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Alan M. Ducatman, MD, MSc West Virginia University School of Medicine

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1 Alan M. Ducatman, MD, MSc West Virginia University School of Medicine

2 What is Lead? Lead is a blush gray metallic element which occurs naturally (in small amounts) in the earth’s crust. It is dense, hence its use as a ballast, ammunition, or radiation shield. Lead is insoluble in water, but some salts are soluble. What is lead? And what are its characteristics? Lead is a blue-gray, heavy, soft metallic element that occurs naturally in the earth’s crust. It is a malleable metal, so it can be easily worked - you can hammer it into protective sheets or make pipes and bend them easily. It is dense, and has good shielding protection against radiation, so it is used as ballast or to shield against penetrating forms of ionizing radiation. Metallic lead is tasteless and odorless, although some of the oxides and salts of lead taste sweet. (This sweet taste of lead salts is a source of problems for children!). Lead is insoluble in water, but some of the salts do dissolve, hence lead salts can be carried long distances in water supplies. Lead fumes will be easily formed when lead is heated. Although there is not a lot of lead in the earth’s crust – lead is ubiquitous, especially in modern industry.

3 Significant Health Characteristics of Lead
Lead has a low melting point and can easily be aerosolized by heating. Lead can be formed into organic compounds by some organisms, and some organic compounds (such as “leaded gasoline”) have industrial uses.

4 Historic Production of Lead
3500 BC-1450 AD: Mostly mined as a byproduct of silver extraction, and mostly converted to… SMOKE. AD: Byproduct of copper smelting. Industrial Revolution: Byproduct of coal and combustion. Taller stacks spread pollution. Peak emissions (400,000 tons/yr). Historic Production of Lead Humans have mined lead and worked with it for many centuries. Measurements of atmospheric lead deposited in arctic ice show increases around 3500BC, probably associated with heated waste from silver mining and extraction. Subsequently, the Romans used lead extensively (the word “plumber” derives from the Latin for lead and reflects its use in water pipes) and may have used lead salts to sweeten wine. Some historians have associated the decline of the Roman Empire with these uses and with lead glazes on wine amphoras and other containers. Use of lead declined for a while in the medieval period. By 1450 AD, lead was a byproduct of copper smelting. Further increases in environmental lead came with the advent of the industrial revolution; lead is a byproduct of coal combustion, as there are trace amounts present in coal.


6 Historic Production of Lead
Lead in paints (never permitted in some alert countries). Banned 1978 in the U.S. Automobile ( depends on country) Emission byproduct of leaded gasoline. Historic Use of Lead: Getting the Lead Out of Gas The historic uses of lead responsible for the most environmental exposure to humans are late 19th and 20th century developments. The key developments were: 1)     The addition of lead to paint (which markedly improves the long-term adhesion of paint to surfaces, especially exterior surfaces); and The use of lead as a fuel additive in “leaded gasoline”, beginning in 1923. We are going to say much more about lead paint later in this session, it is a “gift that keeps on giving”. In the United States, we have largely reversed the problems of lead as a fuel additive by a policy change. Lead, added to gasoline, improves the refining and octane performance of gasoline. Unfortunately, it goes out the tailpipe as exhaust and exposes the general population. The use of lead for this purpose ended in the U.S. only in the 1970’s with the Clean Air Act; most other developed countries and many developing countries have followed suit.

7 Improved Lead Levels in the US
Blood lead levels in children <6 years old showed an approximately 80% decline from the 1970’s to 1994, and a continuing drop from % with elevated BLLS Geometric Mean > > >20 μg/dL Approximate # of children tested= 1.2 million yearly From: MMWR 2000;49: The Effect of Sound Environmental Policies In the past two decades, the average blood lead level (BLL) of U.S. children has fallen dramatically, with an 80-90% total decrease in mean childhood lead levels. Geometric mean blood lead levels were 15 μg/dl in , 3.8 μg/dl in , and 2.7 μg/dl in (Sources: U.S. National Health and Nutrition Examination Survey “NHANES”). This is the result of several sound social policies:  Banning leaded gas  Banning lead paint, and requiring “clean ups“ of indoor lead paint in certain circumstances  Banning of lead in products designed to store food  Medical surveillance of high-risk age groups (children) and workers Although compliance with policies and surveillance strategies is uneven at best, it is clear that the programs have decreased the average childhood lead burden, and also the number of children and adults who are lead poisoned. Extrapolating from the available national surveillance data, much has been accomplished, yet hundreds of thousands US children still have BLLs over 10μg/dl.

8 Childhood Risk Factors for Elevated BLLs (>10μg/dl)
Pre-1946 Housing Non-Hispanic Black % Mexican American % White % Low Income % High Income % NHANES III, and CDC Recommendations for BL Screening of Young Children (Dec. 2000) Uneven Distribution of Risks in Children The risk of lead childhood poisoning is not distributed evenly in society. The poor, especially in inner cities, those living in older housing, and ethnic minorities, all appear to be at greater risk.

9 Lead- It’s Everywhere Storage batteries Automobile radiators
USES OF Pb Storage batteries Automobile radiators Cable Brass and bronze Production Radiation shielding Construction Galvanizing Ammunition Annealing Printing Plating Paint Plastics Soldering Television electronics Glass Petroleum Insecticides Despite policy advances, how do we still get exposed to lead? Lead exposure comes from new products or from lead already distributed into the human environment. Lead remains a component of many useful products. Examples include batteries, circuitry, medical shielding devices, gasoline (in some developing countries), cans and ceramic glazes (again, when regulatory control is poor), cable coatings (for example, as a “plasticizer” in the plastic coating your phone line), some types of printing, brass and bronze manufacture, galvanized metals and metal plating, solder (for example in plumbing) some ceramics, and even insecticides. Lead is also used extensively in ammunition, in both the explosive (lead stearate) and to add weight to the bullet. Workers engaged in the manufacture, use, reclamation, or recycling of any of these common products may be lead poisoned. Children may become exposed when parents purchase products, or when parents bring home contaminated articles from work, for example - lead dust on their clothes or in their car.

10 Sources of Lead- Air Uncontaminated Contaminated 1-2 μg/m3 4-16 μg/m3
Near Smelter Sources in Air Significant amounts of lead can be in the air under certain circumstances. “Uncontaminated” air has, at most, 1-2μg/m³ of lead. This goes up a little downwind of coal burning power plants. The outdoor air near a smelter can be substantially contaminated and may have 16μg/m³ of lead. In occupational environments, such as within bridge repair spaces, the air contamination may be so extensive as to cause lead poisoning in a very short time. A worker misusing a respirator for a matter of minutes may become poisoned, with blood lead well above 40 µg /dl. Other trades with significant respiratory exposure include house painting, rifle range instruction, battery or ammunition production or reclamation, junk yard work and “ship breaking”.

11 SOURCES OF LEAD- Water Uncontaminated Standards vary Internationally.
In U.S. <15 μg/L 99% of water supplies Lead Ingested in Water Lead may be ingested in water. About 70% of the population lead burden is estimated to come from water, although water is generally less important in actual poisoning. All humans carry some chronic lead stores which add to the total lead burden in society. This burden is always undesirable, yet only a minority of us become lead poisoned. Standards for uncontaminated water vary from country to country. The action level for lead in U.S. water is 15ppb since The majority of municipal sources are compliant. This improvement over the1962 Public Health Service Standards of 50ppb, reflecting increased public health vigilance over time. When there is contaminated water in a home, it is most often from some source other than a generally contaminated municipal water supply. Leached lead from old lead pipes or from lead-soldered plumbing joints are more common problems at the level of individual homes. Lead used as a plasticizer in long hose lines is also a potential source in “impromptu” water supplies.

12 SOURCES OF LEAD- Food Uncontaminated Mixed Diet 9.43 μg/kg/day
Bottled Baby Food μg/L Contaminated Older Canned Baby Food 202 μg/L Bone Meal μg/g _______________________________________________ Compare this to a paint chip ,000 μg/g or more Paint Chip ,000 μg/g or more Lead ingested in Food, Paint Chips, and Dust A well balanced diet provides <10 μg lead/kg body weight per day. Bottled baby food has about 3.5 μg/L. Contamination can be introduced by canning, by use of food supplements rich in lead, or by ingestion of contaminants containing lead. Under poor conditions, lead leaches from metal or solder in food containers. An entire arctic expedition is thought to have succumbed to this source in the 19th century. Bone meal (we will see that bone is the body’s storage depot for lead) can have μg lead/g bone. By far the greatest oral source of lead is ingestion of either paint chips (pica) or dust that contains paint. Paint chips can contain 40% (400,000μg/g) or even more lead by weight.

13 Lead- It’s Everywhere Unusual oral sources of lead: Ceramic glazes, art pottery, primitive equipment for making maple syrup, crystal glass used to contain alcohol products, certain cosmetics applied to hands or face, some candle wicks, folk medicines, used lead radiators, moonshine liquor. Slide 13. Unusual Oral Sources of Lead There are some distinctly unusual sources of oral exposure to lead that are worth mentioning. Historically, “moonshine” whisky made in lead glazed vats or even radiator coils was a rich source of folklore and TV shows, as well as a source of lead poisoning. Primitive evaporating equipment for concentrating maple syrup can be a source of lead. Glazed pottery from some developing countries should not be used for food. Ceramic vases are an important source of population lead poisoning internationally – in Mexico, for example. Art pottery belongs on the shelf, not in the kitchen. Lead crystal is expensive and beautiful, yet materials such as fruits and wines, sherries and other alcoholic beverages can leach some of the lead from the crystal. Folk remedies, and cosmetics of certain ethnic groups sometimes contain lead. So do “tin” solders. Lead has been found in the wicks of certain kinds of candles. Children have been poisoned by lead in pool cue chalk. There are many potential, unpredictable sources of lead. All of these unusual sources, together, are far less important in the U.S. than lead from paint and soils.

14 Lead- It’s Everywhere What is Lead Paint?
Lead paint uses LEAD as a pigment. It was advantageous to do this because it “sticks” (coats or penetrates) well. There are 2 types- White lead (basic lead carbonate) Red lead (a form of lead oxide) What is Lead Paint (and why is lead in it)? Lead improves paint both as a pigment and as a binder. Lead paint “sticks” (both penetrates into and coats the painted surface) very well. Furthermore, lead is a surface biocide, and protects against some kinds of microbial overgrowth. White lead is a basic lead carbonate; red lead is a form of lead oxide. These pigments may be used in many different color mixes. The color isn’t as important as the amount of lead present – up to 50% lead by weight. This is a lot of lead, and it is spread (as paint) over a large surface area, “perfect” for creating subsequent exposure.

15 The Role of the Paint Industry
For almost a century, the U.S. paint industry made consistent efforts to sell the advantages of lead paint, ignoring recognized health hazards. Lead was finally regulated and banned as an indoor paint for residences and offices in Some outdoor applications, notably metal structures on land, bridges, and ships at sea, used lead after 1978, and still do. Lead is attractive as an outdoor paint because it offers long lasting protection against corrosion and weather.

16 SOURCES OF LEAD- Soil Uncontaminated Remote area 2-200 µg/g
Urban residential mean 585 µg/g City parks ,357 µg/g Near smelter mean ,600 µg/g Soil - Where Lead from Paint, Gasoline, and the Atmosphere goes. Uncontaminated soil in a remote area, away from industry, may house as little as 2μg lead/g soil in it. In areas where lead is naturally abundant in soils, there may be as much as 200μg lead/g soil. In U.S. urban residential areas, years after the ban on leaded gas, mean soil levels near busy roads or factories can have over 500μg lead/g soil. Soil near a smelter facility can have over 7 000μg lead/g soil

17 SOURCES OF LEAD- House Dust
Uncontaminated- New inner-city home Floor Surface µg/sq ft Contaminated- Old inner-city home Floor Surface µg/sq ft  Lead in House Dust The worst problems with contaminated soil are inside or just outside of older residential structures, including single family dwellings, apartments, schools and institutions. Lead paint chipping or just dusting off walls can create conditions for high exposure. Visible chips do not have to be present. Exterior painted parts of dwellings, such as porches, columns, door frames, window frames and posts, are likely to have the highest lead paint concentrations and therefore leave the largest lead “footprint” in the dust immediately outside and inside the home. High contact areas, such as baseboards, interior door frames, and stair railings may also have significant amounts of lead paint.

18 Children at Risk Children ages 9 months to 2 or 3 years old are most at risk because they crawl on the floor, breathe in a zone nearest the floor, get lead on their hands during floor contact activities, and engage in hand-mouth activities most commonly. This age group at highest risk for lead poisoning, is targeted in recommended childhood surveillance policies. The effects of childhood lead poisoning are not equally distributed in the U.S. (or any) society. Childhood lead poisoning is more common in inner cities, among the poor, and among African Americans.

19 Adults at Risk The slide shows a construction worker scraping paint on a high risk area- an external window (both exterior paints and all window paints are high risk for lead). Workers who scrape, chip, heat (lead can be removed with a “heat gun”), or sandblast old paint are most commonly diagnosed to have lead poisoning in the U.S. Radiator repairmen, battery or ammunition recyclers, rifle range instructors, and junkyard welder/burners are other high risk groups. Furthermore, environmental policies place lead abatement activities inside enclosures, in order to protect the atmosphere and water. This concentrates the removed lead into a small space, and markedly increases the danger to workers. This slide from the front cover of the American Public Health Association’s newsletter is a classic lesson in “how not to do it”. There is no enclosure, so the public is exposed and the building will be contaminated. There is no personal protection such as a respirator visible, and the worker is wearing street clothes which may carry lead into his car and home with him. In this example, building residents, passersby, and certainly the worker and his family, all sustain considerable risk. Those employed in small businesses and construction trades are more likely to be poisoned.

20 Note the exterior mess following uncontrolled deleading.
It is a cause of childhood (and adult worker) lead poisoning. Uncontrolled deleading activities are a target for regulatory activity. Unfortunately, success is spotty because of the high cost of well performed lead abatement. Uncontrolled and “do it yourself” abatements remain common, with potential health and economic consequences to residents and neighbors.

21 How does lead enter the body?
Respiratory Breathing in dust that contain lead. Lead is absorbed and distributed to other parts of the body via the bloodstream.  How Does Lead Enter the Body? Lead is usually encountered by inhalation or oral ingestion. Respiratory exposure is more commonly the primary route in adults, while ingestion is often most important in children. Most cases of lead poisoning feature contributions of both inhalation and ingestion. Most of an inhaled lead dose is absorbed.

22 How Does Lead Enter the Body?
2. Ingestion Adults absorb about 6% of ingested lead. Fasting adults absorb more. Children absorb much more lead (30-50% if well fed, and more, if fasting or malnourished). An interesting aspect of the absorption of ingested lead is how it can vary depending upon metabolic status. A well fed adult might absorb 6% of an ingested lead dose; a fasting adult might absorb more. Children, even when well fed, may absorb 30% of a lead dose, and still more when iron deficient. Pregnant women are also likely to absorb lead more efficiently. Children and pregnant women are supporting bone development. Lead is more likely to be absorbed when the gut is “primed” to absorb Fe and Ca.

23 How Does Lead Enter the Body?
3. Skin Skin is relatively impervious to lead, lead oxides , or lead salts. Some may get through scrapes or wounds, but organic leads (such as in leaded gasoline), will go through skin into the bloodstream quite well. There is a third route of entry. Lead, lead salts, and lead oxides do not penetrate intact skin. Organic lead is different. Like many organic metals, alkyl leads are readily absorbed through the skin. In addition, they are taken up into organs more rapidly. They are very dangerous.

24 Does the Route of Entry Matter?
Lead, lead salts, lead oxide, all have same toxicity (whether inhaled or ingested), but more is absorbed when inhaled. Organic lead has greater affinity for CNS – therefore skin absorption may be SERIOUS Organic Lead Lead is dangerous regardless of the route of entry. Organic lead has the greatest CNS toxicity. Because only organic lead is absorbed through the skin, you might say that the dermal route of entry has particular dangers. Similarly, an ingested dose is less fully absorbed than an inhaled exposure.

25 Lead Metabolism and Nutrition
Low dietary intake of vitamin D, vitamin C, and iron enhance absorption and retention of lead in the body. It is believed that vitamin D modifies lead-bone metabolism, while vitamin C and iron may also modify excretion. Cheny L, et al AJ Epi 1998:147: Nutritional Strategies Some of the variables that affect lead uptake would also affect nutritional strategies for minimizing the effects of lead exposure. Since lead “mimics” calcium and iron in the gut, high intakes of calcium, vitamin D, and iron may reduce lead absorption and offer some protection (especially in deficiency states!). Other strategies that might be helpful include a diet high in vitamin C and low in fat (lead is better absorbed with a high fat meal). Unfortunately, the data that nutritional strategies actually work is lacking, and implementation by parents is difficult.

26 Where does lead go once in the body?
Lead is absorbed into the bloodstream rapidly. It then travels to “soft tissue” such as kidneys, lungs, brain, spleen, muscles, and heart. After several weeks, most lead moves into bones and teeth (and some into hair). About 94% of adults total lead burden is in bones and teeth Only about 73% for children 4. Lead in bones and teeth equilibrates over time and circumstance with other “compartments”. Lead Metabolism (Uptake and Distribution) Lead is rapidly absorbed into the bloodstream via any route of entry. Some is incorporated into the building of hemoglobin molecules in red cells. We will discuss that more when we get to how lead causes anemia. Next, lead travels to “soft tissues” such as kidneys, lungs, brain, spleen, muscles, and heart. This occurs within a matter of days. Blood lead level peaks in the several days following exposure. The half life of lead in blood is approximately equivalent to the half life of the red cell; (thought question for students – why is this so?) around one month. After that, most lead which is not excreted by urine (primary route), feces, or exocrine secretions (including breast milk) moves into the long term storage area, bones (and teeth). About 94% of an average adult’s total lead burden (the total amount of lead in all tissues throughout the body) is in bones and teeth. In children, this is about 73%. Lead is also found in hair. If one is very careful to wash the exterior hair surface, it is possible to “time” the deposition of lead in hair. This requires exquisite attention to laboratory procedures.

27 Lead Compartments    BONE  BLOOD  SOFT TISSUE
10 Days Days Days    TEETH URINE BILE, HAIR, SWEAT, NAIL Figure A simple three-compartment model for absorption, retention, and elimination of lead in humans. Quantitative estimates apply to adult males . Source: derived from Rabinowitz et al. (1975) Lead Compartments Blood, soft tissue, and bone are “compartments”, yet they clearly are in dynamic equilibrium. Lead moves from blood and soft tissue to bone, and, as lead levels in blood decline or as bone is remodeled, lead can move from bone back into blood.

28 How Does Lead Get Out of the Body
Kidneys- urine Bowels- stool Glands- sweat Breast- breast milk Hair, nails, teeth (very slow turnover) It takes >10 years to turn over one half the body’s stored lead. Bone source slowly leaches into the blood. Lead Excretion, Implications for Breast Feeding While the half life of lead in the adult red cell is on the order of 30 days, it is decades in bone. Lead is excreted from the body by various routes, principally in urine, but also in secretions such as breast milk. This implies that nursing mothers who have been lead poisoned even in the remote past, may need to get their breast milk tested. (This has implications for women who are or plan to be pregnant if they have a high body burden of Pb).

29 What Does Lead Do? Lead inhibits certain types of enzymes,
Particularly enzymes dependant upon sulfhydryl groups. Organ systems affected include: Neurologic Endocrine (including BP) Reproductive Musculoskeletal Blood Renal GI What does Lead Do In The Body? Once distributed to organs, lead inhibits certain types of enzymes by binding to sulfhydryl groups. The results are protean, affecting many organ systems. Interference with the synthesis of heme in the red cell is an illustrative example. There is also competition with calcium in several systems including mitochondrial (cellular) respiration and degradation of various nerve cell functions. Lead also affects RNA and DNA, although mechanisms are not clear.

30 Microcytic Anemia with Basophilic Stippling
Lead and The Red Cell: Microcytic Anemia with Basophilic Stippling Inhibition of the enzymes that are involved in the formation of the hemoglobin molecule can be detected at BLLs as low as 10 μg/dL whole blood, and intermediate products of inhibited hemoglobin formation (i.e. protoporphyrins) begin to appear at slightly higher levels. While we might expect that detection of protoporphyrins would be an effective test for lead poisoning, its usefulness is limited, as we will see below. These incomplete hemoglobin molecules break down and are scavenged along with the red blood cells containing them. The accelerated scavenging of cells leads to anemia, initially normochromic and eventually a microcytic, hypochromic anemia with iron deficiency. As lower iron levels also promote increased uptake of lead from the gut, this sets up a “positive feedback loop” for lead poisoning and iron deficiency – each promoting the other. Children have better compensatory erythropoieten responses than adults, and may delay onset of anemia. The broken down molecules accumulate and stain with a basophilic stain. This slide shows the classic microcytic anemia with basophilic stippling of lead poisoning. This picture should be rare! Good hygiene should prevent, and good surveillance will pick up, lead poisoning before it reaches this stage. Eosinophilia is also seen in some cases of lead poisoning. Larger area is a thick thick smear to demonstrate the frequency of basophilic stippling

31 Alternative tests to blood lead
Erythrocyte protoporphyrin and zinc protoporphyrin tend to become elevated as lead-induced hemoglobin salvage increases. These tests are neither sensitive nor specific for detecting lead exposure. They have limited usefulness in the diagnosis, surveillance, or treatment of lead exposure and lead poisoning. Zinc and Erythrocyte Protoporphyrin Tests The break-down of heme products, caused by lead or by inherited disease traits such as thalassemia, are associated with increases of pre-porphyrin ring products (the porphyrin ring is the essential structure of hemoglobin) circulating in the blood. Thus, circulating Zinc Protoporphyrin (“ZPP”) or Erythrocyte Protoporphyrin (“EP”) levels may go up in lead poisoning. These tests are photometric, and rely on the light absorption properties of protoporphyrins. They also have limited usefulness for lead surveillance. They do not reliably detect the early phases of lead poisoning, because considerable hemoglobin breakdown must occur first; therefore the test is both late onset and insensitive. And, as hereditary conditions such as thalessemia trait cause the same outcome, the elevated EP levels are also not specific to the outcome sought. Children with thalassemia trait or similar hemoglobinopathy traits often have higher EP levels than lead poisoned children. A test that is insensitive and nonspecific has real limitations for purposes of surveillance! There is one use. The differences in timing of blood lead levels (where elevations follow immediately after exposure) and protoporphyrin levels (which follow heme breakdown, more closely tied to the appearance of anemia) can sometimes be used to more accurately estimate onset and duration of lead exposure. Promising tests to measure whole body lead burden, such as x-ray fluorescence of bone (tibial XRF) are in research development at several institutions.

32 CNS Symptoms in Adults Early Later Chronic Irritability Ataxia
Hearing Loss Impaired Judgment Hallucinations Diminished Judgment Depression Seizure ↓ Memory ↓ Dexterity Death ↓Cognition CNS Effects In Adults While microcytic anemia and basophilic stippling make great exam questions, there are other more common and more important outcomes of lead poisoning. The socially important outcomes involve the effects upon the nervous system and upon reproduction. Neurologic effects in adults, although less severe than effects in children, were recognized first. Early symptoms include irritability and other personality change (including depression), weakness, lethargy, loss of interest in hobbies, ataxia, headache and impaired judgment. Hyperreflexia and peripheral neuropathy appear if poisoning persists. More severe symptoms in acute intoxications may progress to colic, hallucinations, convulsions, paralysis, and death. During and following exposure, abnormal neuropsychologic tests include short-term memory deficits. CNS deficits may be permanent, even in adults.

33 Peripheral Neuropathy in Lead Poisoning
Distal Symmetric Axonal Polyneuropathy: Wrist Drop Foot Pain Joint Pain Dexterity Peripheral Neuropathy Like most peripheral neurotoxins, lead causes a distal, primarily axonal (with secondary myelin damage), symmetric polyneuropathy. The symmetry is detectable on nerve conduction testing, although patients frequently complain of more severe symptoms on one side. Lead is unusual among common industrial neurotoxins in featuring an early, prominent motor component. The peroneal and radial nerves are often affected, and the resultant wrist and ankle weakness are sometimes called “lead palsy”. The peripheral neuropathy of lead poisoning poses a special acute risk to bridge construction and shipyard workers, who often perform their jobs at heights. Hand and foot weakness, large joint pain, problems with tactile perception in feet or joints, and ataxia pose additional risks in this circumstance.

34 CNS Effects in Children
Following Needleman’s classic 1979 study of the effects of lead body burden in first and second graders, numerous studies from around the globe have verified that lead poisoned children perform worse, intellectually and socially, than children with less exposure. These results are persistently robust to adjustment for socioeconomic status or other potential confounding variables.

35 Cognitive Performance Deficits * in Lead- Exposed Children
Psychomotor performance Auditory and language processing Sustained attention & concentration Measured outcomes: Less likely to graduate High School More likely to be convicted of felonies *Deficits consistent across cultures and controlled for SES Areas of particular deficits in lead-exposed children include psychomotor intelligence, auditory and language processing, and attention compared to low lead exposure controls.  For well studied outcomes, there does not appear to be any threshold effect. Performance correlates with lower lead levels. Children with high lead exposure levels are less likely to become high school graduates, much less likely to be termed “gifted” based upon standardized tests, and more likely to be identified with juvenile delinquency and violent crimes than controls matched for age, region, and socioeconomic status.

36 Lead Poisoned Children as Young Adults
A 20-year follow up by ATSDR of 917 lead poisoned children (mean 50 ug/dl) measured lead bone storage by tibial KXRF. Diminished were: 1. Sural nerve sensory and peroneal motor evoked response amplitude. Vibro-tactile thresholds: Fingers and toes Standing coordination 2. Hand-eye coordination in several types of test performance (Trails B, Symbol Digit, Learning Error). The “Gift that keeps on Giving”: Lead Poisoned Children as Young Adults Adults who were lead poisoned as children also sustain losses in noncognitive aspects of CNS and PNS function, including: persistent peripheral neuropathy, diminished vibrotactile thresholds, diminished coordination including hand-eye coordination, fine tremor and diminished hearing. Although IQ is a limited measure of performance, it helps to note that most studies indicate a loss of 1-3 IQ “points” for each increase in 10 μg/dl blood lead in children. This loss represents a huge social “cost”.

37 Lead Exposure in utero Lead crosses the placenta in plasma.
Pregnancy (and lactation) causes lead release from bone stores into plasma Plasma lead is about 1% of circulating blood lead. Epidemiologic effects on CNS have been documented. Peak transfer is at weeks gestation Lead and Reproduction - Exposure Lead crosses the placenta in plasma. This is 1% of circulating maternal lead. Peak transfer is at weeks of gestation. The likely sources of placental lead originate in maternal bone stores, which are mobilized along with calcium in pregnancy.

38 Lead Outcomes in Children Exposed in Utero
High Dose Lower Dose Spontaneous Abortion Low Birth Weight Stillbirth Neuropsychologic Problems Additional risk from breast milk Lead and Reproduction – Outcomes in Children Exposed in utero High maternal lead exposures cause spontaneous abortion and stillbirth. At lower doses, children exposed in utero are lower birth weight, and more likely to have neural tube deficits. Epidemiologic data indicate cognitive deficits in children following in-utero exposure. They may develop neuropsychiatric syndromes similar to those exposed early in childhood. Because lead is mobilized from bone during pregnancy, findings of higher rates of neuropsychologic problems in children of mothers who were lead poisoned as children, are not surprising. The metabolic pathways of lead allow it to cross generations as well as the placenta.

39 Lead and Adult Reproduction
Reproductive Females - Miscarriage, still birth - Inability to conceive Males - Decreased libido - Decreased fecundity - Sperm abnormalities: counts, abnormal forms Dose response relationship Lead and Adult Reproduction Lead diminishes fertility in exposed men and women, even beyond the well-recognized outcomes of spontaneous abortion and stillbirth in heavily exposed mothers. Additional outcomes in exposed males are diminished libido, decreased sperm production, and decreased sperm motility. A famous U.S. Supreme Court Decision illustrates some of the complex social issues surrounding the use of reproductive toxins. Johnson Controls, a manufacturer, recognized the liability in exposure of pregnant (or even non pregnant but fertile female) workers. Their approach to mitigating the danger was to make medical certification of sterility a job requirement among reproductive age women. This requirement was contested up to the U.S. Supreme Court where it was found to violate basic constitutional rights (and incidentally did nothing to prevent exposures, including exposures to men whose reproductive systems were also at risk). An outcome of this decision is that material substitution, industrial engineering, and personal protection are still preferred workplace approaches to preventing lead poisoning, regardless of gender or reproductive status.

40 Lead & Bones Lead and Bones
The graphs illustrate the complex, non linear relationships among plasma, blood, and stored bone lead. Lead in long bones is the best single indication of total body lead burden. In cases of high dose exposure, a “lead line” may be seen near the growth plate of the bone. In addition, a developing experimental technique called kXRF (X-ray fluorescence) allows semiquantitative estimation of the total amount of lead in bone. The lead in paint on walls and even in bones fluoresces at a specific frequency when x-rayed. This can be used to estimate the amount of lead present. Another way to estimate if bone lead stores are increased is via “provocative chelation”. More will be said about chelation under the discussion of treatment. Provocative chelation is a diagnostic maneuver resembling the initial phase of chelation therapy, accompanied by lead measurements in timed urine collections in order to determine if lead is being mobilized.

41 Lead & Hypertension Lead and Hypertension
A number of studies have examined the relationship between lead exposure and development of hypertension. Using the NHANES database, Pirkle (1985) found whole blood lead significantly related to both systolic and diastolic blood pressure in white males aged This slide plots blood pressure and blood lead levels. The nature of the relationship between lead and hypertension still requires further investigation, and has not been consistent across all studies.

42 Lead and the Kidney Acute and Chronic Disease
Lead nephropathy (Fanconi syndrome) is characterized by aminoacidura, glucosuria, phosphaturia with hypophosphatemia, and deceased uric acid excretion. Chronic kidney disease may also arise, sometimes associated with gout. Lead and the kidney Lead is a cause of both acute and chronic renal disease. Acute nephropathy has been more clearly described, and fortunately it is becoming much rarer. Acute nephropathy is characterized by dysfunction of proximal tubules (Fanconi’s syndrome), manifested as aminoaciduria, glucosuria, phosphaturia with hypophosphatemia, and increased sodium excretion with decreased uric acid excretion. These effects are considered to be largely reversible. The risk of renal damage goes up during chelation treatment, which may present substantial quantities of lead to the tubules in a short time. The nature of chronic nephrotoxicity is less clear, and seems to be characterized by chronic interstitial and peritubular fibrosis. In addition; the gout associated with lead poisoning (“saturnine gout”) is both an effect of altered uric acid excretion and a potential cause of chronic kidney damage.

43 Other Organ Systems Affected by Lead
Hearing (8th nerve damage) Gout GI- Anorexia, colic Endocrine- Vitamin D Metabolism Genotoxicity Other Organ Systems Virtually every organ system can be shown to experience some outcome of lead poisoning. Blood lead levels are inversely associated with circulating vitamin D. This inhibits bone formation and tooth development. It also sets up a “positive feedback loop” between relative calcium deficiency and increased lead absorption. Nervous system damage is quite generalized motor nerves associated with heavy use are affected early compared to other toxins, for instance radial nerves in painters. Lead exposed workers have hearing impairments compared to age matched controls.

44 Key Aspects of the Clinical History*
Home environment (or environment where a child visits) Home remodeling (occupational histories: all family members) Hobbies, making glazed ceramics, fishing sinkers Unusual medications, cosmetics For children, the vast majority of sources will be paint. For adults, it will be occupation. For adults and children, home remodeling is an issue Occupational Histories All family members *The exposure history provides the key to successful Rx! Clinical History The following elements of the history are essential for detection of lead poisoning and its many sources. Nature of household environment, especially paint Adult Occupational History, specific tasks and materials, presence of job activities such as “burning”, sand-blasting, sanding, chipping, or coring. Hobbies (of all family members) Home Remodeling Unusual Medicines, unusual cosmetics, herbal supplements Condition of household pets Use of imported or glazed ceramics Drinking water source and type of pipe Proximity to industrial emissions source or unleaded gasoline use Children - Pica Children – Babysitters house, grandparents house, Time spent elsewhere than home (and environmental conditions there)

45 Key Presenting Symptoms
Mild Moderate Severe Fatigue Paresthesia Paralysis Irritability Myalgia Colic Arthralgia Headache Tremor GI Distress Symptoms Most lead poisoned children are not described by their parents as having symptoms. Most adults present with subtle symptoms, such as irritability, rather than some of the more dramatic symptoms listed on this slide.

46 Physical Findings Early Chronic Wrist Drop Transverse Nail Lines
Distal Sensation Blue-Black Gum Lines Proprioception Vibration Sense Physical Findings Physical findings are usually absent, unless lead poisoning is advanced. A modest goal of hygiene and surveillance policy is to insure that physical findings are rare! Nevertheless, there are a number of physical findings that should be sought: wrist and foot weakness, diminished distal vibration sensation and propioception. Historically important but rarely seen physical findings include transverse furrows on the nails due to nail growth arrest in severe lead poisoning, and a blue-black discoloration of the gum (“lead line”) due to lead sulfide metabolism by sulfide-loving bacteria. The presence of these findings signifies entrenched failure of workplace or environmental protection.

47 Laboratory Findings – Radiologic
We have already mentioned that lead densities can be seen in epiphyses of bone, notably in the phalanges and also in unsuspected places such as; metacarpals, scalpular tips, and iliac crests. A more useful application of radiology is the plain abdominal film in children. This may reveal radiodensities characteristic of “pica” and confirm an ingestion source (most often paint chips). If enough radiodense material is visible in the stomach, induced emesis may unload some of the lead. Otherwise, endoscopy may be used to remove large lead-containing objects. A note of caution about this. First, substantial lead poisoning can occur in children whose abdominal x-rays are normal. Pica is not a precondition for lead poisoning, and not all pica occurs at the time of x-ray! Amounts too small to show on films still cause poisoning. So, the radiograph is useful when it shows lead, and of uncertain meaning otherwise. Second, endoscopic or emetic approaches to removing ingested lead are left to experienced clinicians.

48 Detecting Lead Poisoning in Young Children
Blood Testing and Medical Surveillance in Children Blood lead is the test of choice. In children, CDC recommendations call for the first blood lead test at 9 months-1 year, with yearly follow-up. This is often performed by “finger stick” (capillary blood). Positive results are confirmed with a venous sample. In practice, most children receive only the first lead survey and many are never tested! Because lead may be in dust, and dust adheres to skin, a capillary sample from a child’s finger can be higher than a venous sample which would be more accurate. Nevertheless, good clinical studies have demonstrated that capillary samples are adequate for lead testing in children provided the skin is thoroughly cleaned.

49 CDC “Preventing Lead Poisoning in Young Children” Oct- 1991
Initial Test (12 months) Surveillance Strategy <10 µg/dl µg/dl Repeat at 24 months Retest in 1-3 months >15 µg/dl Individual Case Management Regions of the country that contain only new housing have asked to be excluded from CDC pediatric surveillance recommendations, because pediatric lead poisoning is demonstrably rare in the U.S. in the absence of older dwellings. It should be noted that the 1991 CDC Action Level of 10 µg/dl is not based on a belief that lead burdens below this level are without potential harm. As with all surveillance strategies, the art of the possible is important and we have yet to fully implement even these modest recommendations. For example, there is good evidence that only about half the pediatric population at risk is actually screened. See:

50 Medical Surveillance for Adult Workers
When: Exposure above “action level” >30 days/yr What: Triggers periodic exams and biologic monitoring (including blood level) Removal threshold: 50 µg/dl (repeated) or 60 µg/dl once. Repeat testing: Monthly, depending on lead level Medical Surveillance and Workplace Removal in Adult Workers Possibly because lead work is often performed in small and even marginal businesses, a minority of lead-exposed employees actually receive OSHA-mandated medical surveillance for the early detection of lead poisoning. There are 2 differing OSHA surveillance strategies - the one for construction workers is more generally useful.  Medical surveillance is triggered by air monitoring results (or other knowledge of exposure). It should be noted that additional workers who might be exposed can prudently be put in the program. It is generally easier and safer for employers to be inclusive than exclusive.  In addition to venous blood leads, an EP (or ZPP), creatinine, BUN and CBC should be obtained at baseline and whenever there is a medical rationale for repeat testing.

51 Adult Return to Work Lead poisoned workers can return to the workplace when blood lead is <40 µg/dl. Symptomatic workers can remain out of the workplace at lower levels. Workers whose blood lead is near 40 µg/dl are most likely to be able to remain in the workplace if they can perform modified duty without lead exposure. Workplace Removal and Return to Work Construction Site Inspections are triggered by BLLs>40 μg/dl. Workers should be removed when the blood lead is >50μg/dl, and an OSHA log entry is made. In addition, return to work at 40 μg/dl is a very narrow window of “protection”, and recurrent levels above 50 μg/dl are quite possible with only small additional lead exposure once the worker returns. Finding jobs without lead exposure for recently poisoned workers enhances the chance that they can both return and stay in the workplace. [ OSHA ]

52 The Key to “Treatment” of Lead Poisoning
Remove from exposure, or otherwise prevent exposure. Workplace Home Substitution Move Engineering Identify and Abate Personal Protection Work Practices Job Placement Treatment of Lead Poisoning In a moment, we will describe medical approaches to treatment. None of the drugs have a meaningful chance to help victims who are still exposed, and they may even worsen the severity of illness if exposure persists. So, the real key to treatment is to engineer the home or workplace, or change the living conditions or job of the victim.

53 Chelation Therapy For symptoms, or physical findings.
May prevent dread acute consequences- seizure No longer believed to protect CNS in asymptomatic children Must be considered in light of possible complications- kidney damage and arrhythmia. Will cause increased lead absorption if exposure persists. Treatment of Lead Poisoning-Chelation Chelation is an adjunct to the real treatment in lead poisoning. For children and adults, the real treatment is to decrease exposure. What chelation can do is speed up the process of reducing the lead in circulating blood. Chelation is much less effective at attacking bone stores; a single chelation treatment (for example 5 days of I.V. EDTA) mobilizes much less than 10% of whole body lead burden.  The reason to chelate are to reduce symptoms or physical findings, or because there is legitimate fear of untoward outcomes (such as seizure). The advantages of a quick drop in circulatory blood lead must be weighed against possible complications of chelation such as kidney damage or arrhythmia or even increased blood lead if exposure persists. In addition, the quick decrease in circulating stores is not permanent. The equilibration between “compartments” explains the “bounce back” (increase in blood lead levels) that commonly follows treatment.  Until recently, it was common to chelate symptomatic children whose blood lead was µg/dl, in an effort to preserve and protect CNS function. A recent controlled therapeutic trial found no detectable benefit of this practice in children 1-3 years old with blood lead levels of µg/dl. When followed to grade school, children treated with chelation did not perform better than untreated, lead-poisoned peers. (Rogan WJ et al. The effect of chelation therapy with succimer on neuropsychologic development in children exposed to lead. N Engl J Med 2001; 344: ).

54 Choice of Chelation Agents
Outpatient: Succimer mg/m²x 7 days 700 mg/m²x14-19 days Inpatient: CaNa² -EDTA –1500 mg/m²/dx 5 days Encephalopathy Add: BAL mg/m²/d x 3 days In children Social Danger: Lowering blood level by oral chelation is not a substitute for workplace hygiene!! Chelation Drugs In supervised settings appropriate for outpatient treatment, parents of lead poisoned children can administer oral succimer (dimercaptosuccinic acid). The usual dose is 1050mg/m² of body surface area for 7 days, followed by 700mg/m² for up to 19 days. It is common to give two or three courses of treatment.  Children for whom home treatment is inappropriate can be admitted for IV CaNa2ֹ EDTA at ug/m²/d, in divided doses, and usually given for 5 days. In the event of encephalopathy, BAL mg/m²/d (usually in 4h divisions) is added for 3 days to protect the brain.  In the event of encephalopathy, which is more common in children, treatment of cerebral edema, fluid monitoring, and medical control of seizures are essential.  Adult chelation therapy is more likely to employ EDTA than pediatric chelation. Succimer is approved for pediatric use; there is no physiologic reason why it can’t be used in adults. A concern about outpatient treatment of workplace lead poisoning is that oral agents will be used instead of good hygiene practice to keep worker blood lead levels below removal thresholds (this is in fact forbidden by the OSHA standard). Adult treatment is usually initiated for blood lead levels above 60 µg/dl, or in any symptomatic patient. Using chelation to hasten workplace return is acceptable so long as the emphasis is on industrial hygiene measures to prevent exposure.

55 Prevention of Lead Poisoning
Prevention of lead poisoning is a superior public health measure; medical treatment alone is disappointing. The key to treatment is cessation of exposure, and the public health need is to consider and find other possible victims. The long-term success of our efforts to prevent lead poisoning will ultimately correlate with the amount and availability of lead in the home and work environment. We have taken some effective primary prevention measures, such as removing lead from gasoline and virtually all points. Where lead is already in the home environment, we have relied on secondary prevention measures such as medical surveillance, rather than taking the expensive primary route of attacking the presence of lead by removal. This strategy has been partially effective, and is likely to remain partially effective. Thus, a high degree of alertness and ongoing medical surveillance strategies are needed to diminish the negative outcomes of lead exposure in our children. In this one situation, we must survey our children as carefully as we normally survey more discrete populations of adult workers. For adult workers, industrial hygiene and medical surveillance have worked well in larger, safety conscious organizations. Many businesses working with lead are small or operate at the economic margins. Lead poisoning persists, and is often detected only after the fact, in these work environments.

56 Helpful Web Sites ATSDR  ATSDR Toxicological Profiles ATSDR ToxFAQs ™  CDC-NCEH  NIOSH 

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