound lead on blood and tissue lead levels in rats. '' Abs. of Papers, Society of Toxicology 15th Annual Meeting, Atlanta, Georgia, p. 139 (1976). levander, 0. A. , Morris;, V. C., Higgs, D. 0. , and Ferret,ti, R. J. lead poisoning in vitamin E deficient rats. J. Nutrition 105: 1481 (1975). lin-Fu, J. S. Undue absorption of lead among children -- a new look at an old problem. N. Engl. J. Med, 236: 702 (1972), Mahaffey-Six, K. and Goye.r, R. A.' The influence of iron deficiency on tissue content and toxicity of ingested lead in the rat. <J. Lab. Clin. Med. 79: 128 (1972), Mahaffey, K, R. and Coyer, R. A, Trisodium nitriloacetate in drinking water: metabolic and renal effects in rats. Arch. Environ, With. 25: 271 (1972}. Mahaffey, K. R. and Banks, T. A. Effect of varying diecary ascorbic acid on lead toxicity in guinea pigs. Fed- Prcc. 34: 267 (1975). Mahaffey, K. R., Banks, T. A. , Stone, C. 1., Capar, S., Compton, <1,, and Glubik, M, Effect of varying levels of dietary calcium on susceptibility to lead toxicity. Proc. Inti. Conf. on Heavy Metals in the Environment, Toronto, Canada. In press (1975a). Mahaffey, K, R., Treloar, S., Banks, T, A,, Peacock, B. J., and Parekh, L. E. Differences in dietary intake of calcium, phosphorus and iron in children having normal and elevated blood lead concentrations, Amer. 0. Clin, Nutrition. Manuscript submitted for publication (1976b). Mahaffey, K. R. Unpublished data (1976). National Academy of Sciences, Committee oh Biologic Effects of Atmospheric Pollutants. Airborne lead in perspective, Washington, D. C. p. 47 (1972). Rabinowitz, M,, Wetherm, G. W., and Kopple, j. D. Studies of human lead metabolism by use of stable isotope tracers. Environ. Hlth. Perspec. 7: 145 (1974), Rabinowitz, M., Wetherill, G., and Kopple, J. Absorption, storage and excretion of lead by normal humans. 9th Annual Conference an Trace Substances in Environmental Health, University of Missouri, 351 (1975). ..t v _ C /y DUP040013821 3-2 8Reigert, J. R. and Whitlock, N. H. Longitudinal observations of the relation ship between free erythrocyte porphyrins and whole blood lead. Pediatrics 57: 54 (1976). Shields, J. B. and Mitchell, H. H. The effect of calcium and phosphorus on metabolism of lead. J. Nutr. 21: 541 (1941), Sobel, A. E., Grawon, 0., and Kramer!, B. influence of vitamin D in experimental lead poisoning, Proc. Soc. Exptl. Biol, Med. 38: 433 (1938), * Stone, C. L., Mahaffey, K, R., and Pox., M. R, S. Rapid assay system for lead bioavailability using the Japanese quail, Abs. of papers. Society of Toxicology 15th Annual Meeting, Atlanta, Georgia, p. 167 (1976), Stuik, E. J. Biological response of male and female volunteers to inorganic lead. Int. Arch. Arbeits. Med. 33: 83 (1974). Ter Haar, G. and Aronow, R. New information of lead in dirt and dust as related to the childhood lead problem. Environ. Hlth. Rerspec. 7: 83 (1974a). \ Ter Haar, G. and Aronow, R. Use of tracers to define sources of lead in children. XIV International Congress of Pediatrics, Buenos Aires (1974b). Joint FA0/WH0 Expert Committee on Food Additives, Evaluation of Certain Food Additives, Mercury, Lead and Cadmium. World Health Organizationjechnical Report Series 505. World Health Organization Technical Report Series (1972). Zielhuis, R. L, Oose-response relationships for inorganic lead I Biochemical and hematological response. Int. Arch. Occup. Hlth. 35: 1 (1975a). Zielhuis, R. L. Dose response relationships for ino ganic lead II Subjective and functional responses - chronic sequelae - no response levels. Int. Arch. Occup. tilth. 35: 19 (1975b). ii * \ i DUP040013822 4, LEAD TOXICITY 4-1 1.0 Neurotoxicity of Lead 1.1 Effects of Lead on the Central and Peripheral Nervous System 1.1.1 Encephalopathy: The neurotoxicity of lead at high levels of exposure has been well docu mented for both man and animal species. Acute encephalopathy is one of the most serious consequences of plumbism, since permanent impairment of the central nervous system may occur, particularly in young children. Byers and Lord (1943) showed that lead encephalopathy produced some irreversible neuro logical and psychological sequelae in 19 out of 20 children. The American Academy of Pediatrics (1969) estimates that 255! of children affected with lead encephalopathy will suffer permanent damage to the central nervous system. "0 This damage is usually reflected in behavioral and educational abnormalities, vrith or without accompanying mental retardation. Perl stein and Attala (1966) observed that 82" of children with a history of lead encephalopathy experienced recurrent seizures and mental retardation. Mel 1ins and Jenkins (1955). and Bradley and Baumgartner (1958) found that 60-80% of children treated for plumbism later had impaired visual-motor coordination. Smith (1963) found abnormal LEG tracings in six of ten children affected with encephalopathy. Children who have already experienced lead encephalopathy and are subsequently re-exposed to lead, will almost certainly develop permanent CNS damage (Chisholm and Harrison, 1956). Recently, Albert, et al. (1974) and Rummo (1974) have reconfirmed the detrimental effects of severe lead poisoning on the subsequent behavior and intellectual functioning of children. 1.1.2 Neurological Diseases: Lead exposure has been linked to several chronic neurological diseases (Warren, 1974). Cone (1934) reported that the cerebrospinal fluid of / / DUP040013823 multiple sclerosis patients contained elevated lead levels; however', Butler (.1952) and Westerman (1974) using more sensitive techniques for lead analysis were unable to show an association between lead absorption and multiple sclerosis. The possibility of an association has been revived by Warren (1963, 1967, 1974) by demonstrating that geographical areas with Mgh environmental lead levels have a high incidence of multiple sclerosis. A number of studies (Campbell, et al, 1970; liyesly and Sissons, 1968; Simpson, et al, 1964) have reported an association of exposure to lead with motor neuron disease, but the etiological role of lead is not clear in these studies, lead insult has also been associated with scrapie and swayback in sheep, and kuro and amyotropic lateral sclerosis in humans (see Warren, 1974). These suggestive associations warrant further investigation, but to date, controlled, positive studies are Tacking. 1.1.3 Peripheral Neuropathy: Animal studies have shown that lead produces segmental demyeli nation (Fullerton, 1966; lampert and Schochet, 1968; Sauer, et al. 1970), and interferes with myelin metabolism in tissue culture (Cole and Lynam, 1972). Such damage to the myelin sheath has been shown to impair nerve function, Catton, et al. (1970) and SeppSiainen and Kernberg (1972), using sensitive electrophysiological techniques, observed impaired motor nerve conduction velocities in neurologically symptom-free lead workers, whose blood lead levels exceeded 70 ug/100 ml. Of particular importance are the more recent studies by SeppHlSinen, et al. (1975) which revealed a slowing of motor conduction velocity of the median and ulnar nerves of asymptomatic workers whose blood lead values had never exceeded 70 ug/100 ml. Abnormal measurements Cn DUP040013824 4-3began to occur at blood lead levels of 50-60 ug/100 ml. These abnormalities were not as great as observed in the earlier heavily exposed workers. Thus a dose-response relationship appears to exist., I.'o correlation between biochemical tests of exposure and neurological signs was observed. These preliminary findings do suggest that the acceptable level of blood lead (7.0 ng/100 ml) for occupationally exposed workers may need to be reevaluated. Peripheral neuropathy has been considered to be a rare occurrence in children with lead intoxication (see Seto and Freedman, 1960), However, it is possible that childhood neuropathy is sometimes overlooked and overshadowed by riie clinical symptoms of encephalopathy (Feldman, et al. 1973). These authors observed slightly reduced motor nerve conduction velocities in children with a known history of plumbism. Whether peripheral neuropathy occurs in asymptomatic children with no history of lead poisoning remains a matter of conjecture and is discussed in the following .section. 1,2 Neurological and Behavioral Toxicity of Chronic Lead Exposure in Children: A growing concern, which has received a great deal of publicity recently, is the possibility that chronic, asymptomatic lead exposure may cause "minimal brain dysfunction", behavior problems, and neurological impairment in children exposed to lead In utero and/or during early childhood. Wiener (1970) reviewed the literature up until 1968, He concluded that methodological shortcomings in all of the studies made it impossible to draw definitive conclusions. Wiener notes that: "Those reports which claimed positive findings had either used too few cases from which to generalize or had not provided for controls for relevant variables such as social class, pica; or premorbid status. it Al / U2 DUP040013825 4-4A rigorous statistical and experimental approach has been conspicu ously absent. Further, the variations in diagnostic procedures and definitions lead to unclear conclusions regarding the degree of lead ingestion which may or may not be important for later development." A brief critique of some representative, frequently-cited studies will indicate that such criticism continue to apply, in varying degrees, to all subsequent studies. For example, David, et al. (1972) suggested an associa tion between lead exposure and hyperactivity in children. Children, whose hyperactivity had no known cause, had higher blood lead levels and body burdens of lead than normal children or children whose hyperactivity had a "known cause". However, since the numbers in the "known cause" group were very small, it cannot be ruled out that lead absorption was secondary to hyperactivity, particularly since it has been shown that disturbed children tend to exhibit an increased incidence of pica (Bickoell, 1967; Klein, et al, 1974; Cohen, et al., 1976), The statistical treatment of this study by David, et al. has also been criticized (Bulpitt, 1972). Pueschel, et al. (1972) and de la Burde and Choate (1972, 1975) compared children with a history of pica and elevated blood lead levels (40 ng/lOO ml and above), to control children with no history of pica. The lead exposed children showed mental impairment, irritability, and poor fine motor control. In most cases, lead blood concentration was high (>50 yg/100 ml). Although the groups were matched for race, age, sex, and several socio-economic variables, no lead assessments were made for the control group. Again it can be argued that children with some history of psychological disturbance (i.e. pica) may have other signs of disturbance which are not directly related to lead exposure. i (olf / DUP040013826 4-5Kotok (1972) included pica in addition to age, sex, race, and environ mental factors in matching his controls. He failed to find significant differences in mental development between lead exposed (blood lead > 40 ug/100 ml) and control groups and concluded that the differences observed were related to home environment rather than lead exposure. However, his controls (many of them were siblings of the exposed group) had a mean blood lead of 38 ug/100 ml. Thus, as many of the controls may have been at high risk for lead, and Kotok's data must be considered inconclusive (Niebyrg, 1972). Other studies suggesting a causative association of lead exposure with mental impairment have been equally inconclusive (Perino an.- Ernhart, 1974; Rummp, 1974, Millar, et al. 1970; 3aloh, et al. 175, Beattie, et al. 1975). The studies described up to this point have dealt primarily with urban children whose exposure to lead may come from many sources. Recently, attention has also focused on the effects of chronic lead exposure in children living in the vicinity of ore smelters (Roberts, et al., 1974; Whitworth, et al. 1974; Landrigan, et al. 1975b). McNeil and Ptasnik (1974) evaluated 138 children (21 months - 18 years old) living in Smeltertown, Texas.. Smeltertown is adjacent to a large ore smelter in operation for about eight years. Serial blood lead determinations indicated that these children had prolonged, asymptomatic elevations in blood lead levels (40 - 80 ug/100 ml). They had no neurological symptoms, and nerve conduction tests were normal. The authors found no differences in the activity, measurements, and psychometric evaluations of exposed children and matched controls, living outside of Smeltertown. They concluded that sustained blood lead levels of 40-80 ug/100 ml had not resulted in any apparent deleterious effects (o DUP040013827 4-6- Landrigan, et al. {1975a} evaluated the neuropsychological function of children living near an ore smelter in El Paso, Texas, They concluded that at blood lead levels of 40-80 yg/100 ml subtle impairment of nonverbal cognitive and perceptual-motor skills occurred. However, since their controls were poorly matched with respect to age, history of pica, etc., the etiological role of lead cannot be clearly established. Another study by lansdown, et al. (1974) found no association between blood lead and intelligence and activity levels of school children living near a smelter. These authors concluded that social factors were more important than physical exposure to lead in determining meiital development. However, their social factors were not quantified and very subjective assessments of behavior were used (Bryce-Smith, et al,, Landrigan, et al., David, et al. 1974), thus rendering their conclusions dubious. Neurological and psychological evaluations have also been made on a large, random sample of children living near a primary smelter in Shoshone * County, Idaho (Shoshone y^d Health Project, 1976). Landrigan, et al. (1976) evaluating matched pairs of children (with 40 sjg/100 ml as the standard to divide the children into low and high blood levels ) reported a significant correlation between lead intake and slowing of motor nerve conduction velocity. However, Gregory, et al. (1976) independently forming their own set of matched pairs (also using 40 ug/100 ml as the standard delineating point), found no differences in nerve conduction velocities or intellectual measures between the lead exposed and control children. j DUP040013828 i 4-7Gartside and Pan.ke (1976) have reviewed the matched pairing techniques and statistical analyses used in the Landrigan and Gregory studies. They also noted that in the landrigan study only six children (out of 202) had nerve conduction velocities below the lower limit of normal children with similar ages (Gamstorp, 1963). When other matched pairing' and statistical analyses wqre performed on the same two groups nf children, no significant differences were observed. It should be noted that the use of 40 pg/100 ml blood lead level to divide the pairs is arbitrary. Sets of matchings using different dividing points might produce different statistical results. Since conflicting results are produced using different ways te-jpalyze the same data, a significant relationship between blood lead and nerve conduction velocity in children cannot be established. The crux of the problem, applicable to all the studies cited, is that many of the traditional methodologies, approaches, and data analyses used to assess the behavioral and neuropsychological consequences of lead exposure in young children are open to subjective interpretations. For example, the assessment of "hyperactivity", a syndrome not well-defined operationally. Often relies primarily on the "impressions" of parents and teachers. Baloh, ... et al. (1975) found that many mothers reported overactivity in children with elevated lead levels, but this was not observed in objective behavior ratings by a neurologist or psychologist. On the other hand, it is difficult to validly assess children's behavior outside of their every day en/ironment. Matched controls cannot accommodate all the significant, concomitant variables 5I ;i ' ' I j > : 11 ') . i 5 : i \ DUP040013829  /- - which may affect activity levels and mental functioning. A persistent reliance upon such traditional approaches will only succeed in stimulating controversy. ' Another general criticism of these studies is that testing is performed primarily on school age children. These studies were unable to document whether excessive lead absorption, encephalopathy, etc. occurred In infancy and early childhood; i.e. during the time that suspected brain damage is most likely to occur. Young children's intelligence and behavior must be assessed before exposure to lead to determine whether an elevated lead burden causes or was caused by defects in mental abilities. Sven then, other causative factors must also be considerpd. Thus the data presently available are inadequate to conclude that subtle psychological, emotional, and neurological sequelae occur as a result of lead exposure at levels below those causing clinical symptoms. 1.3 Behavioral Toxicity of Chronic Lead Exposure in Animal Species: Table 4.1 summarizes some of the pertinent literature on the effects of pre natal and neonatal lead exposure on the subsequent development and behavior of several animal species. Delayed nervous system development, deficits in visuo- motor functioning, abnormal social and aggressive behavior, hyperactivity, hypo- activity, and no changes in activity have all been reported. Parameters which measure central cognitive functions (learning, memory, etc.) do not appear to be generally affected. It is difficult to compare these studies, since the dosage, chemical form, route, timing of lead administration, and the technology used to assess the behavioral and psychological parameters vary considerably. Unwarranted generalizations and extrapolations from limited behavioral measures have fre quently been made. A brief analysis of some of the more frequently-cited studies i S' a&ii DUP040013830 4-9indicates that the investigations on animal models have confused rather than clarified the human data. Sibergeld and Goldberg (1973, 1974), exposed suckling mice to 1090-5500 ppm lead acetate through their mother's milk and at weaning directly through the drinking water. They reported a three-fold increase in their spontaneous y locomotor activity as compared to control mice. Although lead toxicity symptoms were not apparent, the growth of the lead exposed offspring was significantly retarded, as indicated by reduced body weights and developmental delays. Thus the nutritional status of the animals was not adequately considered. Hal nutri tion confounded the early studies of Sauerhoff and Michaelson (1973) who also observed an increased spontaneous activity in the offspring of nursing rats exposed to 27,300 ppm lead acetate in the diet. In a subsequent study, Goiter and Michaelson (1975) found that oral administration of lead acetate to suckling rats did not affect their growth rate, but that these rats continued to exhibit periods of Increased motor activity. These investigators tested the activity of six siblings simultaneously without specifying the sexual composition of each litter. Since female-locomotor activity is known to vary with the stage of the estrous cycle. Spurious activity measurements could have occurred in either their control or experimental groups. Exposing pups via the mother's milk may also add the confounding variable of possible maternal effects. The more crucial issue, however, is that the doses of lead administered, resulted in malnourished offspring, Michaelson, et al. (1976) recently reported that early undernutrition, comparable to that frequently reported in leadexposed mice, resulted in enhanced spontaneous locomotor activity. Castellano and Oliverio (1975) also reported that rnalnourishment can cause increased -/ Ciy - . DUP040013831 4-10extrapolatpry activity and impaired avoidance behavior in mice. Sobotka, et at. (1974) found that malnourished weanling rats displayed a stats of heightened 'emotionality' and impaired learning behavior. Thus souse of the behavioral responses seen in lead exposed rodents may be due to early undernutrition. Reiter, et al. (1975, 1976) investigated possible effects of the nutri tional status of lead-exposed rats, as well as some of the parameters used to assay locomotor activity. When Reiter and Ash {1976a} exposed male rat pups to high doses of lead via their mother's milk (nursing mothers received 5% lead carbonate in the diet), and after 16 days directly through the drinking water (50 ppm), they observed that food consumption was reduced in the lead treated dams with a corresponding reduction in the growth of the pups. Delays in the development of the startle response, eye opening, and righting reflex were observed in both lead-treated and pair-fed animals; thus indicating that these developmental delays may be due to malnutrition. Lead treated animals showed an initial hyperactivity at two weeks, which returned to control levels by six weeks. When locomotor activity in a residential maze was measured in adults, no treatment differences were observed. When Reiter, et at. (1975) exposed rats, (40 days prior to and throughout gestation and lactation to adulthood) to low levels of lead acetate in the drinking water (5 or 50 ppm), delays in the development of the righting reflex and in eye opening were observed, but body weights were not affected. Locomotor activity of adults males was monitored day and night for five consecutive days in a residential maze. On the first test day hypoactivity was observed in adult lead treated animals during all periods of the activity cycle. On subsequent days, only nocturnal activity was depressed. tor DUP040013832 Other studies (Grant, et a!., 1975; Hastings, et al., 1975; and Sobotka, et al., 1975) using lead exposures not resulting in reduced body weights have not found any persistent changes in the activity levels of the exposed'rats. Thus, all possible variations in locomotor activity (hypoactivity, hyper- '' 'S activity, no change in activity) as a result of lead treatment have been observed. Some of the confusion is probably due to the wide differences in the doses of lead administered and the concomitant nutritional state of the animals. In most cases no attempts have been made to assess the total body burden of lead, which may vary considerably with the routes of administration utilized. The recent observation by Reiter (1976b), that lead treatment may disrupt the normal activity cycles of rats, may explain some of the conflicting results, since most studies have monitored activity levels for only brief periods of time (hours), rather than for consecutive days. Further research may indicate that depending upon which time period of the daily cycle is monitored, one might observe hypoactivity, hyperactivity, or no changes in activity. Unfortunately, at the present time, the animal data remain inconclusive. I 3L ft DUP040013833 IA X03 4-J > v<J aG <4*- Xc/t UJ O C <v co cl J0D 0o j g3 *V--) 44 WS a UccJ ccn c** G 0 r0-- *o <u lA m 0 L U ,0 o cn e Gc G It* *r- i--0 m <y 0cn c >> 44 J. 0*- xU <>- CL 44 S-f Oe U0 4-> u OJ L~ 40 o ,2S r-- G *4 >rP*r Ji0OC0GE3 V-0>fQQC*J 0441O0U*- > 2: . 4-> 0 0 in O *r- . . c44 d C O vi GEO 44 0 0 O cn i-- 4G *"4 O- b>e con ci cx j 0oc1 0 4GoGEao.j v*4o4<<j4**Ly 4-12 </> 0 UCm y CL) 0lf_ 4- ea <0 'X? 0bz GG gr~ O CL G o E0 .ss i~4 a. BEHAVIORAL EFFECTS OF "LOW-LEVEL" LEAD EXPOSURE IN ANIMALS C4G.0coa<G-Ln>c* xOjJ 5gc030En UOUJJ ccn rcG0O--J 1--00MEf r*'--><3ir/>0- >40CCo*r->->41OiOGEn43 g <G*> 4>4* S-4-> >0) '*r- 43 ff N HrgiatVJu)Wccdl4O-oJr X*1To4OoOc<Cco354-aJ r**.O00fia0g>oacnlnJ>..r*cOcLG^--tnJ-j 4O"br cO .04+=fOi>En04lJJj T--><cOSOQP-noJ--ixQb>bbLf: ' cbr1- X*sOcrr3~n*_ --<i3no* -0cc1Ucr>0-n Go o U 3 > E *b <0 o r- x: u >> >i O 0 b * u > .b r- *r- O 0 > 4-> cn *r* <0 OJ c <0 x> > T- uuo c G0J <o -- m u CX n to 0) X fO Qi 09 UJ c l _j >- (0 in -L L in 0J ro > 0J 0- +j iG *t-- 0s3- XI 0 (O CL :=C O G O f* 4<->0 u M-- 4P O <n *f* in C i- - CD :E 4-> "O 0 E fO U rtj fO 0 CL--1 - cn n c^ *- 3: x C *-- i t-UD cn<o s^. m 0 >i 4P 0 0 XJ 04-> *-- U0 0U 0 XJ > 00 t0--m- in u cn o E **- cn o co .r--..2C G O Cjl4^ XL T3 3 0 0 4-J OIL i. 0 00 >fp a 00 aiu i. 00 in U "b 4000 X ,0 r-- m o 5h .01(0 E *o cn cm o f- CO CM V) 1 J- r^. u 3 r-- O SC->-^4- o 4-3 0 c0n > 0 CL cn.3 CL > XI 0 x: 0U 4P St O 4- 4-> 0r-- * a. * <y ^--4 L> .0 JL 4-3 O 0_ UE 00 X3 XJ 00 0X --1 4^ 0 4- in 0X 44 44 0G 0o o x> o 00 CO .1-- L o cn4- E x Or r-- tn E i cn*> E3 'C UJ o Ou o o 0 0G U. G i-- o 0 ca .3= 04- b> 044 c r* O0 <n 5 -id G r- XJ 0 St* U XJ 0 r-- SO G f-- CT>4- m enj* in ^ 0 $ 44 cn*-- m >** ; G E 3 44 cn0- 0 E r~~ E 4- m u 3 u C * O XJ o o -- ov< Cvj 4- G 44 X cn-o xj *r-- C G 000 3 0C >, u o tj 0`(* O 4- +-> X00 XX cn m in 0 o> x j 3: 0 44 <U L9 C r- 7t O O O X -^ cn4- a>44 E 30 44 O 44 CVJ 0 S. U * *r- x 0 XJ 44 r-r- xj m 0 Lad 05 co 4- OU O cno- B X 0* X 0* b> p-- XJ 0 0c 2 > `X in o r-- X X ~ cnx in -id 5^ r* * 0 X >4J in- 0 JL n- X 0 0 0 44 U O 4O00 >> > 00 r-- 3: 2 00 in o O 0 o1 t 44*r-- G 0 0 O X3 44 3 0 0X 0 cn 0 cn Cu Otrf C 0 cc 0 CO <c G 5L CL O. m CO in 0 c o s: m 3 4A 0 .c Ot <n > 0 Lad C o in 3 in 0 Xat Q. 0 0 X CO 0 j . i0 . +j*^ OC^* I 0 0 r>- ro ' c 0 CO in cn o rc>r>- \ L 0 -- 0 GW> 4- 0 0 44 CC c L-- C O G X 03 i Col oi--> CO r-* O <n r-- r> n -/ C 0 G cn i-- 0 CO r>. 44 Oi 0 rG r 0 XJ O oo *-- -r> 0 0" f-* 44 CTi 0 *-- c 0 r-- 'r-- c *--* 0 r-w, 0* 44 0 cn r-- ' ---------- O in G 0 G? rr- 0 r--> 44 in 0 cn 0 r-- 4d L--' 44 o X o CO I DUP040013834 3-fold increase in a ctivity Locomotor a c tiv ity Nursing mothers receiving 2-10 mg lead acetate/ml drinking water; at weaning d ire c tly through water >r-- *r* 44 <XJ r- 44 p > *r- a r~ Xt 44 44 S- <o CJ 40 JQ 0) & rtJXl L woo SZ ' re c re aoj m Swc x a ai re 4re0 L- >> U 44 C v- > r-- B-S 44 CO re a> to i oc -5^ r- C o *r-- > 44 44 U r* .3 > P G> 44 VO ?*8 rtf OC CO >> 44 r> 4r(04e o cx zc. 4O4 G> Cf - 4re4 JQ *- re e s- c 4<-9*V o re o CL_C C QrCeO E<C9L-CQcJ. 44 > 44*r" U ro S. 4o - o E o u o CJ 44 >, N 44C re 0) *r- E E> ' 44Q. ** .r-- o re 44r-- ,CJ *ri* CJ rtf >. C c j i- c j 44POP tX O cn (DEO 4r-- O V -O QJ o c a: _j 4>41w ^ N re T- g >' 44*r" ***! (tf 44u re 5 .c -O 44OP r O Vi E <U O iO 4O-4 C *4 G (3 44 </ (/) t/1 S- 44 CJ re CL 0J 0-4* ss re pCO osi&d- oc r- CO vrje>- re cn re C7>*r- <E 4-1.3- e p v to *Cr- aL.j CT to o Cren cn >> C 44 p re- o -c > u o 44 p3 owO s: re L. a u cre E 44 fc. *c* to*- *urS- c01 CJ CL P Di C >s 44 U ^CS o sz o >j ^4 :> ,*r* a r> 44 GJ re n i re c re 9lf 44 re p -r- s 44C r* 44 O 4= re P GJ 0 *4- E * re o PP Us- e rtf VI O 3 o C 41 Uu.&L rrtef ou r- 44 0N<E.19) rC<&e9. CL OL. Ore o 3 3 01 o a oo OJ O o P> C-t*- r C*r+J 44 re p re c r- CO tr* E '35 re 44 c 1 VO OL vi S~ r--'" f* 3 *4o- re 3 4 o o cn cr c. co vi a. jc cn u c j *-- re H* O to co re re: CL >44 c r-- O JO 44 Cu 0) E 44 CL re a. 44 q j in u ca re p v re u V) QJ 0) 44 r- x: . 44 3 E O CO CL E CL L 0> o oO 1tz- <*- (O* tJo- 4041 r> 3*r- CM c p 1 x; cn p C 3 ,C r- O O *?** .C 43 44 t - 44 re S- 44 PP U c re c re .p*"T- JL P p o c: re --* re <u si- ac OP Ea.>CO +*r4- Oo o. re re j s P 44 44 O to i in oa- cren3p L ctf O O 44 cso o ir>x o -p in 44 cn re c > PX t-- q j cn 01 r-- 3 up o QJ L L f= -3 r- <,4 VI L (DEL a> 44 rx q j 43 re c l 44 44 c re sE OO U1 2 CCO 4Vu0 o> (C. 4s 3tLo P<re0 p to c fc. F~ P p* o 43 f-- OOU) s, > q j re C 44 P o re ^ C- 44 O 44 P fo re O 1 J3 r- 3. 44 P E c re o *- (B L 4<y=0 *-- H- o3i.+J5J io5 44 0 CU t/VCM $ IoI 44 QJ 40 3 o: cn 4s0- Q. C/1 p>. cn p r-- C-- re c 4- o 4- CO Or-- x: re l - re re -c 3O re t * VIS s? i 44 op0I4 Qro 4c0n s~ cCol pr*ere44.U0 Pi L. *-- re ' 44 rie- cc 0420 v> P to CK re cn i-O re 44 reir-- ac 4> 4>U>4C0I 40 of cn oc to*-- in 4-> P** re cn r-- 44^ rCe L. o cn cnai 44 E p-- -3 E re o to o E Jo Oi QJ CS o u a* CP rs Ul.0 3 **- re p w 44 4- O C > 44 O L- L- O *F- QJ C -Q CLCf- Q) CJ CSJ O re QJ U O 44 - o v re 44 44 >) Vl 44 L. P O re * - , re re a u X5 r-* p #-- re <A OJ L. p-- L- 0' QJ JEO 0144 3 QJ (84 44 44 O E c re 3 QJP L- 44 4- c 44 E re p 2c EO oi--* ccn -*cr-: I -w* to C t-CNJ *- z3: o&p. q j to re -- U QJ re re -- cnc s_ re c o o pPO _CJ 44 4J >> *<- o40 ^ o4- P4C O44OiOrt 4440 LUU. a: o re. 44 re-~* to (A K cncn .Cr- 44 (rAe 33 f--re n cn 44 r-- QJW > Pre u co Mouse (CD-I) Silbergeld and Goldberg (1974) 22 DUP040013835 1 CHAPTER 4 REFERENCES - PART I - Neurotoxicity of lead 4-14- Albert, R, Shore, R. E,, Sayers, A. 3., Strehlow, C., Kneip, T. J., Pasternack, B. S., Friedhoff, A. j,. Covan, F. and Cimino, 3, A, Follow-up of children overexposed to lead. Environ. Hlth. Perspec. 7: 33-40, 1974. Allen, J. R., McWey, P. J. and Suomi, S. Pathobiological and behavioral effects of lead intoxication in the infant rhesus monkey. Environ. Hlth. Perspec. 7: 23S, 1974. American Academy of Pediatrics. Prevention, diagnosis, and treatment of lead poisoning in children. Pediatrics 44: 291-298, 1969, Baloh, R., Sturm, R,, Green, B. and Gleser, G. Neuropsychological effects of chronic asymptomatic increased lead absorption. Arch. Neurol. 32: 326-330, 1975. Beattie, A. 0., Moore, M, R. and Goldberg, A. Role of chronic low-level lead exposure in the aetiology of mental retardation. Lancet I: 589-592, 1975, Bicknell, J, Clayton, B, E. and Delves, H. T, lead in mentally retarded children. J. Mer.t. Detic. Res, 12: 282-292, 1968. Bradley, J. E. and Baumgartner, R. 3. Subsequent mental development of children with lead encephalopathy as related to type of treatment. J. Pediatr, 53: 311315, 1958. Brady, K., Herrera, Y. and Zenick, H. Influence of parental lead exposure on subsequent learning ability of offspring. Pharmacol. Biochem. Behav. 3: 561-565, 1975. Brown, D. R. Long-term effects of lead and organ development In the growing rat. Toxicol, Appl. Pharmacol, 24: 55, 1973, Brown, D. R. Neonatal lead exposure in the rat: Decreased learning as a function of age and blood lead concentration. Toxicol. Appl. Pharmacol. 32: 628-637, 1975. Bryce-Smitb, D, et a!., Landrigan, P. J. et al., and David, 0. J. et al. letters to the editor. Lancet II: 1144, 1972, Bulpitt, C. J. Lead and hyperactivity. Lancet II: 900, 1972. Burde, dela B. and Choate, M. S, Does asymptomatic lead exposure in children have latent sequelae? J. Pediatrics 81: 1088-1091, 1972. Burde, dela B. and Choate, M, S. Early asymptomatic lead exposure and develop ment at school age. 3. Pediatrics 87: 638-642, 1975, 6 C'7 l \\ DUP040013836 4-15- Butler, E. J. Chronic neurological disease as a possible form of lead poisoning. J. Neurol. Neurosurg. Psychiat. 15: 119-128, 1952. Byers, R. K. and Lord, E. . Late effects of lead poisoning on mental develop ment. Amer. J. Ois. Child, 66: 471-490, 1943, Campbell, A. ft. 6., Williams, E. R. and Barltrop, D. Motor neurone disease and exposure to lead, 0. Neurol. Neurosurg. Psychiat. 33: 877-885, 1970. Carson, T. Van Gelder, 6, A., Karas, G. and Buck, W, Development of behavioral tests for the assessmev: of neurologic effects of lead in sheep. Environ. Hltb. Perspec. 7: 233, 1971. Castellano, C. and Oliveria, A. Early malnutrition and postnatal changes in brain and behavior in the mouse. Brain. Res, 101: 317-325, 1976. Catton, ft. J., Harrison, M. J. G., Fullerton, P. M., and Kazantizia, G. Subclinical neuropathy in lead workers. Brit. Med. J. 2: 80-82, 1970. ' ii> Chisholm, J. J. and Harrison, H. . The exposure of children to lead. Pediatrics 18: 943-958, 1956. Cohen, D. 0., Johnson, W. T. and Capary!o, B. K. Pica and elevated blood lead level In autistic and atypical children. Amer. J. Dis. Child. 130: 47-48, 1976. Cole, J. F. and Lynam, 0. R. ILZRO's research to define lead's impact on man. In Proceedings International Symposium Environmental Health Aspects of Lead, p. 169, European Economic Communities, Luxembourg, 1972. Cone, W., Russel, C. and Harwood, R. U. Lead as a possible cause of multiple sclerosis. Arch. Neurol. Psychiat. 31: 236-263, 1934. David, 0. J., Clark, J. and VoeUer, K. Lead and hyperactivity. Lancet II: 900-903, 1972. Felton, R. G., Haddow, J., KopitO, L, and Schwachman, H, Altered peripheral nerve conduction velocity. Chronic lead intoxication in children. Amer. J, Ois. Child, 125, 39-41, 1973. Fullerton, P. M, Chronic peripheral neuropathy produced by lead poisoning in guinea-pigs. J. Neuropath. Exptl, Neurol. 25: 214-236, 1966. Gamstorp, I. Normal conduction velocity of ulna, median, and peroneal nerves in infants, children, and adolescents. Acta Ped. 146: 68-73, 1963. C 30 DUP040013837 4-16 Gartside, P. S. and Panke, R. K. A discussion concerning the significance of results for children tested in the Shoshone project. Shoshone Lead Health Project, pp. 116-119, Boise, Idaho, Idaho Department of Health and Welfare, 1976, Goiter, M. and Michael son, I. A. Growth, behavior, and brain catechalamineses in lead exposed neonatal rats. A Reappraisal. Science 187: 359-361, 1975. Goode, J. W., Johnson, S. and Calandra, J. C. Evaluation of chronic oral administration of lead acetate to rhesus monkeys. Toxicol. Appl. Pharmacol. 24: 53, 1973. Grant, L. (personal communication) 1975. Gregory, R. J., et al. Intelligence test results for children with and without undue lead absorption. Shoshone Lead Health Project, pp. 120-149, Boise, Idaho, Idaho Department of Health and Welfare, 1976. ^ Hastings, L., Cooper, 6. P. and Bornschein, L. The effect of early lead exposure on the behavior of developing rats. Presented at the Society of Toxicology Meeting, Atlanta, 1976. Klein, M, C., Sayre, J. W, and Kotok, D. Lead poisoning; current status of the problem facing pediatricians. Airier. J. Dis. Child. 127: 805, 1974. Kotok, D. Development of children with elevated blood lead levels: A controlled . study, J. Pediatrics 8: 57-61, 1972. Lampert, P. W. and Schochet, S. S. Demyelination and remyelination in lead neuropathy. J. Neuropath. Exptl. Neurol. 27: 527-545, 1968. Landrigan, P, J., Baloh, R, W., Barthel, W. F,, Whitworth, R. H., Staehling, N. W. and Rosenblum, B. F. Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet I: 708-712, 1975a. Landrigan, P. J., Gehlbach, S. H., Rosenblum, B. F., Shoults, J, M., Candelaria, R., Barthel1, W. F., Liddle, J. A., Smrek, A. L., Staehling, N. W, and Saenders, J. F. Epidemic lead absorption near an ore smelter. New Engl. J. Med. 29.2: 123-129, 1975b. Landrigan, P. J., et al. Increased lead absorption with anemia and slowed nerve conduction in children near a lead smelter. Shoshone Lead Health Project, pp, 90-115, Boise, Idaho, Idaho Department of Health and Welfare, 1976, Lansdown, R. G., Clayton, B. E,, Graham, P. J., et al. Blood lead levels, behavior, and intelligence, A population study. Lancet I: 538-541, 1974. 3/ DUP040013838 4-17-' Lives ley, B. and Sissons, C. E. Chronic lead intoxication mimicking motor neurone disease. Brit, Med. J. 4: 387-388, 1968. McNeil, J. I. and Ptasnik, J, A. Evaluation of long-term effects of elevated blood lead concentrations in asymptomatic children. Int. Symposium Recent Advances of Environmental Pollution, ECE-EPA-WHO, Paris, 1974, Mellins, R, B. and Jenkins, C. D, Epidemiological and psychological study of lead poisoning in children. J. Amer. Med. Assoc. 158: 15-20, 1955. / Michael son, I. A., Bomschein, R, L., Fox, D. A. and Loch, ft, EPA Symposium on Biochemical Effects of Environmental Pollutants, Cincinnati, 1978. Millar, 0. A., Battistine, V., Cumming, R. L, C., et al. Lead and delta ALA-D levels in mentally retarded children and in lead poisoned suckling rats. Lancet II: 695, 1970. Nieburg, P. Letters to the editor. J. Pediatrics 8: 6^27, 1972, Perino, J, and Ernhart, C, B. The relation of subclinical lead level to cognitive and sensormotor impairment in black preschoolers. J. Learning Disabilities 7: 26-30, 1974, Perlstein, M. A. and Attala, R, Neurologic sequelae of plumbism in children. Clinical Pediatrics 5: 292-298, 1966, Pueschel, S. M., Kopito, M, S. and Shwachman, H. A screening and follow-up study of children with an increased lead burden. J. Amer, Med. Assoc. 222: 462-466, 1972. Reiter, L, W. Neurotoxicity during lead exposure in the rat. Presented at the Society of Toxicology Meeting, Atlanta, 1976a. Reiter, L. W, (Personal communication), 1976b. Reiter, L. M., Anderson, G. E., Laskey, J. W, and Cahill, D. F. Development and behavioral changes in the rat during chronic exposure to lead. Environ, HTth. Perspec. 12: 119-124, 1975. Roberts, T. M., Hutchinson, T. C., Paciga, J., Chattopadhyay, A., Jervis, R, E,, Van Loon, J. and Parkinson, D. K. Lead contamination around secondary smelters: Estimation of dispersal and accumulation by humans. Science 186: 1120.-1122, 1974. Rummo, 0. Intellectual and behavioral effects of lead poisoning in children. Ph.B. Dissertation, University of North Carolina at Chapel Hill, 1974. ! J C 3-? DUP040013839 i 4-18- Sauer, R. M., Zook, B. C. and Garner, F, M. Demyelinating encepbalomyelopathy associated with lead poisoning in nonhuman primates. Science 169: 1091-1093, 1970. Sauerhoff, M. H. and Michael son, I. A. Hyperactivity and brain catecholamines in lead-exposed developing rats. Science 182: 1022-1024, 1973. Seppfliainen, A. M. and Hernberg, S. Sensitive technique for detecting subclinical lead neuropathy. Brit. 0. Industr. Med, 29: 443-449, 1972. Seppaiainen, A, M., Sakari, T,, Hernberg, S. and Kock, B, Subcl ini cal neuropathy at "safe" levels of lead exposure. Arch. Environ. Hlth. 30: 180, 1975. Seto, 0. and Freedman, J. M. Lead neuropathy in childhood. Amer. J. Ms. Child. 107: 337-342, 1964. Shoshone Lead Health Project, Boise, Idaho, Idaho Department of Health and Welfare, 1976. * Silbergeld, E. K. and Goldberg, A. M. A lead-induced behavioral disorder. Life Sciences 13: 1275-1283, 1973. Silbergeld, E. K. and Goldberg, A. M. Hyperactivity: A lead-induced behavior disorder. Environ. Hlth. Perspee. 1: 227-232, 1974. Simpson, J. A., Sea ton, D. A. and Adams, J. F. Response to treatment with chelating agents of anaemia, chronic encephalopathy and myelopathy due to lead poisoning. J, Neurol, Keurosurg. Psychiat. 27: 536-541, 1964. Smith, H. D., Balkner, R. L., Corney, T. and Majors, W, J. The sequelae of pica with and without lead poisoning. Amer. J. Dis. Child. 105: 609, 1963. Sobotka, T. J., Brodie, R. ., and Cook, M. Psychophysiologic effects of early lead exposure. Toxicology 5: 175-191, 1975. Sobotka, T. J., Cook, M. P. and Brodie, R. E. Neonatal malnutrition: Neurochemical, hormonal, and behavioral manifestations. Brain Research 65: 443-457, 1974. Warren, H. V. Trace elements and epidemiology. J. Coll. Gen. Practit. 6: 517-531, 1963. Warren, H. V. Environmental lead: A survey of its possible physiological significance, j. Biosoc. Sci. 6: 223-238, 1974. S "3 .......................................................................................... /... ...,,J i DUP040013840 4-19- Warren, H. V., Delavault, R. E. and Cross, C. H. Possible correlations between geology and some disease patterns. Ann, N. Y. Acad, Sci- 136: 657-710, 1967, . ' Westerman, M. P., Brue*;man, M. and Pfitzer, E. Lead poisoning and multiple sclerosis. Arch. Environ. Hlth. 29: 355, 1974. Whitworth, R. H., Rosenblum, B. F., Dickerson, M. S. and Baloh, R. W. Follow up on human lead absorption - Texas. Morbidity and Mortality 23: 157, 1974. Wiener, G. Varying psychological sequelae of lead absorption in chi1dren -- A review. Publ. Hlth. Rpts. 85: 19-24, 1970. Xintaras, C., Sabecki, M. F. and Ulrich, C. C. Sleep: changes in rapid eye movement phase in chronic lead absorption. Toxicol. Appl. Pharmacol. 1: 384, 1967. 7' ______________ _: / DUP040013841 4-202.0 Effects of Lead oh Reproduction It has been reported since antiquity that lead compounds can be used as abortifacients and that woman occupationally exposed to lead have a high miscarriage rate. A recent study by Fahim, et al. (1976) suggests that subtoxic lead absorption during pregnancy may be associated with an increased incidence of preterm delivery and early membrane rupture. A high correlation was found between lead concentration in maternal and fetal blood; both were significantly higher in the preterm pregnancies and early membrane ruptures than in term pregnancies. Epidemiologic studies (Oliver, 1914) have demonstrated a reduction in fit the number of offspring in families of workers occupationally exposed to lead. Animal experiments have also shown a reduction in the number of offspring Of rats and mice (Schroeder and Mltchener, 1971), and reduced birthweight and survival of animals fed a lead-containing diet (Stowe and Goyer, 1971). Lancr?njan, et al. (1975) have reported that moderate absorption of lead (blood Pb 50-80 yg/100 ml) resulted in diminished fertility of male workers. This appeared to be due to hypospermia and teratospermia. A slightly increased absorption of lead had no effects on the reproductive capacity of exposed workers. Lead is teratogenic in some species, A urorectocaudal syndrome of malformations was produced in rats exposed to lead during early gestation (McLain and Becker, 1975). Fetal hamsters have shown tail abnormalities when the mother had been given lead (Perm and Carpenter, 1967), Cardiac abnormalities have been reported after treating chick embryos with lead (Gilani, 1973), 3 5" c'JUrnr.-iha DUP040013842 4-21In these studies, high acute doses of lead were administered, usually by intravenous injections. Little is known about the teratogenicity and develop mental toxicity of lead following chronic exposure. Kimmel, et al. (1976) exposed female rats chronically to lead acetate via the drinking water (0.5, 5, 50, 250 ppm) from weaning through mating, gestation, and lactation. Ho teratogenic effects were observed, although exposure to 250 ppm lead acetate caused a slight, but nonsignificant increase in fetal resorptions. The leadtreated animals produced litters of normal numbers, but the offspring from the 50 and 250 nnm groups weighed less at weaning and showed delays in physical development. Reiter, et al. (1975) have also observed developmental delays in offspring exposed to 50 ppm lead throughout gestation and lactation. Whether these delays in development were the result of a direct effect of lead on the nervous system of the pu., or reflect secondary changes (malnutrition, hormonal imbalance, etc.) is not clear. Whatever the mechanisms involved, these studies do suggest that low-level chronic exposure to lead may induce postnatal develop mental delays. There are no convincing reports that lead is teratogenic in humans. An analysis of human fetal tissues (Barltrop, 1969) demonstrated that placental transfer of lead began as early as the 12th week of gestation and that total lead content increases throughout pregnancy, with the highest concentrations occurring in bone, kidney, and liver; but significant amounts were also present in blood, brain, and heart. The quantities of lead present in newborn infants generally reflect that of their mother (Scanlon, 1971); -Harris and Holley, 1972; Gershantk, 1974). However, as Barltrop (1969) pointed out, the distribution of lead within the fetus at different stages of development is probably more important than the total amount present at birth. ? 1, I $ ! DUP040013843 4-22Animal studies indicate that significant amounts of lead may be concentrated in the milk of nursing mothers (Green and Gruener, 1974). L3? DUP040013844- "'X4 tff REFERENCES - PART II - Effects of lead on Reproduction 4-23- Barltrop, 0. Transfer of lead to the human foetus. In "Mineral Metabolism in Paediatrics'', 0. Barltrop and W. L. Burland, eds. p. 135, Blackwell, Oxford, 1969. y Fahim, M. 5,, Fahim, Z. and Hall, 0, G. Effects of subtoxic lead levels on pregnant women in the state of Missouri, Res. Coirni. Chem. Pathol, and Pharmacol. 13: 309-330, 1976. Perm, V. H, and Ferm, 0, W. The specificity of the teratogenic effect of lead in the golden hamster, life Sciences 10: 35-39, 1971. Gershanik, 0. 0., Books, G, G, and little, J. A. Blood lead values in pregnant women and their offspring. Amer. 3. Obster. and Gynecol. 119(4): 508-511, 1974. Gilani, S. H, Pathol. Microbiol. 39: 85-90, 1973.. 4 Green, M. and Gruener, N. Transfer of lead via placenta and milk. Chem, Pathol. 8: 735, 1974, Res. Comm. Harris, P, and Holley, M. R. Pediatrics 49: 606, 1972. Kimmsl, C, A,, Grant, l, 0. and Sloan, C, S. Chronic lead exposure; Assessment of developmental toxicity. Abstract, Teratology Society, Carmel, 1976. Lancranjan, I., Popesca, H, I,, Gavanescu, 0., Klepsch, I. and Serbanescu, M. Reproductive ability of workmen occupationally exposed to lead. Arch. Environ. Hlth. 30: 396-401, 1975. McClain, R, M. and Becker, B. A. Teratogenicity, fetal toxicity, and placental transfer of lead nitrate in rats, Toxicol. Appl. Pharmacol. 31: 72-82, 1975. Oliver, T. lead Poisoning, p. 192, H. K. Lewis, London, 1914, Reiter, L, W,, Anderson, G. E,, Laskey, Y. W. and Cahill, 0, E, Development and behavioral changes in the rat during chronic exposure to lead. Environ. Hlth. Perspee. 12: 119-124, 1975. Scanlon, J. Umbilical cord lead concentration, Amer. 0. Dis. Child. 121: 325, 1961. Schroeder, H. A. and Mitehener, M, Toxic effects of trace elements on the reproduction of mice and rats. Arch. Environ. Hlth. 23: 102-106, 1971. Stowe, H. D. and Goyer, R. A, The reproductive ability and progency of FI lead toxic rats, Fertil. Sterll. 22: 755-760, 1971, i \ DU P040013845 3.0 Effects of Lead on Chromosomes 4-24* Contradictory results have been published in the last few years with respect to an increased occurrence of chromosome aberrations in workers occupationally exposed to lead. Bauchinger and Schmid (1970) and Schmid, et al. (1972) found no evidence of increased chromosome aberrations in lead manufacturing workers; or in policemen with increased blood lead levels (Bauchinger, et al. 1972), or in male workers exposed to lead oxide fumes in a shipbreaking yard (O'Riordan and Evans, 1974). However, an increase in chromosome aberrations In people occupationally exposed to lead has been reported by Forni and Secchi ([1972); Schwanitz, et al. (1970), and QeKnudt, et al. (1973). Unfortunately, most of these studies have evaluated very few (10-20) subjects. A study by Forni and Secchi (1972) showed that the-rates of chromatid changes were higher in 65 workers with preclinical and Clinical signs of lead poisoning but were not significantly raised for workers with past poisoning, Forni, et al. (1975), also examined 11 subjects before and during initial exposure to lead. The increase in rate of abnormal chromatid metaphases was doubled after One month of exposure, was further increased after two months, remained in this stage up to seven months, and then decreased. The fact that most alterations were of the chromatid type (i.e. occurring in cell culture after DNA synthesis) Indicates that these may be culture-produced aberrations, not repaired in the presence of lead, and may not reflect a real in vivo situation. Thus its biological significance is unknown. LZ? wrarwfiffairys^^ y DUP040013846 4-25- REFERENCES - PART III - Effects of Lead on Chromosomes Bauchinger, M., Schmid, E. and Schmidt, D. Chromosomenanalyse bei Verkehrs polizisten mit erhohter Bleilast. Mutation Research 16: 407-412, 1972. Deknudt, G. H., Leonard, A. and Ivanov, 8, Chromosome aberrations observed in male workers occupationally exposed to lead. Environ. Physiol. Biochem, 3; 132-138, 1973. Forni, A. and Secchi, G. C. Incidence of chromosome changes and correlation with clinical and biochemical findings in lead poisoning. In Fachreferate der "I Internationales Symposium der Werksarzte der chemischen Industrie", Ludwigshafen, 442-448, April 27-29, 1972. Forni, A. and Secchi, G. C. Chromosome changes in preclinical and clinical lead poisoning and correlation with biochemical findings. In Proc. of the International Symposium "Environmental Health Aspects of Lead", Amsterdam, 473-482, October 2-6, 1972. v Forni, A., Cambiaghi, G. and Secchi, G. C. Initial occupational exposure to lead. Arch, Environ. HIth, 31: 73, 1976, O'Riordan, M, L. and Evans, H. G. Absence of significant chromosome damage in males occupationally exposed to lead. Nature 247: 50-53, 1974. Schmid, E., Bauchinger, M., Pietruck, $., et al. Die cytogenetische Wirkung von Blei in menschlichen peripheren Lymphocyten in vitro and in vivo. Mutation Research 16: 401-406, 1972. Schwanitz, 6,, Lehnert, G. and Gebhart, E. Chromosomanschaden bei berufliciier Bleibeiaslung. Otsch. Med. Wochenschr. 95: 1636-1641, 1970, i l C1/6 J DUP040013847 4-25a- 3.1 Carcinogenicity of Lead Compounds Lead has been studied for carcinogenicity and was found to be positive in mice and rats. Earlier experiments were frequently negative but many of them were inadequate. . Positive results were obtained with lead acetate and subacetate in rat and mouse feeding studies. A diet containing 0.12 basic lead acetate fed to Swiss mice produced benign and malignant renal tumors (1). The same compound fed to rats at the 0,1 or 12 level in the diet also produced this type of tumors (2). Renal tumors were also observed in rats fed diets containing 12 lead acetate (3). Benign and malignant kidney tumors werte observed in rats fed lead acetate (3 mg/day for 2 months and 4 mg/day for 16 months). Besides the kidney tumors, neoplasms of the testes, adrenals, thyroid, pituitary, and prostate were observed in these Wistar rats (4). In male Sprague-Dawley rats on a diet containing 12 lead subacetate, too gliomas were observed besides 13 kidney tumors in 17 animals (5), Subcutaneous injection of lead phosphate, repeated over a 16-months period, produced adenomas, papillomas, and cystadenomas of the renal cortex in albino rats. The total dose of lead administered varied between 120 and 680 mg Pb in the animals getting tumors (6). No positive findings have been reported on humans exposed to high levels of lead, only negative data were reported by Dingwall-Fordyce and Lane (7) who followed 425 persons who had been exposed to lead in a battery factory. They showed no increases in cancer incidence but an increase in cerebrovascular accidents. This is offerred as a basis for the suggestion that species differences in the case of lead toxicity are distinctly apparent. There are C . f\.. -ni DUP040013848T 4-25bsufficient publications on ill effects of lead exposure of humans that cases of cancer in.these people, even if anecdotal, would have been reported in the literature over the years. Lead is thus not considered a human carcinogen. When the experimental data on rodents are used for extrapolation to human exposure, the equivalent dose for renal tumor development in man would be 550 mg lead per day which appears to exceed the maximum tolerated dose of lead for man (8), > Y3 i i-iifi 5 'DUP040013849 4-25cREFERENCES - PART III-l - Carcinogenicity of Lead Compounds V. Van Esch, G. J. and Kroes, R. (1969). The induction of renal tumours by feeding basic lead acetate to mice and hamsters. Brit. J. Cancer 23: 755. 2, Van Esch, G. J., Van Genderen, H. and Wink, H. H. (1962). The induction of renal tumours by feeding of basic lead acetate to rats. Brit. J. Cancer 16: 289. 3. Boyland, ., Dukes, C. E., Grover, P. L. and Mitchley, B. C. V. (1962). The induction of renal tumours by feeding lead acetate to rats. Brit. J. Cancer 16: 283. 4. Zawirska, B. and Medras, K. (1968). Tumours and disorders of the porphyrin metabolism in rats with chronic experimental lead poisoning. I. Morpho logic studies. Zbl. allg. Path. path. Anat. Ill: 1. 5. Oyasu, R., Battifora, H. A., Clasen, R. A., McDonald, J. H. and Hass, G. M. (1970). induction of cerebral gliomas in rats with dietary lead subacetate and 2-acetyl aminof1uorene. Cancer Res. 30: 1248. 6- Zollinger, H, U. (1953), Durch chronische Bleivergiftung erzeugte Nierenadenome und -carcincme bei Ratten und ihre Beziehungen zu den entsprechenden Neubildungen des Henschen. Virchows Arch. path. Anat. 323: 694. 7. Dingwal1-Fordyce, I. and Lane, R. E. (1963). A follow-up study of lead workers. Brit, j. Industr. Med, 20: 213. 8> IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. 1: 40-50 (1972). IARC, Lyon, France. c y? DUP040013850 4-264.0 Effects of Lead on the Immune System: In a number of animal species, lead has been reported to increase susceptibility to infection. Hemphill, et al. (1971) found that mice injected with subclinieal doses of lead nitrate for 30 days showed a reduced resistance to Salmonella Typhimurium. Selye, et al. (1966) found that rats injected with lead acetate (minimal effective dose 1 mg/100 g body weight) were susceptible to a variety of bacterial endotoxins to which this species Is usually resistant. A number of factors may be involved in producing this decreased resistance to infection. Lead can bind to antibodies (Williams, et al*, 1954) and diminishes the level of circulating antibodies (Koller and Kovacic, 1974). Bingham, et al. (1968) found that the inhalation by rats of lead sesquioxide aerosol (10 pg/m to 150 ug/m ) significantly reduced the number of alveolar macrophages. Bruch, et al. (1972) found that rats inhaling particulate lead oxide (200 ug/m') showed mitochondrial and endoplasmic reticular damage of alveolar macrophages and pneumocytes, and exhibited a considerable loss in the activity of the benzopyrene hydroxylating enzyme. These studies need further substantiation. There do not appear to be any systematic epidemiological investigations on the effects of elevated lead levels on the incidence of infectious diseases in man (Hicks, 1972), CKT X DUP040013851 4-27REFERENCES - PART IV - Effects of Lead on the Immune System Bingham, E., Pfitzer, E. A., Barkley, W., and Radford, E. P. Alveolar macrophages: reduced number in rats after prolonged inhalation of lead sesquioxide, Science 162: 1297-1299, 1968, Bruch, T., Brockhaus, A., and Dehnen, W. In Proceedings International Symposium Environmental Health Aspects of Lead, Amsterdam. 1972, pp. 221-230, Hemphill, F., Kaerberle, M. L., and Buck, W. B, Lead suppression of mouse resistance to Salmonella typhimurium, Science 172: 1031-1032, 1971. Hicks, R. M. Air-Borne lead as an enviornmental toxin. Chern.-Biol. Interact. 5: 361-390, 1972. Roller, L. D. and Kovach, s. Decreased antibody formation in mice exposed to lead. Nature 250: 148-150, 1974, i Selye, H., Tuckwe&er, B., and Bertok, L. Effect of lead acetate on the susceptibility of rats to bacterial endotoxins. J. Bacteriol. 91: 884-890, 1966. Williams, H. W., Caraway, W. T., and DeYoung, W. A. Inactivation of anti bodies. A causative factor of brain pathology in acute lead intoxication. Arch. Neurol. Psychiat. 72: 579-582, 1954. | if r y/ \ DUP040013852 5.0 Experimental Tolerance to Lead 4-28- THj effects of some metals on the toxicity of simultaneously administered metals, and the occurrence of "metal shifts" in the body have been reported, For example, the prior or simultaneous administration of cobalt (Gabbiani, et al,, 1972) or zinc (Webb, 1972) has prevented gonadal atrophy induced by cadmium. Selenium compounds have been found to be protective against the various manifestations of cadmium and mercury toxicity (see Diplock, 1976), Yoshikawa (1968, 1970, 1974) has reported that prior injections of small amounts of some nonessential metals induced tolerance of a lethal dosage of the same metals given 24-48 hrs. later. The metals which could develop tolerance \\ against their own toxic action were silver, arsenic, cadmium, mercury, indium, and lead. Mice pretreated with some of the essential metals (copper, zinc, iron) did not develop such tolerance. It was also reported that those metals which developed the tolerance could promote cross-tolerance, whereas those which did not induce the tolerance did not promote cross-tolerance. These results indicate that whatever the mechanisms involved, they may be nonspecific, even though metals vary greatly in their physiochemical properties. It has been shown (Suzuki and Yoshikawa, 1974) that the protective effect of pretreatment w'th small doses of cadmium is probably due in part to the induction of metallothionein. But this mechanism cannot explain the protective effects of pretreatment with lead, which does not induce metallothionein. Sanai, et al. (1972) and Yoshikawa and Kaneda (1973) have observed that pretreatment with lead results in an increase of fecal lead excretion and a decrease in urinary lead excretion compared to nonpretreated rats. In precreated animals the concentration of blood lead reached a maximum in two i i DUP040013853 ' i T . | hours, decreased abruptly, and remained stable; whereas in nonpretreated animals, blood, lead levels reached a maximum in six hours and then decreased gradually. The ratio of lead levels in red blood cells versus serum was constant in pretreated animals, but increased gradually in nonpretreated y' animus. Th is pretreatment with small doses of lead causes changes in the distribution and excretion of lead following a subsequent injection of the metal. Similar changes in distribution have been reported for cadmium (Suzuki and Yoshikawa, 1971). | It must be stressed that'in all these studies acute doses of the metals are administered via intraperitoneal injections'. Whether these interrelationships !exist via other routes of administration and at low-level chronic exposures I. must be elucidated in order for them to be meaningful in the context of ` environmental pollution. : f / 1I I I C*2 D/UP040013854 REFERENCES - PART V - Experimental Tolerance to lead 4-30- Diplock, A. Metabolic aspects of selenium action and toxicity. Crit. Rev. Toxicol. 4: 271-32v.\ 1976. Gabbiani, G., Basic, 0., and Deziel, G, Studies on tolerance and ionis antagonism for cadmium or mercury. Can. J. Physiol. Pharmacol. 45: 443-450, 1967. Sanai, G., Hasegawa, T., and Yoshikawa, H. Pretreatment of rats with lead in experimental acute lead poisoning. J. Occup. Med. 14: 301-305, 1972. Suzuki, Y. and Yoshikawa, H. Role of metallothionein in the liver in protection against cadmium toxicity. Ind. Hlth. 12: 141, 1974. Webb, M., Protection by zinc against cadmium. Bfochem. Pharmacol. 21: 2767- 2771, 1972. ; .. Yoshikawa, H, Tolerance to lethal doses of metals in mice pretreated with their low doses. Ind. Hlth. 6: 83, 1968. Yoshikawa, H. Preventive effect of pretreatment with low dose of metals on the acute toxicity of metals in mice. Ind. Hlth. 8: 184, 1970. Yoshikawa, H. Tolerance to acute metal toxicity in mice having received a daily injection of its low dose. Ind. Hlth. 12: 175, 1974. Yoshikawa, H. Intracellular distribution of Cd, Cu, and Zn in Cd poisoned rat liver pretreated with and without Kg. Ind, Hlth. 9: 198, 1971. Yoshikawa, H. and Kaneda, M. Distribution of lead in the blood pretreated with small dose of lead. Med. & Biol. 86: 235-238, 1973 (Japanese). V C Hf / / DUP040013855 ' 5-15, EMISSION CONTROL DEVICES AND FUEL LEAD ADDITIVES REPLACEMENTS: CHARACTERISTICS AND FATE OF EXHAUST EMISSIONS 7.0 Exhaust Emissions from the Catalytic Puffier The introduction of the catalytic muffler for automobiles to meet the exhaust emission standards of the Clean Air Act of 1970 for carbon monoxide and hydrocarbons (CFR, Title 40: Part 85.074.1, 1975) has resulted in the use of fuels with lower lead additive contents and fuels with different compositions and fuel additive packages. It was recognized that the exhaust emissions from leaded gasoline could deposit on the active metal surfaces of the catalytic muffler and greatly reduce the oxidizing ability or capacity of the muffler (Bomback, et al. - 1975, Shelef, et al. - 1973). Therefore, in this section of the report, the characteristics and fate of exhaust emissions from the catalytic muffler will be examined in as much detail as possible. Again, the characteristics and fate of the emissions are a function of the fuel composition, and the design features, operating conditions, and age of the catalytic muffler. 1.1 Sulfur Exhaust Emissions from Catalytic Mufflers The public health impact of the release of sulfate emissions from catalytic mufflers has received considerable attention (Finklea, et al. - 1975, French 1975). The increased use of catalytic mufflers on light-duty vehicles at the projected release rate of 0.05 g sulfate/mile was estimated to have a large health impact on people living near roadways and commuters who suffer from asthma and other acute and chronic respiratory diseases. One of the first published records of the increase in sulfate emissions from catalyst-equipped vehicles was reported by Campion (1973). Since that time. Seltzer, et al. (1974) and Somers (1975) have reported on the measurement of particulate sulfate emission rates for many different makes and models of automobiles equipped with catalytic mufflers. 5-2Cadle, et al. (1976) recently reported the results of the General Motors sulfate dispersion experiment with a fleet of 384 automobiles. The maximum sulfate concentration measured in this simulated 4-lane highway driving 3 experiment was 12 ug/m above the background level of sulfate. This level was measured at a location near the roadway. At a distance of 100 feet from the roadway, the maximum level of sulfate was 5 ug/m above background. The emission for sulfates ranged from 0.003 gm/mile to 0.05 gm/mile. During the experimental study, careful measurements of wind speed, wind direction, and relative humidity were made and incorporated into a dispersion mydel for determining sulfate concentrations as a function of time and place. The average particle size of the particulate emissions was between Q.Ol - 0.1 microns. About 70% of the vehicles were equipped with pellet-type converters and the other 30% were equipped with the monolith-type of converter. The analytical method for sulfate did not determine what cation the sulfate anion was associated with. The sulfur content of the fuel ranged from 0.028 - 0.032 weight percent. The other components of the fuel were not specified. In experiments conducted by the EPA during the GM Study, Whitby, et al. (1976) determined aerosol size distributions for sulfate emissions. These emissions were characterized by a trimodal-type of distribution: Mode 1 was nuclei material, 0.005 - 0.05 microns; Mode 2 was fine material, 0.05 - 1.0 microns; and Mode 3 was coarse material, 1-30 microns. Tanner and Newi.an (1976) determined that the sulfate amission was sulfuric acid. The concentration 3 of sulfuric acid mists near the roadway were 3-6 ug/m . This emitted sulfuric acid reacted rapidly with ambient arcmonia to produce (NH^ SO^, The half life of the reaction was about 10-100 seconds, depending on the amount of ammonia available in the atmosphere. r,fj __ _ -- * ....... ............................... . ' ------ DUP040013857 % i f .,w.; i i, ,/ 5-3-' In a different study conducted for the EPA by Exxon Research and Engineeiing (1975), sulfate emission rates for 20 automobiles of various makes and models were determined as a function of accumulated mileage. For sulfate emissions the average results for the 20-car fleet showed a rapid use from 0.006 g/mile at 0 accumulated miles to 0.021 gm/mile at 4,000 miles. This rise was attributed to the storage phenomena of the catalytic muffler. Then the exhaust emission rate declined to 0,006 gm/mile at 32,000 miles.. This decline was attributed to the reduction in oxidizing ability of the catalyst to convert sulfur exhaust emission to SOj, The 20-car fleet was purchased in California. The 1975 California exhaust emission standards for CO are 3.4 gm/ mile, for hydrocarbons 0.41 gm/mile, and nitrogen oxides, 2.0 gm/mile. It was important to note from the results of this test that the CO emission rate ranged from 4.0 - 5.2 gm/mile for 0-32,000 miles; hydrocarbon emission rates ranged from 0.4 - 0.8 gm/mile; and nitrogen oxides ranged from 1.6 - 1.7 gm/mile. The average lead content of the fuel was 0.03 gm Pb/gal. and the average sulfur content was 300 ppm. The poisoning effect of the platinum/palladium catalytic surface by the fuel additive package of TEL and the lead scavengers, ethylene dichion da and ethylene dibromide, has been studied by Otto and Montreuill (1976), TEL at a concentration of 0,5 gm/gal, without scavengers caused the most severe loss of oxidizing ability of the catalytic surface. In this study, oxidizing ability or capacity was related to the amount of Pt/Pd surface area available. For the fuel containing 0.5 gm Pb/gal as Motor Mix (both scavengers present) the oxidizing ability of the catalytic muffler was reduced to about 30X of its original ability after 10,000 accumulated miles. After 50,000 miles, the 5-4oxidizing ability had been reduced to 10 of its original value at 0 accumulated miles. These results were compared to unleaded iso-octane fuels which did not reduce the oxidizing ability of the active surface at such a rapid rate. In addition, it was shown that the scavenger, ethylene dibromide, had the most severe, but reversible effect on oxidation of CO and hydrocarbon emissions. The atmospheric transport of particulate sulfur emissions has been studied by Roberts and Friedlander (1975) for the Los Angeles Basin. From the trans port model used to estimate gas to particle conversion rates for sulfur, it was estimated that the introduction of catalyst-equipped vehicles could add significantly to the particulate sulfur concentrations measured at locations downwind of the release points. 1.2 Release Rate of Catalyst Components to the Environment Along with the sulfate emissions, the release of the components of the catalytic muffler to the environment has been the subject of several experimental studies. The basic components of the muffler are platinum and palladium, about 3 gm/muffler, which areapplied to an alumina Substrate, The two designs of catalytic mufflers are the monolith or fixed bed reactor, and the pelleted or fluidized bed reactor. Brubaker, et al. (1975) raised the issues of release and fate of platinum in the environment. In the GM study (Cadle, et al. - 1976), an. emission rate for platinum of 20 ug/mile was determined. There was no information on chemical form of emitted platinum, and no information on particle size. Taylor and Hanna (1975) have reported on the ability of methylcobalamin (HeB-12) to form a moderately stable methylated form of platinum when incubated with uM levels of KgPtClg. \ A X V. \ ' lbs-. 5-52.0 Exhaust Emissions from Catalytic Mufflers from the Use of Fuels with Higher Aromatic ContentGasolines of all grades contain a certain weight percent of aromatic organic chemicals. The chemicals most frequently used tn benzene, toluene, and the xylene isomers because they increase the Research Octane Number (RON) and prevent pre-ignition or knock of gasoline. The highest percentages of aromatics are used in premium grades of fuel. The percentage of aromatics in unleaded premium fuel is greater than leaded premium fuels. The major public health concern with the combustion of unleaded fuels containing high weight percents of aromatics is the exhaust emission of particulate matter which has polynuclear aromatic compounds adsorbed to a carbon core {NAS-1972). Gross (1973) presented da.a on how exhaust emission of polynuclear aromatic {PNA) compounds were a function of the engine modification emission control system, the amount of polynuclear aromatic content of the fuel and the oil consumption rate. For the 1968 vehicles, the emission control system was an air-injected RAM thermal reactor; the 1970 vehicle control System was a monel + platinum catalytic muffler, Engelhard PTX-5. Emission control systems for 1968 and 1970 model vehicles reduced PNA emissions by 65-852 relative to the uncontrolled vehicle. PNA content in fuel was linearly related to the PNA emission rate. The indicator PNA chosen for identification was benzo(a)pyrene (BaP). High oil consumption caused higher emission rates of PNAVs. The major variables effecting BaP emission rate were sumnarized by Gross (1973) as follows: CS-9 - --^-_^-DUP040013860^ SaP in Fuel Dom 0.01 0.4 - 0.5 3 - 3.2 0.4 - 0.5 0.4 - 0.5 Oil Consumotion No. Emission Control Normal 130 Normal 290 Normal 800 High due to valve seal removal - High due to oil ring removal - BaP Emission uq/qal Engine Modification 1968 1970 41 26 68 47 200 170 150 7600 - A minor factor in the emission rate of PNA's was the synthesis of PNA' from simpler aromatic molecules. Previous data from Gross (1972) had showed that PNA emission rate increased sharply as aromatic content increased from IIS to 46* by weight- Fuel lead and phosphorous content of fuel did not have much influence on emission rates. PNA's tended to accumulate in engine motor oil. The mechanism of PNA emission was similar to emission of lead particulate emission; i.e. a strong function of mode of driving and age of the exhaust system. Other PNA'S which have carcinogenic activity and have been identified by Grimmer, et al. (1972) and Boyer and Laitinen (1975) are dibenz(a.h)anthracene, chrysene, and benzo(a)anthracene. C-ST.r i f i 5-7* 3.0 Exhaust Emissions from the Fuel Additive Methyl Cyclopentadienyl Manganese Tricarbonyl; ' KMT 1 ` '......... ' '' The manganese fuel additive methyl cyclopantadienyl manganese tricarbonyl (MMT) is currently used in the motor mix fuel additive package. It acts both as a promoter for TEl and as an antiknock compound in its own right. Recently, consideration has been given to using MMT as a replacement for TEL, No scavenger compounds would be required, and the optimal concentration for use in gasoline would be 0.125 gm Mn/gal. (Ethyl Corporation - 1971, 1972, and 1974a), At this use level, the road octane number of gasolines would be increased by approximately 2.2 units. In addition, it was stated that manganese ' * exhaust emissions would not effect the efficient operation of the catalytic muffler. There was no data given to support this claim. At higher use levels (1 - 2 g Mn/gal.) spark plug life was significantly shortened. The major form of manganese in exhaust emissions was MrigO^. Typically about 0,1% of the MMT was emitted from the tailpipe unturned. In the 1975 lean reactor cars, this level of unburned MMT in the exhaust was reduced to 0,01 - 0.022. Ter Hear, et al, (1974) have studied the photolytic decomposition of 'MMT in the vapor phase. Major decomposition products were manganese oxides and carbonates. Mn2 (C0)10 was not detected. The organic portion of the solid materials appeared to be a complex mixture of acids, esters, and hydrocarbon -iI amorphous polymers resulting from the partial oxidation of the cyclopantadienyl ring, CO insertion reactions, and polymerization of multifunctional compounds. It was estimated that the half life of this reaction was 15 seconds. Using the 7-mode Federal Test Cycle, Ter Hear, et al. (1974) reported that the average KMED for manganese exhaust emissions from the combustion of j i " \ Ctt 5-8fuel containing 0.125 g Mn/gal., were 0.38 u for cold cycles and 0.30 y for > hot cycles. A comparison with lead emissions from a fuel containing 0.5 g Pb/gal. gave an average MMED of 0.4 y for cold cycles and 0.32 y for hot cycles. There was no information given on emission rates of manganese particulate emissions. It was stated that 2/3 of the particles were of a size that they would remain suspended for some time. There has been considerable concern about the role of particulate manganese in the catalytic oxidation of S02 to SO^. Gerhard and Johnstone (1955) found that the photochemical oxidation rate of S02 to S03 was 0..!^ - 0.2% per hour, with the rate being dependent on the relative humidity. Assuming first order kinetics, this gave a rate constant of about 0.002 (hours)-1. McKay (1971) studied the atmospheric oxidation of S02 in the presence of Nh^. At NH3 levels Of 10 ug/m3, McKay predicted that the conversion of S02 to sulfate would be greater than 50% per hour. Again assuming first order kinetics, the rate constant was 0.69 (hours)-1. Ambient levels of NH3 have been reported by the PHS (1966) are above 20 yg/m . In simulated atmospheres containing NH,, SO^, and Manganese particulate emissions, Wright, et al, (1974) have studied the effect of manganese exhaust emissions on the oxidation of S02 in air. It.was estimated that if all gasoline contained 0.1 gm Mn/gal., thi.s would increase ambient manganese concentrations in urban air by 0.02 to 0.2 yg/m'. Average, yearly ambient concentrations of 0.02 - 0.05 yg/m3 (NAS-1973). Wright, et al. (1974) demonstrated that in their simulated atmosphere contained in a black bag, that manganese concentrations did not have a significant effect on the rate constant for oxidation of S02 until levels greater than 20 yg/ro were reached. Below this concentraton, the rate constant was constant at 0.14 (hours) 1' < <?? /' ------ - T7buP040013863^ 5-9 Ethyl Corporation (1974b) has stated that the presence of manganese exhaust emissions resulting r'rom the combustion of gasoline containing 0.125 gm Mn/gal. does not pose a public health problem. From the lack of information on emission rates, site of particles, deposition rates and partitioning in the environment, the bases for this statement is questionable. In addition, there is very limited information on chronic exposure to low levels of manganese oxide (Stara - 1973). High levels of industrial exposure to Mn02 particles in air (50 - 60 mg/m ) have produced a neurological disorder similar to Parkinsonism and a respiratory disease similar to acute lobar pneumonia (Mena, et al. - 1967, Canavan, et al, - 1924, Van Beukering - 1966, Mena, et al. 1969, Emara, et al. - 1971, Davies - 1946, Rodier - 1955, Morichau-Beauchant 1964, Gabuniya - 1964, Tanaka and Lieben - 1969, and Louria, et al. - 1972). In addition there is no information on chronic exposure to low levels of manganese oxides both in ambient air and dust and dirt for young children, pregnant women, and susceptible segments of the population. The parent compound, KMT, has an LD5q value of 56 mg/kg by oral admioistra tion to mice (Strohmeier - 1964). The TLV (ACGIH - 1974) for MMT has been given as 0.1 ppm. Additional information on the geochemistry, uptake by plants, and discussion of manganese as an essential trace element are reviewed by the NAS (1973). DUP040013864 4,0 Alternative Fuels 5-10- The use of alternative fuels for gasoline has been suggested and practiced to some degree since the early 1930*s. In Europe, particularly, the use of ethanol and methanol blended with gasoline nas been a common practice. It has only been recently, however, as a result of uncertain supplies of crude oil that serious consideration has been given to alternative fuel use on a massive scale in the United States, The NAS (1973b) has reviewed the status of proposed alternative fuels. The three candidate fuels are liquified natural gas (ING), hydrogen, and alcohols. Natural gass, composed mainly of methane and propane, is expensive, does not improve drivability, and does not offer any great advantage over current grades of gasoline in reducing the quantities and types of air pollutants. Hydrogen, however, offers many advantages in terms of air pollution reduction since there is no carbon present. Therefore, exhaust emissions of CO and unburned hydro carbons do not exist. Its high flammability range means that very lean mixtures can be used so that nitrogen oxide emission rates are reduced because of the lower combustion chamber temperatures. Another advantage is the absence of sulfur, thereby eliminating exhaust emissions of SOg. However, neither the industrial capacity nor the automotive engine-fuel delivery system are available on a large scale. Alcohols, particularly methanol, alone or blended with gasoline have been used for fuels in spark-ignited engines for some time. Reed and Lerner (1973) reviewed the benefits of methanol as a fuel in many applications. As an alternative fuel for gasoline, methanol has a lower heating value and requires the addition of volatile chemicals to aid in starting during cold weather. The main advantage of methanol as a fuel was given by the NAS Report (1973b) i iSJ r \ \ 1 DUP040013865 as the reduction of nitrogen Oxide emission rates. These lower emission rates were the result of leaner mixtures which produced lower combustion chamber temperatures. This reduction in nitrogen oxide emission rates was supported by the research reports of Adelman, et al. (1972), Ebersole and Manning (1972), Tillman, et al. (1975), Most and Longwell (1975), and Ingamells and Lindquist (1975). Bolt (1964) and the API (1971) contended that the use of alcohols as fuels in automobiles did not appreciably reduce air pollution. This view was supported by Brinkman, et al. (1975), who demonstrated reductions for CO emissions, but no significant changes- jn hydrocarbon or nitrogen oxide emission rates for a 10% methanol - 90% gasoline blend. In addition, drivability and fuel economy were reduced. The API (1971) report states that use of alcohols results in increased emissions of aldehydes. Aldehydes are very reactive chemicals which can significantly contribute to the atmospheric chemical reactions which convert. NO to NOg without consuming ozone. This reaction sequence is given by Seinfeld (1975) as: Jxv_ n \ RCO OH- Acyl Radical o. P NO RC000- 4 RC00- Peroxyacyl Acylate __Radical...... ..-.Radical... NO NO *H\*- HO, _5,H0- -h o 3 OH' HC (hydrocarbons) C$0 DUP040013866 5-12Posner (1975) recently reviewed the biohazards of methanol in its proposed new uses. The human biohazards were discussed in eight categories: hazards at young ages; potential interactions; abuse; delayed and irreversible toxicity; dermal and inhalation hazards; toxicity of formaldehyde combustion products; nearly invisible flame; and a larger storage volume required for an equivalent energy return as compared to gasoline. Several suggestions were given to reduce the hazards associated with methanol use, but it was concluded that methanol produced known delayed and irreversible effects and was a difficult chemical to control. j * \ / DUP040013867 CHAP1ER 5 REFERENCES 5-13- ACGIH. (1974). Documentation of the Threshold limit Values (TLV's) for substances in Workroom Air. ACGIH, P.0. Box 1937, Cincinnati, Ohio. Adelman, H. G., Andrews, D. G., and Devoto, R. S. (1972). Exhaust emissions from a methanol-fueled automobile. SAE Paper No. 720693, Presented at SAE National West Coast Meeting, San Francisco, August, American Petroleum Institute (1971), Use of alcohol in motor gasoline -- a review. API Publ. No. 4082. Washington, D. C., August. Seltzer, M., Campion, R. J., Peterson, W, L. (1974), Measurement of vehicle particulate emissions. SAE Paper No. 740286, SAE Meeting, Detroit, Michigan, February-March. Bolt, J. A, (1964). A survey of alcohol as a motor fuel. SAE Special Publ. SP-254. Society of Automotive Engineers, Inc., 2 Pennsylvania Plaza, New York, New York, June. Bombaek, J. 1., Wheeler, M, A., Tabock, J., and Janowski, 0. D, (1975), Distri bution of contaminants in used automobile emission catilysts. Environ, Sci, & Technol. 9(2): 139-143. I Boyer* K. W. and Laitinen, H. A, (1975). Automobile exhaust particulatesProperties of environmental significance. Environ. Sci. & Technol. 8(5): 457-469. Brandt, M., Faggan, <3, E,, Gautroaux, K. F., Rifkin, E. B., and Ter Haar, G, 1, (1972). Information for NRC concerning methylcyclo-pentadienyl manganese tricarbonyl. Ethyl Corporation, Detroit, Michigan, September. Brinkman, H. D,, Gallopoulos, N. E., and Jackson, M, W. (1975). Exhaust emissions, fuel economy, and drivability of vehicles'fueled with alcohol-gasoline blends. SAE Paper No. 750120. Presented at SAE Meeting, Detroit, Michigan, February. Brubaker, P. E., Moran, J. B-, Bridbord, K, and Hueter* F. G. (1975). Noble metals: a toxicological appraisal of potential new environmental contaminants. Environ, Health Perspec. 10; 39-56. Cadle, S. H-, Chock, D. P,, Heuss, J, M., and Monson, P. R, (1976). Results of the General Motors sulfate dispersion experiment. Research Publ. GMR-2107, Research Laboratories, General Motors Corporation, Warren, Michigan, March. Campion, R. J. (1973). S02 particulates. Paper presented at Hearings on a Review of the Health Effects of Sulfur Oxides, David P. Rail, Chairman, Washington, 0, C., September, m li ..... ------------ ----jJ , DU P040013868 5-14- Campion, R, 0., (1975). Fleet test of 20-1975 catalyst-equipped vehicles Which meet 1975 California Emission Standards. Progress Report to EPA, October. '* Canavan, M, M., Cobb, S., and Drinker, C. K. (1934). Chronic manganese poisoning. Report of a case with autopsy. Arch. Neurol. Psychiat. 32: 501-513. Davies, T. A. L. (1946). Manganese pneumonitis. Brit, J. Ind. Med, 3: 111-135. Ebersole, G. D. and Manning, F. S. (1372), Engine performance and exhaust emissions: Methanol versus isooctane. SAE paper No, 720692, presented at SAE National West Coast Meeting, San Francisco, August. Emara, A. M., El-Ghawabi, S. H., .Madkcur, 0. I,, and El-Samra, G. 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