LEAD

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Blei-metall
2) Bleichromat
3) Chromate de Plomb
4) C.I. Pigment Metal 4
5) Dianichi chrome yellow G
6) Giallo cromo
7) Glover
8) Lead(II) Nitrate (1:2)
9) Lead dust
10) Lead, elemental
11) Lead flake
12) Lead fume
13) Lead, inorganic
14) Lead metal
15) Lead S2
16) Lead SZ
17) Metallic lead
18) Orow (Polish)
19) Olow
20) Pb
21) Pigment metal
22) Pigment metal 4
23) Plomo (Spanish)
24) Plumbum
25) Molecular Formula: Pb
26) CAS 7439-92-1

1.2.1) MOLECULAR FORMULA
1) Pb

Available Forms Sources

1) Elemental lead exists as a highly lustrous, heavy, silvery-gray metal with a cubic crystal structure that assumes a bluish tint as it tarnishes in air. It is quite soft and malleable (Lewis, 2001; Budavari, 2000) .
2) It is predominantly found in a number of ores, the most common of which is lead sulfide, also known as galena (Bingham et al, 2001; (ATSDR, 1999)).
3) Lead is available in a wide range of solid forms such as sheets, ingots, rod, pipe, shot, buckles or straps, grids, wire, paste, single crystals, or powder. Grades include high purity (less than 10 ppm impurity), pure (99.9+%), powdered (99% pure), low bismuth, low silver, pure lead (99.995%), refined pure (99.97%), chemical copper-lead (99.90%), pig lead, or paste (HSDB , 2002; Lewis, 2001).

1) Lead is a naturally-occurring metallic element found in the earth's crust at about 15-30 mg/kg. Lead does not generally occur in pure elemental form, but exists in several mineral ores including galena (lead sulfide), anglesite (lead sulfate), cerussite (lead carbonate), mimetite (lead chloroarsenate), and pyromorphite (lead chlorophosphate) (Bingham et al, 2001; Budavari, 2000; Lewis, 2000; (ATSDR, 1999); ACGIH, 1996a).
2) In 1996, 93% of domestically mined lead was produced in Missouri and Alaska, contributing to a total domestic production of 436,000 metric tons. Approximately 268,000 metric tons of lead metal and 14,800 metric tons of lead scrap and waste were imported during that same year ((ATSDR, 1999)).
3) Pure lead is derived through the roasting and reduction of galena, anglesite, and cerussite, that is then purified through the following methods: desilvering (Parkes process); electrolytic refining (Betts process); pyrometallurgical refining (Harris process); or the Betterton- Kroll process (for the removal of bismuth) (Ashford, 1994; Lewis, 2001).
4) ROUTE OF EXPOSURE

a) Exposure to lead in the general population occurs from inhalation of contaminated air and dust of various types or ingestion of food and water containing lead with a fairly even split between ingestion and inhalation exposure routes. About 5-15% of ingested lead is absorbed by adults with less than 5% retained. Children, however, absorb approximately 50% of ingested lead and retain about 30% (Lewis, 2000).

5) SOURCES OF LEAD EXPOSURE

1) Autoclave tapes (Davis, 1987)
2) Automobile storage battery casing; battery repair shops (Wong A, Castro Jr G & Duarte JG et al, 1994; MMWR, 1989; Dolcourt et al, 1981)
3) Automobile fumes (Reith et al, 2003; Morgan et al, 2001; Landrigan, 1982)
4) Bone meal or dolomite supplements (Jones et al, 1999; Miller, 1987)
5) Bootleg whiskey (moonshine, corn liquor) (Reith et al, 2003; Morgan et al, 2001; Morgan et al, 2001; Landrigan, 1982)
6) Brewing kettle (imported samovar from Iran; used for reconstitution of powdered infant formula) (Shannon, 1998)
7) Calcium supplements (Ross et al, 2000)
8) Candle with lead-containing wicks (Sobel et al, 2000)
9) Ceramic-coated capacitor manufacturing (Kaye et al, 1987)
10) Ceramic glazes (found on pottery, earthenware, bone china, and porcelain) (Shiri et al, 2007; Anon, 2004; Reith et al, 2003; Morgan et al, 2001; Vance et al, 1990; Phan et al, 1998; Roberge et al, 1994; Matte et al, 1994; Chassaing et al, 1991; Zuckerman et al, 1989; Bradley et al, 1987; Landrigan, 1982; Natelson & Fred, 1976)
11) Clay pots used for tamarind jelly (contained 58,000 mcg lead/g) (Fuortes & Bauer, 2000)
12) Contaminated animal feed from mining waste (Lund & Brown, 1989)
13) Contaminated flour from a stone mill repaired with molten lead (Kokori et al, 1999; Jones et al, 1999; Dona et al, 1999; Carton et al, 1987; Kocak et al, 1989)
14) Contaminated infant formula from water boiled in imported kettle from Iran (Frankel et al, 1992; Shannon, 1998).
15) Cosmetics (traditional, Surma, Kohl, or Kajal mascara/eyeliner may contain 17.3 to 79.5% lead; from Saudi Arabia, India, Pakistan, and Iran) (Al-Ashban et al, 2004; Reith et al, 2003; Morgan et al, 2001; Jones et al, 1999; Kulshrestha, 1996; Nir et al, 1992; Healy & Aslam, 1986; Pontifex & Garg, 1985; Landrigan, 1982)
16) Crystal (may contain 24% to 32% lead oxide) (Graziano & Blum, 1991; Appel et al, 1992)
17) Dental films stored in lead-lined table-top containers ((Anon, 2001))
18) Firing ranges (Beaucham et al, 2014; Stromness et al, 2000; Shannon, 1999; Chau et al, 1995; Ozonoff, 1994; Brewer, 1989; Valway et al, 1989; Fisher-Fischbein et al, 1987; Norotny et al, 1987; Goldberg et al, 1991; Fischbein, 1992a; Tripathi et al, 1990)
19) Folk remedies or traditional medicines (see below for more specific terms) (Reith et al, 2003; Morgan et al, 2001; Landrigan, 1982; Bose et al, 1983)
20) Gold ore processed using artisanal techniques (Burton, 2012)
21) Hair spray (older brands) (Raasch et al, 1983; Curry et al, 1986; Landrigan et al, 1975)
22) Heroin (Parras et al, 1987)
23) Hongdans (lead tetraoxide) traditional chinese medicine (Lin et al, 2012)
24) Home battery manufacture (Reith et al, 2003; Morgan et al, 2001; Landrigan, 1982)
25) Homemade traditional alcoholic beverage (tsipouro) (Kokori et al, 1999)
26) Illicit methamphetamine (may contain lead acetate as an impurity or direct contamination) (Allcott et al, 1987; Norton et al, 1989; CDC, 1989)
27) Imported candy wrappers (cellophane) (Fuortes & Bauer, 2000)
28) Ink (Cohen et al, 1986)
29) Ingested bullets or pellets (McNutt et al, 2000; Lyons & Filston, 1994; Gellert et al, 1993; Greensher et al, 1974)
30) Ingested fish sinkers (Fergusson et al, 1997).
31) Jewelry (low-cost children's and costume jewelry imported and sold in the US) (Weidenhamer & Clement, 2007; Berkowitz & Tarrago, 2006)
32) Lead-contaminated flour (lead used to repair grindstones for flour mills) (Dona et al, 1999; Kocak et al, 1989; Carton et al, 1987)
33) Lead-contaminated ground paprika (lead tetroxide or red lead) used in home-made sausages (Kakosy et al, 1996)
34) Lead-contaminated spices used in food preparation (Swanuri marili; Kharchos suneli [zafron]; Kozhambu) (Woolf & Woolf, 2005)
35) Lead-contaminated water used in infant formulas (Liebelt et al, 1992)
36) Lead crystal alcoholic beverage decanters (Appel et al, 1992).
37) Lead curtain weights (Blank & Howieson, 1983; Hugelmeyer et al, 1988)
38) Lead pipes (Reith et al, 2003; Morgan et al, 2001; Landrigan, 1982)
39) Lead shot ingestion (McKinney, 2000; Selbst et al, 1986; Greensher et al, 1974)
40) Lead stabilizers (eg; lead sulfate, lead stearate) as additives in plastics to coat or insulate wire and cables in the formulation of polyvinyl chloride plastic (Coyle et al, 2005)
41) Litargirio (a yellow or peach-colored powder used as a antiperspirant/deodorant or as a folk remedy in the Hispanic community) (Anon, 2005)
42) Lozeena (Iraq) food coloring, orange powder (Jones et al, 1999)
43) Necklace with beads; medallion pendant (Anon, 2004a; Jones et al, 1999)
44) Nipple shields for breastfeeding (Kokori et al, 1999)
45) Paint chips and dust (on houses, toys and furniture) (Reith et al, 2003; Morgan et al, 2001; ATSDR , 1997; Budavari, 1996; ACGIH, 1996a; Landrigan, 1982)
46) Plastic wire coating (from chewing the plastic insulation stripped off electrical wires; plastic coating lead content 10,000 to 39,000 mcg lead/g of coating) (CDC, 1993; Franco et al, 1994)
47) Pool cue chalk (mostly contained less than 30 ppm lead; however, 3 kinds of chalk contained lead concentrations in excess of 6000 ppm [Master green, Pioneer green and tangerine])(Dargan et al, 2000; Miller et al, 1995; Miller et al, 1996)
48) Radiator mechanics (Tribe, 1997; Goldman et al, 1987; Lussenhop et al, 1989)
49) Renovation/modernization of old homes (Curran & Nunez, 1989; Gonzalez & Ungaro, 1982)
50) Retained bullets (Akhtar et al, 2003; Madureira et al, 2001; DeMartini et al, 2001; McQuirter et al, 2001; Murdock et al, 1999; Viegas & Calhoun, 1986; Aly et al, 1993; Farber et al, 1994; Meggs et al, 1994; John & Boatright, 1999)
51) Silver jewelry workers (Kachru et al, 1989)
52) Soil contaminated with lead (Reith et al, 2003; Budavari, 1996; ACGIH, 1996a; ATSDR , 1997; Prpic-Majic et al, 1992).
53) Toy necklace (a medallion pendant contained 38.8% lead (388,000 mg/kg), 3.6% antimony, and 0.5% tin; from India, recalled in the US) (VanArsdale et al, 2004; Anon, 2004a)
54) Wine (metallic lead sheets enclosing many European wine bottles) (Rovira et al, 1989; Nriagu, 1985; Elias, 1985)
55) Wine leachate from bathtubs (homemade red wine) (Mangas et al, 2001)

a) CALCIUM SUPPLEMENTS

1) In one study, four commercial calcium preparations labeled as being "natural" (i.e., oyster shell) had measurable lead content (approximately 1 mcg/d for 800 mg/d of calcium, 2 mcg/d for 1500 mg/d of calcium, and up to 10 mcg/d for renal dosage). However, no lead was found in the calcium acetate or polymer products (Ross et al, 2000).
2) Calcium supplements from bone meal may have lead concentrations of up to 12.8 mcg/g, although no cases of lead toxicity have been reported from ingestion (Miller, 1987).

b) DIET

1) In many countries, the intake of lead from diet can approach or exceed the PTWI (Provisional Tolerable Weekly Intake; 25 mcg/kg body weight or 1500 mcg/person). In Brazil, lead was detected in medicinal herbs prepared with the leaves, fruits or barks of the plants, casara buckthorn, horse chestnut, centella asiatic, celastraceae and ginkgo biloba. Three horse chestnut samples contained 153, 156, and 1480 mcg lead/gram, with the estimated lead intake through the consumption of horse chestnut reaching 440% of PTWI (Caldas & Machado, 2004).

c) DUST/FUMES

1) CANDLES WITH A METALLIC WICK: In a study of lead exposure from candles, it was shown that approximately 10% (n=86) of candles with metallic wicks contain lead. After burning these candles for 3 hours, they would produce air lead concentrations ranging from 15.2 to 54.0 mcg/m(3) in 24 hours. This is 10.1 to 36.0 times the US EPA standard of 1.5 mcg/m(3) (Sobel et al, 2000).
2) FIRES: In a case-controlled evaluation of victims (n=66) of severe smoke inhalation following a closed-space fire, patients with severe smoke inhalation had a statistically significant 2-fold increase in whole blood lead level (mean lead level among cases was 6.64 mcg/dL vs 2.89 mcg/dL among controls). The authors, however, noted that these findings were unlikely to be of clinical significance. Currently, treatment recommendations for adults are based on blood lead levels of 40 mcg/dL or greater. Based on these findings, widespread testing for lead intoxication in adult victims of smoke inhalation is not necessary. It was suggested, that repeated acute adult exposures (e.g., firefighters) or pediatric exposures may require further evaluation (Lahn et al, 2003).
3) SECOND HAND TOBACCO SMOKE: In a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III), a stratified multistage clustered probability design was used to select a representative sample of the US population. A dataset of 5592 children was used to estimate 37 million children between the ages of 4 to 16 years. The study found that children with high cotinine levels, due to second hand tobacco smoke exposure, were more likely to have high blood lead levels (>/= to 10 mcg/dL) than those with low cotinine levels. It has been estimated that main stream tobacco smoke contains 60 ng of lead per cigarette, and that sidestream smoke contains 5 to 10 ng of lead per cigarette (Mannino et al, 2003).

a) The adjusted linear regression model indicated that geometric mean blood lead levels were 38% higher (95% CI) in children with high cotinine levels as compared with low cotinine levels. The study suggested that second-hand smoke could be associated with elevated blood lead levels with the strongest association being in younger children.

4) GOLD ORE PROCESSING: In 2010, children (n=463 less than 5 years of age) of 4 villages in Zamfara state in rural northwestern Nigeria developed massive childhood lead poisoning after exposure to lead contaminated gold ore-processing in family compounds. It was found that approximately 25% (118 of 463) of children under the age 5 died within a year of lead exposure. An initial blood tests revealed 8 children with BLLs of 168 to 370 mcg/dL. BLLs of 59% of surviving children were then collected; 97% of these BLLs were at least 45 mg/dL and 85% surpassed the portable sampling devices' maximum detection limit of 65 mcg/dL (Burton, 2012; Dooyema et al, 2012).

d) FOLK REMEDIES

1) Folk/traditional medicines may be found in the following locations: Korea, Pakistan, India, China, Mexico and the Middle East (Anon, 2004b; Shrestha & Greenberg, 2002; Traub et al, 2002; van Vonderen et al, 2000; Jones et al, 1999; Spriewald et al, 1999; Dolan et al, 1991; Mitchell-Heggs et al, 1990; Smitherman & Harber, 1991; McElvaine et al, 1990; Markowitz et al, 1994; Chi et al, 1994; Perharic et al, 1994).

1) Alarcon (almost pure lead tetroxide) (Jones et al, 1999; Bose et al, 1983)
2) Albayalde (lead carbonate) (Mexico; most prevalent among migrant workers in south Texas, Florida, and California) (Jones et al, 1999; Cueto et al, 1989; CDC, 1993)
3) Amratanshta (India) (Frith et al, 2005)
4) Azarcon (a bright orange powder containing approximately 92% to 97% lead tetroxide) (Jones et al, 1999; Bose et al, 1983)
5) Bala goli (India) (Jones et al, 1999)
6) Bao ning dan (a Chinese herbal pill) (Auyeung et al, 2002)
7) Bruhat Vata Chintamani Rasa (India) (Meiman et al, 2015)
8) Coral (almost pure lead tetroxide) (Jones et al, 1999; Bose et al, 1983)
9) Deshi Dewa (a white powder from Asia) (Kulshrestha, 1996)
10) EX and ADISSA (Ayurvedic medications from India) (Shrestha & Greenberg, 2002)
11) Ghasard (India) (Jones et al, 1999)
12) Greta (Lead oxide) (Mexico; most prevalent among migrant workers in south Texas, Florida, and California) (Jones et al, 1999; Cueto et al, 1989; CDC, 1993)
13) Hau ge fen (a Chinese herbal tea) (Markowitz et al, 1994)
14) Hongdans (containing lead tetraoxide) traditional chinese medicine (Lin et al, 2012)
15) Kandu (India) (Jones et al, 1999)
16) Liga (almost pure lead tetroxide) (Jones et al, 1999; Bose et al, 1983)
17) Maharasanadi Kashayam (India) (Frith et al, 2005)
18) Mahayogaraj Guggulu (India; in one case, it contained 7052 mg/kg of lead (1.75 mg per tablet) and 12,756 mg/kg of mercury (3.5 mg per tablet)) (Frith et al, 2005; Meiman et al, 2015)
19) Maha yogran guggulu (India; contains 6.47% lead by weight) (Saryan, 1991).
20) Maria Luisa (almost pure lead tetroxide) (Jones et al, 1999; Bose et al, 1983)
21) Nzu (Salted Nzu) (U.S. Food and Drug Administration, 2009)
22) Pay-loo-ah (among Hmong Laotian refugees; a bright orange-red powder, containing 1% to 90% lead and 70% to 80% arsenic) (Jones et al, 1999; CDC, 1983)
23) Rueda (almost pure lead tetroxide) (Jones et al, 1999; Bose et al, 1983)
24) Pushap and Sharti (Indian Ayurvedic herbal formulations) (van Vonderen et al, 2000; Spriewald et al, 1999; Dundabin et al, 1992)
25) Satrinj and bint dahab (traditional medications available in Oman, contain 98% and 90% lead oxide, respectively) (Woolf et al, 1990)
26) Tibetan herbal vitamin tablets (Moore & Adler, 2000)

2) Litargirio (also known as litharge or lead monoxide, is a yellow or peach-colored powder) is used as an antiperspirant/deodorant and a folk remedy for burns and fungal infections of the feet. It is also used in the manufacture of batteries, glass, ceramics, or rubber products and as a paint pigment. Litargirio is manufactured and/or packaged by Dominican Republic laboratories and is available locally in botanicas (shops selling herbs) or bodegas ( grocery stores) in the Hispanic community. In one report, the litargirio sample contained 790,000 ppm (79%) lead (Anon, 2005).
3) Nzu, found in African specialty stores, is marketed as a traditional remedy for treatment of morning sickness in pregnant women. Nzu appears as a ball of clay or mud and is typically sold in small plastic bags with handwritten labels identifying it as "Nzu" or "Salted Nzu". Laboratory analysis of a sample of Nzu, by the Texas Department of State Health Services (DSHS), found that it contained high concentrations of lead and arsenic (U.S. Food and Drug Administration, 2009).
4) Hongdan (red lead) is a traditional Chinese medicine containing lead tetraoxide. In one study, 16 Hongdans samples had an average lead content of 817,000 mg/kg. Two Chinese children (a 3-year-old boy and a 6-month-old girl) with lead toxicity after using Hongdan (a lead concentration of 214,000 mg/kg) with talcum baby powder had blood lead concentrations of 303 mcg/L and 385 mcg/L, respectively (Lin et al, 2012)

e) LEAD BULLETS

1) Lead intoxication from retained bullets or shrapnel has been reported. Almost all cases involve lodging of the missile in or near a joint. Inflammatory changes from development of arthritis or re-injury have often precipitated symptoms. Synovial fluid is a better solvent for lead than serum or bone and synovial lead levels can be much higher than blood levels (Akhtar et al, 2003; Madureira et al, 2001; DeMartini et al, 2001; McQuirter et al, 2001; John & Boatright, 1999; Farber et al, 1994; Aly et al, 1993; Meggs et al, 1994; John & Boatright, 1999; Viegas & Calhoun, 1986; Roberts et al, 1983; DiMaio & Garriott, 1980; Dillman et al, 1979; Switz et al, 1976) .
2) Fifteen emergency department patients with radiographic evidence of retained lead bullets or shrapnel had statistically significant increased blood lead levels (mean 17 mcg/dL) compared to matched controls (mean 7 mcg/dL). Time since initial exposure ranged from 1 to 45 years. Actual composition of retained bullets was not determined (Farrell et al, 1999).
3) One study of 240 emergency department patients reported that persons with extra-articular retained missiles (EARMS) had significantly higher whole blood lead levels than matched controls. A positive correlation between whole blood lead levels and a history of recent fractures (the last 30 days) was found. This can be explained by the fact that bone lead stores are released into the circulation during instances of bone injury and remodeling. In addition, no correlation between whole blood lead levels and the number of reported symptoms of lead toxicity in persons with or without EARMS was observed. Overall, elevated lead levels were not clinically significant and did not change patient management in 96% of the patients (Nguyen et al, 2005).
4) In one study, changes in blood lead levels in subjects (n=451) were evaluated during the first year after a gunshot wound with a retained bullet. It was shown that blood lead concentrations increased significantly with time after injury up to 3 months, with number of retained fragments (p<0.0005), and with increasing age (p<0.0005). Blood lead increase as a function of fragmentation was 29.5% higher among subjects who had suffered a torso bone fracture (chest, abdomen, and pelvic regions) than in subjects without a fracture (p<0.0005). Higher blood lead levels were noted in subjects with bullets or fragments lodged near bone (p<0.0005) or near joints (p=0.032). In addition, logistic models correctly reported a blood lead elevation of equal to greater than 20 mcg/dL in 81% and 85% of subjects at 3 and 6 months postinjury, respectively. At 3 months and 12 months, the prevalence of elevated blood lead were 11.8% and 2.6%. respectively. Continued surveillance of blood lead levels after gunshot injury for these patients was recommended (McQuirter et al, 2004).
5) INDOOR FIRING RANGES: In a study of 41 states that participated in Adult Blood Lead Epidemiology and Surveillance (ABLES) program (years: 2002 to 2012), it was found that 2056 persons had BLLs 10 mcg/dL or greater (1271 with BLLs 10 to 24 mcg/dL; 785 with BLLs of 25 mcg/dL or greater) after exposure to lead at work (631 were employed in police protection and 1425 were employed in other amusement and recreation industries, including indoor firing ranges). In addition, 2673 persons were exposed to lead in non-work-related target shooting and had elevated BLLs (1290 with BLLs of 25 mcg/dL or greater and 1388 with BLLs of 10 to 24 mcg/dL) (Beaucham et al, 2014).

f) LIPSTICKS

1) In 2010, testing of 400 lipsticks by the US FDA revealed a maximum lead concentration of 7.19 ppm. Based on this concentration, average (2/3 of a 3-g tube/year) and high (2.5 3-g tubes/year) lipstick use by a child will not increase BLLs and at least 90 tubes of lipstick is needed to be ingested over a year to increase a child's BLL by 1 mcg/dL (Monnot et al, 2015).

g) OCCUPATIONAL EXPOSURE

1) In an industrial setting, exposure to lead mainly occurs from inhalation of dust or fumes (Budavari, 1996; ACGIH, 1996a; ATSDR , 1997) Lead dust carried home from work on contaminated clothing or equipment can contaminate the home, causing elevated blood lead levels in family members (Baker et al, 1977; Nunez et al, 1993).
2) Occupational exposure to lead may occur in the following settings:

1) Autoclave indicator strips (use the color change of white lead carbonate to black lead sulfide to indicate adequacy of sterilization) (Davis, 1987)
2) Bricklaying (by using a special brick mortar, containing 71% lead oxide, formulated to resist acid in an accumulation tank at a paper mil) (CDC, 1991a)
3) Capacitor manufacturing (Kaye et al, 1987)
4) High voltage tower conservators (Krawczyk et al, 2006)
5) Construction and repair of lead-painted bridges (CDC, 1995; CDC, 1993; Rae et al, 1991; Marino et al, 1989)
6) Dye factory (Ger et al, 1994)
7) Leaded or stained glass production, laboratories, or ceramics (ACGIH, 1991)
8) Lead recycling plant (Chao & Wang, 1994)
9) Precious metals refinery (Kern, 1994)
10) Producing lead carbonate (Ger et al, 1994)
11) Radiator repair (inhalation of lead fumes generated during soldering joints and dust generated by blasting the radiator cores) (Nunez et al, 1993; CDC, 1991b; Goldman et al, 1987)
12) Wire and cable company (lead stearate stabilizer) (Ger et al, 1994)
13) Working with lead naphthenate (a metallic soap used as a drying agent in paint and as a high pressure lubricant) (Goldberg et al, 1987)

3) TAKE-HOME LEAD POISONING - All industries in which lead is used (eg; furniture refinishing and construction) present occupational hazards. Industrial lead dust, carried on the clothes of parents, is an exposure source for children (Baker et al, 1977). Employers in these industries should arrange personal exposure monitoring and surface wipe sampling for lead and implement workplace improvements, including a respiratory protection program; use of HEPA vaccum-attached power sanders; use of a high-efficiency toxic dust HEPA vacuum; daily clean uniforms; separate storage lockers, changing area with showers, and lunch room; warning signs; safety training addressing take-home lead; and a lead medical surveillance program (Centers for Disease Control and Prevention, 2001).

a) In one report, family members of workers exposed to lead had elevated BLLs (Centers for Disease Control and Prevention, 2001).

h) PAINT

1) Lead in paint is usually in the form of lead carbonate. It enters the body when paint chips are eaten, when paint is sucked, when the dust of the paint is picked up on the hands of toddlers, during house renovation, or when painted metal is cut with an acetylene torch.
2) Since 1977, household paint must contain no more than 0.06% (600 ppm) lead by dry weight. Overt lead poisoning usually occurs in housing built before World War II. A chip of old or industrial paint the size of a thumbnail may contain 50 to 200 mg of lead. For comparison, the average dietary intake of lead in children is only 20 to 80 mcg/day (Anon, 1987).
3) In a lead screening of 5168 children aged 1 to 3 years in Salt Lake County, Utah, high serum lead levels (>20 mcg/dL) were found in 7 (0.1%) children. In 5 of the 7 cases, the source of exposure was traced to deteriorating lead-based paint in their homes (CDC, 1997).
4) Lead-containing pigments that have been used in paints include (Joly et al, 1987):

1) calcium plumbate
2) ceruse (basic lead carbonate)
3) chromium yellows
4) lead phosphite
5) lead cyanamide
6) metallic lead
7) minium
8) molybdenum reds

5) The solubility of lead-based pigments in gastric fluid determines the hazard after ingestion. Pigments with partial solubility include lead minimum, basic lead carbonate, and metallic lead. Other pigments that are practically insoluble in gastric fluid include lead chromate, lead silicochromate, lead sulfochromate, and lead sulfochromomolybdate (Joly et al, 1987).
6) Alkyl paints may contain drying agents, such as lead naphthenate or lead octoate. Usual concentrations are 0.1 to 0.3% (Joly et al, 1987).

i) WATER SUPPLY

1) FLINT, MICHIGAN: In 2014, residents of Flint, Michigan were exposed to lead after their water supply was changed from Detroit-supplied Lake Huron water to Flint River water. Flint has aging water distribution system with old lead pipes and lead plumbing. In addition, the city water has high levels of chloride, high chloride-to-sulfate mass ratio, and no corrosion inhibitors. Authorities detected high rates of lead leaching into drinking water and very high water lead levels (WLLs). A retrospective study evaluated blood lead levels (BLLs) of 1473 children (age, less than 5 years) from Flint before (2013) and after (2015) water source change. The incidence of elevated blood lead levels (EBLL) before and after the water source change were 2.4% to 4.9% (P less than .05), respectively. Children from disadvantaged neighborhoods had the greatest EBLL increases. The change in EBLL outside of Flint was not statistically significant (0.7% to 1.2%; P greater than .05) (Hanna-Attisha et al, 2016).

1) The metal is widely used for its malleability, density, low melting point, corrosion resistance, chemical stability and opacity to x-rays and atomic radiation. It is a poor electrical conductor but a good sound and vibration absorber. Despite its usefulness, lead is toxic to humans (Lewis, 2001; Budavari, 2000; (ATSDR, 1999); ACGIH, 1996a).
2) At least half, and perhaps as much as 70%, of the worldwide lead usage is for the production of lead-acid batteries used in automobiles and other industrial applications (Bingham et al, 2001; (ATSDR, 1999)).
3) Other uses of lead include an ingredient in pigments for paints, enamels, ceramic glazes, and glass, and as an ingredient in plastics and rubbers. Lead is used in metallurgy to make lead alloys, such as those used to make alloys for bearings. It has been used to make solder, foils, caulking, coverings for cable, and ammunition. Lead has been widely used in storage batteries and as shielding for x-ray and atomic radiation (Lewis, 2001; Baselt, 2000; Budavari, 2000; (ATSDR, 1999); Sittig, 1991).
4) In the construction industry it has been used to dampen vibration. Lead is often used to line tanks, piping and other equipment used in the production of sulfuric acid. It is used in petroleum refining and other chemical processes. Tetraethyl lead, an organic lead, has been used widely as an anti-knock agent in gasoline, though its use has been phased out by the Environmental Protection Agency (Lewis, 2001; Budavari, 2000; (ATSDR, 1999); Sittig, 1991).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Lead is a soft metal that is used in a variety of industrial processes. It has been used in paint and gasoline, but the use of lead in house paint and gasoline has been outlawed for decades in the United States (US). Folk medications may also contain large amounts of lead salts. Soil may have large amounts of lead contamination from industrial processes or old paint. Some products manufactured outside the US (eg, pottery, jewelry, toys, makeup) may contain lead.
B) TOXICOLOGY: Lead exerts its toxic effects through a variety of mechanisms and effects many organ systems. It binds sulfhydryl groups, impacting various enzymes, receptors and proteins. Lead interferes with metabolic pathways in mitochondria, and in systems that regulate cellular energy and metabolism. It causes activation/inactivation of many enzymes via its competing effects with other cations, notably calcium, ferrous iron, and zinc. Lead inhibits several enzymes involved in heme synthesis, and impairs erythrocyte membrane stability, causing anemia.
C) EPIDEMIOLOGY: There are several thousand cases of lead poisoning reported to poison centers in the US every year. However, severe toxicity is very uncommon and deaths are rare. In children with chronic lead poisoning, ingestion of lead paint chips and dust in older dilapidated housing is the most common source of exposure. Inhalational exposure is the most common cause of adult/occupational lead toxicity.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: The primary concerns of mild to moderate toxicity from lead exposure in young children are neurodevelopmental, specifically lower intelligence quotient scores and behavioral problems. Population studies suggest that mild cognitive impairment develops at low levels of lead exposure (blood lead concentrations of 10 mcg/dL). Intermittent vomiting, anorexia and abdominal pain may also develop. In mild to moderate exposures in adults, concerns include hypertension, spontaneous abortion and sperm abnormalities, and more subtle neurocognitive effects. Fatigue, mild somnolence, headache, insomnia, abdominal pain, constipation, mild anemia, myalgias and arthralgias, and mild weakness may also develop.
2) SEVERE TOXICITY: Acute ingestions of very large amounts of lead are rare, but may cause abdominal pain, nausea, vomiting, anemia (usually hemolytic), toxic hepatitis, and encephalopathy. In children, severe toxicity manifests as encephalopathy (ie, coma, seizures, ataxia, incoordination, cranial nerve palsies, increased intracranial pressure, bizarre behavior or altered mentation), persistent vomiting, and anemia. More severe subacute or chronic exposures in adults can lead to symptoms such as fatigue, malaise, irritability, anorexia, insomnia, weight loss, decreased libido, arthralgias, myalgias, hypertension, crampy abdominal pain, nausea, constipation or diarrhea (less commonly), impaired concentration, headache, diminished visual-motor coordination, tremor, encephalopathy, a peripheral motor neuropathy (especially affecting the upper extremities causing wrist drops), a normochromatic or microcytic anemia (the hallmark of which is basophilic stippling), nephrotoxicity (a reversible acute tubular dysfunction and chronic interstitial fibrosis), hyperuricemia, and associated gout.

0.2.20)

A) Lead is transferred across the placenta. It can affect reproduction in males and females, and affects neurodevelopmental milestones in children with both prenatal and postnatal exposure.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) The most important treatment is to identify the source of lead exposure (generally requires an environmental evaluation of the home, an occupational history of patient and/or family members, and evaluation of hobbies) and removal from further exposure. Chelation therapy is recommended for levels of 45 mcg/dL or more in children. Adults with symptoms or blood lead concentrations above 50 mcg/dL, should also be chelated. Levels that high also merit follow-up blood lead testing, a lab screening for anemia, and possibly radiographs to look for lead in the GI tract. Outpatient chelation can be achieved with oral succimer. D-Penicillamine is another oral agent used for chelation in children, but is considered a second-line agent after succimer.

B) MANAGEMENT OF SEVERE TOXICITY

1) In children, a blood lead concentration of 70 mcg/dL or more is an indication for hospitalization. Whole bowel irrigation with polyethylene glycol should be performed if there is evidence of lead in the GI tract on radiograph. Oral chelation (succimer) can be performed in children with blood lead concentrations less than 70 mcg/dL without evidence of encephalopathy. In patients with encephalopathy or in children with blood lead concentrations of 70 mcg/dL or more, parenteral chelation (intramuscular dimercaprol (BAL) should be initiated first, followed by intravenous edetate calcium disodium. Treat seizures with IV benzodiazepines. Seizures from lead encephalopathy may be resistant to anticonvulsant therapy; barbiturate-induced coma and aggressive control of intracranial pressure may be needed. Cerebral edema may be managed by ventilation and the administration of mannitol and/or dexamethasone. Lumbar puncture is be dangerous in the presence of increased intracranial pressure.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal may be used after an acute ingestion. For dermal, eye or inhalational exposures, treatment is standard decontamination including removal of contaminated clothing and washing the exposed area with soap and water.
2) HOSPITAL: Activated charcoal may be used after an acute ingestion. There is no evidence to support the use of gastric lavage in lead ingestions. Whole bowel irrigation with polyethylene glycol solution should be considered when there is radiographic evidence of lead foreign bodies in the GI tract.

D) AIRWAY MANAGEMENT

1) Airway management is not likely to be directly an issue with lead toxicity unless the patient has encephalopathy. If lead encephalopathy is suspected, the patient should be evaluated and treated for increased intracranial pressure.

E) ANTIDOTE

1) Several chelating agents are effective in increasing lead excretion. Parenteral chelators are generally reserved for patients with very high blood lead concentrations (BLL) (70 mcg/dL or more in children), evidence of encephalopathy, or patients who cannot tolerate oral medications. The following guidelines have been recommended:
2) ENCEPHALOPATHY: ADULTS or CHILDREN: BAL: 450 mg/m(2)/day (24 mg/kg/day) (regimen, 75 mg/m(2) IM every 4 hours) for 5 days. IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1500 mg/m(2)/day (50 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
3) SYMPTOMATIC ADULTS WITH BLL GREATER THAN 100 mcg/dL and CHILDREN WITH BLL GREATER THAN 69 mcg/dL: BAL: 300 to 450 mg/m(2)/day (18 to 24 mg/kg/day) (regimen, 50 to 75 mg/m(2) every 4 hours for 3 to 5 days). IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1000 to 1500 mg/m(2)/day (50 to 75 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
4) ADULTS WITH MILD SYMPTOMS or BLL 70 to 100 mcg/dL: Succimer 700 to 1050 mg/m(2)/day (regimen, 350 mg/m(2) (10 mg/kg) orally every 8 hours for 5 days and then every 12 hours for 14 days).
5) ASYMPTOMATIC CHILDREN WITH BLL BETWEEN 45 to 69 mcg/dL: Succimer 700 to 1050 mg/m(2)/day (regimen, 350 mg/m(2) (10 mg/kg) orally every 8 hours for 5 days, and then every 12 hours for 14 days) OR IV edetate calcium disodium 1000 mg/m(2)/day continuous infusion or 2 to 4 divided IV doses for 5 days OR D-penicillamine 25 to 35 mg/kg/day in divided doses. Treatment is usually initiated at 25% of this dose and gradually increased to the full dose over 2 to 3 weeks to minimize adverse reactions. Do not use D-penicillamine in patients with known penicillin allergy.
6) ASYMPTOMATIC ADULTS and BLL LESS THAN 70 mcg/dL: No routine chelation is indicated.
7) ASYMPTOMATIC CHILDREN and BLL 20 to 44 mcg/dL: No routine chelation is indicated. Succimer (same regimen as above) has been used.
8) NOTE: When the BLL is improving per the guidelines and the patient is able to tolerate oral medications, BAL can be replaced with succimer with no waiting period between treatments. If Monitor blood lead concentrations at the end of chelation and for several weeks to months after the completion of therapy to detect rebound or reexposure, and guide the need for further courses of chelation.

F) ENHANCED ELIMINATION

1) Chelators enhance lead excretion. There is no evidence to support the use of any of the following: dialysis, hemoperfusion, urinary alkalinization and multiple dose charcoal.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Most asymptomatic lead exposures can be managed on an outpatient basis, as long as further lead exposure can be prevented and patient follow-up can be established.
2) OBSERVATION CRITERIA: Symptomatic lead exposures or patients with a potentially significant oral ingestion (eg, ingestion of a known lead figurine or key chain) merit immediate evaluation at a health care facility. If a significant ingestion can be ruled out (eg, via radiographs), asymptomatic patients may be discharged to home.
3) ADMISSION CRITERIA: Symptomatic patients or patients with a potentially high lead exposure/levels (for children, whole blood lead levels 70 mcg/dL or more) should be admitted. The patient’s clinical status should determine whether or not the patient should go to the ward or ICU (eg, encephalopathic patients merit an ICU admission). Criteria for discharge should include improvement/resolution of symptoms, transition to oral chelation, and known removal of lead exposure.
4) CONSULT CRITERIA: Consultation with your local poison center/toxicologist is advised. Public health departments should also be notified to arrange home visit and environmental assessment. Notify OSHA for occupational lead poisoning.

H) PITFALLS

1) Diagnosis may be missed without standard lead screenings in infants/toddlers or if a careful history is not obtained. Identification of lead source and its removal is paramount. Diagnosis of lead poisoning may be delayed as the patient may present with pancytopenia and dysplastic changes in bone marrow, mimicking a malignancy.

I) TOXICOKINETICS

1) Inorganic lead is absorbed after ingestion (more readily by children than adults) or inhalation. Dermal absorption of inorganic lead is minimal, but skin irritation and increased absorption may occur with organic lead compounds. Lead accumulates in the human body over one’s lifetime. The half-life of lead is estimated at 0.4 to 3.6 years. Blood lead is 99% bound to erythrocytes. Over 90% of absorbed lead is incorporated in bone, but lead distributes throughout the body. Excretion occurs primarily via the kidneys (65%) and to a lesser extent bile (35%). Rebound of blood lead concentrations is typical after chelation and is due to redistribution from bone stores.

J) PREDISPOSING CONDITIONS

1) Young children are more sensitive to lead’s negative effects on neurodevelopment. Patients with pica and iron-deficiency may also be more sensitive to lead’s effects.

K) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis includes other causes of abdominal pain, anemia, and encephalopathy, which includes infectious and nutritional etiologies. Diagnosis of lead poisoning may be delayed as the patient may present with pancytopenia and dysplastic changes in bone marrow, mimicking a malignancy.

0.4.3)

A) Initial treatment is removal from exposure and fresh air.

0.4.4)

A) Standard eye care decontamination is recommended; remove any foreign bodies.

0.4.5)

A) OVERVIEW

1) Initial treatment is removal from exposure and washing with soap and water.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) CASE REPORT: A 4-year-old boy presented with vomiting, low-grade fever, and dehydration after ingesting a heart-shaped locket that contained 99% lead. Laboratory results revealed a blood lead level of 180 mcg/dL (reference level: less than 10 mcg/dL). His condition deteriorated over the next 12 hours with brain herniation leading to brain death (Berkowitz & Tarrago, 2006).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPERTENSION

a) Blood pressure was significantly elevated in a group of lead-exposed workers when compared to a cohort of unexposed workers (de Kort et al, 1987).
b) Increase of diastolic pressure has been found in workers exposed to low levels of lead for up to 45 years, and higher diastolic value has been found in workers with blood lead levels over 40 mcg/dL without any effect on the systolic measurement (Harbison, 1998).
c) In a study of hypertension in perimenopausal and postmenopausal women, it was reported that lead appears to increase blood pressure (both systolic and diastolic) at levels well below the current US occupational exposure limit guidelines (40 mcg/dL). This association was most pronounced in postmenopausal women (Nash et al, 2003).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) Lead metal foreign bodies in the human eye have been considered to cause little reaction and rarely any toxic effect. However, systemic lead poisoning can cause visual and ocular disturbances (eg, transient visual loss) mainly through its effects on the neurological system (Kakosy et al, 1996; Grant, 1993).
2) CATARACT: In a Boston-based longitudinal study of aging in men, it was determined that the cumulative lead exposure is a risk factor for cataract. Although both tibia and patella lead were associated with an increased risk of cataract, tibia lead level remained a significant predictor of cataract after controlling for age, pack-years of cigarette smoking, blood lead levels, diabetes, and dietary intake of vitamin C, vitamin E, and carotenoids. After controlling for age, no significant association of patella lead level with cataract were observed (Schaumberg et al, 2004).

3.4.4)

A) WITH POISONING/EXPOSURE

1) HEARING LOSS: Mild hearing loss has been associated with increased blood lead levels in children and adults (Schwartz & Otto, 1987; Schwartz & Otto, 1991; Rybak, 1992).

3.4.6)

A) WITH POISONING/EXPOSURE

1) BURTON'S LINES: Lead sulfide precipitates in gum margins causing dark gray-blue-black lines (Camuglia et al, 2008; Aly et al, 1993; ILO, 1983). Present in older children and adults; rarely in children <5 years as the sulfide comes from bacteria rarely found in the mouths of young children (Aly et al, 1993; ILO, 1983).
2) DENTAL CARIES: Moss et al (1999) observed an increased prevalence of dental caries in children exposed to lead after adjustment for demographics, diet, and dental care (Moss et al, 1999).

a) In children 5 to 17 years of age, a 5 mcg/dL change in blood lead level was associated with an elevated risk (odds ratio 1.8) for caries. Confounding variables in the exposed group such as lack of fluoridated water or behavioral factors have been suggested (Matte, 1999).

3) METALLIC TASTE: Patients may complain of a metallic taste in the mouth (Grimsley & Adams-Mount, 1994).

Cardiovascular

3.5.2)

A) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Blood pressure was significantly elevated in a group of lead-exposed workers when compared to a cohort of unexposed workers (de Kort et al, 1987).
b) Increase of diastolic pressure has been found in workers exposed to low levels of lead for up to 45 years, and higher diastolic value has been found in workers with blood lead levels over 40 mcg/dL without any effect on the systolic measurement (Harbison, 1998a).
c) In a study of hypertension in perimenopausal and postmenopausal women, it was reported that lead appears to increase blood pressure (both systolic and diastolic) at levels well below the current US occupational exposure limit guidelines (40 mcg/dL). This association was most pronounced in postmenopausal women (Nash et al, 2003).
d) In one study, higher BLL was associated with higher rates of hypertension among non-Hispanic blacks and Mexican Americans (Muntner et al, 2005).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) An adult male construction worker developed colic, anemia, and a blood lead level of 10.3 micromoles/liter (213 micrograms/deciliter) after blasting and cutting a bridge with lead paint for 3 months. The ECG showed low voltage, frequent multifocal premature ventricular complexes, couplets, and some nodal escape beats. The dysrhythmias resolved with chelation (Restek-Samarzija et al, 1994).

C) PERIPHERAL VASCULAR DISEASE

1) WITH POISONING/EXPOSURE

a) One study reported that higher BLLs are significantly associated with chronic kidney disease and peripheral arterial disease in the overall US adult population. When multivariable-adjusted models were used, persons in the highest quartile of BLL (>/=2.47 mcg/dL) were 2.72 (1.47-5.04) times more likely to have chronic kidney disease, and 1.92 (1.02-3.61) times more likely to have peripheral arterial disease compared with to the lowest quartile of BLL (<1.06 mcg/dL) (Muntner et al, 2005).

Neurologic

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Fatalities and serious long term effects from lead poisoning result from acute encephalopathy with increased intracranial pressure. The encephalopathic syndrome includes depressed sensorium, headache, vomiting, ataxia, extreme irritability, papilledema, impaired consciousness, coma, seizures, and lateralizing neurologic signs (Srisuma et al, 2015; Fluri et al, 2007; Kokori et al, 1999; Whitfield et al, 1972; Harrington et al, 1986; Wiley et al, 1995; Perelman et al, 1993). Brain MRI of one patient with lead poisoning revealed hyperintense lesions in the basal ganglia (Fluri et al, 2007).
b) DIFFERENTIAL DIAGNOSIS: Patients may be misdiagnosed as having amyotrophic lateral sclerosis since lead poisoning may mimic the clinical features of a motor neuron disease (Fluri et al, 2007).

B) HEADACHE

1) WITH POISONING/EXPOSURE

a) More obscure symptoms of lead poisoning include: malaise, fatigue, headache, and irritability (Astudillo et al, 2003; Traub et al, 2002; Mangas et al, 2001; Grimsley & Adams-Mount, 1994).
b) Lead intoxication was reported in 53 adults following the ingestion of lead-contaminated (lead tetroxide or red lead) ground paprika used in home-made sausages. Headache and dizziness were reported in 17 patients(Kakosy et al, 1996).

C) DISTURBANCE IN THINKING

1) WITH POISONING/EXPOSURE

a) COGNITIVE DEVELOPMENT: PEDIATRICS: In a meta-analysis of 12 lead studies evaluating the relationship between blood and tooth lead levels and IQ in children, Needleman & Gatsonis (1990) concluded that a link exists between low-dose lead exposures and intelligence deficits in children (Needleman & Gatsonis, 1990).

1) Children with BLLs of 10 mcg/dL or greater are more likely to have learning and behavioral effects than children with levels of less than 10 mcg/dL ( CDC, 1997). In one study, authors reported that BLLs, even those below 10 mcg/dL, are inversely associated with children's IQ scores at 3 and 5 years of age (Canfield et al, 2003).
2) The principal target system for lead toxicity in children is considered to be the developing central nervous system (Mushak et al, 1989).
3) Increasing blood lead levels in children have also been correlated with hearing impairment, developmental delay (Schwartz & Otto, 1987), aggressive, hyperactive and antisocial behavior (Thomson et al, 1989), visual motor integration (Baghurst et al, 1995) word recognition (Fergusson & Horwood, 1993) and growth retardation (Angle & Kuntzelman, 1989; Shukla et al, 1989; Shukla et al, 1991).
4) A Cincinnati study found increased prenatal and postnatal blood levels were associated with lower scores on tests of motor development (Dietrich et al, 1993). In a study of school performance among children in the Chicago Public schools (n=47,168), it was determined that early childhood lead exposure can cause poorer achievement on standardized reading and math tests in the third grade, even at very low blood lead levels (below 10 mcg/dL). These results were observed after adjusting for poverty, race/ethnicity, gender, maternal education, and very low birth weight or preterm-birth. The risk of failing increased by 32% for reading and math after a 5 mcg/dL increase in blood lead level, and 13% of reading failure and 14.8% of math failure were associated with BLLs of 5 to 9 mcg/dL as versus 0 to 4 mcg/dL. In addition, 25% of reading failure and 27% of math failure were associated with BLLs of 5 to 100 mcg/dL versus 0 to 4 mcg/dL (Evens et al, 2015).
5) Several studies have shown that asymptomatic children with mildly elevated (10 to 25 mcg/dL) as well as moderately elevated (25 to 45 mcg/dL) blood lead levels have significant decrements in IQ when compared to unexposed children. Social and environmental (other than lead) factors may also have contributed to IQ decrements (Landrigan & Graef, 1987; Pocock et al, 1987; Faust & Brown, 1987; McMichael et al, 1988; Needleman et al, 1979; Needleman & Gatsonis, 1990; Needleman & Gatsonis, 1990; Bellinger et al, 1991; Baghurst et al, 1992; Bellinger et al, 1992; Wasserman et al, 1994; Pocock et al, 1994; Dietrich et al, 1993).
6) The relationship between low blood lead levels and neonatal and early cognitive development has been controversial and somewhat inconclusive (Ernhart et al, 1986; Bellinger et al, 1987; Ernhart & Needleman, 1987; Wolf et al, 1994).
7) Several studies have found an association between low level prenatal and neonatal lead exposure and deficits in early development and neurobehavioral performance (Emory et al, 1999; Dietrich et al, 1987; Bellinger et al, 1987) Mushaketal et al, 1989; (Bellinger et al, 1989).
8) Concurrent iron deficiency anemia may contribute to the cognitive deficits seen in children with low level lead poisoning (Wasserman et al, 1992).
9) Several studies have found a correlation between low level lead exposure (as assessed by lead levels in shed deciduous teeth) and decreased school performance, learning disabilities, inattention, and restlessness (Fergusson et al, 1988a; Fergusson et al, 1988b; Lyngbye et al, 1990; Leviton et al, 1993; Greene & Ernhart, 1993; McMichael et al, 1994). The methodologies of some studies have been challenged (Greene & Ernhart, 1993).
10) One study demonstrated that patients with symptomatic lead poisoning before age 4 had persistent cognitive deficits as demonstrated by neuropsychological tests and occupational status compared with matched controls (White et al, 1992). In a long-term prospective study, it was reported that the cognitive deficits after environmental lead exposure in early childhood appear to be only partially reversed by a decline in blood lead level (Tong et al, 1998).

b) COGNITIVE FUNCTION: ADULTS: Neurobehavioral tests in lead workers show deficits in cognitive function including decrease in memory, attention, concentration, and psychomotor performance (Schwartz et al, 2000; Mangas et al, 2001; Arnvig et al, 1980; Valciukas et al, 1986; Williamson & Teo, 1986).
c) One study concluded that past, cumulative adult exposure can result in progressive decline, particularly in learning and memory, long after lead exposure ceases (Schwartz et al, 2000).
d) Another study reported an absence of an association between past high lead exposure and verbal memory in a group of smelter workers (the H-L pattern group; those with 90% of levels below 40 mcg/dL). The authors concluded that changes in neuropsychological performance may be reversible when proximate blood lead levels are maintained below 40 mcg/dL (Lindgren et al, 2003).
e) A study in 39 adults found a positive correlation between blood lead levels and working memory reaction times. Blood lead levels ranged from 1 mcg/L to 65.6 mcg/L (mean 27.4 +/- 16.2 mcg/L) (Kunert et al, 2004).
f) In one study, increased blood and bone lead levels were inversely associated with cognitive performance among elderly men (mean 69 years). The authors concluded that lead exposure might accelerate neurodegeneration with aging (Wright et al, 2003).

D) SECONDARY PERIPHERAL NEUROPATHY

1) WITH POISONING/EXPOSURE

a) The development of peripheral neuropathy does not seem to correlate with blood lead levels or length of exposure. Weakness and focal palsy (e.g., wrist drop or other) are common manifestations and occur much more commonly in adults than in children. Sensory deficit has been reported less commonly (Ehle, 1986; Angle, 1993).
b) Several studies have shown that peripheral nerve conduction velocities rates are slow in asymptomatic lead exposed workers compared with controls (Araki, 1986; Hirata & Kosaka, 1993; Murata et al, 1993; Araki et al, 1993).
c) Blood lead level in children has a significant negative association with maximal motor nerve conduction velocity (Schwartz et al, 1988). Measurement of maximal motor nerve conduction is an insensitive screen for low-level lead toxicity (Schwartz et al, 1988).
d) CASE REPORT: A 41-year-old Hispanic woman developed lead toxicity (maximal total blood lead of 69 mcg/dL) after exposure to lead-based ceramic ware. Clinical effects included end-stage renal failure, seizures, and severe bilateral wrist drop. The wrist drop resolved after one month of intravenous calcium sodium edetate (Barats et al, 2000).
e) CASE REPORT: A 66-year-old man developed peripheral sensory neuropathy, primarily affecting his lower limbs with some decrease in proprioception as a result of drinking a homemade red wine. The patient used a highly corroded enamel bathtub to crush and store the wine. He experienced paresthesia, severe headache, unsteady gait and muscle weakness. His PbB level was 98 micrograms/dL two weeks after admission and prior to chelation therapy (Mangas et al, 2001).
f) Wrists drop, weakness of the wrists and fingers extensor developed in a 25-year-old man who had a 15-year history of a pottery glazing. Needle electromyography of the arms and hands revealed signs of motor nerve neuropathy including reduction of the compound muscle action potential amplitudes, segmental demyelinisation and axonal degeneration. Following chelating treatment, he recovered completely (Shiri et al, 2007).
g) CASE REPORT: A man developed pancytopenia and dysplastic changes in bone marrow with mediastinal lymphadenopathy after using an ayurvedic therapy for 2 years. Following aggressive supportive care, he gradually recovered and his chest CT showed near total resolution of lymph nodes and lung infiltrates. His serum lead concentration was 32.5 mcg/dL 3 month after discontinuation of ayurvedic medicine. Nerve conduction studies after the initial recovery showed sensorimotor axonopathic neuropathy (Nair et al, 2011).

E) COORDINATION PROBLEM

1) WITH POISONING/EXPOSURE

a) BALANCE: One study found that lead exposed workers had decreased postural stability with eyes closed than non-exposed controls. No difference was found in tests performed with the eyes open (Chia et al, 1994).
b) CASE REPORT: A developmentally delayed, non-verbal 15-year-old boy with a history of pica, presented with a 3-week history of nausea, vomiting, anorexia, diarrhea, constipation, and a decreased level of activity. He appeared sleepy, but arousable following commands. He was too weak to stand independently and had hyperactive patellar and brachioradialis reflexes without clonus. Because of the risk of detonation from electrocautery during surgery, he underwent an endoscopy procedure using a snare to remove 3 intact, partially corroded 30-mm rifle cartridges. Laboratory results revealed normocytic anemia. Following treatment with parenteral and oral chelation (BAL, calcium disodium-EDTA, and succimer), his blood lead concentration gradually decreased from 146 mcg/dL (12 hours after endoscopy) to 38-mcg/dL (91 days after endoscopy) (Hatten et al, 2013).

F) SEIZURE

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Seizures secondary to SIADH due to lead poisoning were reported in 2 patients. One patient, a 7-year-old boy, developed hyponatremia (125 mEq/L) and seizures with lethargy 3 days after presenting with lead poisoning (initial lead level 127 mcg/dL). The second patient, a 30-year-old female, developed hyponatremia (117 mEq/L) and seizures on day 2 of treatment for lead poisoning. Both patients were treated with BAL and CaEDTA prior to the onset of hyponatremia and seizures. The boy recovered after fluid restriction and hypertonic saline over 2 days, while the woman's condition normalized over 3 days after fluid restriction and furosemide treatment (Ruha et al, 1998).
b) CASE REPORT: Severe lead poisoning in a 5-month-old girl from breastfeeding was reported. The mother had been using nipple shields made of lead. The patient developed generalized tonic-clonic seizures, vomiting, constipation, weight loss, pallor, sluggishness, loss of consciousness, and coma (score 7 on the Glasgow scale). She was treated with intravenous edetate calcium disodium (40 mg/kg per 24 hours, in two doses for the first 5 days) and intramuscular dimercaprol (2.5 mg/kg per 24 hours in six doses for 2 days). Lead levels gradually dropped to 10 mcg/dL from 240 mcg/dL (Kokori et al, 1999).
c) CASE REPORT: A 40-year-old female suffered two generalized tonic-clonic seizures after ingesting several tablets of an herbal medication from India. Her blood lead level was 98 mcg/dL on admission (Traub et al, 2002).
d) CASE SERIES: In one study, 15 severely lead-poisoned pregnant women (16 to 38 weeks gestation; mean maternal BLL 55 mcg/dL; range 33-104 mcg/dL) presented with malaise, fatigue, anemia, and basophilic stippling. One woman with a maternal BLL of 104 mcg/dL also had a generalized seizure (Shannon, 2003).

G) BRAIN STEM HERNIATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 4-year-old boy presented with vomiting, low-grade fever, and dehydration after ingesting a heart-shaped locket that contained 99% lead. Laboratory results revealed a blood lead level of 180 mcg/dL (reference level: less than 10 mcg/dL). His condition deteriorated over the next 12 hours with brain herniation leading to brain death (Berkowitz & Tarrago, 2006).

H) COMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Coma (score 7 on the Glasgow scale) was reported in a 5-month-old girl from breastfeeding using nipple shield made of lead. Following chelation therapy with edetate calcium disodium and dimercaprol, lead levels gradually dropped from 240 mcg/dL to 10 mcg/dL (Kokori et al, 1999).

I) ASTHENIA

1) WITH POISONING/EXPOSURE

a) Weakness, malaise, somnolence and fatigue have been reported following lead exposure (Hatten et al, 2013; Frith et al, 2005; Shrestha & Greenberg, 2002; Mangas et al, 2001; Kakosy et al, 1996).
b) Lead intoxication was reported in 53 adults following the ingestion of lead-contaminated (lead tetroxide or red lead) ground paprika used in home-made sausages. Weakness, somnolence and fatigue were reported in 29 patients (Kakosy et al, 1996).
c) CASE REPORT: A 41-year-old man developed malaise, weakness, abdominal pain, anemia and weight loss after taking Ayurvedic medications (EX and ADISSA) from India to treat oligospermia. A blood lead level of 78 mcg/dL was obtained on admission; it was estimated that a total of 1.26 grams of lead was ingested during the course of his therapy (Shrestha & Greenberg, 2002).
d) CASE REPORT: A developmentally delayed, non-verbal 15-year-old boy with a history of pica, presented with a 3-week history of nausea, vomiting, anorexia, diarrhea, constipation, and a decreased level of activity. He appeared sleepy, but arousable following commands. He was too weak to stand independently and had hyperactive patellar and brachioradialis reflexes without clonus. Because of the risk of detonation from electrocautery during surgery, he underwent an endoscopy procedure using a snare to remove 3 intact, partially corroded 30-mm rifle cartridges. Laboratory results revealed normocytic anemia. Following treatment with parenteral and oral chelation (BAL, calcium disodium-EDTA, and succimer), his blood lead concentration gradually decreased from 146 mcg/dL (12 hours after endoscopy) to 38-mcg/dL (91 days after endoscopy) (Hatten et al, 2013).

J) SYNCOPE

1) WITH POISONING/EXPOSURE

a) Lead intoxication was reported in 53 adults following the ingestion of lead-contaminated (lead tetroxide or red lead) ground paprika used in home-made sausages. Syncope was reported in 2 patients (Kakosy et al, 1996).

K) CHOREOATHETOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Choreoathetosis developed in a man with lead toxicity (blood lead concentrations, range 65 to 112 mcg/dL) due to a retained bullet lodged in his spinal column for 7 years. A few weeks after an unsuccessful attempt to surgically remove the bullet, the patient experienced involuntary movements of the hands, trunk and feet. The neurological examination showed generalized, partially-suppressible choreoathetoid movements involving the face and the proximal limbs, including toes and fingers. He had rigidity in four limbs and a dystonic posture on the right upper limb. CT scan revealed bilateral and symmetric pallidal calcifications and slight hypoattenuation in both putamen and caudate nuclei. An MRI of the brain showed some volumetric reduction in both caudate and lentiform nuclei, associated with bilateral and symmetric T2 hyperintensity and T1 hypointensity of these structures. He received chelation therapy for 4 months and his blood level concentrations gradually returned to normal (Spitz et al, 2008).

L) TREMOR

1) WITH POISONING/EXPOSURE

a) In one study, an association between blood lead levels and essential tremor was found. Since it is not clear if this association is due to increased exposure to lead or a difference in lead kinetics in these patients, the authors recommended further investigation (Louis et al, 2003).

M) PARALYSIS

1) WITH POISONING/EXPOSURE

a) Peripheral nervous paralysis (or lead palsy) typically affects extensor muscles and is characterized by selective involvement of motor neurons, with little or no sensory abnormalities (Zenz, 1994).
b) Quadriplegia developed in a 40-year-old man who presented with headache, nausea, abdominal pain, anemia, mildly elevated liver enzymes and total bilirubin, and paresthesia in both lower and upper extremities after using lead-contaminated opium. Electromyography, nerve conduction velocity results and neurologic examination were suggestive for Guillain-Barre (acute motor axonal neuropathy). Despite treatment with five sessions of plasmapheresis, his condition didn't improve and he developed severe respiratory failure. At this time, laboratory results revealed a BLL of greater than 200 mcg/dL. Following supportive therapy, including treatment with dimercaprol, calcium disodium edetate, and succimer, his condition improved gradually. He was discharged from the ICU with a BLL of less than 20 mcg/dL and no sensory loss, but motor neuropathy in upper and lower extremities was still present (Beigmohammadi et al, 2008).

N) ATTENTION DEFICIT HYPERACTIVITY DISORDER

1) WITH POISONING/EXPOSURE

a) A pair-matching case-control study of 630 ADHD cases and 630 non-ADHD controls (ages 4-12 years; average 7.9 +/- 2.1 years) evaluated the association between ADHD and blood lead levels (BLLs) in Chinese children. The mean BLLs in the ADHD and control groups were 8.77 +/- 3.89 mcg/dL and 5.76 +/- 3.39 mcg/dL, respectively (p less than 0.05). Approximately 24% of ADHD children had BLLs greater than 10 mcg/dL compared with 10.1% of children in the control group (p less than 0.01). In addition, 74.7% of children in the ADHD group had BLLs greater than 5 mcg/dL compared with 49.8% of children in the control group (p less than 0.01). Overall, it was determined that children with BLLs greater than 10 mcg/dL had 4.1- to 8.7-fold higher risk for ADHD; children with BLLs greater than 5 mcg/dL had 3.5- to 7-fold higher risk for ADHD (Wang et al, 2008).

O) ATROPHY

1) WITH POISONING/EXPOSURE

a) A study of 157 Cincinnati Lead Study participants (ages 19 to 24 years old) used MR imaging to examine the relationship between childhood lead exposure and adult brain volume. It was revealed that higher mean childhood blood lead concentration was associated with region-specific reductions in adult gray matter volume, specifically in portions of the prefrontal cortex (eg; medial and the superior frontal gyri comprising the ventrolateral prefrontal cortex, anterior cingulate cortex, postcentral gyri, the inferior parietal lobule, cerebellar hemispheres), mainly responsible for executive functions, mood regulation, and decision-making. However, there was no significant volume changes within white matter or CSF volume. Overall, these areas of gray matter volume loss were much larger and more significant in men than women (Cecil et al, 2008).

3.7.3)

A) ANIMAL STUDIES

1) BLOOD-BRAIN BARRIER PERMEABILITY

a) In a study published by Struzynska et al (1997), when three week old adult male Wistar rats are fed with lead acetate-containing water (at the concentration of 200 mg/L) for three months, significant increase of lead level in capillaries and synaptosomes in the brains were found. This was taken as an indication of a blood-brain barrier dysfunction. Ultrastructural changes in endothelial cells, inter-endothelial tight junctions, perivascular cells, etc suggest that altered lipid composition of membrane may cause a change in membrane permeability (Struzynska et al, 1997).

Gastrointestinal

3.8.2)

A) GASTROINTESTINAL TRACT FINDING

1) WITH POISONING/EXPOSURE

a) Abdominal pain, vomiting, constipation, diarrhea and anorexia are common in patients with chronic toxicity. A metallic taste in the mouth and weight loss may also develop (Srisuma et al, 2015; Mongolu & Sharp, 2013; Hatten et al, 2013; Lin et al, 2012a; Nair et al, 2011; Smith, 2007; Berkowitz & Tarrago, 2006; Coyle et al, 2005; Astudillo et al, 2003; Shrestha & Greenberg, 2002; Traub et al, 2002; Mangas et al, 2001; Berg et al, 2000; Stromness et al, 2000; van Vonderen et al, 2000; McNutt et al, 2000; Kokori et al, 1999; Jongnarangsin et al, 1999; Kakosy et al, 1996; Fischbein, 1992a; Aly et al, 1993; Meggs et al, 1994; Grimsley & Adams-Mount, 1994; Dahlgren, 1978).
b) CASE REPORT: Recurrent severe abdominal pain, nausea, vomiting, constipation and anemia developed in 3 adult brothers who were involved in pottery glazing. Following chelating treatment, they recovered completely (Shiri et al, 2007).
c) CASE REPORT: A 44-year-old woman was shot in the left lower back and right axilla with shotgun blasts during a mall shooting spree. Initial evaluation with x-ray showed a large number of scattered metallic pellets. After initial surgical debridement, imaging was still remarkable for numerous retained pellets. On day 16 post-injury, her whole-blood lead level was elevated (23 mcg/dL; reference range: 0 to 25 mcg/dL) and she reported nausea, fatigue, and myalgias one month later with her whole-blood lead level having increased (35 mcg/dL). Her whole blood lead levels decreased (5 mcg/dL) after treatment with oral succimer 500 mg twice daily, however became elevated (21 mcg/dL) one month later with accompanying nausea, fatigue, and myalgias. Her succimer dosing frequency was subsequently decreased to 100 mg twice daily and then 100 mg once daily with mild improvement in her nausea over the next 6 months and lead levels remaining between 16 and 18 mcg/dL. Eighteen months later, once daily succimer continues with persistent nausea and fatigue (Cyrus et al, 2011).

B) GASTROINTESTINAL HEMORRHAGE

1) Gastrointestinal bleeding following the ingestion of lead has been reported rarely (Frith et al, 2005; McNutt et al, 2000).

C) DRUG-INDUCED ILEUS

1) WITH POISONING/EXPOSURE

a) RARE EFFECT: INTESTINAL ILEUS: A 35-month-old child presented with unremitting paralytic intestinal ileus associated with acute lead poisoning (Zwiener et al, 1990).

D) ACQUIRED OBSTRUCTION OF PYLORUS

1) WITH POISONING/EXPOSURE

a) RARE EFFECT: PYLORIC OBSTRUCTION: Ingestion of 15 mL (estimate) lead glaze frit was associated with pyloric obstruction, and an elevated whole blood lead concentration of 81 mcg/dL in a 79-year-old nursing home resident (Snook et al, 1992).

Hepatic

3.9.2)

A) INJURY OF LIVER

1) WITH POISONING/EXPOSURE

a) ACUTE TOXICITY

1) CASE REPORTS

a) Liver injury has been reported following acute ingestion of 7 g of lead acetate (Karpatkin, 1961; Sixel-Dietrich et al, 1985).
b) Hepatic injury and hemolysis developed following acute ingestion of red lead (lead oxide) in a 21-year-old male (Nortier, 1980).
c) Hepatic injury was reported in 3 young men, aged 19 to 21 years, after acute ingestion of more than 50 g of lead oxide (Pach et al, 1992).
d) Hepatic injury was demonstrated on scintography in 3 men with acute lead poisoning (Goszcz et al, 1995).

B) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Elevated liver enzymes and total bilirubin have been reported in patients with lead poisoning (Nair et al, 2011; Beigmohammadi et al, 2008; Markowitz et al, 1994; Auyeung et al, 2002).
b) Elevated liver enzymes developed in 14 men who ingested lead tetroxide (Marek et al, 1994).
c) CHRONIC TOXICITY

1) CASE REPORT: A 45-year-old man presented with abdominal pain, anemia and elevated liver function tests (ALT 703 U/L, AST 459 U/L, Alk Phos 233 U/L, bilirubin 2.6 milligrams/deciliter) after ingesting an herbal medication containing lead for one month (blood lead level 76 micrograms/deciliter) (Markowitz et al, 1994).
2) CASE REPORT: A 23-year-old woman developed non-specific musculoskeletal pain, severe anemia, and elevated liver function tests (serum alkaline phosphatase 138 U/L, serum alanine aminotransferase 181 U/L) after taking a Chinese herbal pill (Bao ning dan) 4 to 6 times daily for 2 months. Her first blood lead concentration was 3.03 mcmol/L (Auyeung et al, 2002).

Genitourinary

3.10.2)

A) RENAL TUBULAR DISORDER

1) WITH POISONING/EXPOSURE

a) Tubular injury noted by proteinuria, glycosuria, and aminoaciduria has been described (a Fanconi-like syndrome). Acute renal failure has been reported in a child (Khan et al, 1983).
b) Elevated urinary levels of N-acetyl-3-D-glucosaminidase, beta-2-microglobulin, alpha-1-microglobulin, and glutathione S-transferase may serve as early markers of subclinical renal injury (El-Safty et al, 2004; Kumar & Krishnaswamy, 1995; Lin et al, 1993; Kumar & Krishnaswamy, 1995).
c) In one study, benchmark dose (BMD) (developed by EPA) and the lower confidence limit on the benchmark dose (BMDL) of blood lead were studied to evaluate the biologic exposure limits for renal dysfunction caused by lead. The relationship between the blood lead concentration and the urinary excretion of total protein (TP), beta-2-microglobulin [beta2-MG], and N-acetyl-3-D-glucosaminidase (NAG), the three indices for renal dysfunction, were evaluated. NAG had the lowest BMDL of blood lead (highest TP> beta2-MG>NAG lowest). NAG was more sensitive than any other index (eg; beta-2-microglobulin [beta2-MG]; total protein [TP]) of renal dysfunction. It was suggested that a blood lead level of 250 mcg/L should serve as a warning signal, and prompt evaluation of renal function in workers occupationally exposed to lead (Lin & Tai-Yi, 2007).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Lead deposits in the kidneys may produce glycosuria and aminoaciduria. Reversible acute renal failure has been reported in a 26-month-old female (with glucose-6-phosphate dehydrogenase deficiency) following chronic lead poisoning and prolonged chelation therapy with EDTA and BAL (Khan et al, 1983).

C) PRERENAL AZOTEMIA

1) WITH POISONING/EXPOSURE

a) Long term lead exposure can result in azotemia and hypertension. Gout (Sauterine gout) may develop as a result of diminished clearance of urate (Niamane et al, 2002; Shadick et al, 2000; Colleoni & D'Amico, 1986).
b) CASE REPORT: A plastic compounder developed reversible azotemia (serum creatinine 2.9 mg/dL [normal 0.7-1.3]; BUN 34 mg/dL [7-18]), abdominal pain, constipation, fatigue, and normocytic anemia after being severely lead-poisoned following the long-term uncontrolled use of powdered lead sulfate stabilizer. Blood lead level at the time of diagnosis was 164 mcg/dL. Bone lead levels were 102, 219, and 182 ppm in his tibia, calcaneous, and patella, respectively. These values were approximately 10-fold greater than predicted for a male of his age (Coyle et al, 2005).

D) SPERM FINDING

1) WITH POISONING/EXPOSURE

a) DECREASED SPERM COUNT and motility, increases in abnormal sperm, and infertility have been reported with occupational exposure (Assennato et al, 1987; Fisher-Fischbein et al, 1987; Lerda, 1992).

E) ABNORMAL RENAL FUNCTION

1) WITH POISONING/EXPOSURE

a) In one prospective study, it was found that low-level environmental lead exposure may accelerate deterioration of renal function in patients with chronic renal insufficiency. In 121 patients with chronic renal insufficiency and a normal body lead burden as determined by EDTA mobilization testing (range of blood lead levels 1 to 13.4 mcg/dL), 15 of 63 patients with a high normal body burden of lead (80 to 530 mcg lead) had a doubling of serum creatinine over 48 months. In the group of 58 patients with a low normal body burden of lead (less than 80 mcg), only 2 patients went on to double serum creatinine over 48 months (Yu et al, 2004).

Hematologic

3.13.2)

A) ANEMIA

1) WITH POISONING/EXPOSURE

a) Anemia has been reported in patients with lead poisoning (Hatten et al, 2013; Beigmohammadi et al, 2008; Traub et al, 2002; Moore & Adler, 2000; Kakosy et al, 1996).
b) Anemia is an early indication of chronic exposure to lead with 4 to 4.5 million total red cells per cubic centimeter and at 70 to 80 percent hemoglobin level (Harbison, 1998a).
c) Early in the course of poisoning, and particularly in children, lead-induced anemia is microcytic and hypochromic, but in the chronic stage, it often changes to normochromic and normocytic. It seems that the more acute the poisoning is, the more important is the shortening of erythrocyte life span; in chronic poisoning, the heme synthesis inhibition is more significant (Zenz, 1994).
d) In one Korean study, significantly lower hemoglobin, hematocrit, serum iron levels, percentage of transferrin saturation, and dietary iron intake were observed in lead workers than in non-lead workers. In addition, lead workers had significantly higher total iron-binding capacity. Lead workers had significantly higher occurrence of iron-deficiency anemia (as evaluated by hematocrit values) than did non-lead workers, and the prevalence of iron deficiency was associated with high blood lead levels. The authors recommended an adequate intake of dietary iron to prevent toxic effects of lead exposure (Kim et al, 2003).
e) CASE REPORT: A 5-year-old Indian boy with static encephalopathy, seizures, and developmental delay from neonatal asphyxia developed persistent anemia (hemoglobin 9.2 g/dL) without basophilic stippling after taking Tibetan herbal vitamin tablets (3 times daily) for 4 years. His blood lead level was 86 mcg/dL (Moore & Adler, 2000).
f) CASE REPORT: A 40-year-old woman developed mild anemia (hematocrit 34%) after ingesting several tablets of an herbal medication from India. Her blood lead level was 98 mcg/dL on admission (Traub et al, 2002).
g) CASE SERIES: Lead intoxication was reported in 53 adults following the ingestion of lead-contaminated (lead tetroxide or red lead) ground paprika used in home-made sausages. Anemia was reported in 26 patients (Kakosy et al, 1996).
h) CASE REPORT: A plastic compounder developed reversible azotemia, abdominal pain, constipation, fatigue, and normocytic anemia (hemoglobin 11 g/dL [normal 13.5-17.5]; hematocrit 33.6% [40-54]; MCV 87 c/mcu [80-94]) after being severely lead-poisoned following the long-term uncontrolled use of powdered lead sulfate stabilizer. Blood lead level at the time of diagnosis was 164 mcg/dL. Bone lead levels were 102, 219, and 182 ppm in his tibia, calcaneous, and patella, respectively. These values were approximately 10-fold greater than predicted for a male of his age (Coyle et al, 2005).
i) In one study, 27 workers developed lead poisoning after removing old paint while restoring high voltage towers. Nineteen workers (70.4%) had anemia (hemoglobin concentration below 13 g/dL) on admission. Basophilic stippling of the erythrocytes was observed in 13 patients (48.1%). After treatment, anemia and basophilic stippling were present in 7 (25.1%) and 2 (7.4%) of patients, respectively (Krawczyk et al, 2006).
j) CASE SERIES: In one study, 15 severely lead-poisoned pregnant women (16 to 38 weeks gestation; mean maternal BLL 55 mcg/dL; range 33-104 mcg/dL) presented with malaise, fatigue, anemia, and basophilic stippling (Shannon, 2003).

B) HEMOLYTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) Severe lead intoxication accompanied by hemolytic anemia has been reported (Miwa et al, 1981). Hemolysis has also been reported following acute ingestion of red lead (lead oxide) (Nortier, 1980).
b) CASE REPORT: Hemolytic anemia developed in a man with lead poisoning from retained shotgun pellets (Aly et al, 1993).

C) MICROCYTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) HEME SYNTHESIS is affected at several enzymatic steps. This leads to the build-up of the diagnostically important substrates delta-aminolevulinic acid, coproporphyrin (measured in the urine) and zinc protoporphyrin (measured in the red cell as erythrocyte protoporphyrin or EP).
b) The result of these enzymatic inhibitions is microcytic, hypochromic anemia (Meggs et al, 1994). There is no permanent effect of lead on blood production.
c) Hence, synthesis is affected at lead levels as low as 10 micrograms/deciliter (Piomelli et al, 1982). Blockade of erythrocyte pyrimidine nucleotidase (Cook et al, 1986) leads to stippling. Basophilic stippling is useful in suggesting the diagnosis of lead poisoning, but not in assessing severity or monitoring the course or therapy.
d) Even when hemoglobin and hematocrit values are within the normal range, they decrease as the blood lead increases over 10 mcg/dL (Poulos et al, 1986).
e) Microcytic anemia is fairly common in patients with lead poisoning (Srisuma et al, 2015; Anon, 2004b; Lavoie & Bailey, 2004; Mangas et al, 2001).
f) CASE REPORT: A 66-year-old man developed microcytic anemia (no iron deficiency, normal hemoglobin electrophoresis) after drinking a homemade red wine. The patient used a highly corroded enamel bathtub to crush and store the wine. Basophilic stippling was observed in a subsequent blood film. His PbB level was 98 micrograms/dL two weeks after admission and prior to chelation therapy (Mangas et al, 2001).
g) CASE REPORT: A 3-year-old child developed lead poisoning and microcytic, hypochromic anemia following the ingestion of snooker chalk (lead content 7200 mcg/g) (Dargan et al, 2000).
h) CASE REPORT: A 25-year-old man presented with a 2-month history of dyspnea and abdominal pain after taking a traditional Chinese herbal medicine containing lead (Qushangjieyu-san powder; lead content, 80,309.95 mcg/g; normal, less than 5 ppm) for 3 months. Laboratory results showed hypochromic, microcytic anemia (hemoglobin 8.3 g/dL) and the red blood cell morphology revealed anisocytosis with basophilic stippling. His blood lead concentration was 75.5 mcg/dL (normal, less than 35 mcg/dL). Following the discontinuation of the herbal medicine and chelation therapy with calcium disodium ethylenediaminetetraacetate (CaNa2EDTA) for 3 weeks, his condition resolved (Lin et al, 2012a).
i) CASE REPORT: A 4-year-old boy developed lead poisoning (PbB level 4.70 mcmol/L; normal less than 0.48 mcmol/L) and microcytic anemia (hemoglobin 65 g/L; mean corpuscular volume 52 fL; low serum iron level 1.8 mcmol/L) after eating paint stripped from the walls of his home. The paint scrapings were found to contain lead with levels being within the legal limits (paint is considered "lead free" with less than 0.5% dry weight) (Lavoie & Bailey, 2004).
j) CASE REPORT: Recurrent severe abdominal pain, nausea, vomiting, constipation and microcytic microchromic anemia with basophilic stippling of the erythrocytes developed in 3 adult brothers who were involved in pottery glazing. Following chelating treatment, they recovered completely (Shiri et al, 2007).

D) NORMOCYTIC HYPOCHROMIC ANEMIA

1) WITH POISONING/EXPOSURE

a) IRON DEFICIENCY: Children with high blood lead concentrations are more likely to have biochemical iron deficiency than anemia (Rajkumar et al, 1987). Screening for iron deficiency in children with elevated blood lead should not be based solely on elevation in FEP, but also on dietary and socioeconomic risk factors (Carraccio et al, 1987; Linakis & Shannon, 1989).
b) In a study of children aged 11 to 33 months old, no differences in iron depletion or iron deficiency anemia were observed between children with moderate exposure to lead (lead blood level 20 to 44 mcg/dL) compared to demographically similar children with low lead exposure (less than 10 mcg/dL) (Serwint et al, 1999).
c) In a study of 86 children (mean age, 34 months), blood lead level was correlated with decreased erythropoietin concentrations. Median lead and erythropoietin levels were 18 mcg/dL and 5.9 mIU/mL, respectively (Liebelt et al, 1999).
d) In a 35-year-old woman, lead intoxication from Indian traditional medicine caused severe gastrointestinal symptoms and hypochromic, normocytic anemia (hemoglobin 5.2 mmol/L) (van Vonderen et al, 2000).

E) NORMOCYTIC NORMOCHROMIC ANEMIA

1) WITH POISONING/EXPOSURE

a) Normocytic normochromic anemia has been reported in several patients after taking complementary and alternative medicines (Frith et al, 2005; Auyeung et al, 2002; Spriewald et al, 1999).
b) CASE REPORT: Severe normochromic anemia with a hemoglobin concentration of 78 g/L (normal 13-17 g/L) developed in a 37-year-old man with lead poisoning (blood lead concentration of 580 mcg/L) from several ayurvedic drugs from India. The anemia resolved following chelation treatment with D-penicillamine (Spriewald et al, 1999).
c) CASE SERIES: A 23-year-old female developed severe anemia (hemoglobin level 72 g/L), with normochromic and normocytic indices, after taking a Chinese herbal pill (Bao ning dan) 4 to 6 times daily for 2 months. In addition, the reticulocyte count was grossly elevated to 0.12 proportion of red blood cells, and the lymphocyte count was low (1.0x10(9)/L). A peripheral blood smear revealed polychromasia, anisocytosis, target cells, and basophilic stippling. Increased sideroblasts and occasional ringed sideroblasts were observed in bone marrow biopsy. Her first blood lead concentration was 3.03 mcmol/L (Auyeung et al, 2002).
d) Another patient had hemoglobin level of 98 g/L, with normochromic and normocytic indices, after taking 4 Bao ning dan pills daily for only 3 days. She also had symptoms of common cold. Her blood lead level was 6.7 mcmol/L (Auyeung et al, 2002).

F) PANCYTOPENIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 51-year-old man presented with a 3-month history of low to moderate grade fever, fatigue, weight loss, and upper abdominal pain. Laboratory results showed a low hemoglobin (9.8 g/dL) with normal blood counts and elevated liver enzymes. He underwent laparoscopic cholecystectomy after a CT of the abdomen showed pericholecystic fluid, indicating chronic cholecystitis with acute exacerbation. A liver biopsy revealed only fatty changes. Because of a lack of response to oral antibiotics, a chest CT was performed which revealed bilateral parenchymal infiltrates with mediastinal lymphadenopathy. He later developed pancytopenia. Bone marrow aspiration and biopsy revealed megaloblastosis, erythroid hyperplasia, and dysmegakaryopoiesis, and myelodysplastic syndrome (MDS) was suspected. His condition worsened within 3 days and he developed respiratory distress, necessitating mechanical ventilation. Another chest CT showed the same earlier findings with bilateral pleural effusion. A review of his medical history revealed that he had been taking an ayurvedic medicine for asthma for 2 years, which he discontinued 2 months prior to presentation. Laboratory analysis of the ayurvedic drug revealed a lead concentration of 185 ppm (normal, less than 1 ppm). Following aggressive supportive care, he gradually recovered and his chest CT showed near total resolution of lymph nodes and lung infiltrates. His serum lead concentration was 32.5 mcg/dL 3 month after discontinuation of ayurvedic medicine. Nerve conduction studies showed sensorimotor axonopathic neuropathy (Nair et al, 2011).

Dermatologic

3.14.2)

A) SYSTEMIC DISEASE

1) WITH POISONING/EXPOSURE

a) Dermal application of lead acetate solution on eczematous skin has resulted in intoxication (Triebig, 1984).

Musculoskeletal

3.15.2)

A) MUSCLE PAIN

1) WITH POISONING/EXPOSURE

a) Myalgia and arthralgia are common symptoms in adults (Mangas et al, 2001; Kakosy et al, 1996; Fischbein, 1992a; Grimsley & Adams-Mount, 1994; Gittleman et al, 1994; Angle, 1993).
b) CASE REPORT: A 23-year-old woman developed non-specific musculoskeletal pain after taking a Chinese herbal pill (Bao ning dan) 4 to 6 times daily for 2 months. Her first blood lead concentration was 3.03 mcmol/L (Auyeung et al, 2002).
c) CASE REPORT: A 44-year-old woman was shot in the left lower back and right axilla with shotgun blasts during a mall shooting spree. Initial evaluation with x-ray showed a large number of scattered metallic pellets. After initial surgical debridement, imaging was still remarkable for numerous retained pellets. On day 16 post-injury, her whole-blood lead level was elevated (23 mcg/dL; reference range: 0 to 25 mcg/dL) and she reported nausea, fatigue, and myalgias one month later with her whole-blood lead level having increased (35 mcg/dL). Her whole blood lead levels decreased (5 mcg/dL) after treatment with oral succimer 500 mg twice daily, however became elevated (21 mcg/dL) one month later with accompanying nausea, fatigue, and myalgias. Her succimer dosing frequency was subsequently decreased to 100 mg twice daily and then 100 mg once daily with mild improvement in her nausea over the next 6 months and lead levels remaining between 16 and 18 mcg/dL. Eighteen months later, once daily succimer continues with persistent nausea and fatigue (Cyrus et al, 2011).

B) MUSCLE WEAKNESS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe lead poisoning developed in a 31-year-old man with retained bullet fragments 6 weeks after being shot by a shotgun in his left chest. He presented with abdominal pain and constipation. Ten weeks after injury, he developed proximal muscle weakness and laboratory results revealed microcytic anemia (hematocrit, 24%) with basophilic stippling. After a transfer to a tertiary hospital, physical examination revealed an agitated and restless man with generalized weakness predominate in proximal limbs. Laboratory analysis revealed a whole blood lead level of 126 mcg/dL and transient increased thyroxine (T4) level of 2.19 ng/dL (0.7 to 1.48). Despite supportive care, including 4 days of chelation with dimercaprol and calcium disodium ethylenediaminetetraacetic acid (EDTA), as well as packed red blood cell transfusion, he developed worsening encephalopathy, motor weakness, and respiratory failure, necessitating intubation. On day 10, his blood lead level was 23 mcg/dL and dimercaprol therapy was discontinued. His condition gradually improved after surgical debulking of the retained fragments. On day 33, he was extubated and oral d-penicillamine (750 mg/day) was started. His condition continued to improve with his blood lead level stabilized at around 40 mcg/dL (Srisuma et al, 2015).

C) DISORDER OF BONE DEVELOPMENT

1) WITH POISONING/EXPOSURE

a) Lead is deposited in the metaphyses of growing bones and slows linear growth (Schwartz & Otto, 1986).

1) In a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III), blood lead levels were associated with decreased height and head circumference. Each 10 mcg/dL increase in blood lead level was estimated to correlate with a 1.57 cm decrease in height and 0.52 cm decrease in head circumference (Ballew et al, 1999).

D) DISORDER OF BONE

1) WITH POISONING/EXPOSURE

a) BONE LEAD LEVELS: Ninety percent of the lead body burden may be found in bone. The mean initial bone lead level in a group of smelter workers was 97 mcg/gram (range 61 to 131) with an average half-life of 6.7 years (range 3.4 to 15) after exposure was terminated (Christoffersson et al, 1986).
b) One study evaluated the relationship between bone mineral density (BMD) and blood lead levels among peri- and postmenopausal women in the US. It was determined that menopause and bone status are predictors of blood lead level among women 40 to 50 years of age. When adjusted for other factors traditionally associated with blood lead (eg; age, race-ethnicity, smoking, education, household income, alcohol use, and residence (urban/rural)), BMD was significantly inversely associated with blood lead level. Menopausal women (naturally or surgically) had adjusted median blood lead levels 25% to 30% higher than those of premenopausal women (2.0 mcg/dL). In addition, current users of hormone replacement therapy had adjusted blood lead levels lower than those of past or never users, independently of age (Nash et al, 2004).

E) ARTHRITIS

1) WITH POISONING/EXPOSURE

a) LEAD ARTHROPATHY with synovitis, degenerative arthritis, and mechanical difficulties caused by the bullet, may develop years after the initial injury when lead bullet fragments are lodged near articular surfaces. Systemic lead poisoning may develop as synovial fluid dissolves lead (DeMartini et al, 2001; Farber et al, 1994).

3.15.3)

A) ANIMAL STUDIES

a) In a study done by Buchheim et al (1998), rhesus monkeys were exposed prenatally to 350 ppm of lead acetate or postnatally to 600 ppm of lead acetate in the diet for 9 years, followed by a lead free period for 32 months.

1) Myopathy was noted when vastus medialis muscle was examined; this included increasing scatter of fiber diameter, number of split fibers, number of internal nuclei, and separation of fibers.

Endocrine

3.16.2)

A) DISORDER OF ENDOCRINE SYSTEM

1) WITH POISONING/EXPOSURE

a) GROWTH: Neuroendocrine dysfunction as been implicated as a contributing factor in the decreased stature of children with high blood lead levels (Schwartz et al, 1986).

B) VITAMIN DEFICIENCY

1) WITH POISONING/EXPOSURE

a) VITAMIN D: Decreased concentrations of 1,25 dihydroxy vitamin D have been associated with low level lead exposure (Rosen et al, 1980).

C) DECREASED BODY GROWTH

1) WITH POISONING/EXPOSURE

a) GROWTH HORMONE: Lead-induced short stature may be due to diminished growth hormone secretion (Huseman et al, 1992)

D) CATECHOLAMINE LEVEL - FINDING

1) WITH POISONING/EXPOSURE

a) Plasma epinephrine and norepinephrine levels were significantly elevated in 15 lead exposed children compared with controls (deCastro, 1990). These findings may relate to hypertension and hyperactivity associated with lead exposure.

Immunologic

3.19.2)

A) WHITE BLOOD CELL ABNORMALITY

1) WITH POISONING/EXPOSURE

a) NEUTROPHIL chemotaxis was significantly decreased in lead exposed workers in two studies (Bergeret et al, 1990) Quieroz et al, 1993). Neutrophils from lead-exposed workers were shown to have normal phagocytosis, but decreased ability to kill Candida albicans in another study (Queiroz et al, 1994). The clinical significance of these findings is unclear.
b) T CELLS: Firearms instructors who were chronically exposed to lead were found to have toxic effects on T-lymphocytes and T-helper cells at 25 mcg/L and above (Fischbein et al, 1993).

Reproductive

3.20.1)

A) Lead is transferred across the placenta. It can affect reproduction in males and females, and affects neurodevelopmental milestones in children with both prenatal and postnatal exposure.

3.20.2)

A) CONGENITAL ANOMALY

1) Minor congenital anomalies (most commonly hemangiomas and lymphangiomas, hydrocele, skin tags) were associated with higher cord lead levels in a prospective study of 5183 deliveries (Needleman et al, 1984).
2) One study suggested a possible weak association between prenatal lead exposure and strabismus (Hakim et al, 1991).
3) An infant with VACTERL association (a pattern of malformations with vertebral anomalies, anal atresia, cardiac, renal and limb anomalies) was born to a woman exposed to high levels of lead during the first trimester (Levine & Muenke, 1991).
4) High-level lead exposure has been reported to cause birth defects with paternal exposure (Lancranjan, 1975).
5) Paternal lead exposure (documented in Norwegian union records) was associated with a 4.1-fold increased risk of cleft palate (Kristensen et al, 1993).
6) Lead may decrease gestation time at maternal blood levels lower than 25 mcg/dL (Dietrich et al, 1986). At maternal blood lead levels greater than 15 mcg/dL, there may be a modest risk for intrauterine growth retardation, based on a study of 4354 pregnancies in the USA (Bellinger et al, 1991). Lead poisoning during pregnancy has been associated with prematurity, low birth weight, and impaired fetal growth (Bellinger & Needleman, 1985). Prenatal lead exposure at maternal blood levels less than 25 mcg/dL has been associated with lower birthweights (Dietrich et al, 1986; Gonzalez-Cossio et al, 1997).
7) High-level prenatal lead exposure has been associated with fetal wastage (EOSH, 1982). In one pregnant woman exposed to high levels of lead during the 8th month of gestation, there was only slightly impaired cognitive development in the child (Schardein, 1993).
8) No increases in overall or specific birth defects were seen in 2724 children born to women living close to a lead smelter in Sweden between 1973 and 1990; this study group was too small to detect a small increase, however (Wulff et al, 1996).

B) LACK OF EFFECT

1) CASE SERIES - In one study of 15 severely lead-poisoned pregnant women (16 to 38 weeks gestation; mean maternal BLL 55 mcg/dL; range 33-104 mcg/dL), the newborns also had severely elevated BLL (BLL 37-207 mcg/dL; at delivery mean neonatal BLL 74 mcg/dL) and were treated with EDTA, BAL or succimer within the first 28 days of life. No identifiable birth defects were observed in any infant (Shannon, 2003).
2) CASE REPORT - A pregnant woman with chronic lead toxicity (BLL 57 mcg/dL) delivered a healthy-appearing neonate (a cord blood lead 126 mcg/dL). The mother was treated with a single course of oral succimer late in the third trimester of pregnancy without any appreciable change in BLL. Her newborn was treated with intramuscular dimercaprol and intravenous edetate calcium disodium for 3 days and then two 19-day courses of succimer. At 5 months of age, the infant's BLL was 21.5 mcg/dL (Horowitz & Mirkin, 2001).

C) ANIMAL STUDIES

1) Various inorganic lead salts are teratogenic in experimental animals (Schardein, 1993), in contrast to human experience, where except for a few isolated cases which cannot be adequately interpreted, lead is not regarded as a structural teratogen. In rats, lead readily crosses the placenta and also is concentrated in breast milk, with milk:blood ratio of 2.5:1 (Hallen et al, 1995).
2) Prenatal lead exposure in rats can affect reproductive function in the offspring (McGivern et al, 1993; (Coffigny et al, 1994). Lead-exposed female rats had prolonged and irregular diestrous, and males had reduced sperm counts, EVEN THOUGH LEAD WAS UNDETECTABLE IN THE BLOOD AT THE TIME OF WEANING (McGivern et al, 1991).
3) Lead given during pregnancy, as measured by the ratio of Pb-206/Pb-204 isotopes, preferentially accumulated in fetal rather than maternal bone in cynomolgus monkeys (Inskip et al, 1992).
4) Mice receiving up to 1000 ppm lead acetate in the drinking water from day 12 of gestation to 4 weeks postpartum developed dose-related renal tumors (Waalkes et al, 1995).
5) Multiple animal studies have demonstrated behavioral abnormalities following intrauterine lead exposure (Rodrigues et al, 1996) Newland et al, 1996; Tang et al, 1994; (Newland et al, 1994).
6) Multiple studies have also documented changes in neurotransmitter concentrations, receptor concentrations, or other measures of structural components in the brain (Ma et al, 1997; Antonio et al, 1996; Harry et al, 1996; Zawia & Harry, 1996; Jett & Guilarte, 1995).

3.20.3)

A) PLACENTAL BARRIER

1) Lead crosses the placenta (Mycyk et al, 2002; Korpela et al, 1986). In utero exposure has been associated with impaired cognitive function, and minor congenital anomalies.
2) Lead is freely transferred across the placenta as early as the 12th to 14th week of gestation (Schardein, 1993). In general, blood lead levels in the fetus are comparable to those in the mother (EOSH, 1982).

a) One study reported that higher blood pressure and maternal alcohol use were associated with relatively greater cord BLLs compared with maternal BLLs. In contrast, sickle cell trait and higher hemoglobin were associated with a lower cord BLLs relative to maternal BLLs. Differences between maternal and cord BLLs were not observed with smoking, physical exertion, or calcium consumption (Harville et al, 2005).

3) The mean level of umbilical cord blood lead in newborns in Quebec, Canada was 0.0094 mcmol/L; higher levels were found in infants born to mothers who lived near environmental lead sources (Rhainds & Levallois, 1993).
4) Paternal exposure to high doses of lead 6 months before pregnancy was associated with a 5-fold increased odds for low birth weight (Min et al, 1996).
5) In one study, women with pregnancy complications (anemia, toxemia, proteinuria, arterial hypertension and hyperemesis) were found to have significantly higher blood lead levels as compared to those with normal pregnancies. In addition, incremental increases in blood lead levels were associated with statistically significant decreases in neonatal birthweight (Kaul et al, 2002).

B) BLOOD LEAD LEVELS

1) Blood lead levels in the neonate may be higher than maternal lead levels. In one study of 15 severely lead-poisoned pregnant women (16 to 38 weeks gestation; mean maternal BLL 55 mcg/dL; range 33-104 mcg/dL) the newborns had higher BLL than the mothers (BLL 37-207 mcg/dL; at delivery mean neonatal BLL 74 mcg/dL) were treated with EDTA, BAL or succimer within the first 28 days of life (Shannon, 2003).
2) CASE REPORT: A 22-year-old pregnant woman with chronic lead poisoning (average BLL ranged between 20 to 40 mcg/dL) from a retained bullet fragments delivered her first child after receiving oral succimer chelation. The infant's BLLs at the time of delivery and 323 days later were 6 mcg/dL and 8 mcg/dL, respectively. She delivered her second child without receiving chelation during pregnancy. This child received oral succimer 15 days after birth and had BLLs of 9.1 mcg/dL and 7 mcg/dL 15 days and 260 days after birth, respectively. The mother delivered her third child without receiving any chelation during pregnancy or after birth. The infant's BLLs were 13 mcg/dL and 7.7 mcg/dL 25 days and 306 days after birth, respectively. Overall, chelation therapy did not decrease the infants BLL significantly over time (Karpen et al, 2015).

C) COGNITIVE DELAY

1) Cord blood lead is 80% of the maternal lead level. The development of children born with levels above 10 mcg/dL has been found to lag behind controls with lower levels (Bellinger, 1986; Bellinger et al, 1987). Beattie et al (1975) reported an increased prevalence of mental retardation in populations with high water lead.
2) In a large population study on children of disadvantaged urban mothers in the Cleveland area, there was somewhat lower performance in the Soft Sign (one of a battery of behavioral and functional tests given to the newborns) which correlated with cord (but not maternal) blood lead levels (Ernhart et al, 1986).
3) In the large ongoing Boston Lead Study, an inverse correlation has been found between cord blood lead levels at birth and performance on tests of mental development at the ages of 6 months (Bellinger, 1984), 12 months (Bellinger, 1984), and 24 months (Assennato, 1986). In this study of children of middle- and upper-middle class parents, the mean cord blood lead concentration at birth was 6.6 mcg/dL, and blood lead levels were 6.2 mcg/dL at 6 months and 7.7 mcg/dL at 12 months (Bellinger, 1984).

a) There was considerable variation in blood lead levels in individual children during the first 12 months of life, however, and performance on mental development tests was correlated only with lead levels at birth, suggesting that prenatal lead exposure may affect postnatal mental development. The greatest effects were seen in fine-motor function, visually-directed reaching, and social responsiveness. These effects were dose-related in the HIGH EXPOSURE group (children with blood lead levels greater than 10 mcg/dL at birth). The mean blood lead level in this high exposure group was only 14.6 mcg/dL (Bellinger, 1984).

4) Poorer performance on tests of motor coordination was seen in children with higher neonatal blood lead levels in the Cincinnati prospective lead study. Defects were seen in gross and fine-motor skills (Dietrich et al, 1993). In another study, slightly poorer attention and motor control performance were noted among neonatal offspring of African American mothers with higher maternal blood lead levels; levels were obtained from these women in the sixth and seventh prenatal months (Emory et al, 1999).
5) Elevated blood lead levels at age 24 months, even though in the "normal" range with a mean of 6.5 mcg/dL (0.31 mcmol/L), were associated with lower IQs and performance on neuropsychological tests, EVEN IN MIDDLE-CLASS AND UPPER-CLASS CHILDREN. With blood lead levels in the range of 0 to 25 mcg/dL, an increase of 10 mcg/dL was associated with a decline in IQ of 5.8 points (Bellinger et al, 1992). Poor correlation was seen between performance on neuropsychological tests at age 10 years and previous blood lead levels (Stiles & Bellinger, 1993).
6) By the age of 4 years, mean scores on the McCarthy Scales General Cognitive Index were reduced from 86.6 to 81.3 in Yugoslavian children of lead-exposed mothers, as compared with a control group. An increase in blood lead from 10 to 25 mcg/dL was associated with a decline in the Cognitive Index of 3.8 points (Wasserman et al, 1994).
7) In the Port Pirie lead study, the IQ of children measured at 11 to 13 years of age was inversely associated with both pre- and postnatal blood lead concentrations, especially exposures between age 15 months to 7 years, with no apparent threshold (Tong et al, 1996).
8) Poorer performance on tests of motor coordination was seen in children with higher neonatal blood lead levels in the Cincinnati prospective lead study. Defects were seen in gross and fine-motor skills (Dietrich et al, 1993).
9) Maternal alcohol abuse was shown to affect fetal lead levels in the Cleveland study. Maternal alcohol abuse or other stressors might cause the fetus to accumulate or mobilize lead (Ernhart, 1985).
10) In a group of Mexican pregnant women (n=105), maternal blood lead (PbB) levels averaged around 7.0 mcg/dL, with a range of 1.0-35.5 mcg/dL throughout pregnancy. A significant decrease in mean PbB from week 12 to week 20 (1.1 mcg/dL) and various significant increases in mean PbB from 20 to parturition (1.6 mcg/dL) were noted. It is suggested that mobilization of bone lead, increased gut absorption, and increased retention of lead in the last half of pregnancy, may have contributed to increasing blood lead levels. In addition, low calcium diet, reproductive history, coffee drinking, and the use of indigenous lead-glazed pottery may have contributed to increasing blood lead levels (Rothenberg et al, 1994).
11) In one study, about 30% of mothers delivered infants with cord blood lead levels higher than their own. However, overall, maternal lead significantly exceeded cord lead at delivery. The use of lead-glazed ceramic ware, consumption of canned foods, and maternal age were associated with increased cord PbB. However, frequency of maternal milk use, history of abortions (spontaneous), and use of alcohol during pregnancy were associated with decreased cord PbB (Rothenberg et al, 1996).
12) CASE REPORT - A healthy-appearing neonate with a cord blood lead of 126 mcg/dL (Hct of 48) was born to a woman with chronic lead toxicity and a BLL of 57.6 mcg/dL (Hct of 15). The authors suggested that a threefold difference in hematocrit between mother and child, presence of fetal hemoglobin, and mobilization of bone lead during parturition, may have contributed to differences among maternal, cord and fetal blood lead levels of healthy neonate (Mirkin et al, 2000a).
13) CASE REPORT - A neonate with congenital lead intoxication (BLL 17-37 mcg/dL) was treated with IV calcium EDTA and oral DMSA. The authors supported the need of prenatal screening in mothers who are at high risk for elevated BLL, such as recent immigrants from areas with a high prevalence of lead exposure or those with other children with elevated BLL (Guzman et al, 2000).

D) ABORTION

1) Lead has been known to affect female reproduction for more than 100 years (Sibergeld, 1983); lead oxide has been used as an abortifacient (Schardein, 1993). Women exposed to high lead levels had stunted and abnormal infants and increased stillbirths and miscarriages. In 1930, the spontaneous abortion rate in the general population of Milan, Italy was 4 to 4.5%, while wives of male printers exposed to lead in inks had a spontaneous abortion rate of 14%; in female printers, the rate was 25% (Schardein, 1993).
2) Earlier studies showed a greater incidence of spontaneous abortion in pregnant women living near lead smelters and worked at the smelter before and during pregnancy. A more recent study of women in two cities, one close to a lead smelter and one 25 miles away, showed no significant differences in spontaneous abortion rate (Harbison, 1998). Low-to-moderate lead exposures may increase the risk for spontaneous abortion.
3) In England, lead-exposed women had an 11% rate of miscarriages, associated with a 40% neonatal mortality (Schardein, 1993). In a French study, a 60% spontaneous abortion frequency was found; in Germany, spontaneous abortions were three times more common in female lead-exposed printers (Schardein, 1993).
4) In a large non-occupational study of 253 women in the center of the so-called "LEAD BELT" in Rolla, Missouri, there were fewer full-term deliveries, a greater incidence of premature rupture of membranes, and more premature deliveries (Schardein, 1993). Women living near Suwalki in Eastern Poland, with naturally high levels of lead and cadmium in the soil but little other industrial pollution, had fewer full-term deliveries, multiple pregnancies, and more preterm infants with lower birth weights, than women in a control group. Blood lead levels of exposed and control women were not significantly different, however (6.7 versus 6.2 mcg/dL). Cadmium levels were higher in the exposed group (0.29 versus 0.25 mcg/dL) (Laudanski et al, 1991).

E) LEAD MOBILIZATION

1) Pregnancy may increase the mobilization of lead from the maternal skeleton. As the bone calcium is needed during pregnancy, stored lead will become solubilized (Gulson et al, 1997). Blood lead increased during pregnancy by 20% in a group of pregnant women living near a smelter, versus a 15% increase in a pregnant control group (Lagerkvist et al, 1996).
2) Blood lead levels were lower in African-American pregnant women who took vitamin-mineral supplements than in women who did not (West et al, 1994).
3) In a group of Mexican pregnant women (n=105), maternal blood lead (PbB) levels averaged around 7.0 mcg/dL, with a range of 1.0-35.5 mcg/dL throughout pregnancy. A significant decrease in mean PbB from week 12 to week 20 (1.1 mcg/dL) and various significant increases in mean PbB from 20 to parturition (1.6 mcg/dL) were noted. It is suggested that mobilization of bone lead, increased gut absorption, and increased retention of lead in the last half of pregnancy, may have contributed to increasing blood lead levels. In addition, low calcium diet, reproductive history, coffee drinking, and the use of indigenous lead-glazed pottery may have contributed to increasing blood lead levels (Rothenberg et al, 1994).
4) In one study, about 30% of mothers delivered infants with cord blood lead levels higher than their own. However, overall, maternal lead significantly exceeded cord lead at delivery. The use of lead-glazed ceramic ware, consumption of canned foods, and maternal age were associated with increased cord PbB. However, frequency of maternal milk use, history of abortions (spontaneous), and use of alcohol during pregnancy were associated with decreased cord PbB (Rothenberg et al, 1996).

F) LOW BIRTHWEIGHT

1) Paternal exposure to high doses of lead 6 months before pregnancy was associated with a 5-fold increased odds for low birth weight (Min et al, 1996).
2) Lead may decrease gestation time at maternal blood levels lower than 25 mcg/dL (Dietrich et al, 1986). At maternal blood lead levels greater than 15 mcg/dL, there may be a modest risk for intrauterine growth retardation, based on a study of 4354 pregnancies in the USA (Bellinger et al, 1991). Lead poisoning during pregnancy has been associated with prematurity, low birth weight, and impaired fetal growth (Bellinger & Needleman, 1985). Prenatal lead exposure at maternal blood levels less than 25 mcg/dL has been associated with lower birthweights (Dietrich et al, 1986; (Gonzalez-Cossio et al, 1997).
3) Reduced gestational age and reduced birth weight have been linked with maternal blood lead levels. The risk of preterm deliveries with a maternal blood lead level of 14 mcg/dL was 8.7 times that of 8 mcg/dL (Mushak et al, 1989).
4) PATERNAL lead exposure (documented in Norwegian union records) was associated with an 8.6-fold elevated risk of preterm delivery, and with a 2.4-fold elevation of perinatal death (Kristensen et al, 1993).
5) In one study, increased maternal blood lead levels were associated with a statistically significant decrease in neonatal birthweight (Kaul et al, 2002).

G) DELAYED PUBERTY

1) The relationship between blood lead concentrations and puberty in girls was evaluated in the third National Health and Nutrition Examination Survey that was conducted from 1988 to 1994. This cross-sectional, nationally representative study was designed to estimate the status of the general population. Blood lead concentrations of 3 mcg/dL were associated with decreased height, and significant delays in breast and pubic-hair development in African-American and Mexican-American girls. No significant delays in any pubertal measures occurred in white girls at the same lead concentration. Although the findings suggested that environmental lead exposure may delay growth and pubertal development, prospective studies were recommended (Selevan et al, 2003).

H) ENCEPHALOPATHY

1) An infant, born to a woman with lead poisoning, developed seizures and encephalopathy with peripheral neuropathy 8 hours after delivery. A chest radiograph revealed dense bands, described as sclerotic changes, at the proximal ends of the humeri. At 11 and 13 months of age, the infants BLL was 3.46 mcmoles/L (normal, less than 0.48 mcmole/L) and 2.69 mcmoles/L, respectively. The child was treated with two courses of oral succimer (Fleece & Robinson, 2007).

I) DEVELOPMENTAL DELAY

1) A woman who had sniffed petrol since childhood, delivered an infant with a cord blood lead level 8 times the accepted limit. Chelation with oral succimer reduced the infant's BLL.. On follow-up at the age of 12 months, the infant had global developmental delay (Powell et al, 2006).

3.20.4)

A) BREAST MILK

1) Lead is present in human breast milk at typical concentrations of 2 to 30 mcg/L, and blood lead levels are generally similar in infants and mothers (Mattison et al, 1983).
2) One study of 367 lactating women evaluated the effect of cumulative lead exposure, breastfeeding practices, and calcium intake on breast milk lead levels over the course of lactation. The relations among maternal blood, bone, and breast milk lead levels were evaluated at 1, 4, and 7 months postpartum. It was determined that the amount of lead release from bone was related to lactation intensity and to levels of lead in breast milk. Overall, breast milk lead levels decreased over the course of lactation (1.4, 1.2, and 0.9 mcg/L at 1, 4, and 7 months postpartum, respectively). However, among those women who were exclusively breastfeeding, patients with high patella lead, assigned to the calcium supplement group, or currently using lead-glazed ceramics, tended to have breast milk lead levels that increased over the course of lactation. The rate of decline in breast milk lead was increased by 5% to 10% with dietary calcium supplementation (Ettinger et al, 2006).
3) In two women with lead poisoning (blood lead levels of 29 and 33 micrograms/deciliter) breast milk levels were less than 0.005 and 0.010 micrograms/milliliter respectively (Baum & Shannon, 1995).
4) Mexico City study showed that a blood level of 45.88 mcg/dL produced a breast milk level of 2.47 mcg/100 mL (Namihira et al, 1993).

3.20.5)

A) HUMANS

1) There is a dose-response correlation between blood lead and fertility (Gandley et al, 1999).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS7439-92-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Lead, organic compounds
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

2) IARC Classification

a) Listed as: Lead
b) Carcinogen Rating: 2B

1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

3) IARC Classification

a) Listed as: Lead compounds, inorganic
b) Carcinogen Rating: 2A

1) The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

3.21.3)

A) CARCINOGENICITY RISK

1) Lead has been assigned a rating of "B2 - a probable human carcinogen"(IRIS , 1998).
2) In a study on 20,700 Finnish workers who had been monitored for blood lead between 1973 and 1983, there was a 1.4-fold increase in incidence of all cancers and a 1.8-fold increase in lung cancers among those who had ever had blood lead of at least 1 mcmol/L. Odds ratio was greater for those who had also been exposed to engine exhaust (Anttila et al, 1995). Some lead salts have produced tumors in experimental animal studies.
3) In a study of 3979 primary smelter workers, 46 respiratory malignancies were reported. Smoking and cumulative lead exposure were not identified as risk factors for the development of lung cancer (OR 0.99; 95% CI 0.95 to 1.02) (Lundstrom et al, 2006).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Capillary screens are generally reliable, but do carry the risk of contamination, and thus should be confirmed with whole blood lead levels.
B) Current federal Medicaid guidelines require lead screening in children at 12 and 24 months of age. In addition, lead screening is required in all children between the ages of 36 to 72 months who previously have not been screened for lead.
C) Refugee children are at higher risk, and the CDC recommends lead testing in all refugee children from the age of 6 months to 16 years upon entry to the United States. Repeat lead testing is recommended in children ages 6 months to 6 years after 6 months in a permanent residence. Other residents should be tested if a blood lead level comes back elevated.
D) In children with blood lead levels between 20 to 44 mcg/dL, obtain a hemoglobin or hematocrit level and evaluate the child’s iron status. Consider abdominal radiographs with bowel decontamination if particulate lead ingestion is suspected.
E) Zinc protoporphyrin and erythrocyte protoporphyrin assays are not sensitive at lower BLLs. In addition, they are not specific to lead, and have a lag time of approximately 120 days before showing effects of an exposure.
F) Hypochromia and basophilic stippling suggest lead intoxication, but they are nonspecific and their absence does not rule out the diagnosis.
G) Employees whose blood lead level is equal to or greater than 50 mcg/dL should be temporarily removed from exposure until their blood lead level is at 40 mcg/dL or below.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) A BLOOD LEAD LEVEL (BLL) test is currently the most commonly used test to determine an individual's relative lead concentration (ATSDR, 2000; CDC, 1997; Mushak et al, 1989; Carton et al, 1987). Although accuracy to within 4 mcg/dL has been reported, it may vary from one laboratory to another (sensitivity of 87.5% for blood lead values greater or equal to 10 mcg/dL and specificity of 100% for values less than 10 mcg/dL) (Lane & Kemper, 2001).

a) BLLs may be obtained using either venous or capillary (fingerstick) samples. Although capillary sampling is easier to perform, it may be less accurate due to the skin contamination by lead. It is recommended that an elevated BLL obtained through finger-sticking be confirmed through venipuncture (Lane & Kemper, 2001; ATSDR, 2000; CDC, 2000).
b) BLLs change rapidly in response to lead intake (eg; ingestion of lead paint chips). For short exposure periods, it usually has a linear relationship to intake levels (ATSDR, 2000). Blood lead levels reflect recent exposure or exposure over a period of up to 3 to 5 weeks (Mushak et al, 1989). In individuals with high or chronic past exposure, BLLS usually under-represent the total body burden because most lead is stored in the bone and may be found at normal levels in the blood. However, during stressful circumstances, patients with a high body burden may have elevated BLLS because of the release of lead stored in bones (ATSDR, 2000).

2) CHILDREN

a) It should be kept in mind that lead has no biologic value. An ideal blood lead level is zero; therefore, physiologic changes may be seen with blood lead levels far below 25 mcg/dL (Anon, 1987).
b) The following information may be used for decision making in interpreting blood lead results in children and the need for follow-up activities (Lane & Kemper, 2001; ATSDR, 2000; CDC, 1997).

1) BLL less than 10 mcg/dL - Re-evaluate and rescreen patients in 1 year. No additional actions required.

a) In 2012, CDC changed the "actionable" reference BLL from 10 mcg/dL to 5 mcg/dL, a level that is based on the 97.5th percentile of the National Health and Nutrition Examination Survey's BLL distribution in children. Using this new BLL, CDC estimated that 450,000 children have been exposed to lead in the US (Leafe et al, 2015; Centers for Disease Control and Prevention (CDC), 2014).

2) BLL 10-19 mcg/dL - Lead education and referrals should be provided. If the result of screening test is 10-14 mcg/dL, perform diagnostic test for lead on venous blood within 3 months, and at least one follow-up test within 3 months. If the result of screening test is 15-19 mcg/dL, perform diagnostic test for lead on venous blood within 2 months, and at least one follow-up test within 2 months. Follow according to guidelines in 20-44 mcg/dL range if BLLs persist in 15-19 mcg/dL range. If a large proportion of children are in the 10-14 mcg/dL range, community-wide lead poisoning prevention should be considered.
3) BLL 20-44 mcg/dL - Lead education and referrals should be provided. Provide clinical evaluation and management. If the result of screening test is 20-29 mcg/dL, perform diagnostic test for lead on venous blood within 1 month. If the result of screening test is 30-44 mcg/dL, perform diagnostic test for lead on venous blood within 1 week. Follow-up testing should be performed every 1 to 2 months. Aggressive environmental intervention should be performed.
4) BLL 45-69 mcg/dL - Lead education and referrals should be provided. Provide coordination of care (case management) within 48 hours. Perform clinical evaluation and management within 48 hours. Provide diagnostic testing within 24-48 hours and follow-up testing (in accordance with chelation therapy, at least once a month). Aggressive environmental intervention and appropriate chelation therapy should be performed.
5) BLL equal to or greater than 70 mcg/dL) - A medical emergency. Diagnostic testing immediately as an emergency laboratory test. Hospitalize the patient and begin immediate chelation therapy.

c) BLL LESS THAN 10 MCG/DL: In 2012, CDC changed the "actionable" reference BLL from 10 mcg/dL to 5 mcg/dL, a level that is based on the 97.5th percentile of the National Health and Nutrition Examination Survey's BLL distribution in children. Using this new BLL, CDC estimated that 450,000 children have been exposed to lead in the US (Leafe et al, 2015; Centers for Disease Control and Prevention (CDC), 2014). To decide on follow-up BLL testing, consider the child's age, season of testing, and exposure history. Binns et al (2007) recommended more frequent BLL screening (eg; more often than annually) for a child whose BLL is approaching 10 mcg/dL, especially if the child is less than 2 years of age, was tested at the start of warm weather (when BLLs tend to increase), or is at high risk for lead exposure (Binns et al, 2007).
d) BLLS FOLLOWING FOREIGN BODY INGESTION: Children from areas with a high prevalence of lead poisoning presenting to emergency departments with a history of ingesting non-leaded substances (Hammer et al, 1985) or with aural, nasal or gastrointestinal foreign bodies(Wiley et al, 1992) have been found to have increased lead levels compared with controls.
e) In a large follow-up study of children aged 0 to 4 years, special diagnostic testing (within 90 days) of children that had a previous marginally elevated (10 to 14 mcg/dL) capillary or venous lead blood screening test did not result in further identification of venous diagnostic lead levels greater than 20 mcg/dL (Sargent et al, 1999). The authors suggested that the screening set point for diagnostic testing should be raised to 15 mcg/dL, which could eliminate unnecessary follow-up of many children and decrease misclassifications of lead poisoning.
f) Blood lead levels in capillary samples were shown to correlate highly with those in venous blood from 295 inner-city children at high risk for lead exposure (R >/= 0.96) (Schlenker et al, 1994).
g) Capillary blood lead levels yielded a false positive rate (using a threshold blood lead level of 15 micrograms/deciliter) of 14% in one study (Schonfeld et al, 1994). Using an adhesive dressing as a barrier may decrease the contamination of samples obtained by capillary stick (Sargent et al, 1994).

3) ADULTS - OCCUPATIONAL

a) OSHA STANDARDS: If airborne lead exposure is 30 mcg/m(3) (8-hour time-weighted average) or greater for longer than 30 days/year, employers should provide medical surveillance to workers which includes biological monitoring with BLLs performed by an OSHA-approved laboratories. Employees, whose single blood lead level is equal to or greater than 60 mcg/dL or if three determinations over 6 months average is equal to or greater than 50 mcg/dL, should be temporarily removed from exposure until their blood lead level is at or below 40 mcg/dL. Employees may also be removed from exposure if the worker has a "detected medical condition" that places him or her at increase risk of " material impairment to health" from lead exposure (Schwartz & Hu, 2007; Ottlinger, 2002) .
b) FOLLOW-UP TESTING AFTER REMOVAL FROM EXPOSURE: A study of removed workers with elevated BLLs showed that on average the BLL falls by about 13 to 26 mcg/dL, one month after the original sample. The authors recommend a follow-up testing around 3 to 4 weeks after removal of the worker. However, this period may be adjusted based on the patient's past history of lead exposure. Some continuing lead exposure should be suspected if the decline in BLL is 7-8 mcg/dL or less in the month after the removal of the worker (Mason & Williams, 2005).
c) CDC, RECOMMENDATION: All adults with work lead exposure should have BLLs of less than 25 mcg/dL by 2010 as a preventive health measure (Ottlinger, 2002).
d) Increased lead levels may not be limited to those who work with lead. Other "bystander" employees may also have increased levels.
e) The ACGIH has reported that women of childbearing age who have blood levels in excess of 10 mcg/dL have an increased risk of delivering a child with a blood lead level in excess of the 10 mcg/dL (Ottlinger, 2002).
f) TAKE-HOME LEAD POISONING: All industries in which lead is used (eg; furniture refinishing and construction) present occupational hazards. Industrial lead dust, carried on the clothes of parents, is an exposure source for children (Baker et al, 1977). Employers in these industries should arrange personal exposure monitoring and surface wipe sampling for lead and implement workplace improvements, including a respiratory protection program; use of HEPA vaccum-attached power sanders; use of a high-efficiency toxic dust HEPA vacuum; daily clean uniforms; separate storage lockers, changing area with showers, and lunch room; warning signs; safety training addressing take-home lead; and a lead medical surveillance program (Centers for Disease Control and Prevention, 2001).

4) K X-RAY FLUORESCENCE (K-XRF)

a) K-XRF is a new test used to evaluate long-term lead levels. It measures lead levels in trabecular bone at the patella or calcaneus and cortical bone at the tibia. K-XRF is mostly used in research and is not widely available to clinicians (ATSDR, 2000; Todd et al, 1992).

5) ERYTHROCYTE PROTOPORPHYRIN (EP)

a) EP (commonly assayed as zinc protoporphyrin or ZPP; bound to zinc rather than to iron) - Is no longer as useful as once thought. EP/ZPP assays are not sensitive at lower BLLS. In addition, they are not specific to lead and have a lag time of approximately 120 days before showing effects of an exposure (ATSDR, 2000; Rolfe et al, 1993; Leung et al, 1993; Clark et al, 1988).

1) The frequency distribution of the zinc protoporphyrin content of circulating red blood cells may provide information on the duration of lead exposure. Patients with recent exposure have a small percentage of red blood cells with elevated ZPP despite high blood lead concentrations, while with chronic exposure the majority of red blood cells will have elevated ZPP levels despite more modest elevations of blood lead concentration (Markowitz et al, 1994).
2) One study determined that ZPP elevations in both chronic and acute exposures lag approximately 8 to 12 weeks behind elevation in whole-blood lead levels. Therefore, ZPP has no role in monitoring treatment efficacy. However, it may be used in conjunction with whole-blood lead determination in cases of overexposure to determine how long an individual may have been overexposed to lead. ZPP can be used to distinguish between acute and chronic lead intoxication, or to detect the surreptitious use of chelation. ZPP has no role in screening programs due to poor sensitivity, poor specificity, high individual variability, a lag in changes when exposure is unstable and conflicting data on the correlation with other biological indicators (Martin et al, 2004).

6) DELTA AMINOLAEVULINIC ACID (ALA)

a) ALA is not a sensitive marker of lead poisoning at low lead levels and may give false positive results in patients with iron deficiency (Chalevelakis et al, 1995).

7) ERYTHROCYTE PYRIMIDINE-5'-NUCLEOTIDASE (P5N)

a) P5N activity can be measured by high performance liquid chromatography and may serve as a useful screen for lead toxicity (Sakai & Ushio, 1986).

8) PREVENTIVE MEASURES

a) CHILDREN - Because of preventive measures in the recent years (eg, removing lead from gasoline, banning lead-based paint), the average BLL for children 1 to 5 years of age has decreased from 15.0 mcg/dL (1976-1980) to 2.7 mcg/dL (1991-1994) (Lane & Kemper, 2001; ATSDR, 2000). Blood lead levels in Chicago children declined between 1974 and 1988 from median levels of 30 mcg/dL to 12 mcg/dL, apparently in response to reductions in airborne lead (Hayes et al, 1994).
b) ADULTS/OCCUPATIONAL: Because of preventive measures in the recent years (eg, removing lead from gasoline, banning lead-based paint), the average BLL for adults has decreased from 14.2 mcg/dL (1976-1980) to 3.0 mcg/dL (1988-1991) (Lane & Kemper, 2001; ATSDR, 2000), and to 1.64 mcg/dL (1999-2002). Between 1988-1994 to 1999-2002, substantial declines in BLLs occurred in the overall US adult population, among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. The percentage of adults with BLL of 10 mcg/dL or higher declined from 3.3% in 1988-1994 to 0.7% in 1999-2002 (P<0.001). In 1999-2002, the multivariable-adjusted odds ratio of having a blood lead level of 10 mcg/dL or higher was 2.91 (95% CI, 1.74-4.84) and 3.26 (1.83-5.81) for non-Hispanic blacks and Mexican Americans, respectively, compared with non-Hispanic whites (Muntner et al, 2005).

9) RETAINED BULLETS

a) Lead intoxication from retained bullets or shrapnel has been reported. Almost all cases involve lodging of the missile in or near a joint. Synovial fluid is a better solvent for lead than serum or bone and synovial lead levels can be much higher than blood levels (Madureira et al, 2001; DeMartini et al, 2001; McQuirter et al, 2001; John & Boatright, 1999; Farber et al, 1994; Meggs et al, 1994; Aly et al, 1993) .
b) In several studies, it has been reported that the length of time retained projectiles remain in the body, fragmentation of the retained lead projectile, and location of bullets or fragments (especially those near synovial fluids) are strong predictors of blood lead elevation (McQuirter et al, 2001) .

10) HEMATOLOGY

a) Obtain a CBC to assess for anemia and perform a peripheral blood smear. Hypochromia and basophilic stippling are suggestive of lead intoxication, although there absence does not rule out lead poisoning (Lawrence, 1999).
b) Any increase in blood levels, even within what may be considered "normal" levels, may result in hematologic abnormalities (Poulos et al, 1986).
c) A nonlinear, dose-response relationship between blood lead concentration and depression of hematocrit was observed in a study of 579 one- to five-year-old children living near a primary lead smelter (Schwartz et al, 1990).

4.1.3)

A) URINARY LEVELS

1) LEAD MOBILIZATION TESTS (LMT)(challenge/provocative/provocation test): A urine mobilization test will be more definitive as to total body burden or mobilizable pool. In patients with previous extensive lead exposure but low recent exposure, BLL may be only slightly increased whereas the mobilizable pool may be significantly increased (Hoet et al, 2006).

a) In one study, LMT was found to be a short, easy, practical, and inexpensive test. It involves a 4-hour urine collection after a single oral dose of 1 g of succimer which can be used to detect a lead pool that is not reflected by BLL. The authors proposed 22 mcg/4 hours as a tentative reference value for the adult general population. It showed that succimer acts quickly, inducing a peak BLL within 2 hours, and that the 4- and 24-hour cumulative lead excretion rates were highly correlated (Hoet et al, 2006).

2) Obtain a 24 hour quantitative urine lead output, with and without DMSA, D-penicillamine or EDTA mobilization.
3) Beta-aminoisobutyric acid may be elevated in urine of lead exposed workers (Farkas et al, 1987).
4) TUBULAR DYSFUNCTION: Elevated urinary levels of N-acetyl-3-D-glucosaminidase, beta-2-microglobulin, alpha-1-microglobulin, and glutathione S-transferase may serve as early markers of subclinical renal injury (El-Safty et al, 2004; Kumar & Krishnaswamy, 1995; Kumar & Krishnaswamy, 1995; Lin et al, 1993; Fischbein, 1992a).
5) In one study, benchmark dose (BMD) (developed by EPA) and the lower confidence limit on the benchmark dose (BMDL) of blood lead were studied to evaluate the biologic exposure limits for renal dysfunction caused by lead. The relationship between the blood lead concentration and the urinary excretion of total protein (TP), beta-2-microglobulin [beta2-MG], and N-acetyl-3-D-glucosaminidase (NAG), the three indices for renal dysfunction, were evaluated. It was determined that the levels of NAG, beta2-MG, and TP in lead-exposed workers were higher than those of control group, and levels of indices increased with the elevated blood lead. BMD and BMDL of blood lead were 299.4 to 588.7 mcg/L and from 253.4 to 402.3 mcg/L, respectively. NAG had the lowest BMDL of blood lead (highest TP> beta2-MG>NAG lowest). NAG was more sensitive than any other indices (eg, beta-2-microglobulin [beta2-MG]; total protein [TP]) of renal dysfunction. It was suggested that a blood lead level of 250 mcg/L should serve as a warning signal when evaluating renal function in workers occupationally exposed to lead (Lin & Tai-Yi, 2007).
6) In renal failure patients without undue lead exposure and with blood leads of less than 40 mcg/dL, decreases in blood lead after EDTA injection correlated with creatinine decrease and urine protein but not with urine lead excretion (Osterloh & Becker, 1986).
7) Sokas et al (1988) found that a 6-hour urine lead result will account for 88% of the variability of a full 24-hour diagnostic CaNa2EDTA chelation in patients with serum creatinine levels less than 2 mg/dL and no known current lead exposure in a study of 35 adult male volunteers (Sokas et al, 1988).
8) Young children (age 1 to 3.5 years) given the EDTA mobilization test producing a single urine lead concentration of 1 mcg/mL or greater were associated with positive mobilization ratios in a retrospective study of 58 patients (Shannon et al, 1989).

a) This method (r=0.63) may be useful in cases where inadequate 6 to 8 hour urine samples are obtained, and a mobilization ratio cannot be determined. Additional studies are needed to confirm this in larger populations.

9) Berger et al (1990) reported that a lead excretion ratio of greater than 1 micromoles of urinary lead excretion to millimoles calcium disodium EDTA administered corresponded to a cutoff value for 24-hour, unstimulated urinary lead excretion of 10.4 micrograms. Additional studies are needed to verify these results (Berger et al, 1990).
10) PORPHYRINS

a) Patients with lead poisoning may excrete elevated levels of porphyrins in the urine (Tutunji & Al-Mahasneh, 1994).

4.1.4)

A) OTHER

1) BONE

a) Bone lead may show long-term exposure and total body burden. Finger bone, patella, tibia and calcaneus have been analyzed in vivo. The trabecular bones (eg, calcaneus and patella) have a faster turnover than the cortical ones (eg, tibia), showing a shorter timespan than the cortical ones (Bergdahl & Skerfving, 2008).

2) TEETH

a) Teeth lead may show a cumulative index of the exposure from the prenatal period, when the tooth is formed, until the time of shredding (Bergdahl & Skerfving, 2008).

Radiographic Studies

1) X-ray of the wrists and knees is useful in the diagnosis of chronic lead poisoning in children. Normally, in the smaller bone (ulna or fibula), there is no increased opacity in the metaphyseal area whereas the adjacent radius and tibia normally show increased metaphyseal density. Increased density in the small bones is indication of lead exposure of several months duration (Blickman et al, 1986).
2) Other bones where densities can be seen include bones of arm and hand, thigh and foot, ribs, and clavicles. In infants lead lines may be seen in the vertebrae and pelvis (Woolf et al, 1990).
3) Abdominal films reveal lead-containing paint or objects as radio-opacities (Woolf et al, 1990).
4) In one patient, plain abdominal x-ray showed radiopaque flecks in the gut (Kulshrestha, 1996).
5) X-rays of suspect folk or other medications may serve as a rapid screening tool for the possible presence of lead (Kulshrestha et al, 1994).
6) L shell (LXRF) and K shell (KXRF) x-ray fluorescence techniques for measuring bone lead non-invasively have been developed (Wielopolski et al, 1986; Wielopolski et al, 1989 in press; Tell et al, 1992; Rosen & Markowitz, 1993; Kosnett et al, 1994).
7) Rosen et al (1989) reported 90% of lead-toxic children were correctly classified as being CaNa2EDTA- positive or -negative from blood lead and LXRF alone. Decreasing bone lead concentrations have been documented by LXRF following chelation therapy (Rosen et al, 1989; Rosen et al, 1991; Batuman et al, 1989).
8) In one series of 4 patients with elevated lead levels the 3 with clinical evidence of neurologic injury had normal CT and MRI studies of the brain but abnormal SPECT scans (Harchelroad, 1993).
9) CASE REPORT: Serial x-rays were used to ensure the passage of seven lead bullets in a 14-month-old girl who was treated with outpatient whole bowel irrigation (Schwarz & Alsop, 2008).

1) Computerized tomography may detect cerebral edema in patients with lead encephalopathy (Perelman et al, 1993).
2) A 23-month-old female who died from lead encephalopathy had a negative CT scan for cerebral edema prior to death. Cerebral edema was noted at autopsy (Hugelmeyer et al, 1988).

1) MRI may also be used to demonstrate brain edema patients with lead encephalopathy (Perelman et al, 1993).
2) A study of 157 Cincinnati Lead Study participants (ages 19 to 24 years old) used MR imaging to examine the relationship between childhood lead exposure and adult brain volume. It was revealed that higher mean childhood blood lead concentration was associated with region-specific reductions in adult gray matter volume, specifically in portions of the prefrontal cortex (eg, medial and the superior frontal gyri comprising the ventrolateral prefrontal cortex, anterior cingulate cortex, postcentral gyri, the inferior parietal lobule, cerebellar hemispheres), mainly responsible for executive functions, mood regulation, and decision-making. However, there was no significant volume changes within white matter or CSF volume. Overall, these areas of gray matter volume loss were much larger and more significant in men than women (Cecil et al, 2008).

Methods

1) LEAD TESTING

a) LeadCare II Blood Lead Test System (from ESA Biosciences (Chelmsford, Mass) is used to test for presence of lead using a finger stick or venous whole blood sample. It may be used while the patient is present, in as little as 3 minutes, by applying an electrical current to the patient's blood sample, causing lead to collect on disposable sensors. LeadCare II Blood Lead test System is available only at certain hospitals, private and public health laboratories, and other testing facilities. Patient's with borderline or positive test results should be tested again during a follow-up testing (United States Food and Drug Administration, 2006).
b) K X-RAY FLUORESCENCE (K-XRF) is a new test used to evaluate long-term lead levels. It measures lead levels in trabecular bone at the patella or calcaneus and cortical bone at the tibia. K-XRF is mostly used in research and is not widely available to clinicians (ATSDR, 2000; Todd et al, 1992).
c) Lead Check(TM) swabs (from HybriVet Systems, Incorporated (1-800-262-LEAD)) are available for consumer use to instantly test for the presence of lead in paint and ceramics. Lead Check(TM) (HybriVet Systems, Inc.) was found to be sensitive for detecting lead in paint at levels of 0.5% but not sensitive in detecting soil lead at 1000 ppm (Scharman & Krenzelok, 1993).

2) Lead is assayed in whole blood as most is in the RBC. Either atomic absorption spectrometry or anodic stripping voltammetry may be used successfully for both blood and urine.
3) Erythrocyte protoporphyrin (EP) and zinc protoporphyrin (ZPP or Zn PP) are measured in a wet drop of blood in a special fluorometer (Hematofluorometer).
4) Measurement of coproporphyrin or delta-aminolevulinic acid concentrations or red cell delta-aminolevulinic acid dehydratase activity are no longer necessary clinical procedures.
5) Nieburg et al (1974) demonstrated a high correlation between red cell delta-aminolevulinic acid dehydratase (ALAD) with chelatable lead (Nieburg et al, 1974).
6) Morris et al (1988) found that ALAD in combination with blood lead was a marginally better predictor of urinary lead excretion than was EP at either time point in a study of 20 pediatric patients (Morris et al, 1988).
7) Measurement of maximal motor nerve conduction velocity is an insensitive screen for low-level lead toxicity (Schwartz et al, 1988).
8) Lille et al (1988) reported decreased peripheral conduction velocities in 13 workers occupationally exposed to inorganic lead (Lille et al, 1988).

1) In one case of lead poisoning due to the ingestion of snooker chalk, graphite furnace spectrophotometry was used to analyze blood lead. Flame spectrophotometry was used to analyze environmental samples (Dargan et al, 2000). In another study, graphite furnace atomic absorption spectrophotometry was used to measure blood lead in cases with zinc protoporphyrin/heme ratio exceeding 70 mcmol/mol heme (Kakosy et al, 1996).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Symptomatic patients or patients with concern of high lead exposure/levels (for children, whole blood lead levels 70 mcg/dL or more) should be admitted. The patient’s clinical status should determine whether or not the patient should go to the ward or ICU (eg, encephalopathic patients merit an ICU admission). Criteria for discharge should include improvement/resolution of symptoms, transition to oral chelation, and known removal of lead exposure.
B) CHILDREN

1) Hospitalize any child with a BLL of 45-69 micrograms/deciliter (mcg/dL) and symptoms (significant CNS or protracted gastrointestinal symptoms), or with BLL of greater than or equal to 70 mcg/dL, with or without symptoms ( CDC, 1997).
2) Chelation therapy should be instituted in all patients with a blood lead level of 45 micrograms/deciliter (2.2 micromoles/liter) or greater using venous blood lead measurement. The child should be in a lead-safe environment before beginning chelation therapy ( CDC, 1997).

6.3.1.2) HOME CRITERIA/ORAL

A) Most asymptomatic lead exposures can be managed on an outpatient basis, as long as further lead exposure can be prevented and patient follow-up can be established.
B) REEXPOSURE

1) Reexposure needs to be ruled out as a source for rebound. Significantly increased exposure with elevation of blood lead has been seen in households during deleading of the dwelling (Rey-Alvarez & Menke-Hargrave, 1987; Amitai et al, 1987).

C) REBOUND

1) Rebound has been reported in children that were not re-exposed to lead. "Rebound" occurs when chelation is stopped, and consists of blood lead levels rising due only to re-equilibration with the bone. Typically, blood lead levels are very low during chelation, and values return to 1/2 to 2/3 of pre-chelation values when chelation is stopped. However, rises in blood levels after chelation can never be assumed to be due to rebound. Careful history and sometimes environmental investigation is necessary to be sure reexposure is not occurring. When blood lead levels rebound above 70 micrograms/deciliter, additional courses of chelation may be necessary (Moel et al, 1986).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consultation with your local poison center/toxicologist is advised. Public health departments should also be notified to arrange home visit and environmental assessment. Notify OSHA for occupational lead poisoning.
B) All patients with increased intracranial pressure should be seen by a neurosurgeon for assistance in monitoring and controlling ICP.
C) Refer children of industrially exposed workers for lead screening.
D) Refer children to the Public Health Department or other resources for assistance in identifying lead source.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Symptomatic lead exposures or patients with a potentially significant oral ingestion (eg, ingestion of a known lead figurine or key chain) merit immediate evaluation at a health care facility. If a significant ingestion can be ruled out (eg, via radiographs), asymptomatic patients may be discharged to home.

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Activated charcoal may be used after an acute ingestion. For dermal, eye or inhalational exposures, treatment is standard decontamination including removal of contaminated clothing and washing the exposed area with soap and water.

6.5.2)

A) ACTIVATED CHARCOAL

1) Activated charcoal adsorbs lead acetate in vitro, with a maximum adsorptive capacity of 9.1 milligrams lead per gram of activated charcoal in one study (Traub et al, 2001). While this is far less efficient than the adsorption typically seen with drugs, it is not insignificant. Activated charcoal is recommended after acute ingestion or in patients with evidence of radiopaque foreign bodies on abdominal radiographs.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

B) WHOLE BOWEL IRRIGATION (WBI)

1) Whole bowel irrigation has been used successfully in the management of lead ingestion (Hatten et al, 2013; Schwarz & Alsop, 2008; McNutt et al, 2000; Murphy et al, 1991; Roberge et al, 1991). No controlled studies have been done to prove the efficacy of whole bowel irrigation in lead ingestion; its use should be considered when evidence of radiopaque lead in the GI tract persists despite efforts at decontamination.

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

3) CASE REPORT: A 14-month-old girl ingested seven lead bullets and was successfully treated with outpatient whole bowel irrigation over 4 days. Serial x-rays were used to ensure the passage of the bullets (Schwarz & Alsop, 2008).

C) GASTRIC LAVAGE

1) There is no evidence to support the use of gastric lavage in lead ingestions. Consider gastric lavage in patients with recent ingestions of liquid or powdered lead-based products (paint, ceramic glaze, etc).
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

D) LEAD BULLETS

1) Lead-containing buckshot, shrapnel or bullets lodged in or adjacent to synovial spaces should be surgically removed.
2) ENDOSCOPIC REMOVAL OF INGESTED FIREARM CARTRIDGES: Two patients developed lead toxicity after ingesting intact firearm cartridges. Because of the risk of detonation from electrocautery during surgery, both patients underwent endoscopy procedures using a snare to remove the cartridges (Hatten et al, 2013).

a) The first patient, a developmentally delayed, non-verbal 15-year-old boy, presented with a 3-week history of nausea, vomiting, anorexia, diarrhea, constipation, and a decreased level of activity. He appeared sleepy, but arousable following commands. He was too weak to stand independently and had hyperactive patellar and brachioradialis reflexes without clonus. Because of the risk of detonation from electrocautery during surgery, he underwent an endoscopy procedure using a snare to remove 3 intact, partially corroded 30-mm rifle cartridges. Laboratory results revealed normocytic anemia, a hemoglobin level of 6.3 g/dL, a hematocrits of 18.6%, and basophilic stippling on the peripheral blood smear. Following treatment with parenteral and oral chelation, his blood lead concentration gradually decreased from 146 mcg/dL (12 hours after endoscopy) to 38-mcg/dL (91 days after endoscopy). Chelation therapy included the following dosing regimen: initially, BAL 75 mg/m(2) by deep intramuscular injection every 4 hours, calcium disodium-EDTA 1500 mg/m(2)/day continuous infusion, then transitioned to oral succimer 10 mg/kg every 8 hours on day 4, then twice daily after day 9 to complete a 19-day course of succimer (Hatten et al, 2013).
b) The second patient, a 65-year-old woman ingested an unknown quantity of bullets in a suicide attempt and arrived to the ED 5 hours later. An initial blood lead concentration was 9.7 mcg/dL. Despite treatment with whole bowel irrigation with polyethylene glycol for 6 hours and multiple bowel movements, cartridges were not excreted. On day 2, she underwent upper endoscopy and 26 (0.22 caliber) bullets were removed using a snare. She was discharged 3 days after ingestion to the psychiatry ward. Her blood lead concentrations were 40.5 mcg/dL, 29.3 mcg/dL, and 17.2 mcg/dL on days, 3, 24, and 60, respectively. Chelation therapy was not administered (Hatten et al, 2013).

E) LEAD FOREIGN BODIES

1) Ingestion of a lead-containing foreign body generally does not produce lead toxicity unless it is not eliminated within 2 weeks of the ingestion (Durback et al, 1989). More recently, acute elevation of blood lead levels (up to 89 mcg/dL 48 hours post ingestion) have occurred, especially when the foreign body has remained in the stomach (Holstege et al, 2001).
2) Patients ingesting a lead-containing foreign body should be monitored for signs of lead toxicity including blood lead monitoring until the elimination of the foreign body is documented.
3) Endoscopic removal of the lead foreign body is indicated if the object remains in the stomach. Surgery may be indicated if unable to retrieve the foreign body, or if it has not been eliminated by 2 weeks after ingestion (Holstege et al, 2001; Berg et al, 2000).
4) CERAMIC GLAZES - Ingestion of as little as 15 milliliters of a lead-containing ceramic glaze was visualized on abdominal x-ray in a child (Sturm, 1988). Patients with any significant exposure (more than a taste) should receive gastric decontamination, abdominal x-ray, and blood lead level.

6.5.3)

A) MONITORING OF PATIENT

1) Capillary screens are generally reliable but do carry risk of contamination, and thus should be confirmed with whole blood lead levels.
2) Current federal Medicaid guidelines require lead screening in children at 12 and 24 months of age. In addition, lead screening is required in all children between the ages of 36 to 72 months who previously have not been screened for lead.
3) Refugee children are at higher risk, and the CDC recommends lead testing in all refugee children from the ages of 6 months to 16 years upon entry to the United States. Repeat lead testing is recommended in children ages 6 months to 6 years after 6 months in a permanent residence. Other residents should be tested if a blood lead level comes back elevated.
4) In children with blood lead levels between 20 to 44 mcg/dL, obtain hemoglobin or hematocrit levels and evaluate the child’s iron status. Consider abdominal radiographs with bowel decontamination if particulate lead ingestion is suspected.
5) Zinc protoporphyrin and erythrocyte protoporphyrin assays are not sensitive at lower BLLs. In addition, they are not specific to lead and have a lag time of approximately 120 days before showing effects of an exposure.
6) Hypochromia and basophilic stippling suggest lead intoxication, but they are nonspecific and their absence does not rule out the diagnosis.
7) Employees whose blood lead level is equal to or greater than 50 mcg/dL shall be temporarily removed from exposure until their blood lead level is at or below 40 mcg/dL.

B) FLUID/ELECTROLYTE BALANCE REGULATION

1) Evaluate fluid balance status; if CNS status permits, establish adequate urine flow of 1 to 2 mL/kg/hr but do not force fluids. High urine flow may protect kidneys from damage by lead and by chelation; however, if any signs of increased ICP are present, high fluid administration may increase risk to brain.

C) CHELATION THERAPY

1) INDICATIONS

a) CHILDREN: Hospitalize any child with a BLL of 45-69 micrograms/deciliter (mcg/dL) and symptoms (significant CNS or protracted gastrointestinal symptoms), or with BLL of greater than or equal to 70 mcg/dL, with or without symptoms ( CDC, 1997).
b) Chelation therapy should be instituted in all patients with a blood lead level of 45 micrograms/deciliter (2.2 micromoles/liter) or greater using venous blood lead measurement ( CDC, 1997).

2) DOSING

a) Several chelating agents are effective in increasing lead excretion. The following guidelines have been recommended (Henretig, 2006; Centers for Disease Control and Prevention, 2010):

1) ENCEPHALOPATHY: ADULTS or CHILDREN: BAL 450 mg/m(2)/day (24 mg/kg/day) (regimen, 75 mg/m(2) IM every 4 hours) for 5 days. IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1500 mg/m(2)/day (50 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
2) SYMPTOMATIC ADULTS WITH BLL GREATER THAN 100 mcg/dL and CHILDREN WITH BLL GREATER THAN 69 mcg/dL: BAL 300 to 450 mg/m(2)/day (18 to 24 mg/kg/day) (regimen, 50 to 75 mg/m(2) every 4 hours for 3 to 5 days). IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1000 to 1500 mg/m(2)/day (50 to 75 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
3) ADULTS WITH MILD SYMPTOMS OR BLL 70 TO 100 mcg/dL: Succimer 700 to 1050 mg/m(2)/day (regimen, 350 mg/m(2) (10 mg/kg) orally every 8 hours for 5 days and then every 12 hours for 14 days).
4) ASYMPTOMATIC CHILDREN WITH BLL BETWEEN 45 to 69 mcg/dL: Succimer 700 to 1050 mg/m(2)/day (regimen, 350 mg/m(2) (10 mg/kg) orally every 8 hours for 5 days and then every 12 hours for 14 days) OR IV edetate calcium disodium 1000 mg/m(2)/day continuous infusion or 2 to 4 divided IV doses for 5 days OR D-penicillamine 25 to 35 mg/kg/day in divided doses. Treatment is usually initiated at 25% of this dose and gradually increased to the full dose over 2 to 3 weeks to minimize adverse reactions. Do not use D-penicillamine in patients with known penicillin allergy.
5) ASYMPTOMATIC ADULTS AND BLL LESS THAN 70 mcg/dL: No routine chelation is indicated.
6) ASYMPTOMATIC CHILDREN AND BLL 20 to 44 mcg/dL: No routine chelation is indicated. Succimer (same regimen as described above) has been used.
7) NOTE: Monitor blood lead concentrations at the end of chelation and for several weeks to months after the completion of therapy to detect rebound or reexposure, and guide the need for further courses of chelation. When the BLL is improving per the guidelines and the patient is able to tolerate oral medications, BAL can be replaced with succimer with no waiting period between treatments.

3) PROPHYLACTIC CHELATION THERAPY PROHIBITED - The OSHA lead standard specifically PROHIBITS the use of prophylactic chelation therapy to prevent elevated blood lead levels in employees exposed to lead (CFR, 1988), or to keep elevated levels from reaching mandated action levels.
4) CHILDREN: Chelating agents should only be given to children who reside in environments free of lead during and after treatment ( CDC, 1997).
5) In one study, it was suggested that chelation therapy may slow the progression of renal insufficiency in patients with mildly elevated body lead burden (Lin et al, 1999).
6) COMBINATION THERAPY/COMPARATIVE EFFICACY: In a retrospective review of medical records of children with a whole blood lead (BPb) concentration of 2.17 mcmol/L (45 mcg/dL) or more (or less than 2.17 mcmol/L and not a candidate for outpatient oral chelation), treatment with DMSA or BAL in combination with EDTA resulted in a comparable reduction in postchelation BPb levels (at follow-up, reduction of 38.5% and 34.4%, respectively). Children were treated with BAL plus EDTA (n=23) or DMSA plus EDTA (n=22). The mean BPb values at the end of therapy and at 14 and 33 days after chelation were compared with pretreatment BPb. Overall, children in the BAL plus EDTA group experienced elevated liver enzyme concentrations and multiple episodes of vomiting more frequently compared with DMSA plus EDTA group (Besunder et al, 1997).
7) CASE REPORTS

a) NEONATES - Combined exchange transfusion and chelation therapy with BAL and Ca Na2EDTA were used in a neonate with an elevated cord BLL of 100 mcg/dL. The infant's mother had a long history of eating glazed pottery (Mycyk et al, 2002).
b) NEONATES - A neonate with congenital lead intoxication (BLL 17-37 mcg/dL; hemoglobin 12.2 g/dL; Hct 35.1%) was treated with IV calcium EDTA and oral DMSA (Guzman et al, 2000).

D) LEAD SCREENING

1) Calcium Disodium EDTA lead mobilization test: May be useful in determining necessity for therapeutic chelation in children with blood lead levels of 25 to 44 micrograms/deciliter. Because of the difficulties in administering the test and the uncertainties in interpreting results it is rarely used any more (Mortensen & Walson, 1993).

a) Children whose blood levels are >44 micrograms/deciliter should not receive a provocative chelation test; they should be immediately referred for chelation therapy (CDC, 1991).
b) The CaNa2EDTA provocative test may be performed as an outpatient if the patient remains in the clinic (Piomelli et al, 1984).
c) 76 percent of children with blood lead levels 35 to 44 micrograms/deciliter and 35 percent of children with levels of 25 to 34 micrograms/deciliter had positive test results (Markowitz & Rosen, 1991).
d) A study in the UK indicated that 75 milligrams/kilogram/day of calcium disodium EDTA was approximately 4 times more effective in producing lead excretion than 30 milligrams/kilogram/day of DMSA (Vale et al, 1992).
e) Chelation of moderately lead poisoned children with EDTA had no short term (7 weeks) effect on cognitive scores, but lowering of blood levels did improve scores at 6 month (Ruff et al, 1993).

2) PROCEDURE - Test child for iron deficiency and restore normal body iron stores prior to beginning the test. Low iron status may affect test outcome (CDC, 1991).

a) Obtain baseline blood lead level, have patient empty bladder.
b) Administer CaNa2EDTA 500 milligrams/square meter intravenously, or intramuscularly with procaine. Some authors recommend 1 gram as a maximum daily dose.
c) Collect all urine in lead-free containers for 8 hours.
d) The lead excretion ratio is calculated using the following equation:

Total urine lead excreted (mcg)
---------------------------------
Total amount of Ca EDTA given (mg)

e) Weinberger et al (1987) suggested that a test is positive if the lead excretion ratio is equal to or greater than 0.5 based on an analysis of 248 initial mobilization tests performed on an ambulatory basis (Weinberger et al, 1987).
f) Other authors have suggested a 4-hour collection period be used for the outpatient CaNa2EDTA challenge test (Aronow et al, 1989).
g) INTERNAL REDISTRIBUTION - In rat model of chronic low-level lead exposure, single dose calcium disodium edetate increased urine, brain, and hepatic lead levels and decreased blood and renal lead levels (Cory-Slechta et al, 1988 (in press)) .

1) Brain lead level increased by 100 percent over controls, suggesting concerns about the safety of calcium disodium edetate mobilization test (Chisolm, 1987).
2) Five daily injections of calcium disodium edetate in rats showed no net loss in brain, hepatic, and bone lead compared with controls (Cory-Slechta et al, 1988 (in press)).

E) DIMERCAPROL

1) INDICATION: Dimercaprol is used in combination with Edetate Calcium Disodium injection to treat patients with acute lead poisoning (Prod Info BAL In Oil intramuscular injection, 2008).
2) Dimercaprol is a small molecule drug which will cross into cells and may prevent the worsening of clinical and biochemical status on the first day of EDTA therapy (Chisolm, 1971).
3) DOSE

a) ENCEPHALOPATHY: ADULTS or CHILDREN: BAL 450 mg/m(2)/day (24 mg/kg/day) (regimen, 75 mg/m(2) IM every 4 hours) for 5 days. IV edetate calcium disodium should be given immediately after the second dose of BAL (Henretig, 2006; Centers for Disease Control and Prevention, 2010).
b) SYMPTOMATIC ADULTS WITH BLL GREATER THAN 100 mcg/dL and CHILDREN WITH BLL GREATER THAN 69 mcg/dL: BAL 300 to 450 mg/m(2)/day (18 to 24 mg/kg/day) (regimen, 50 to 75 mg/m(2) every 4 hours for 3 to 5 days). IV edetate calcium disodium should be given immediately after the second dose of BAL (Henretig, 2006; Centers for Disease Control and Prevention, 2010).

4) ADVERSE EFFECTS

a) Common effects include pain at the injection site and fever (especially in children). Other effects include hypertension, tachycardia, nausea, vomiting, headache, burning sensations of the mouth and throat, a sensation of constriction in the throat, chest, or hands, conjunctivitis, lacrimation, salivation, tingling of the extremities, diaphoresis, abdominal pain, and anxiety. Dimercaprol injection contains peanut oil. Avoid in patients with peanut allergy (Prod Info BAL In Oil intramuscular injection, 2008).

5) PRECAUTIONS

a) Dimercaprol is generally contraindicated in patients with hepatic insufficiency, with the exception of postarsenical jaundice (Prod Info BAL In Oil intramuscular injection, 2008). May cause hemolysis in G6PD deficient patients. BAL metal chelate disassociates in acid environment; urinary alkalinization is usually recommended. Do not administer with iron therapy as BAL iron complex may cause vomiting (Howland, 2002).

F) EDETATE CALCIUM DISODIUM

1) SUMMARY: The most efficient parenteral chelating agent is calcium disodium ethylene diamine tetraacetic acid (edathamil, EDTA, or CaVersinate).
2) INDICATIONS: Edetate calcium disodium (CaNa2EDTA) is indicated for reducing blood levels and depot stores of lead in acute and chronic lead poisoning and lead encephalopathy in adults and pediatric populations (Prod Info Calcium disodium versenate, 2004).

a) CHILDREN: Only CALCIUM disodium EDTA, not disodium edetate, may be used in children with lead poisoning. Disodium edetate may induce tetany and possibly fatal hypocalcemia (CDC, 1991).

3) DOSING

a) ADULTS

1) ENCEPHALOPATHY: IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1500 mg/m(2)/day (50 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
2) SYMPTOMATIC ADULTS WITH BLL GREATER THAN 100 mcg/dL: . IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1000 to 1500 mg/m(2)/day (50 to 75 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
3) The dosing recommended by the manufacturer for asymptomatic adults whose blood lead level is between 20 and 70 micrograms/deciliter is 1000 milligrams/square meter/day as a continuous infusion. The same dose may be administered intramuscularly divided in equal doses administered every 8 or 12 hours, however this is rarely dose because of the associated pain. Whether given intramuscularly or intravenously, it is continued for a period of 5 days. After 5 days, therapy is interrupted for 2 to 4 days to allow redistribution of the lead and prevent depletion of zinc and other essential metals. Two courses of therapy are usually given; however, it depends on the patient's tolerance of the drug and the severity of the lead toxicity (Prod Info Calcium disodium versenate, 2004).
4) For adults with lead nephropathy, the suggested dosing regimen is 500 milligrams/square meter every 24 hours for 5 days for patients with serum creatinine levels 2 to 3 milligrams/deciliter, every 48 hours for 3 doses for patients with serum creatinine levels 3 to 4 milligrams/deciliter, and once a week for those with serum creatinine levels above 4 milligrams/deciliter. These may be repeated at 1 month intervals (Prod Info Calcium disodium versenate, 2004).

b) CHILDREN

1) ENCEPHALOPATHY: IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1500 mg/m(2)/day (50 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
2) SYMPTOMATIC CHILDREN WITH BLL GREATER THAN 69 mcg/dL: . IV edetate calcium disodium should be given immediately after the second dose of BAL. Dose: 1000 to 1500 mg/m(2)/day (50 to 75 mg/kg/day) continuous infusion or 2 to 4 divided IV doses for 5 days.
3) ASYMPTOMATIC CHILDREN WITH BLL BETWEEN 45 to 69 mcg/dL: Oral Succimer or D-Pennicilamine are generally preferred in this population, but IV edetate calcium disodium may be gives at 1000 mg/m(2)/day as a continuous infusion or in 2 to 4 divided IV doses for 5 days
4) Per the manufacturer the recommended dose for asymptomatic pediatric patients whose blood lead level is between 20 and 70 micrograms/deciliter is 1000 milligrams/square meter/day given as an intravenous infusion over 24 hours and continued for a period of 5 days. Intramuscular administration of 1000 mg/m(2)/day divided in equal doses every 8 or 12 hours is another option that is rarely used because of the pain associated with administration. After 5 days, therapy is interrupted for 2 to 4 days to allow redistribution of the lead and prevent depletion of zinc and other essential metals. Two courses of therapy are usually given; however, it depends on the patient's tolerance of the drug and the severity of the lead toxicity (Prod Info Calcium disodium versenate, 2004).

c) INTRAVENOUS ADMINISTRATION

1) AVOID RAPID INFUSION - Add the total daily dose of 1000 milligrams/square meter/day to 250 to 500 milliliters of 5% dextrose or 0.9% sodium chloride injection. This should be infused over 8 to 24 hours (Prod Info Calcium disodium versenate, 2004).

d) INTRAMUSCULAR ADMINISTRATION

1) The total daily dose of 1000 milligrams/square meter/day should be divided into equal doses spaced 8 to 12 hours apart. Lidocaine or procaine should be added to the injection to minimize pain at the injection site. Because of the pain associated with this method of administration it is rarely used.

a) The final concentration of lidocaine or procaine (5 milligrams/milliliter; 0.5%) can be obtained as follows: 0.25 milliliters of 10% lidocaine solution per 5 milliliters of concentrated edetate calcium disodium or 1 milliliter of 1% lidocaine or procaine solution per milliliter of concentrated edetate calcium disodium.

e) Edetate calcium disodium, used alone, may aggravate symptoms in patients with very high blood lead levels. When clinical symptoms consistent with lead poisoning or when blood lead levels are greater than 70 micrograms/deciliter, it is recommended that edetate calcium disodium be used in conjunction with dimercaprol (Prod Info Calcium disodium versenate, 2004).
f) Acutely ill patients may be dehydrated from vomiting. Edetate calcium disodium is primarily excreted in the urine; therefore it is very important to establish urine flow with intravenous fluids before the first dose is given. Excessive fluid must be avoided in patients with encephalopathy. Once urine flow is established, additional intravenous fluids are restricted to electrolyte and basal water requirements. Whenever there is cessation of urine flow, administration of edetate calcium disodium should be stopped to avoid unduly high tissue levels of the drug. Reduced doses must be used in patients with pre-existing mild renal disease (Prod Info Calcium disodium versenate, 2004).

4) FORMS

a) Edetate calcium disodium is a sterile, injectable concentrated solution for intravenous infusion or intramuscular injection. It is available in 5 mL ampules each containing 1000 mg of edetate calcium disodium in water for injection (equivalent to 200 mg/mL) in water for injection (Prod Info Calcium disodium versenate, 2004)

5) ADVERSE EFFECTS

a) The following adverse effects have been reported with the use of edetate calcium disodium: Inverted T waves and cardiac rhythm irregularities, transient decreases in blood pressure, acute necrosis of the proximal tubules, microscopic hematuria, glycosuria, proteinuria, nephrotoxicity, acute renal failure, dermatitis and exfoliative dermatitis of the scrotum, injection site pain following intramuscular injection, hypocalcemia, hypercalcemia, nausea, vomiting, abdominal pain, diarrhea, mild elevations in SGOT and SGPT, anemia, bone marrow depression, fatigue, myalgia, zinc deficiency, headache, tremors, numbness, and tingling (Prod Info Calcium disodium versenate, 2004; Klaasen, 2001; Moel & Kumar, 1982; Chisholm, 1968; Seven, 1960).
b) In patients with lead encephalopathy, edetate calcium disodium may worsen cerebral edema. For patients with lead encephalopathy, edetate calcium disodium should be begun 4 hours after administration of dimercaprol (Prod Info Calcium disodium versenate, 2004)l.
c) OVERDOSE - No ill effects were observed following inadvertent administration of 5 times the recommended dose, infused intravenously over a 24-hour period of time, to an asymptomatic 16-month-old with a blood lead level of 56 mcg/dL (Prod Info Calcium disodium versenate, 2004).
d) EDTA chelates zinc. While serum zinc returns rapidly to normal, some administer zinc after therapy.
e) If iron stores are marginal or questionable, or ferritin is low, administer iron after therapy.

6) REBOUND - If the blood lead level rebounds to its pretreatment level or is greater than 50 micrograms/deciliter, a repeat course of chelation should be considered.
7) PRECAUTIONS: Calcium EDTA should only be administered after adequate urine flow is established (Chisolm, 1971). If urine flow has NOT been established in a symptomatic child after 3 hours of fluids, administer the EDTA and initiate simultaneous hemodialysis to remove the EDTA-Pb complex which is nephrotoxic.

a) Up to 16 percent of children receiving calcium EDTA and BAL for lead poisoning may develop a nephrotoxic reaction (Moel & Kumar, 1982a). At least every other day urinalysis and serum creatinine are recommended.

8) INTERNAL REDISTRIBUTION - In a rat model of chronic low-level lead exposure, single dose calcium disodium edetate increased urine, brain, and hepatic lead levels and decreased blood and renal lead levels (Cory-Slechta, 1988).

a) Brain lead level increased by 100 percent over control suggesting concerns about the safety of calcium disodium edetate mobilization test (Chisolm, 1987).
b) Five daily injections of calcium disodium edetate in rats showed no net loss in brain, hepatic, and bone lead compared with controls (Cory-Slechta, 1988).

9) PROPHYLACTIC CHELATION THERAPY PROHIBITED - The OSHA lead standard specifically PROHIBITS the use of prophylactic chelation therapy to prevent elevated blood lead levels in employees exposed to lead (CFR, 1988).
10) INTRAPERITONEAL EDTA has been used to treat lead intoxication in a patient with renal failure (Roger et al, 1990).
11) EFFICACY

a) In one study of children with moderate lead poisoning (levels between 25 and 55 micrograms/deciliter, asymptomatic) those with positive EDTA mobilization tests were treated with 5 days of EDTA chelation while those with negative lead mobilization tests were not. Lead abatement was performed in all homes. After 6 or 7 weeks, the children who received EDTA therapy did not have greater decreases in blood or bone lead levels (determined by L x-ray fluorescence) than the unchelated group once differences in initial blood and bone lead levels were controlled (Markowitz et al, 1993) .

G) SUCCIMER

1) INDICATIONS: Succimer (2,3-dimercaptosuccinic acid)(DMSA) is an orally administered chelator approved for use in children with lead poisoning and blood lead levels above 45 micrograms/deciliter (Prod Info CHEMET(R) oral capsules, 2005). It is the drug of choice for this indication, and should be considered also for adults with acute or chronic lead poisoning, in the absence of encephalopathy or protracted vomiting.
2) SUCCIMER/DOSE/ADMINISTRATION

a) PEDIATRIC: Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).

1) The dosing interval is then increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless blood lead concentrations indicate the need for prompt retreatment.
2) Succimer capsule contents may be administered mixed in a small amount of food (Prod Info CHEMET(R) oral capsules, 2011).

b) ADULT: Succimer is not FDA approved for use in adults, however it has been shown to be safe and effective when used to treat adults with poisoning from a variety of heavy metals (Fournier et al, 1988a). Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).

1) The dosing interval then is increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless the patient's symptoms or blood concentrations indicate a need for more prompt treatment (Prod Info CHEMET(R) oral capsules, 2011).

3) MONITORING PARAMETERS

a) The manufacturer recommends monitoring liver enzymes and complete blood count with differential and platelet count prior to the start of therapy and at least weekly during therapy (Prod Info CHEMET(R) oral capsules, 2011).
b) Succimer therapy did not worsen preexisting borderline abnormal liver enzyme levels in a prospective evaluation of 15 children with lead poisoning (Kuntzelman & Angle, 1992).

4) SUCCIMER/ADVERSE EFFECTS: The following adverse events have occurred in children and adults during clinical trials: nausea, vomiting and diarrhea; transient liver enzyme elevations; rash, pruritus; drowsiness and paresthesia. Events reported infrequently include: sore throat, rhinorrhea, mucosal vesicular eruption, thrombocytosis, eosinophilia, and mild to moderate neutropenia (Prod Info CHEMET(R) oral capsules, 2011).
5) ODOR: Succimer has a sulfurous odor that may be evident in the patient's breath or urine (Prod Info CHEMET(R) oral capsules, 2005).
6) HYPERTHERMIA: One adult developed acute severe hyperthermia associated with hypotension; rechallenge resulted in hyperthermia with shaking chills and hypertension (Marcus et al, 1991).
7) AVAILABLE FORMS: Succimer (Chemet (R)), 100 mg capsules (Prod Info CHEMET(R) oral capsules, 2011).
8) CASE REPORT - Hemolytic anemia developed in a man with G6PD deficiency during treatment with DMSA (Gerr et al, 1994). However, DMSA was well tolerated in 2 children with homozygous G6PD deficiency (Graziano et al, 1992).
9) EFFICACY

a) SUMMARY: It has been shown to be an effective chelator of lead in animal studies (Graziano et al, 1978; Kapoor et al, 1989), lead-poisoned workers (Friedheim et al, 1978; Graziano et al, 1985), a patient poisoned with lead contaminated bread (Bentur et al, 1987), children (Graziano et al, 1986; Graziano et al, 1988; Graziano & Blum, 1991; Liebelt et al, 1994), and adult lead-poisoned patients (Fournier et al, 1988; Thomas & Ashton, 1991; Meggs et al, 1994).
b) BLOOD LEAD LEVELS: DMSA was equally effective in lowering blood lead in children with low (mean 31 mcg/dL) versus high (mean 51 mcg/dL) blood lead levels, but significant rebound occurred by about 40 days (Liebelt et al, 1994).

1) Lead levels remained relatively constant in a 21-month-old girl with retained lead pellets until the pellets were removed by endoscopy and WBI, indicating that DMSA may have prevented further absorption until the procedure was performed (Clifton et al, 2002; Sigg et al, 1999).
2) In one study of children with moderately elevated lead levels (BLL range 30-45 mcg/dL), DMSA did not improve long-term blood lead levels. It was suggested that these children should receive environmental evaluation and remediation (O'Connor & Rich, 1999). In a randomized, double blind, placebo controlled trial of succimer therapy in children with moderate lead poisoning (blood lead levels (BLLs) between 20 and 44 mcg/dL), DMSA lowered BLLs but did not improve scores on tests of cognition, behavior, or neuropsychological function (Rogan et al, 2001).When this same group of children was evaluated at age 7 years, succimer treatment was still not associated with any improvement in cognition, behavior or neuromotor performance(Dietrich et al, 2004).
3) CASE SERIES: In a study of 17 adult lead poisoned patients (BLL 50 mcg/dL or greater), 35 courses of oral succimer (30 mg/kg/day), administered for at least 5 days, increased urine lead excretion and reduced blood lead concentrations significantly (p less than 0.0001). Overall, succimer was well-tolerated, however, a transient increase in liver enzymes (ALT) was observed during 14% of chelations. One patient experienced a mucocutaneous skin reaction (Bradberry et al, 2009).
4) CASE REPORT: A 44-year-old woman was shot in the left lower back and right axilla with shotgun blasts during a mall shooting spree. Initial evaluation with x-ray showed a large number of scattered metallic pellets. After initial surgical debridement, imaging was still remarkable for numerous retained pellets. On day 16 post-injury, her whole-blood lead level was elevated (23 mcg/dL; reference range: 0 to 25 mcg/dL) and she reported nausea, fatigue, and myalgias one month later with her whole-blood lead level having increased (35 mcg/dL). Her whole blood lead levels decreased (5 mcg/dL) after treatment with oral succimer 500 mg twice daily, however became elevated (21 mcg/dL) one month later with accompanying nausea, fatigue, and myalgias. Her succimer dosing frequency was subsequently decreased to 100 mg twice daily and then 100 mg once daily with mild improvement in her nausea over the next 6 months and lead levels remaining between 16 and 18 mcg/dL. Eighteen months later, once daily succimer continues with persistent nausea and fatigue (Cyrus et al, 2011).
5) CASE REPORT: A 35-year-old man involved in a small shooting spree was shot with 2 shotgun blasts and was transported to the ED. Metallic pellets were seen with computed tomography and x-ray and the patient underwent exploratory laparotomy. His whole blood lead level was elevated (29 mcg/dL) 4 months later; he was treated with 1000 mg oral succimer twice daily and his lead levels declined (6 mcg/dL). His oral succimer was subsequently dose-adjusted to 100 mg twice daily and then 100 mg 3 times daily and he is asymptomatic one year later with blood lead level of 9 mcg/dL (Cyrus et al, 2011).

c) EFFECTS ON POSTURAL BALANCE AND GAIT/LOCOMOTION IN CHILDREN - In a randomized, placebo-controlled, double blind clinical trial of 161 children with early exposure to environmental lead (succimer group, n=77; placebo, n=80), succimer-treated group showed significantly lower postural sway during dynamic task performance indicating improved postural balance. In addition, significant improvements in functional task of obstacle crossing and normal walking were observed during locomotion tests in succimer-treated group (Bhattacharya et al, 2007).
d) EFFECTS ON GROWTH - One study reported that succimer lowered blood lead in moderately lead-poisoned children; however, it did not have a beneficial effect on growth during or after active treatment, and may even have an adverse effect on growth (Peterson et al, 2004).
e) PREGNANCY

1) A single course of oral DMSA (for 18 days) given to a woman in the 25th week of pregnancy did not change the maternal BLL (44 mcg/dL before chelation; 43.9 mcg/dL after chelation). The authors suggested that the ongoing mobilization of maternal blood lead or continued unrecognized environmental lead exposure may have affected the DMSA efficacy (Mirkin et al, 2000b).
2) A pregnant woman with chronic lead toxicity (BLL 57 mcg/dL) delivered a healthy-appearing neonate (a cord blood lead 126 mcg/dL). The mother was treated with a single course of oral succimer late in the third trimester of pregnancy without any appreciable change in BLL. Her newborn was treated with intramuscular dimercaprol and intravenous edetate calcium disodium for 3 days and then two 19-day courses of succimer. At 5 months of age, the infant's BLL was 21.5 mcg/dL (Horowitz & Mirkin, 2001).
3) In one study, 13 newborns (BLL 26-207 mcg/dL; at delivery mean neonatal BLL 74 mcg/dL and mean maternal BLL 55 mcg/dL) were treated with EDTA, BAL or succimer within the first 28 days of life. No adverse effects were noted in the neonates. No identifiable birth defects were observed in any infant. The authors concluded that BLLs in the neonate are higher than simultaneous maternal lead levels (Shannon, 2003).
4) An infant, born to a woman with lead poisoning, developed seizures and encephalopathy with peripheral neuropathy 8 hours after delivery. A chest radiograph revealed dense bands, described as sclerotic changes, at the proximal ends of the humeri. At 11 and 13 months of age, the infants BLL was 3.46 mcmoles/L (normal, less than 0.48 mcmole/L) and 2.69 mcmoles/L, respectively. The child was treated with two courses of oral succimer (Fleece & Robinson, 2007).
5) A woman who had sniffed petrol since childhood, delivered an infant with a cord blood lead level 8 times the accepted limit. Chelation with oral succimer reduced the infant's BLL. On follow-up at the age of 12 months, the infant had global developmental delay (Powell et al, 2006).

10) PHARMACOKINETICS

a) ABSORPTION - Succimer is absorbed rapidly orally, reaching peak blood levels in 1 to 2 hours.

1) TIME TO PEAK - Dart et al (1992) report Tmax values of 2.67 +/- 1.15 hours in 3 children and 3.33 +/- 1.15 hours in 3 adults with lead poisoning (Dart et al, 1992).
2) PEAK CONCENTRATIONS - DMSA peak concentrations ranged from 9.5 to 34.7 nanomoles/milliliter in 3 children and 17.2 to 35.8 nanomoles/milliliter in 3 adults with lead poisoning (Dart et al, 1992).

b) METABOLISM - Extensive metabolism of succimer is reported (Aposhian et al, 1989).
c) EXCRETION - Only 9 to 12 percent of administered succimer is excreted unchanged in the urine (Aposhian et al, 1989; Prod Info CHEMET(R) oral capsules, 2005).

1) RENAL CLEARANCE - Dart et al (1992) report renal clearance values of 12.9 +/- 9.6 milliliters/minute/square meter in 3 children and 24.7 +/- 3.3 milliliters/minute/square meter in 3 adults with lead poisoning. Renal clearance may be diminished in lead poisoned patients compared with normal adults (Dart et al, 1994).

d) ELIMINATION - DMSA elimination half-life ranged from 2.8 to 3.3 hours in 3 children and 1.5 to 2.4 in 3 adults with lead poisoning (Dart et al, 1994).

11) OTHER METALS CHELATED

a) Aposhian et al (1989) reported small increases in excretion of zinc, copper, and lead after succimer administration. The increased excretion was not statistically significant. Succimer did not influence the excretion of 27 elements and other metals (Aposhian et al, 1989).
b) Succimer did not interfere with parenteral administration of iron in a lead poisoned adult (Haust et al, 1989).

12) IRON DEFICIENCY - Concomitant administration of iron and DMSA is well tolerated in children with lead poisoning and iron deficiency (Graziano et al, 1992a).
13) AVAILABILITY - Succimer (Chemet(R)) is manufactured by McNeil Consumer Products as a 100 milligram capsule (Prod Info CHEMET(R) oral capsules, 2005).
14) ANIMAL STUDIES - Oral administration of DMSA does not enhance gastrointestinal absorption of lead in rats (Kapoor et al, 1989).

H) PENICILLAMINE

1) SUMMARY: Can be used orally as outpatient chelation therapy when the patient is in lead free surroundings (Vitale et al, 1973). Due to lesser efficacy and increased adverse reactions and precautions associated with penicillamine, succimer is the drug of choice when oral therapy is indicated.

a) In one study in 27 children, penicillamine was effective in lowering blood lead levels in children presenting with blood lead levels of 20 to 30 micrograms/deciliter (Shannon et al, 1989a). Another study suggests that lower doses of d-penicillamine (15 mg/kg/d) may reduce the rate of adverse effects without a significant reduction in the drug's efficacy (Shannon & Townsend, 2000).

2) DOSING FOR ASYMPTOMATIC CHILDREN WITH BLL BETWEEN 45 to 69 mcg/dL: D-penicillamine 25 to 35 mg/kg/day in divided doses. Treatment is usually initiated at 25% of this dose and gradually increased to the full dose over 2 to 3 weeks to minimize adverse reactions. Do not use D-penicillamine in patients with known penicillin allergy.
3) ADVERSE EFFECTS

a) Adverse effects in children receiving D-penicillamine include eosinophilia, leukopenia, thrombocytopenia, elevations of blood urea nitrogen, proteinuria, microscopic hematuria, incontinence, abdominal pain and upset, rash, urticarial eruptions, and erythema multiforme (Shannon & Townsend, 2000; Marcus, 1982; Shannon et al, 1989; Sue et al, 1991).
b) Rashes: Urticaria, erythema multiforme, toxic erythema, and an "ampicillin" type rash. All but the last require cessation of therapy.
c) Neutropenia: Requires a neutrophil count on a biweekly basis as continued therapy with a neutropenic response may result in aplastic anemia.
d) Eosinophilia commonly occurs in the first to third week of therapy though usually of little consequence.
e) Hypogeusia has been reported in adults.
f) CHRONIC - Chronic administration (weeks to months) of penicillamine is associated with a high incidence of adverse reactions including proteinuria, thrombocytopenia, leukopenia, pruritic mucocutaneous rash and gastrointestinal intolerance (Halverson et al, 1978).
g) PREGNANCY - Penicillamine can cause congenital tissue defects when used throughout pregnancy (Linares et al, 1979; Solomon et al, 1977; Anon, 1981). However, the teratogenic effect when used in low doses or for short periods of time such as in metal chelation has yet to be determined.

4) EFFICACY

a) D-penicillamine at a mean daily dose of 27.5 milligrams/kilogram over a mean duration of 76 days is reported effective for low-level lead poisoning in a retrospective cohort study of 84 treated and 37 control pediatric patients (Shannon et al, 1988).
b) At a daily dose of 15 to 30 milligrams/kilogram for 11 weeks, D-penicillamine was reported to decrease the mean peak blood lead level from 26 to 12 micrograms/deciliter in a study of 37 pediatric patients (Shannon et al, 1989).
c) RETROSPECTIVE STUDY - In a study of 55 children who received 66 courses of penicillamine therapy at a reduced dose of 15 mg/kg/day for lead poisoning, 3 children (4.5%) developed rash and 7 children (9.7%) had decreased white blood cell counts below 5000/mL. These effects were transient and efficacy of penicillamine was retained at this dose (Shannon & Townsend, 2000).

I) UNITHIOL

1) DMPS/INDICATIONS: Chelating agent for heavy metal toxicities associated with arsenic, bismuth, copper, lead and mercury (Blanusa et al, 2005).
2) DMPS/DOSING

a) ACUTE TOXICITY

1) ADULT ORAL DOSE:

a) 1200 to 2400 mg/day in equally divided doses (100 to 200 mg 12 times daily) (Prod Info DIMAVAL(R) oral capsules, 2004).

2) ADULT INTRAVENOUS DOSE (Arbeitsgruppe BGVV, 1996; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013):

a) If oral DMPS therapy is not feasible or in severe toxicity, it may be given intravenously.
b) ADMINISTRATION: DMPS should be injected immediately after breaking open the ampule and should not be mixed with other solutions. DMPS should be injected slowly over 3 to 5 minutes. The opened ampules cannot be reused.
c) First 24 hours: 250 mg intravenously every 3 to 4 hours (1500 to 2000 mg total).
d) Day two: 250 mg intravenously every 4 to 6 hours (1000 to 1500 mg total).
e) Day three: 250 mg intravenously every 6 to 8 hours (750 to 1000 mg total).
f) Day four: 250 mg intravenously every 8 to 12 hours (500 to 750 mg total).
g) Subsequent days: 250 mg intravenously every 8 to 24 hours (250 to 750 mg total).
h) Depending on the patient's clinical status, therapy may be changed to the oral route.

3) PEDIATRIC ORAL DOSE (Arbeitsgruppe BGVV, 1996; Blanusa et al, 2005):

a) There are insufficient clinical data regarding the pediatric use of DMPS. It should be used only if medically necessary.
b) Initial dose: 20 to 30 mg/kg/day orally in many equal divided doses.
c) Maintenance dose: 1.5 to 15 mg/kg/day.

4) PEDIATRIC INTRAVENOUS DOSE (Arbeitsgruppe BGVV, 1996; Blanusa et al, 2005; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013):

a) There are insufficient clinical data regarding the pediatric use of DMPS. It should be used only if medically necessary.
b) If oral DMPS therapy is not feasible or in severe toxicity, it may be given intravenously.
c) ADMINISTRATION: DMPS should be injected immediately after breaking open the ampule and should not be mixed with other solutions. DMPS should be injected slowly over 3 to 5 minutes. The opened ampules cannot be reused.
d) First 24 hours: 5 mg/kg intravenously every four hours (total 30 mg/kg).
e) Day two: 5 mg/kg intravenously every six hours (total 20 mg/kg).
f) Days three and four: 5 mg/kg intravenously every 8 to 24 hours (total 5 to 15 mg/kg).

b) CHRONIC TOXICITY

1) ADULT DOSE

a) 300 to 400 mg/day orally (in single doses of 100 to 200 mg). The dose may be increased in severe toxicity (Arbeitsgruppe BGVV, 1996; Prod Info DIMAVAL(R) oral capsules, 2004).

c) DMPS/ADVERSE REACTIONS

1) Chills, fever, and allergic skin reactions such as itching, exanthema or maculopapular rash are possible (Hla et al, 1992; Prod Info DIMAVAL(R) oral capsules, 2004). Cardiovascular effects such as hypotension, nausea, dizziness or weakness may occur with too rapid injection of DMPS. Hypotensive effects are irreversible at very high doses (300 mg/kg) (Prod Info DIMAVAL(R) oral capsules, 2004; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013).

3) SOURCES

a) DMPS is not FDA-approved, but is available outside of the US from Heyl Chem-pharm Fabrik in Germany (Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013; Prod Info DIMAVAL(R) oral capsules, 2004). In the US it may be obtained from some compounding pharmacies.

4) In one study of 12 children, DMPS reduced lead concentrations in blood and increased the urinary excretion of lead, copper, and zinc. However, the concentrations of copper or zinc in plasma were not affected (S Sweetman , 2000).

J) DISORDER OF BRAIN

1) Lead encephalopathy is a medical emergency. Patient should be hospitalized in an intensive care setting. Prompt neurosurgical and toxicological consultation should be obtained to assist in management. Withhold spinal tap until status of intracranial pressure has been fully considered. An intracranial pressure probe may be indicated.
2) CEREBRAL EDEMA

a) Controlled hyperventilation, maintaining an arterial CO2 tension of 25 to 30 mmHg, can reduce intracranial pressure in patients with rapidly worsening mental status, lateralizing neurologic findings or evidence of impending herniation. Prolonged hyperventilation is not desirable in general. Monitor intracranial pressure continuously. Monitor cardiovascular function, renal function, and serum electrolytes carefully (Heinemeyer, 1987).
b) DIURETICS

1) MANNITOL 20%

a) ADULT: 1 to 1.5 grams/kilogram by infusion over 10 to 20 minutes (Heinemeyer, 1987).
b) CHILD: 0.5 to 1 gram/kilogram by intravenous infusion over 10 to 20 minutes (Heinemeyer, 1987).
c) Mannitol 0.25 gram/kilogram was reported as effective at reducing intracranial hypertension as larger doses while avoiding dehydration and electrolyte imbalance (Marshall, 1980).

2) GLYCEROL - 0.3 to 1 gram/kilogram orally (Heinemeyer, 1987).
3) LOOP DIURETICS - Furosemide and/or ethacrynic acid may be useful as an adjunct in the treatment of cerebral edema (Marshall, 1980; Heinemeyer, 1987; de los Reyes et al, 1981).
4) ACETAZOLAMIDE - Has been used in the treatment of cerebral edema associated with pseudotumor cerebri (de los Reyes et al, 1981). Acetazolamide has been demonstrated to be effective in a laboratory model of cerebral edema, however, it possessed the undesirable property of causing cerebral vasodilation (Marshall, 1980).

c) CORTICOSTEROIDS

1) DEXAMETHASONE - There seems to be good evidence that dexamethasone improves cerebral edema associated with malignancy. There is controversy as to whether it is effective in acute cytotoxic cerebral edema and as to what the appropriate dose should be.
2) LOW DOSE - 16 milligrams/day in divided doses (de los Reyes et al, 1981).
3) HIGH DOSE - 1 to 2 milligrams/kilogram/day in divided doses (Heinemeyer, 1987).

d) BARBITURATES

1) Pentobarbital at a mean dosage of 30 milligrams/kilogram/day by intravenous infusion has been used in patients refractory to other methods of treatment for cerebral edema (Heinemeyer, 1987; de los Reyes et al, 1981; Marshall, 1980).

3) SEIZURES

a) Treat seizures with intravenous diazepam (Adult: up to 10 milligrams slowly, repeat if necessary; Children: 0.1 to 0.3 milligram/kilogram slowly). Seizures from lead encephalopathy may be resistant to anticonvulsant therapy; barbiturate-induced coma and aggressive control of ICP may be needed.

K) IRON

1) IRON DEFICIENCY - In one study, the following 5 groups of infants were chosen to evaluate the effects of iron therapy on blood lead levels (Wolf et al, 2003):

1) Group 1 - anemic iron-deficient with hemoglobin levels equal or less than 105 g/L - this group received either intramuscular iron or 3 months of oral iron
2) Group 2 - iron-deficient with intermediate hemoglobin levels 106 to 119 g/L - this group received either intramuscular iron or 3 months of oral iron
3) Group 3 - nonanemic iron-deficient - this group received 3 months of oral iron
4) Group 4 - nonanemic iron-depleted - this group received 3 months of oral iron
5) Group 5 - iron-sufficient-this group received oral placebo

2) Following 3 months of oral iron therapy, group 4 infants (nonanemic iron-depleted) had the most reduction in lead levels, followed by group 3 (nonanemic iron-deficient infants) and iron-deficient infants with hemoglobin levels less than 120 g/L. Lead levels were higher among iron-deficient infants with hemoglobin levels less than 120 g/L who received intramuscular iron and group 5 (iron-sufficient nonanemic infants) who received placebo. The authors concluded that iron therapy can decrease lead levels in children whose iron status has been compromised (Wolf et al, 2003).
3) Concomitant administration of iron and DMSA is well tolerated in children with lead poisoning and iron deficiency (Graziano et al, 1992a).
4) A double-blind, randomized trial evaluated the effect of iron (ferrous fumarate 30 mg) and zinc (zinc oxide 30 mg) supplementation on behavior ratings of lead-exposed children. First-grade children (n=602) received either 30 mg of ferrous fumarate, 30 mg of zinc oxide, both, or placebo daily for 6 months. Conners Rating Scales was used by parents and teachers to rate the children's behavior. The mean blood lead level was 11.5 (6.1) mcg/dL at baseline, and 51% of children had lead blood levels equal or greater than 10 mcg/dL. According to both parents and teachers, 6% of children exhibited ADHD-like symptoms. At follow-up, there was a mean decrease of 1.5 points (P=0.002), 1.2 points (P=0.016), 2.5 points (P<0.001), and 3.4 points (P<0.001) in parent ratings of oppositional, hyperactive, cognitive problem, and ADHD behaviors, respectively. There was an increase of 1.1 points (P=0.008) in teacher ratings of hyperactivity; the mean cognitive problem score decreased from baseline by 0.7 points (P=0.038). Overall, the supplements did not result in consistent improvements in ratings of behavior in lead-exposed children over 6 months (Kordas et al, 2005).

L) PATIENT EDUCATION

1) Educating patients and parents on measures such as hand washing, keeping nails short, controlling pica and hand to mouth behavior, housekeeping, diet, and information on the safe removal of paint has been shown to help reduce children's blood lead levels (Kimbrough et al, 1994).

M) ENVIRONMENTAL INTERVENTION

1) SOIL - Soil abatement may be an important step in areas of high contamination (Weitzman et al, 1993; Aschengrau et al, 1994).
2) HOME - Home abatement appears to be most effective in lowering blood lead levels in children with higher blood lead levels before intervention.

a) In one study home abatement was associated with lowering of blood lead levels in 32 of 33 children with pre-abatement levels of greater than 30 micrograms/deciliter and 64 of 79 children with pre-abatement levels of greater than 20 micrograms/deciliter (Swindell et al, 1994). Only 7 of 20 children with pre-abatement blood lead levels of less than 20 micrograms/deciliter had decreased blood lead level after home abatement.
b) Another study found that children with blood lead levels greater than 35 micrograms/deciliter appeared to benefit more from home abatement than those with blood lead levels between 25 and 34 micrograms/deciliter (Staes et al, 1994).
c) In a randomized, prospective study of 275 urban children, dust control measures to decrease exposure to residential lead hazards were not effective in the prevention of childhood lead exposure (Lanphear et al, 1999).

1) Dust control measures consisted of up to 8 visits by dust control advisors, education of families regarding lead exposure prevention, and provision of cleaning supplies.
2) Baseline mean lead level of the children was 2.9 mcg/dL at 6 months of age. Of 246 children available for 2 year follow-up, mean lead level in the intervention group and control group was 7.3 mcg/dL and 7.8 mcg/dL, respectively.

N) EXPERIMENTAL THERAPY

1) ASCORBIC ACID

a) Animal studies have suggested that ascorbic acid may have the ability to chelate lead and decrease toxic effects. In a study of youths (6 to 16 years old) and adults enrolled in the National Health and Nutrition Examination Survey (NHANES III), serum ascorbic acid was inversely related to blood lead level. However, no relationship was found between vitamin C intake and blood lead levels (Simon & Hudes, 1999; Matte, 1999).

1) The role of ascorbic acid in the treatment or prevention of lead toxicity warrants further study (Simon & Hudes, 1999; Matte, 1999).
2) One animal study reported that ascorbic acid given to suckling rats during or after lead exposure did not have a beneficial effect on either decreasing lead retention or DMSA chelation effectiveness (Varnai et al, 2003).

b) Another animal study has suggested that thiamine, ascorbic acid, and becozinc (a pharmacological preparation containing vitamins of the B-complex group, vitamin C, and zinc) are effective in mobilizing lead from blood, liver, and kidney into urine and/or feces and in restoring partially blood zinc protoporphyrin level. These vitamins were effective in reversing the lead-induced increase in blood and renal calcium levels, and restoring the decreased hepatic and tibia zinc content. However, the lead-induced inhibition of blood delta-aminolevulinic acid dehydratase activity and the increase in urinary aminolevulinic acid excretion were not influenced (Tandon et al, 2001; Tandon & Singh, 2000).

2) CALCIUM

a) One study reported that calcium supplementation (liquid form) to achieve 1800 mg of calcium per day was not effective for the treatment of children (1 to 6 years of age) with mild to moderate BPb levels (10 to 44 mcg/dL) (Markowitz et al, 2004).
b) In one randomized study, calcium supplementation (1200 mg/day) was associated with only a modest reduction in blood lead levels among lactating women with relatively high lead burden; however, the effect was more apparent among women who were more compliant and breastfed for 6 or more months (Hernandez-Avila et al, 2003).

3) TAURINE

a) One animal study evaluated the combined use of taurine (an antioxidant and an amino acid found in the tissues of most animal species) with DMSA in the treatment of lead poisoning. Lead exposure produces a significant inhibition of ALAD activity, reduction in glutathione (GSH), and an increase in zinc protoporphyrin (ZPP), indicating an altered heme synthesis pathway. Although DMSA alone was able to increase the activity of ALAD, the combined use of DMSA and taurine (50 or 100 mg/kg) significantly increased the depleted blood glutathione (GSH) levels. Combined administration of DMSA and taurine reduced the blood ZPP levels to near normal levels. Taurine administration reduced thiobarbituric acid substance levels significantly in liver, kidney and red blood cells of animals, recovered the activity of superoxide dismutase (SOD) in blood and brain of animals, and increased the depletion of blood, liver, and brain lead (compared to DMSA alone). The authors concluded that concurrent administration of an antioxidant could reduce a number of toxic effects of lead when used along with the thiol chelators (Flora et al, 2004).

4) CHELATION/ANIMAL DATA

a) Animal studies suggest that simultaneous chelation with an agent that mobilizes bone lead (such as CaNa2EDTA) and one that mobilizes soft tissue lead (such as DMSA) may be more effective that either agent alone at reducing lead body burden (Tandon et al, 1994). This has not been studied in humans.

5) ZINC

a) A double-blind, randomized trial evaluated the effect of iron (ferrous fumarate 30 mg) and zinc (zinc oxide 30 mg) supplementation on behavior ratings of lead-exposed children. First-grade children (n=602) received either 30 mg of ferrous fumarate, 30 mg of zinc oxide, both, or placebo daily for 6 months. Conners Rating Scales was used by parents and teachers to rate the children's behavior. The mean blood lead level was 11.5 (6.1) mcg/dL at baseline, and 51% of children had lead blood levels equal or greater than 10 mcg/dL. According to both parents and teachers, 6% of children exhibited ADHD-like symptoms. At follow-up, there was a mean decrease of 1.5 points (P=0.002), 1.2 points (P=0.016), 2.5 points (P<0.001), and 3.4 points (P<0.001) in parent ratings of oppositional, hyperactive, cognitive problem, and ADHD behaviors, respectively. There was an increase of 1.1 points (P=0.008) in teacher ratings of hyperactivity; the mean cognitive problem score decreased from baseline by 0.7 points (P=0.038). Overall, the supplements did not result in consistent improvements in ratings of behavior in lead-exposed children over 6 months (Kordas et al, 2005).

Enhanced Elimination

1) NEONATES - Combined exchange transfusion and chelation therapy with BAL and Ca Na2EDTA have been used in several neonates with elevated cord BLL following chronic in utero lead exposure. Lead levels rapidly decreased following treatment (Mycyk & Leikin, 2004; Mycyk et al, 2002).
2) CASE REPORT - Combined single volume exchange transfusion and chelation therapy were used in a neonate with an elevated cord BLL of 100 mcg/dL. The infant's mother had a long history of eating glazed pottery. Following the exchange transfusion, the BLL was 28 mcg/dL (Mycyk et al, 2002).

1) CASE REPORT: A 52-year-old dialysis-dependent man with uncontrolled type II diabetes, presented with a 3-month history of mild abdominal pain and hair loss. Lead toxicity was suspected after he admitted to ingesting supplements from Mexico and small pieces of Mexican ceramics. Laboratory results revealed a BLL of 99 mcg/dL (reference range less than 5 mcg/dL) and a hemoglobin concentration of 15 g/dL. A CT scan did not show any radio-opaque material in his GI. Following 7 days of supportive care, including 4 rounds of chelation with calcium EDTA followed by high-flux hemodialysis, his BLL decreased to 33 mcg/dL and he was discharged home with improved symptoms (Durrani et al, 2015).

Abstracts

Case Reports

1) ORAL

a) Unusual sources of lead poisoning have included ingestion of lead containing ceramic glazes (Bradley et al, 1987; Sturm, 1988), lead curtain weights (Hugelmeyer et al, 1988), lead napthalate solution (Aleguas et al, 1986), chewing leaded foil from wine bottles (Rovira et al, 1989), and home production of lead figurines (Montalvan et al, 1989).

1) MALINGERING: After ingesting lead compounds, a 51-year-old man with a history of occupational lead exposure complained of asthenia, weight loss (4 kg), headaches, and constipation. Abdominal radiography revealed multiple radiopaque foreign bodies (ranging from 0.5 to 15 mm in size) in the large intestine. The extracted foreign bodies (from some collected stools) were analyzed using electrothermal atomic absorption spectrometry and were found to contain 301 mg of lead per gram. Lab values included: BLL ranged from 2.6 to 5.2 mcmol/L (53.9 to 107.7 mcg/dL); erythrocyte protoporphyrin concentration 2 mcg/g Hb, delta aminolevulinate level elevated at 80 mcmol/L; urinary lead level after an edetate calcium disodium challenge test was 70 mcmol/24 hr (Astudillo et al, 2003).

1) IMMOBILIZATION: Elevated lead levels have also developed following immobilization from paraplegia or treatment of long bone fractures in children with previous lead poisoning (Shannon et al, 1987; Markowitz & Weinberger, 1990).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) GENERAL

1) There are neither a biologic need for nor any accepted therapeutic uses of lead.

7.2.2)

A) GENERAL

1) FDA standard: Children less than 7 years of age should not consume more than 6 mcg lead daily from foodstuffs (Fuortes & Bauer, 2000).
2) Other limits:

1) 0.5 ppm lead in candy
2) 0.5 ppm lead in high fructose corn and syrups and sucrose
3) 0.5 mcg/mL for leaching from cups, mugs, and pitchers
4) 3 mcg/mL for ceramic ware (plates or bowls)
5) 7 mcg/mL for silver-plated hollowware products
6) (Fuortes & Bauer, 2000)

Minimum Lethal Exposure

1) The minimum lethal human dose to this agent has not been delineated.
2) Acute lead poisoning is rare; it is estimated that ingestion of 10 to 30 grams of a lead salt would result in death after 1 to 2 days (Baselt, 2000).

1) A 4-year-old child died one week after treatment with Chinese herbal formulations that contained up to 7.5 mg/dose. At the time of death, the child's lead levels were measured at 3 mg/kg in the brain and 17 mg/kg in the liver (Baselt, 2000).
2) A 2-year-old boy died after drinking apple juice out of a glazed earthenware container over the duration of several weeks. Blood lead levels at the time of death were 0.4-2.2 mg/kg lead in the brain, 13 mg/kg lead in the liver, and 18 mg/kg lead in the kidney (Baselt, 2000).
3) A 2-year-old girl died after ingesting paint (containing 5-35% lead) and playing in areas with lead dust concentrations of 6,732 mcg/ft(2). Blood lead levels at the time of diagnosis were 391 mcg/dl, and despite a reduction to 72 mcg/dl and treatment, she died of diffuse cerebral edema two days after being admitted to the hospital (CDC, 2001).
4) A 20-month-old boy died from severe lead toxicity after eating paint chips containing 0.2-33.1% lead, and exposure to lead in house dust at levels up to 31,128 mcg/ft(2) (CDC, 1991).

Maximum Tolerated Exposure

1) The maximum tolerated human exposure to this agent has not been delineated.
2) The normal upper limit for blood lead is considered to be approximately 0.40 mg/L (Baselt, 2000).
3) Adults are at increased risk of developing symptoms and signs with levels above 40 mcg/dL (OSHA) although effects at lower levels have been observed (Wang et al, 1985).
4) Lead in excess of 0.07 mg per 100 cc (70 mcg/dL) in whole blood frequently indicates severe lead poisoning. Lead excretion in urine generally exceeds 0.1 mg/L of urine (Lewis, 1996).
5) Workers with blood lead levels of 40 to 60 mcg/100 mL blood may have subtle neurologic effects (Hathaway et al, 1996).
6) Abdominal pain, anemia, basophilic stippling of red blood cells, elevated blood lead concentrations, and elevated urinary lead excretions during chelation were noted in some of the 8 patients ingesting liquid lead-based ceramic glazes (Vance et al, 1990).
7) Lead affects heme synthesis, as is evidenced by a decrease in delta- aminolevulinic acid dehydrase (ALA-D) activity in lead-exposed individuals. No threshold has been found for inhibition of ALA-D activity down to a blood lead concentration of 12 mcg/dl (ACGIH, 1996a).
8) A 59-year old woman complaining of joint pain, insomnia, and irritability was found to have a blood lead level of 0.90 mg/L (Baselt, 2000).
9) CASE REPORT: A man suffered the symptoms of severe lead poisoning as a result of drinking a homemade red wine. The patient used a highly corroded enamel bathtub to crush and store the wine. His PbB level was 98 mcg/dL two weeks after admission and prior to chelation therapy (Mangas et al, 2001).
10) Toxicity of lead salts vary by compound. Please refer to the data on chemical of interest for information specific to a compound.
11) CASE REPORT: A 41-year-old man developed lead poisoning symptoms after taking Ayurvedic medications (EX and ADISSA) from India to treat oligospermia. A blood lead level of 78 mcg/dL was obtained on admission; it was estimated that a total of 1.26 grams of lead was ingested during the course of his therapy (Shrestha & Greenberg, 2002).
12) CASE SERIES: Three patients with lead poisoning had varying degrees of exposure to a Chinese herbal pill (Bao ning dan). The authors reported that blood lead concentrations did not correlated with clinical severity. One patient had the highest blood lead level after taking the pills for only 3 days. Although the second patient took the pills for 2 months, she had the lowest blood lead concentration. She developed liver derangement and severe anemia. The third patient was asymptomatic; however, she had the longest exposure to the pills (Auyeung et al, 2002).
13) CASE REPORT: A 45-year-old male with a history of schizophrenia developed severe lead poisoning (BLL 391 mcg/dL) after ingesting 206 22-caliber lead bullets. He recovered following aggressive GI decontamination and chelation therapy (McNutt et al, 2000).

BLL (mcg/dL)	NEUROLOGICAL EFFECTS	HEME SYNTHESIS EFFECTS	OTHER EFFECTS
10-15	Deficits in neurobehavioral development; electrophysiological changes	ALA-D inhibition	Reduced gestational age and weight at birth; reduced size up to age 7-8 years
15-20	.	EP elevation	Impaired vitamin D metabolism; pyrimidine-5'-nucleotidase inhibition
25	Lower IQ, slower reaction time	.	.
30	Slowed nerve conduction velocity	.	.
40	.	Reduced hemoglobin; elevated coproporphyrin and urinary ALA	.
70	Peripheral neuropathies	Frank anemia	.
80-100	Encephalopathy	.	Colic, other GI effects; renal effects

1) CASE REPORT: Severe congenital lead poisoning (cord blood lead 7.6 mcmol/L or 157.5 mcg/dL; BLL of 11.8 mcmol/L) has been reported in a preterm infant born to a woman using lead-contaminated herbal tablets (maternal BLL of 5.2 mcmol/L or 107.7 mcg/dL on admission; maternal BLL 2.3 mcmol/L 12 hours before birth). This neonatal BLL has been the highest recorded for a surviving infant. The infant recovered following chelation therapy (Tait et al, 2002).
2) CASE REPORT: A healthy-appearing neonate with a cord blood lead of 126 mcg/dL (Hct of 48) was born to a woman with chronic lead toxicity and a maternal BLL of 57.6 mcg/dL (Hct of 15). The authors suggested that a threefold difference in hematocrit between mother and child, presence of fetal hemoglobin, and mobilization of bone lead during parturition, may have contributed to differences among maternal, cord and fetal blood lead levels of healthy neonate (Mirkin et al, 2000b).
3) CASE REPORT: A neonate with congenital lead intoxication (BLL 17-37 mcg/dL; hemoglobin 12.2 g/dL; Hct 35.1%) was treated with IV calcium EDTA and oral DMSA. The authors recommended prenatal screening in mothers who are at high risk for elevated BLL, such as recent immigrants from areas with a high prevalence of lead exposure or those with other children with elevated BLL (Guzman et al, 2000).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Because of preventive measures in the recent years (eg, removing lead from gasoline, banning lead-based paint), the average BLL for children 1 to 5 years of age has decreased from 15.0 mcg/dL (1976-1980) to 2.7 mcg/dL (1991-1994); the average BLL for adults has decreased from 14.2 mcg/dL (1976-1970) to 3.0 mcg/dL (1988-1991) (Lane & Kemper, 2001; ATSDR, 2000).
b) Normally, 0.40 mg/L is considered the upper limit for blood lead concentration. The majority (96%) of the blood lead is contained in erythrocytes (Baselt, 1997).
c) DECAY OF BLL: A study of removed workers with elevated BLLs showed that on average the BLL falls by about 13 to 26 mcg/dL, one month after the original sample. Some continuing lead exposure should be suspected if the decline in BLL is 7 to 8 mcg/dL or less in the month after the removal of the worker (Mason & Williams, 2005).

2) NEONATE

a) Lead levels above 10 micrograms/deciliter in the cord blood are associated with slowed development (Bellinger, 1986; Bellinger et al, 1987).
b) The effect on EP begins at blood lead levels of 10 to 20 micrograms/deciliter, however, only a small percentage of children with these levels will have EP changes. Blood lead level measurement is the preferred screening tool (CDC, 1991).

3) PEDIATRIC

a) CASE REPORT: A 17-year-old girl developed only nausea and abdominal pain after ingesting 20 g of lead nitrate (12.6 g or 6 mmol of lead). Her blood lead concentration was 20.4 mcmol/L (447 mcg/dL) 90 minutes after ingestion. Following chelation therapy with calcium disodium EDTA for 5 days, she recovered completely (Mikler et al, 2009).
b) CASE REPORT: A 3-year-old presented with left lower quadrant abdominal pain, vomiting, and no bowel movement for 2 days after chronic exposure to lead paint at home. Serial abdominal x-ray revealed entrapment of a large amount of radio-opaque material in the appendix. Laboratory results revealed a blood lead level of 644 mcg/dL. Following chelation therapy for several months, his BLL decreased to 15 mcg/dL (Smith, 2007).
c) CASE REPORT: A 4-year-old boy presented with vomiting, low-grade fever, and dehydration after ingesting a heart-shaped locket that contained 99% lead. Laboratory results revealed a blood lead level of 180 mcg/dL (reference level: less than 10 mcg/dL). His condition deteriorated over the next 12 hours with brain herniation leading to brain death (Berkowitz & Tarrago, 2006).
d) At blood lead levels above 15 micrograms/deciliter, associated with EP elevation, impaired vitamin D metabolism and Py-5-N inhibition occur (Piomelli et al, 1982; Rosen et al, 1980; CDC, 1988).
e) Children with BLLs of 10 mcg/dL or greater are more likely to have learning and behavioral effects than children with levels of less than 10 mcg/dL ( CDC, 1997). In one study, authors reported that BLLs, even those below 10 mcg/dL, are inversely associated with children's IQ scores at 3 and 5 years of age. In addition, associated declines in IQ were greater at these levels than at higher levels (Canfield et al, 2003).
f) Above 70 micrograms/deciliter, associated with some risk of seizures and other signs of encephalopathy ( CDC, 1997).
g) Above 100 micrograms/deciliter, almost always associated with encephalopathy (Kokori et al, 1999; CDC, 1997). Lower levels may cause neurobehavioral disorders and poor intellectual growth in children (Kokori et al, 1999).
h) In a study of 408 children raised in urban China ranging in age from 3 to 6 years, blood lead levels (BLLs) and activities of delta-aminolevulinic acid dehydratase (ALAD), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) and the contents of glutathione (GSH) in erythrocyte and levels of plasma malondialdehyde (MDA) were analyzed spectrophotometrically. Children with BLLs greater than or equal to 100 mcg/L had significantly increased plasma MDA levels and significantly decreased ALAD compared with the children with BLLs less than 100 mcg/L. No significant changes were noted in the other measurements. The authors noted that this data indicates that oxidative damage could be induced in children with higher blood lead levels and might contribute to lead-induced intellectual impairment (Jin et al, 2006).
i) GOLD ORE PROCESSING: In 2010, children (n=463 less than 5 years of age) of 4 villages in Zamfara state in rural northwestern Nigeria developed massive childhood lead poisoning after exposure to lead contaminated gold ore-processing in family compounds. It was found that approximately 25% (118 of 463) of children under the age 5 died within a year of lead exposure. An initial blood tests revealed 8 children with BLLs of 168 to 370 mcg/dL. BLLs of 59% of surviving children were then collected; 97% of these BLLs were at least 45 mg/dL and 85% surpassed the portable sampling devices' maximum detection limit of 65 mcg/dL (Burton, 2012; Dooyema et al, 2012).

4) ADULT

a) Blood lead levels above 40 micrograms/deciliter are associated with increased risk of signs and symptoms; work-site or home evaluation is recommended.
b) Above 60 micrograms/deciliter, requires removal from exposure because of risk of symptoms and signs; work-site or home evaluation is recommended.
c) PREGNANCY: In a group of Mexican pregnant women (n=105), maternal blood lead (PbB) levels averaged around 7.0 mcg/dL, with a range of 1.0 to 35.5 mcg/dL throughout pregnancy. A significant decrease in mean PbB from week 12 to week 20 (1.1 mcg/dL) and various significant increases in mean PbB from 20 to parturition (1.6 mcg/dL) were noted (Rothenberg et al, 1994).

Workplace Standards

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Lead

a) TLV:

1) TLV-TWA: 0.05 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A3
2) Codes: BEI
3) Definitions:

a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
b) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.

c) TLV Basis - Critical Effect(s): CNS and PNS impair; hematologic eff
d) Molecular Weight: 207.20

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

b) Adopted Value

1) Lead and inorganic compounds, as Pb

a) TLV:

1) TLV-TWA: 0.05 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A3
2) Codes: BEI
3) Definitions:

c) TLV Basis - Critical Effect(s): CNS and PNS impair; hematologic eff
d) Molecular Weight: Varies

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS7439-92-1 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Lead and compounds (as Pb)
2) REL:

a) TWA: 0.050 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): See Appendix C; [*Note: The REL and PEL also applies to other lead compounds (as Pb) -- see Appendix C.]

3) IDLH:

a) IDLH: 100 mg Pb/m3 (as Pb)
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS7439-92-1 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Lead

2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Lead and inorganic compounds, as Pb

3) EPA (U.S. Environmental Protection Agency, 2011): B2 ; Listed as: Lead and compounds (inorganic)

a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.

4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Lead, organic compounds

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

5) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: Lead

a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

6) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2A ; Listed as: Lead compounds, inorganic

a) 2A : The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

7) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Lead and compounds (as Pb)
8) MAK (DFG, 2002): Category 3B ; Listed as: Lead and its inorganic compounds except lead arsenate

a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)

9) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Lead and Lead Compounds

a) R : RAHC = Reasonably anticipated to be a human carcinogen

D) OSHA PEL Values for CAS7439-92-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Lead, inorganic (as Pb); see 29 CFR 1910.1025
2) Table Z-1 for Lead, inorganic (as Pb); see 29 CFR 1910.1025:

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3:

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) TCLo- (INHALATION)HUMAN:

1) 10 mcg/m(3) -- gastritis, changes to the liver (RTECS, 2004)

B) TCLo- (INHALATION)RAT:

1) female, 3 mg/m(3) for 24H at 1-21D of pregnancy -- biochemical and metabolic effects on the offspring (RTECS, 2004)
2) female, 10 mg/m(3) for 24H at 1-21D of pregnancy -- fetotoxicity, developmental abnormalities of the blood and lymphatic system (including spleen and marrow) in the offspring (RTECS, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

1) No information found at the time of this review.

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.1)

A) RAPTORS are commonly exposed to lead by ingesting the remains of birds killed with lead shot. Common clinical signs include anorexia, weakness, closed eyelids and abnormal posture. Lab analysis will reveal heterophilic leukocytosis, regenerative anemia, and possibly dense metal fragments on a radiograph (Garner, 1991).
B) TRUMPETER SWANS may develop lead poisoning from ingesting lead shot. Clinical findings include impaction of the proventriculus and esophagus and aspergillosis (Langelier et al, 1990).
C) CAGE BIRDS ingesting lead weights and solder may develop bloody diarrhea, polydypsia, dyspnea, depression, disorientation, weakness, and anemia (Kirk, 1989).

11.1.13)

A) OTHER

1) SIGNS - Vomiting, diarrhea, anorexia, constipation, abdominal tenderness excessive salivation, and rarely megaesophagus may occur early. Later neurologic findings include seizures, hysteria, ataxia, ruminal atony, depression. tremors, blindness, mydriasis, peripheral neuropathy, and aggression (Maddison & Allan, 1990; Hoffheimer, 1989; Dickson, 1990; Berny et al, 1992; Morgan et al, 1991; McEvoy & McCoy, 1993).

a) LABORATORY - Findings include nucleated red blood cells, basophilic stippling, leukocytosis, anemia, and increased liver function tests (Morgan et al, 1991; Berny et al, 1992)

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm.
3) Sample vomitus, blood, urine and feces for analysis.
4) If skin exposure has occurred, wash animal thoroughly with a mild detergent and flush with copious amounts of water.
5) CHELATION - As with humans, chelation is possible. McEvoy & McCoy (1993) used Animalcare(R) (sodium calcium edetate) in normal saline over several days to treat a herd of cattle.
6) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) Induce emesis with Syrup of Ipecac, 10 to 30 mL orally or hydrogen peroxide 5 to 25 mL orally repeated in 5 to 10 minutes if there is no response. DOGS ONLY may receive apomorphine 0.05 to 0.10 mg/kg IV, IM, or subcutaneously.
b) Gastric lavage may be performed using tap water or normal saline.
c) Administer activated charcoal, 5 to 50 g, orally, as a slurry in water.
d) Then administer Milk of Magnesia 1 to 15 mL orally, mineral oil 2 to 15 mL orally, sodium sulfate 20%, 2 to 25 g orally or magnesium sulfate 20% 2 to 25 g orally, for catharsis.

2) LARGE ANIMALS

a) Give 250 to 500 g of activated charcoal in a water slurry, orally, to adsorb the toxic agent.
b) Administer an oral cathartic: mineral oil (1 to 3 liters), 20% sodium sulfate (25 to 10,000 g), 20% magnesium sulfate (25 to 1,000 g) or milk of magnesia (20 to 30 mL).
c) Ruminants (cattle and sheep) cannot be made to vomit. Horses should not be made to vomit.

11.2.5)

A) SMALL ANIMALS

1) Calcium disodium EDTA 27.5 mg/kg QID for 5 days. Give initial dose IV, then subcutaneous as 10 mg/mL in 5% dextrose.
2) D-penicillamine is also effective in doses ranging from 33 to 110 mg/kg/day divided in four doses for 1 to 2 weeks. Lower doses are effective and have fewer associated side effects (Morgamn et al, 1991; (Rice, 1989).
3) Supportive treatment, including fluids, antibiotics, and vitamin and mineral supplements, may be indicated (Garner, 1991).

B) LARGE ANIMALS

1) Calcium disodium EDTA: 28.5 mg/kg QID for 5 days. Initial dose IV, then subcutaneous as 10 mg/mL in 5% dextrose.

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

2) LARGE ANIMALS

References

General Bibliography

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FeedBack

LEAD

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Clinical Effects

Treatment

Continuing Care

General Bibliography