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ENVpRONMENTAL ttESEA,iCH Sl, 1-24 (1990) REVIEW 1989 Alice Hamilton Lecture' Lead and Human Health: Background and Recent Findings MORTON LIPPMANN New York University Medical Center, lrtstitr+te ojG'itviromttenta! Medicine, Tuxedo, New York 10987 Received March 22, 1989 This paper, prepared in tribute to Dr. Alice Hamilton on her 120th birthday, reviews her pioneering studies of occupational lead poisoning and its control, her IarYely unheeded warnings about the possible consequences of widespread lead exposure to the general public through the use of leaded fuel, and the results of recent studies of human exposure to and health effects of tead in the general environment. Evidence is presented for dose-related non-threshold effects for children with blood lead concentrations below 25 µgldl for a variety of effects including verbal IQ; mental development; physical size; and age at phys- ical m1'lestones such as first steps, hearing thresholds, and postural sway. For adults, various studies have produced associations between blood pressure and blood lead concentrations below 35 p.gfdl, suggesting possible etfects on cardiovascular health. Wlu7e the biological rnechanisms responsible for these effects remain poorly understood, recent and current efforts to reduce exposure to kad by the virtual elimination of lead in psoline and food packaging show that we have learned one of Dr. Harulton's important kst:ons, i.e., that the most effective means of reducing excessive exposures are through control of the enviroit- ftlental smiSrces. e H90 Asadamic Press, inc. INTRODUCTION The invitation to present the second Alice Hamilton lecture led me to reread her autobiography (Hamilton, 1943) FxpdoriRg the Dangerous Trades (Fig. 1) which, in turn, led me to select lead's effects on human health as the focus of this lecture. The systematic study of lead poisoning among industrial workers which Dr. Ham- ilton performed so well, virtually single-handedly, in Illinois in 1910 led her, and those she influenced, to new careers in occupational medicine and worker health protection. Her emphasis on exposure prevention through the application of en- gineering controls to process technology gave powerful impetus to the develop- ment of the fieid of industrial hygiene in this country. Dr. Hamilton was personally persuasive. She had to be. As she has written: Our procedure in the Illinois survey and in the work that I carried on later for the Federal government was completely informal. We had no authority to enter any plant, we had no instructions as to which we should visit, we simply explored the state. When we found a place which seemed to belong in our field, we asked permission to enter it. Never were we refused, never did 1, at kast, meet with anything but courtesy in those very early days. t Presentation: National Institute for Occupational Safety and Health, Cincinnati, Ohio. February 27, 1989. 0013-9351/90 S3.®0 Cor.1rijht C 1990 b> Academie Prcu. Inc. All rijht- of ttproductioo in an> fam rcscrveE.

MORTON LIPPMANN EXPLORING THE DANGEROUS TRADES ^ At.tce ttA%nt.TOx. st.n. N'ui !G'.rnawe, h V..A AV ATl.IYTIr YI»1111 P Pkf.N R,w,A LIT7L1.. RROt%V.\\U f.U4R%%\ - Nti14.\ w+: Fto. 1. Frontispiece and titk page of Erplosinj the Dangerous Trodes. As Dr. Hamilton noted, however, it was usually difricult to convince manage- ment that the conditions and exposures she observed were sufficient to warrant controls. As a good example she cites the following: ... the National Lead Company ,.. had several white-lead and tead-oxide works in and near Chicago. I visited them and found much dangerous work;oing on in alt of them. One ogthe vice•presidents, Edward Cornish, later president, came to Chicago and I went to see him in the Sangamon Street works. He was both indignant and incredulous when I told him I was sure men were being poisoned in those plants. He had never heard of such a thing; it could not be true; they were model plants. He went to the door and shouted to a passing workman to come in. "Did the lead ever make you sick?" he demanded. The man, a badly scared Slav stammered. "No, no, never sick." "Any other men sick?" demanded Mr. Cornish. "no, no, all good." and the poor man escaped quickly. "There", said Mr. Cor- nish, "you see!" "But I do not see: " I answered. "Your men are breathing white•kad dust and red lead and litharge and the fumes from the oxide furnaces. They are no different from other men; a poison is a poison to them as it is to any man." He thought a moment and then he said, "Now, see here. I don't believe you are right, but I can see you do. Very well then, it is up to you to convince me. Come back here with proof that my men are being leaded and I give you my word I wTll follow all your directions, even to employing plant doctors." It was not an easy task I faced, tncking down actual, proved cases of lead poisoning among men who came from the Serbian, Bulgarian, and Polish sections of West and Northwest Chicago, and Kere known to the employing office only as Joe. Jim. or Charlie, with no record of their street and number! It meant digging up hospital records, for I had to be sure of the diagnosis. then a search for the home, and finally an interview with the wife to discover where the man had been working, for of course no hospital interne ever noted where the victim of plumbism had acquired the lead. Hospital history sheets noted

LEAD AND HUMAN HEALTH 3 carefully all the facts about tobacco, alcohol, and even coffee consumed by the leaded man, though obviously he was not suffering from those poisons; but curiosity as to how he became poisoned with lead was not in the interne's mental make-up. In the end I was able to present Mr. Cornish with authentic records of twentytwo cases of plumbism severe enough to require hospital care. He was better than his word. Begin- ning with the SanYamon Street works, he went on to reform all the plants in the Chicago region, and this meant dust and fume prevention, often by methods which had never before been worked out. There were no models to follow: the engineers faced new problems. As each was solved, Mr. Cornish sent the blueprints to the plants in other states and later on. when I visited these, invariably I found the same changes being introduced. I had told Mr. Comish he could never fully protect his men unless he employed doctors to keep strict watch over their condition, to make at least a brief inspection of each lead worker once a week. He accepted this recommendation without protest and before our report was pub- tished there was a medical department in each plant of the National Lead Company in Illinois. I have met many admirable men in industry throughout these thirtytwo years, but my warmest gratitude and admiration goes to Edward Cornish. In commenting on the lack of adequate governmental regulation of occupational exposures, and the apparently automatic opposition of industry to tighter regula- tion Dr. Hamilton remarked: Perhnps it is our instinctive American lawlessness that prompts us to oppose all legal controt, even when we are willing to do of our own accord what the law requires. It is clear that Dr. Hamilton was a shrewd and wise observer as well as an inquisitive investigator and pioneer. It is now also clear that failure to pay close attention to her farsighted concerns about tetraethyl lead in 1925 has had serious public health consequences. The use of organic compounds of lead as antiknock motor vehicle fuel additives has clearly been the dominant source of a worldwide dispersion of lead into the environment and into people. Since leaded gasoline was introduced in 1923, it has increased background levels everywhere, including the Greenland ice cap (Fig. 2). Several years ago. Rosner and Markowitz (1985) reviewed the public health controversy over leaded gasoline during the early 1920s. including the role played by Dr. Hamilton. The following is a selective condensation of their review. The introduction of leaded gasoline led to a series of fatalities and severe poisonings among employees of the producing companies in Bayway. New Jersey; Dayton, Ohio; and Deepwater, Delaware. On the other hand, in February 1924 the Bureau of Mines concluded that ethyl gas posed no threat to the public on the basis of a series of toxicological studies it performed in its laboratories with funds donated by!the industry. In response to the public controversy which ensued, Dr. Ham- ilton wrote to Surgeon General Hugh Cumming in February 1925 suggesting the '°desirabiiity of having an investigation made by a public body which will be beyond suspicion." In Apr1'1 1925, the Surgeon General announced that he was calling together experts from business, labor, and public health to assess the tetraethyl lead sit- uation. The conference convened on May 20, 1925. According to Rosner and Markowitz, the industry position could be summed up as follows: (1) "leaded gasoline was essential to the industrial progress of America"; (2) "any innova- tions entails certain risks"; and (3) "the major reason that deaths and illnesses

4 0.20 F- 0.15 0.04 0 t300 _~ 1750 1800 1850 1900 1950 A.O. AGE OF SAMPLES 1Fao. 2. Lead concentration, profile in snow strata of Northern Greenland (EPA, 1986). occurred at their plants was that the men who worked with the materials were careless and did not follow instructions." The strongest and most authoritative critic of industry was Dr. Yandell Henderson, a noted physiologist at Yale. The following are excerpts from Rosner and Markowitz (1985). He (Henderson) told the conference that lead was a serious public bealth menace that could be equated to the serious infectious diseases then affecting the nation's health. Unlike industry spokespeople who defined the problem as one of occupational health and main- tzined that individual vigilance on the part of workers could solve the problem, Henderson believed that leaded gasoline was a public health and environmental health issue that required federal action. He expressed horror at the thought that hundreds of thousands of pounds of lead would be deposited in the streets of every major city in America. His warning to the conference of the long-term dangers proved to be an accurate prediction: "conditions would grow worse so gradually and the development of lead poisoning wt7t come on so insid'wusly ... that leaded jasoline w9 be in nearly universal use and large numbers of cars will have been sold ... before the public and the Bovernment awaken to the situation." Dr. Hamilton agreed with those opposed to tetr.ethyl lead. At the conference she ex• pressed her belief that the environmental health issues were far more important than the occupational health and safety issues, adding that she doubted that any effective measures could be implemented to protect the general public from the hazards of widespread use of leaded gasoline. "You may control conditions within a factory; ' she said, "but how are you going to control the whole country?" In an extended commentary after the conference on the issues that it raised, Hamilton stated, "I am not one of those who believe that the use of this leaded gasoline can ever be made safe. No lead industry has ever, even under the strictest control, lost all its dangers. Where there is lead some cases of lead poisoning sooner or later develops, even under the strictest supervision." Most public health professionals did not agree with Henderson and Hartulton, however. Many took the position that it was unfair to ban this new gasoline additive until definitive proof existed that it was a real danger. In the face of industry arguments that oil supplies were limited and that there was an extraordinary need to conserve fuel by making com- MORTON LIPPMANN t.

LEAD AND HUMAN HEALTH 5 bustion more efficient, most public health workers believed that there should be over- whelming evidence that leaded gasoline actually harmed people before it was banned. Dr. Henry F. Vaughan, president of the American Public Health Association, said that such evidence did not exist. "Certainly in a study of the statistics in our large cities there is nothing which would warrant a health commissioner in suying that you could not sell ethyl gasoline," he pointed out. Vaughan acknowledged that there should be further tests and studies of the problem but that "so far as the present situation is concerned, as a health administrator I feel that it is entirely negative." Despite the widespread ambivalence on the part of public health professionals and the opposition to any curbs on production on the part of industry spokespeople, the public suspicions aroused by the preceding year's events led to a significant victory for those who opposed the sale of leaded gasoline. At the end of the conference, the Ethyl Corporation announced that it was suspending the production and distribution of leaded gasoline until the scientifc and public health issues involved in its manufacture could be resolved. The conference also called upon the Surgeon General to organize a blue ribbon committee of the nation's foremost public health scientists to conduct an investigation of leaded gasoline. Among those asked to participate were David Edsall of Harvard University, Julius Steiglitz of the University of Chicago. C: E. A. Winslow of Yale University and the American Public Health Association. For Atice Hamilton and other opponents of leaded;asoline, the conference appeared to be a major victory for it wrested from industry the power to decide on the future of an important industrial poison, and placed it in the hands of university scientists. "To anyone who had followed the course of industrial medicine for as much as ten years; " Alice Hamilton remarked one month after the conference, "this conference marks a great progress from the days when we used to meet the underlings of the great munition makers (during World War I) and coax and pl-.ad with them to put in the pre- autiotnry measures . . . This time it was possible to bring together in the office of the Surgeon General the foremost men in industrial medicine and pubGc health and the men who are in real authority in industry and to have a blaze of publicity turned on their dehberations." As a result of their study, the committee concluded seven months after the conference that "in its opinion there are at present no good grounds for prohibiting the use of ethyl gasoEine ... provided that its distribution and use are controlled by proper regulations." They suggested that the Surgeon General formulate specific regulations with enforcement by the states. This group saw their study as only an interim report, to be followed by longer tange follow-up studies in ensuing years. In their final report to the Surgeon Genetal, the cornmittce warned: '•it remains possibk that if the use of leaded gasoline becomes wide- spread conditions may arise very different from those studied by us which would render its use tnae of a hazard than would appeu to be the case from this investigation. Longer experience may show that even such slight storage of lead as was observed in these studies may lead eventually in susceptible individuals to recognizable or to chronic degenerative diseases of a less obvious character." Recognizing that their shon-tetm investigation was incapable of detecting such danger, the committee concluded that further study by the government was essential: ••ln view of such possibilities the committee feels that the investigation begun under their direction must not be allowed to lapse ... It should be possible to follow closely the outcome of a more extended use of this fuel and to determine whether or not it may constitute a menace to the health of the general public after prolonged use or other conditions not now foreseen ...`!i he vast increase in the number of automobiles throughout the country makes the study of all such questions a matter of real importance from the standpoint of public health and the committee urges strongly that a suitable appropriation be requested from Congress for the continuance of these investigations under the supervision of the Surgeon General of the Public Health Service." In view of what we now know about the health effects of low levels of lead in the body, it is quite unfortunate that the further investigations called for by the

6 MORTON LIPPMANN Surgeon General's committee did not take place for more than four decades, during which lead was spread far and wide in quantities which the committee could hardly have envisaged. For example, in 1970, when lead use in gasoline peaked, 252,654 metric tons were used and the total consumption over the period 1929-1983 was 6,635,059 metric tons. Of this, approximately 10% was retained in the engine oil, 15% deposited in the exhaust system, 35% emitted as submicrome- ter-sized aerosol, and 40% emitted as > 10-µm particles (EPA, 1986). REVIEW OF HUMAN EXPOSURE AND HEALTH EFFECTS Quoting once again from Dr. Hamilton's Exploring the Dangerous Trades: Lead is the oldest of the industrial poisons except carbon monflxide, which must have begun to take its toll soon after Prometheus made the gift of fire to man. In Roman days, lead poisoning was known, for Pliny the Elder includes it among the "diseases of slaves," which were potters' and knife grinders' phthisis, lexd and mercurial poisoning. ThrouYhout all the centuries since then men have used this valuable metal in many ways, and from time to time an observant physician has seen the results and described them, notably Ramazzini in the eighteenth century, and early in the nineteenth century the grtat Frenchman, Tanquerel des Planches. It is a poison which can act in many different ways. some of them so unusual and outside the experience of the ordinary physician that be fai7s to recognize the cause. I could never feel that I had uncovered all the cases in any com- munity, no matter how small, even after I had talked with all the doctors and gone through the hospital records, for some doctors would not pronounce a case to be due to lead poisoning unless there was either colic or palsy, which is as if he refused to recognize alcoholism unless there were an attack of delirium tremens. It is true that a severe attack of co6c is the most characteristic symptom of lead poisoa- una, and palsy-usually in the form of wristdrop-is the one most easily recognized, but there are many other manifestations of this protean malady, as every physician knows today. Thirty years ago it was not hard to f nd extremely severe forans, such as could come only from an exposure so great as to seem criminal to us now, but which then attracted no attention. Dr. Hamilton was writing about the situation as of 1942. By then, as now, overt clinical symptoms of lead poisoning only occurred when available knowledge about lead toxicity and exposure control are not taken into account. In 1970, 3 months after Dr. Hamilton passed away, the federal Occupational Safety and Health Act (OSHA) was passed. This led, in 1971, to the adoption of an interim Permissible Exposure Level (PEL) of 200 µg/ms for lead dust in air. In 1979, a permanent OSHA standard was implemented. It specified a PEL of 40 µg/m3. as well as a blood lead concentration limit of SO µgldl. More subtle health effects, resulting from exposures below the PEL, are known to occur and were addressed by the Environmental Protection Agency (EPA) in preparing the 1978 National Ambient Air Quality Standard (NAAQS) of 1.5 µg/m3 as a 3-month average. While EPA has completed its latest criteria document for lead in ambient air (EPA, 1986), it has not yet proposed a revised NAAQS. However, concern about low-level lead exposure has led EPA to propose, on 8/18l88, a maximum contaminant level goal (MCLG) for drinking water of zero (CFR 53 (160) 31516). EPA is also considering regulating lead as a carinogen, as a toxic component in incinerator ash, and as a leachable constituent in Superfund sites.

LEAD AND HUMAN HEALTH 7 For infants and small children, significant body burdens of lead can be acquired from ingested soil and paint chips. Household dust and garden soil, especially in urban areas can be greatly enriched in lead from the fallout of airborne particles from motor vehicles burning leaded fuels. Another major source in older homes is paint flakes and chips containing lead-based pigments. It has been illegal to use such pigments in interior paint for more than 50 years, but there are large inven- tories within older buildings which can be readily mobilized and dispersed during maintenance and renovations. ATSDR (1988) indicates that 40 million households in the United States contain hazardous quantities of leaded paint. Yaffe et al. (1983) reported that the isotopic ratios of lead in the blood of children were close to the average lead ratios of paints from exterior walls and to the lead ratios of surface soils in adjacent areas where the children played. Their data suggest that the lead in the soil was derived mainly from weathering of leaa-based exterior paints, and that the lead-contaminated soil was a proximate source of lead in the blood of the children. As shown in Fig. 3, the most significant contributors to current body burdens of lead include direct air inhalation, inhalation or direct ingestion of settled dust, and the ingbstion of food and water. Some old housing stock has lead pipe which can elevate potable water concentrations substantially. Lesser, but still significant, elevations can occur in water delivered via modem copper and brass pipe due to leaching of lead from the solder in the joints. Foods can be enriched in lead from a variety of sources. Lead in the air can deposit on leafy vegetables and fruits and IN REO t B100Q --~ n~ ~ UYER KIDNEY A( )X Ftc. 3. FECES UR1NE BONES Pathways of lead from the environment to and within man (EPA. 1986).

~ MORTON LIPPMANN leave residues which are ingested. Lead in the soil can be incorporated into the growing plant. Canned foods can also extract lead from solder used to seal the can. Lead exposures and blood lead levels among the general population have de- clined substantially in recent years. The most substantial reduction has been due to the switch from leaded to unleaded gasoline as motor vehicle fuel. This had an immediate effect on air lead (Fig. 4) and a parallel reduction in average blood lead (PbS) concentration which lagged by -3 months (Fig. 5). The lag occurred be- cause most of the tailpipe lead reached people indirectly through exposure to resuspended soil and through incorporation into foodstuffs. Further reductions have occurred as the food packaging industry has reduced the use of solder in cans. Table I from the 1986 EPA Criteria Document summarizes the contributions to lead in blood from the major sources for 2-year-old children in the early 1980s. RECENT HEALTH EFFECTS FINDINGS The literature on human exposures to lead and their health effects is volumi- nous. The 1986 EPA criteria document was published in four volumes containing 1336 pages. This discussion will be limited to the more descriptive research rel- ative to low-level population exposures and the chronic health effects associated with such exposures. In most cases, this limits the review to studies of the asso- ciations between exposure and health effects in humans, since the low-dose ef- fects of interest have seldom been seen in animal toxicology studies conducted at higher levels of exposure. The disturbing implication that conventional animal J 2°r ~ ® t t t t t t t t t o~ 1975 1977 1979 1981 1983 CALENDAR YEAR Ftrr. 4. Lead consumed in gasoline and ambient lead concentrations. 1975-1983 (EPA. 1986).

LEAD AND HUMAN HEALTH 16 9 9 1976 1977 1976 1979" 1980 YEAR FtG. S. Parallel decreases in blood lead values observed in the NHANES 11 Study and amounts of lead used in gasoline during 1976-1980 (EPA. 1986). toxicology provides little useful information about some 'serious human chronic health issues is a subject for another paper and will not be discussed further here. The effects that have been associated with blood lead (PbB) concentrations <40 µg/dl will be the main focus of this selective review. These include the effects of prenatal and early childhood exposures on physical and neurobehavioral devel- opment of children, and the influence of chronic low-level exposure on cardio- vascular function in adults. These low-exposure-related effects are of interest in relation to both occupational and general environmental exposures. The effects in young children may be due to exposures in utero of working mothers (Wang et al., 1989), and to lead brought into the home on work clothing of family members with occupational exposures (Baker et al., 1977; Kaye et al., 1987; Wang et al., 1989). TABLE I C_ ONTRltiUTiONS FROM VARIOUS MEDIA TO BLOOD LEAD LEVELS (µL!dl) OF U.S. CHILDREN (AGE - 2 YEARS): BACKGROUND LEVELS AND INCREMENTAL CONTRlBUT1oNS FROM AdR Air 1ead. µ;4as Saurce 0 0.25 0.50 0.75 1.00 1.23 1.50 BackSramd-oon-air Food. w2ter, and beveraps 2.37 2.37 2.37 2.37 2.37 2.37 2.37 Dust 0.30 0.30 0.30 0.30 0.30 0.30 0.30 SuhtoW . 2.67 2.67 2.67 2.67 2.67 2.67 2.67 BacEcSmnd-asr Food. Kater, and beverates 1.65 1.63 1.63' 1.63 1.65 1.65 1.65 Ingested dust (with Pb _'deposited from air) 0.00 1.37 3.09 4.70 6.27 744 9.40 Inhaled air 0.00 0.50 1.00 1.50 2.00 2.50 3.00 Total 4.32 6.39 11.41 10.52 12.59 14.66 16.72

10 MORTON LIPPMANN Table 2 shows PbB levels in children of workers from a Colorado plant making capacitors and resistors (Kaye et al., 1987). IVerarobeftavioral and Developmental Effects in Children The 1986 EPA criteria document on lead contains a thorough critical review of the literature on the neurobehavioral effects of chronic lowlevel lead exposures in children. While various maladaptive behaviors, neuropsychological deficits, and neuroanatomical changes have been associated with chronic exposures to rela- tively low concentrations of lead, no single mechanism appears sufficient to ac- count for the diverse effects. It is more likely that lead acts at several cellular and subcellular sites. Lead readily enters the brain and appears to be selectively deposited in the hippocampus and cortex as well as in nonneuronal elements that are amportant in the maintenance of "blood-brain barrier" functions. Once de- posited, lead is retained in the brain for long periods of time even after external exposure ceases and PbB levels decline. These spatial and temporal patterns of brain lead accumulation correspond to neurobehavioral and morphologic abnor- malities associated with lead exposure. The sensitivity of the brain during the period of maximal brain growth and differentiation in the first 2 years of life tends to magnify the severity of the long-term consequences. Low PbB levels may contribute to behavioral disorders, such as attentional deficits and distractibility in essentially normal children not diagnosed as hyper- active. A study by Bellinger et al. (1984) suggests that measures of classroom performance may show long-term effects of early lead exposure. Silva et al. (1986) found similar results on 11•year-old children. Winneke et al. (1983) found that behavioral and attentional deficits as rated by teachers (e.g., disordered class- room activity, restless, easily distracted, not persistent, does not follow direc- tioas, low overall functioning) were significantly associated with children's tooth and'PbB levels, which was consistent with the earlier association reported by Needhmatt et a!. (1979). The 1986 EPA criteria document has interpreted the Winneke et al. (1983) study, which also assessed lead-induced deficits in IQ and other psychometric tests, as showing overall neurobehavioral deficits at PbB levels possibly.below 30 µg/dl. In addition; lead levels in young children have been consistently associated, TABLE 2 BLOOD LEAD IN LEAD WORlCERS* CHILDREN, !•v AGE STIUTA` Blood lead (µg/dl) AXe category (years) Exposed mean (rantt) Unexposed mean (range) <6 t3.4(4-23) 7.1• (1-13) 6-10 4 11.1 (3-22) 7.0 (5-9) > 11 :/ E.0 (1-22) 5.0* (2-i l) Atl ages • 10.2 6.2• • Statistically significant (P < 0.001) between exposed and uncxposed groups, Student's test. ° Kaye et ol.. 1987.

LEAD AND HUMAN HEALTH 1I following appropriate adjustments, with deficits in reaction time under varying intervals, which is an index of attentiveness, and with reaction behavior. The 1986 EPA criteria document concluded that these findings argue for probable effects of lead on attention and vigilance functions at PbB levels extending below 30 µg/dl, and possibly, down to as low as 15-20 p.g/dl. There is also evidence that low levels of lead may be associated with effects on some complex cognitive functions including learning, visual-perception skills, and IQ scores. The studies on children have attracted controversy because of d'afficulties associated with attributing subtle deficits in child development to lead exposure rather than to effects due to genetics, nutrition, medical history, access to education, and parental and social_influences, all of which interact in potentially complex ways to mold an individual. On the basis of five methodological criteria (adequate markers of lead exposure, sensitive measures of neurobehavioral function, appropriate subject selection, control of confounding covariates, and appropriate statistical analysis), the 1986 EPA criteria document identified a group of neurobehavioral studies that were conducted rigorously enough to warrant at least some consideration. The general indication from the better investigations is that PbB levels persistently elevated in the range of 50-70 µg/dI tend to be associated with about a 5-point reduction in IQ, even among asymptomatic children and after controlling for potentially confound- ing variables. However, considerable uncertainty has existed regarding lead's impact on IQ scores of children with PbB levels below 40 µg/dl. This uncertainty stems largely from the complex interaction between lead exposure over time, social factors, and intelligence scores, from the statistical and methodological limitations of cross- sectional studies to untangle these variables, and the range of interpretations that result from these studies. 1°he 1986 EPA criteria document concluded from the Needleman et ol. (1979) stpdy and subsequent reanalyses (Needleman, 1984) that, after controlling for coitfounding variables including pica, average IQ decrements of about 4 points and other neurobehavioral deficits appear to be associated with lead exposures of U.S. children resulting in dentine lead values that exceed 20-30 ppm and likely average PbB levels in the 30-SO µg/dl range. Needleman et al. (1982) calculated that a 4-point decrement in the mean IQ of a normal population distribution would be'associated with a threefold increase in the number of children with severe defcits (IQ < 80) along with a 5% reduction in the number of children who attain superior function (IQ > 125) (see Fig. 6). In order to avoid the normal array of confounding factors, Bellinger rt al. (1987) performed a longitudinal analysis of prenatal and postnatal lead exposure and early cognitive development in 249 children. In general, the infants were healthy products of unremarkable pregnancies, with few of the characteristics of infants at increased risk of developmental handicap. Eighty-seven percent of the families were white, and 92% were intact. The differences among the families with infants in the three cord-blood lead groups were slight and generally not in the direction expected on the basis of studies of the social correlates of childhood lead expo- sure. On the basis of lead levels in umbilical-cord blood, children were assigned

12 100 0 MORTON LIPPMANN 0 1E] 60 80 100 VERBAL 1.A. 0 120 140 FtG. 6. Cumulative frequency distribution of verbal IQ scores in subjects with low or hi$h levels of lead (Pdeedleman et aL, 1982). to one of three prenatal-exposure groups: low (<3 µg/dl), medium (6 to 7 µg/dl), or high (;~--10 µg/dl). Development was assessed semiannually, beginning at the age of 6 months, with use of the Mental Development Index of the Bayley Scales of Infant Development. Regression methods for longitudinal data were used to evaluate the association between infants' lead levels and their development scores after adjustment for potential confounders. At all ages, infants in the high-prenatal-exposure group scored lower than infants in the other two groups. The results are summarized in Fig. 7. Scores were not related to infants' postnatal blood lead levels. McMichael rt al. (1988) studied the effect of environmental exposure to lead on children's abilities at the age of 4 years in a cohort of 537 children born during 1979 to 1932 to women living in a community situated near a lead smelter at Port Pirie in Australia. Samples for measuring blood lead levels were obtained from the mothers antenatally, at delivery from the mothers and umbilical cords, and at the ages of 6, 15, and 24 months and then annually from the children. Concurrently, the mothers were interviewed about personal, family, medical, and environmental factors. Maternal intelligence, the home environment, and the children's mental development (as evaluated with use of the McCarthy Scales of Children's Abili- ties) were formally assessed. The mean blood lead concentration varied from 9.1 µg/dt in midpregnancy to a peak of 21.2 µg/dl at the age of 2 years. The blood lead concentration at each age, particularly at 2 and 3 years, and the integrated postnatal average concentration were inversely related to development at the age of 4. Results of multivariate

LEAD AND HUMAN HEALTH 120 104 13 6 12 18 24 AGE AT TESTING (monttts) Fae. 7. Prenatal exposure to lead, as measured by umbilical cord blood lead levels vs early mental development index. Low is c3 µg/dl, medium is 6.7 µp'dt, and high is a 10 ;Wdl (Bellinger et al.. 1987). analysis are illustrated in Fig. 8. Within the range of exposure studied, no thresh- old:dose for an effect of lead was evident. This cohort study indicates that a raised blood lead concentration in early childhood has an independent deleterious effect on mental development as eval- uated at the age of 4 years. This effect was not accounted for by the known and measurable influences of obstetrical, parental, family, and social environmental factors on mental development. The results of this analysis and those of an earlier analysis of the children at the age of 2 years suggest that increased exposure to lead results in a developmental deficit, not just developmental delay. Bhattacharya et al. (1988) found that abnormalities in children's abilities to maintain physical balance were significantly associated with PbB. Their postural sway on a balance increased by -2.8 cm2lµg/dl. These data suggest that low levels of PbB affect the peripheral nervous system as well as the central nervous system. A sample of their results are illustrated in Fig. 9. Schwartz and Otto (1987) used the large database available from the Second National Health and Nutrition Examination Survey (NHANES II), conducted between E976 and 1980 on population samples selected as being representative of the civilian, noninstitutionalized U.S. population. For a subsample of 4519 youths ages 4-19 years, there were data available on blood Pb, audiometry, and various indicators of neurological development, such as age at which a child first sat up, walked, and spoke. The presence of speech difficulties and hyperactivity was also

14 MORTON LIPPMANN 120 110 I , % Mccarthy scal.: m ! V 1 .. . _ ~ ...._~_. ~ 1M .a QUal1tI~wi W tatIVe n D.....~ e~~ ~ (GCi) 90 Mmory Mctor 50 40 0.5 10.3 1.0 1.5 2.0 µmot/1 20.6 30.9 41.2 µg / d Blood Lead Concentration „,,,,,,,,,,,,k,,ch,,,,,, n,U) Fte. 8. McCarthy scales of children's abilities (MSCA) scores at the age of 4 vs blood lead con- centration at 3 years of a=e (McMichael et ot.. 1988). examined to determine if they were significantly related to lead exposure. The probability of elevated hearing thresholds a4 500, 1000, 2000, and 4000 Hz in- creased significantly (P < 0.0001) with increasing PbB (Fig. 10). PbB levels were also significantly related to delays in the age at which children first sat up (Fig. 11), walked, and spoke and to the probability that a child was hyperactive. Lead was not related to the probability of a child having a previously diagnosed speech impairment. Table 3 shows the variables considered in the stepwise multiple regressions, while Table 4 shows the levels of significance of the associations between blood lead and the developmental variables. The results of this large population study are clearly consistent with, and strongly supportive of, the validity of the asso- ciations between blood lead and neurobehavioral effects in the smatler popula- tions reviewed earlier. In another examination of NHANES 11 data, Schwartz tt ol. (1986) incorpo- rated medical history, physical examination, anthropometric measurements, di- etary information (24-hr recall and food frequency), labbratory tests, and radio- graphs in linear regressions of adjusted data from 2695 children ages 7 years and younger. They reported that 91% of the variance in height, 72% of the variance in weight, and 58% of the variance in chest circumference (Fig. 12) were explained by six variables: age, race, sex, blood lead level, total calories or protein, and hcmatocrit or transferrin saturation level. In summary, there are a number of well-designed studies which indicate that very low levels of exposure to lead affect neurobehavioral function and develop- ment in young children. nese various effects appear to be consistent with the

LEAD AND HUMAN HEALTH ~ TEST CONDITION: EYES CLOSED, NO FOAM (p . 0.0025, r Z. 0.41) 0 • • •• 1.6 0 • M • ® ® (uea of swayl-1.49 - o.00002 fntirt w presw.t ~-01 1 (lop maz PDe i+ i a yr.l + o.e9lbp m= Pb8 n 2td yr.1 I 1 I I I I I I I I r I 1.4 2.0 2.4 2.8 3.2 3.6 Log Max. PbB Durinp S®cond Year of Life (µp / d) 4.0 15 Fto. 9. National logarithm of postural sway of children at 6 years of age vs natural log blood lead concentration during second year of tife after controlling for blood lead during first year of life (Bhattacharya et al., 1988). effects of lead on heme biosynthesis which have been postulated to lead to eryth- ropoaetic, neural, renal endocrine, and hepatic effects in the body, as summarized in Fig. 13 from the 1986 EPA criteria document. Effects ojl.ead in the Blood on Blood Pressure Tlae 1986 EPA criteria document on lead also provided a critical review of ; studies showing associations between blood lead concentrations less than 40 µg/dl and blood pressure. It reviewed the influence of a number of environmental and nutritional factors affecting blood pressure in experimental and epidemiological studies. Among environmental factors that have been associated with blood pres- sures are lead (Pb) and noise. Among dietary factors associated with blood pres- sure are calcium (Ca), zinc (Zn), phosphorus (P), alcohol consumption, and vita- mins A and C. The role of Pb as a pollutant stressor for elevated blood pressure could well be confounded by the well-established role of Ca as a suppressor of blood pressure. It is possible that persons with high Ca consumption have both decreased blood pressure and reduced blood Pb due to the competition of both Pb and Ca for the same binding sites. The influence of the other cofactors known to affect blood pressure further complicates the task of establishing the extent to which Pb con- stitutes a significant risk factor for elevated blood pressure. A consistent pattern of results emerges from recent investigations of the rela- tions between lower-level lead exposures and increases in blood pressure or hy- pertension. pertension. Khera et a!. (1980) reported higher blood lead levels in hypertensive

16 MORTON LIPPMANN ~+ 11 m v • a 4 * • • • Z 31 • t 1 t 1 1 0 10 20 30 40 50 BLOOD LEAD LEVEL. µQ / d Fto. 10. Relationship of 2 kHz pure tone hearing threshold (right eu) and blood levels in 4519 NHANES II subjects ages 4-19 years. Each point represents the mean hearing threshold of all persons in a 3 µ" blood lead range, except for the last point, which represents the mean hearing threshold and ysuan blood lead for all children with blood lead levels over 35 Wdl (Schwartz and Otto, 1987). patients and those with other cardiovascular diseases than for hospital control subjects. Kromhout and Couland (1984) and Kromhout et al. (1985) reported associations between hypertension and blood lead among elderly men in the Neth- erlands. Batuman et al. (1983) reported an association between hypertension and chelatable lead burdens in veterans. Moreau et al. (1982) reported significant associations (P < 0.001) between blood lead levels and a continuous measure of blood pressure among French policemen after controlling for important potential confounding variables such as age, body mass index, smoking, and drinking. Weiss et al. (1986) reported that after correction for previous systolic blood pres- sure, body mass index, age, and smoking, a high level of blood lead was a sig- nificant predictor of subsequent elevation of systolic pressure in policemen in Boston. Sharp et a!. (1988) examined relationships between blood lead concen- tration and blood pressure in San Francisco bus drivers. The analysis was limited to subjects not on treatment for hypertension (n = 288). The blood lead concen- tration varied from 2 to 15 µg/dl. While the findings were not statistically signif- icant, they did suggest effects of lead exposure at lower blood lead concentrations than those previously linked with increases in blood pressure. In a follow-up study, Sharp et al. (1989) examined the relationship between blood pressure and blood lead concentration in 51 bus drivers who were treated for hypertension. •'These drivers were a subset of a representative sample (n = 342) of the driver population (n r--2000) and were not selected for hypertension or lead exposure. Blood lead concentrations ranged from 2 to 24 µg/dl. There were 33 subjects

LEAD AND HUMAN HEALTH ~ < W < 5.5 .3 • ® • • • • • • • • 17 • ® • • • 1 1 1 t t t t 1 1 20 40 60 80 100 LEAD PERCENTILE RANK FtG. I 1. Relationship of developmental mileston: attainment and blood lead levels in NHANES 11 subjects. Plots of age at which a child first sat up (in months) vs PbB, after adjusting for other significant covariates. Each point represents the mean adjusted developmental index for 99 consecu- tive observations ordered by mean blood lead level. Regression lines were derived from individual data (Schwarsz and Otto, 1987). treated primarily with diuretics, and 18 subjects were treated with beta blockers. There was a significant mean difference of 12 mm Hg in diastolic BP over the range of observed Pb in blood (2.0 to 11.4 µg/dl) in subjects treated with beta blockers (see Fig. 14). Thus, beta blocker therapy may be less effective in reduc- TABLE 3 VARIAa1.ES C/SED /Ft STEPWISE REGRESSIOIiS Rac.e t.eM Ear discharge Cold in last 2 weeks Other ear condition Chronic ear discharge Income Dietary calcium Race Lead Size Dietary protein . A. Audiometric analyses Sex Current cold Ringing in ear{s) Earache Previous running ear Diagnosed hearing impairment Degree of urbanization Head of household education level Developmental milestone analyses Sex Income Head of household education level Total iron binding capacity Transferrin saturation Serum iron Hemoglobin Dietary calories Weight

18 MORTON LIPPMANN TABLE4 RESULTS OF DEVELOPMENTAL MILESTONE ANALYSES Effect Coefficient P value A. A41e (in years) at first word Intercept 1.25 Sex -0.027 0.0277 Lead rank 0.0024 0.0094 B. Age (in months) when first walked Intercept 10.E8 Rare -0.655 0.0006 Lead rank 0.0070 0.0020 C. Age (in months) when first tat up Intercept 5.68 Protein intake -0.0039 0.0361 Lead rank 0.0061 0.0239 D. Probability of being hyperactive (log;stic regression) Intercept -4.503 - Lead rank _ 0.0116 0.0130 ing diastolic pressure in individuals with elevated PbB, even at PbB levels asso- ciated with exposures below the current ambient standard and far below the current occupational standard. In a large population study, Pocock et al. (1984) evaluated the relationships between blood lead concentrations, hypertension, and renal function indicators in a clinical survey of 7735 middle-aged men from 24 British towns. The association ~ W 55'50 U Z W Q ~ 55.00 ~ ~ U Q U 5450 H ~ Wy ® 54.00 y 50 ~ 53 S 10 15 20 ' ADJUSTED t3LOOD LEAD (Juq / d) 25 FIG. 12. Adjusted chest eircumference and adjusted blood lead levels for children ages 7 years and younger in NHANES 11. Both chest circumference and blood lead level have been adjusted by regression for effects of age, sex, and all other variables significant at 0.05 level. Each point is mean chest circumference and mean blood lead level for approximately 95 consecutive observations, or- dered by blood lead levels. Regression line reflects slope of coefficient obtained from multiple regres- sion analyses of all 2671 points with no missinp data (Schwartz et al., 1986).

LEAD AND HUMAN HEALTH EXACERBATION OF HYPOXfC EFFECTS OF OTHER STRESS AGENTS EFFECTS ON MEUHOMS,AXOP6 AND SCHwANN CELLS hicur~l Effscts REDUCED HEMOPROTEINS (e.g. CYTCCHROSIES) F-++ I~PAJRED IMPAIRED CELLULAR lfYEUFlATqN AND ENERGET~CS kERVE CONDUCTION t4lPA1RED DEVELOPMENT OF tdERVWS SYSTEM R.w Erdoaiiw Eff~cta REDUCED 125 {OH): - ViTAMSN D DISTURBED ttdMUHO f~IPAIRED REGULATORY ROLE MINERAL T1SSW OF CALCIUM FObtEOSTASfS ~---~+ DISTUABED RCIE W TUMORIGENESIS CONTROL Hcpatk Etf~ REDUCED HEME FOR HEME REGULATED TRANSFORIdATiONS •-a IMPAIRED G1LCtUY ROIE AS SECOt~D MESSENGER CARDIOVASCULAR DYSFUNCTION AND OTHER HYPOXIC EFFECTS utPAJRED BONE AND TOOTH DEVELOPIIENT IMPAlRED CALCriJY RO(E Dl CT'CLIC MUCLEOTIDE METABOLISM IMPAIRED DETOxnCAT10!! OF XENO8JOTICS IMPAIRED 61ETA80USIi CF EHDOGENOtlS AGOAnSTS IMPAIRED DETOXIFICATIOt OF EHVIRONAtENTA1 TDX7kS IMPAIRED DETOXtFICAT10/1 OF DRUGS r'1 ALTERED METABOLISM OF TRYPTOPMJW ucPAfRED 1 HYDROXYLATBON CF CORTISOL ELEVATED BRAW LEVELS OF TRYPTOPF{AN, SEROTONiN AAD MAA I DISTURBED INDOLEAlAkE NEUROTRANSAUTTER FUNCTION 19 Fto. 13. Multiorgan impact of reductions of heme body pool by lead. Impairment of heme synthesis by lead results in disruption of a wide variety of important physiotogical processes in many organs and tissues. Particularly weTl documented are erythropoietic, neural, renal-endocrine, and hepatic effects ii,dicated above by solid arrows. Plausible further consequences of heme synthesis interference by k:ad are indicated by dashed arrows (EPA, 1956). DISTURBED CALCIUM METABOLISM

MORTON LIPPMANN . 6 s 0 0=14.3 tS.69ft" 10 - ADJUSTED Pa@.sg/dL (log scaii) rto.14. Plot of adjusted diastolic blood pressure vs tdjusted natural lo& of blood lead concentration in male bus drivets treated for hypertension with beta blockers. Adjusted for age, aYe=, race, body mass index, and frequencies of catfeine, akohol, and tobacco use. Diastolic blood pressure is the average of three measured diastolic blood pressures on each subject (Sharp et at., 1989). between systolic blood pressure and blood lead levels, though small in magnitude, was statistically significant (P < 0.01). Analyses of data for men categorized according to blood level concentrations indicated increases in blood pressure only at lower blood lead levels; no further significant increments in blood pressure were observed at higher blood lead levels. • • ~t t t I I I I I I t 5 15 25 35 45 BLOOD LEAD LEVEL (Np / d) 6'ia. 15. Adjusted diastolic blood pressure and adjusted blood lead levels for males ages 20 to 74 from NHANES Il. Both blood pressure and blood lead were adjusted by regression for the effects o[ age, age', body mass, and other significant variables. Each point represents the mean blood pressure and mean blood lead for 50 consecutive observations, sorted in increasing order of blood lead (Schwartz, t488).

LEAD AND HUMAN HEALTH 138 126 I • o • I I 5 15 25 BLOOD LEAD LEVEL (µp / d) I 35 • 21 ;Fto. 16. Adjusted systolic blood pressure and adjusted blood lead levels from males ages 20 to 74 from NHANES !I. Both blood pressure and blood lead have been adjusted by regression for the eftects of age, mge=, body mus, and other signifi,cant variables. Each point represents the mean blood pres- sure and mean blood lead for 24 consecutive observations, sorted in increasing order of blood lead (Schwartz, 1988). An ideal opportunity to separate the role of Pb from a wide range of potentially confounding nutritional factors was presented by the large data set from NHANES II, a random stratified sample of the U.S. population. Pirkle et al. (1985) described the results of their analyses of the data for 40- to 59-year-old white males from this survey population. After adjustment for age, body mass index, all measured nutritional factors, and blood biochemistry factors in a mul- tiple linear regression model, the relationships of both systolic and diastolic blood pressures to blood Pb was statistically significant (P < 0.01). Figures 15 and 16 show the results of NHANES II analyses for adults ages 20-74 years from a review paper by Schwartz (1988). The Pirkle tt cl. (1985) analyses incorporated additional variables with partic- ular attention directed at the stability and significance of the Pb coefficient in the presence of nutritional factors and blood biochemistries. Their objective was to estimate conservatively the strength and independence of the relationship be- tween blood pressure and blood Pb. Therefore, to provide an unusually rigorous test of the independent significance of blood Pb, 87 nutritional and biochemical variab(es in NHANES II were included in the stepwise regression. In addition, to accoun¢ for possible curvilinear relationships, squared and natural logarithmic transformation of almost all these variables were also included. ''I se population mean blood Pb levels dropped by 37% between 1976 and 1980, due to reductions in the amount of Pb used in gasoline (Fig. 7). This much reduc- tion in blood Pb in this population would be expected to result in a 17.5% decrease in diastolic blood pressure ;--90 mm Hg, a level used to define hypertension. Considering the relatively unusual nature of the blood-Pb/blood-pressure rela- tion (i.e., characterized by large initial increments in blood pressure at relatively • •• 0

22 MORTON LIPPMANN low blood Pb levels, followed by leveling off of blood pressure increments at high blood Pb levels), it is not surprising that it was not anticipated by results of studies in animals. Many animal studies emphasize results from exposures at higher dose levels, where results tend to be more definitive. The human results were, how- ever, consistent with biphasic blood pressure increases observed in response to small PbB increases in the rat (Victery el ad., 1982a, b; Perry et al., 1988) when rats were treated with low dose of lead. The unusual exposure-response relation may also account for the failure of earlier human studies to find consistent rela- tions between blood pressure and blood Pb in study groups with mild-to-moderate elevations of blood Pb concentrations. In summary, the use of a very large set of high-quality data covering a wide range of possibly confounding variables allowed a clean-cut determination of the effects of blood Pb on blood pressure for a relatively low range of blood Pb concentrations (5-35 µg/dl). This association between relatively small elevations of PbB and elevated blood pressure may have significant public health impact because hypertension is a recognized risk factor for cardiovascular disease. CONCLUSIONS In 1943 Alice Hamilton looked back on her 33 years of experience with lead as an occupational toxicant and reminded us that there were many subclinical "man- ifestations of this protean malady." At that time, she remained concerned about subclinical effects in industrial workers. She could not have known that our failure to heed her doubts, expressed in 1925, that any effective measures could be implemented to protect the general public from the hazards of widespread use of leaded gasoline would lead, in this decade of the 1980s, to our current concerns about fairly well-documented neurobehavioral and developmental deficits in cht7- dren throughout the country, or to our concerns for lead as a cardiovascular stress factor for adults. Our most sophisticated tools for investigation, and our increased knowledge of exposure-response relationships for lead, would certainly impress Alice Hamilton if she could be with us again. However, in this era of emphasis on biological mechanisms of xenobiotic response, it is remarkable how little we now know about how chronic low-level lead exposure leads to such a remarkable array of toxic responses. Dr. Hamilton, trained in pathology, would surely be disappointed with our progress. On the other hand, Dr. Hamilton, our first, full-time U.S. hygienist and occupational health physician, would, I think, be pleased with our recent progress in controlling the spread of lead and the consequent reduction in general population exposure. The virtual removal of lead from gasoline and canned foods, and the current attempts to reduce lead in drinking water show that we have learned some of the important lessons she tried to teach us. ACKNOWLEDGMENTS The preparation of this paper was supported as part of a Center Program supported by Grant ES-00260 from the National Institute of Environmental Health Sciences and Grant CA 13343 from the National Cancer Institute.

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24 MORTON LIPPkdANN Pocock. S. J., Shaper, A. 0., Ashby, D., and Delves, T. (1985). Blood lead and blood pressure in middie-aged men. "International Conference: Heavy Metals in the Environment, September, Athens, Greece" (T. D. Lekkas, Ed.), Vol. 1, pp. 303-305. CEP Consultants, Edinburgh, United ICingdom. Pocock, S. J., Shaper, A. G., Ashby, D., Delves, T., and Whitehead, T. P. (1984). Blood lead con- centrztion, blood pressure, and renal function. Prit. Med. J. 289, E72-E74. Rosner, D., and Maricowiu, G. (1985). A'jitt of God'?: The public health controversy over leaded gaso°une during the 1920s. Amer. J. Public Health 75. 344-352. Schwartz, J. (1988). The relationship between blood lead and blood pressure in the NHANES 11 Survey. Environ. Health Perspect. 78. 15-22. Schwartz, J., Angle, C., and Pitcher, H. (1986). Relationship between childhood blood lead levels and stature. Pediatrics 77, 2a1-2Ed. Schwartz, J., and Otto, D. (19E7). Blood lead, hearing thresholds, and neurobehavioral development in children and youth. Arch. Ens-iron. Health 42, 13Tr-160. Sharp, D. S., Osterloh, J., Becker, C. E., Bernard, B., Smith, A. H., Fisher, J. M., Syme, S. L., f7olman, B. L., and Johnston. T. (1985). Blood pressure and blood lead concentration in bus drivers. Environ. Health Perspect. 78. 131-137. Sharp, D. S., Smith, A. H., Holman, B. L., isher, J. H.. Osterloh, J., and Becker, C. E. (I989). Elevated blood pressure in treated hypertensives with low-level lead accumulation. Arch. Envi- roR. Health 44, 1a-22. Silva, P. A., Hughes, P., Wt7liams, S., and Faed,1. (1986). Blood kad, intepieence, reading attain• ment, and behaviour in eleven year old children in Dunedin. New Zealand. J. Child Psychol. Psychiatry, in press. Victery, W., Vander, A. J., Markel, H., Katzman, L., Shulak. J. M., and Germain, C. (1982a). Lead exposure, begun ie wtero. decreases renin and anSiote.nsin ll in adult rats (41398). Proc. Soc. Esp. Bdo1. Med.170, 63-67. Victery, W., Vander, A. J., Shulak. J. M., Schoeps, P., and Julius, S. (1982b). Lead, hypertension, and the renin-anjiotensin system in rats.l. Lab. C&. Med. 99, 354-362. Wang, l.-D., Shy, W.•Y., Chen, J: S.. and Yang, K: H., (1489). Parental occupational lead exposure and lead concentration of newborn cord blood. Amer. J. lnd. Med. 15. 11/-113. Weiss, S. T., Munoz, A., Stein, A., Sparrow. D., and Speizer, F. E. (1986). The relationship of blood k-Ld to blood pressure in a longitudinal study of working men. A+nrr. !. Epidemiof.122, E0040. @Vinneke, G., Kramer, U., Brockhaus, A., Ewers, U.. Kujanek, G., Lechner, H., and Janke, W. (1983). Neuropsychological studies in children with ekvaled tooth lead concentrations. 11. Ex- tended study. Int. Arch. Occup. EAt-iron. Health S1, 231-252. Yaffe, Y., Fkssel, C. P., Wesolowski, J. J., del Rosar'a. A., Guirpuis. G. N., Matias, V., Degarnw, T. E., Coleman, G. C., Grarnlich,l. W., and Kelly. W. R. (1983). Identification of lead sources in California children using the stable isotope ratio technique. Arch. fieriron. Health 3E(4), 227- 243.