Biomarkers blood lead levels

Lead is one of the most intensively studied hazardous compounds of the twentieth century. The more toxicologists and other researchers investigated the health effects of lead, the more they realized that even very low levels of lead exposure were hazardous. The most common biomarker of lead exposure is the blood lead level, usually measured in micrograms (jig) per one hundredth of a liter of blood (dl) or jlg/dl. For example, many regulatory agencies set 40 jlg/dl as a level of concern for adult male workers. Typically, at this level workers would be removed from the environment responsible for the exposure and ideally some determination would be made as to the cause of the exposure. The blood level of concern for children has dropped steadily, as shown in Figure 7.1. 

Figure 30. One of the best biomarkers for lead poisoning is the second enzyme in the heme biosynthetic pathway, ALAD, which is inhibited by femtomolar concentrations of lead (467). Activity of ALAD in red blood cells correlates inversely with blood lead level. [Figure reprinted with permission from Elsevier Science (J. A. Millar, V. Battistini, R. L. Gumming, F. Carswell, and A. Goldberg, The Lancet, 1970, Vol. 2, 695-698).]...

Van Larabeke, N., Koppen, G., Nelen, V., Schoeters, G., Van Loon, H., Albering, H., et al., 2004. Differences in HPRT mutant frequency among middle-aged Flemish women in association with area of residence and blood lead levels. Biomarkers 9, 71—84. 

ALAD may not be well suited as a biomarker of lead exposure at blood lead levels greater than 50//g/dl. The decrease in ALAD activity is accompanied by a concomitant increase in the total amount of ALAD protein in erythrocyte precursors. At blood lead levels of 40-50//g/dl the amount of ALAD reaches a plateau corresponding to about two times the normal concentration, probably reflecting the maximum capacity of ALAD synthesis (Bernard and Lauwerys 1987). The practical consequence of this phenomenon is that assessment of ALAD activity alone does not accurately reflect the extent of enzyme inhibition at higher blood lead levels. 

Elucidation of some of the mechanisms of lead toxicity on the cellular and biochemical level has led to the development of several relatively sensitive biomarkers of lead exposure and toxicity, including measurements of the effects of lead on enzymes of the hematopoietic system. Lead-induced alterations in blood zinc protoporphyrin (ZPP) and erythrocyte 6-aminolevu-linic acid dehydratase (ALAD) activity have been established as relatively specific biomarkers of lead toxicity to the heme biosynthetic pathway (NRC 1993 USEPA 1986). Increases in blood ZPP occur as a result of inhibition of ferrochelatase (FC) by lead. Inhibition of ALAD by lead, which begins at a blood lead level of about 5 tg/dL (Chisolm et al. 1985 USEPA 1986), is considered to be one of the most sensitive biomarkers currently available. 

Reduction in the serum 1,25-dihydroxyvitamin D concentration has been reported as an indicator of increased lead absorption or lead levels in the blood (Rosen et al. 1980). Lead inhibits the formation of this active metabolite of vitamin D, which occurs in bone mineral metabolism (EPA 1986a Landrigan 1989). Children with PbB concentrations of 12-120 pg/dL lead showed decreased serum 1,25-dihydroxyvitamin D concentrations comparable to those found in patients with hypoparathyroidism, uremia, and metabolic bone disease (Mahaffey et al. 1982 Rosen et al. 1980). This biomarker is clearly not specific for lead exposure and several diseases can influence this measurement. 

ALAD in blood is a sensitive indicator of recent exposure to lead. Urinary ALA becomes elevated at PbB levels 50 pg/dL, and is not as sensitive an indicator as ALAD. EP becomes elevated at PbB levels of 25-30 pg/dL and is a good indicator of past exposure to lead. It should be noted, however, that ALAD, ALA, and EP are not specific biomarkers for lead. 

One of the most sensitive systems affected by lead exposure is the nervous system. Encephalopathy is characterized by symptoms such as coma, seizures, ataxia, apathy, bizarre behavior, and incoordination (CDC 1985). Children are more sensitive to neurological changes. In children, encephalopathy has been associated with PbB levels as low as 70 pg/dL (CDC 1985). The most sensitive peripheral index of neurotoxicity of lead is reported to be slowed conduction in small motor libers of the ulnar nerve in workers with 30-40 pg/dL lead in blood (Landrigan 1989). Other potential biomarkers of lead suggested for neurotoxicity in workers are neurological and behavioral tests, as well as cognitive and visual sensory function tests (Williamson and Teo 1986). However, these tests are not specific to elevated lead exposure... 

Because control of renal function and blood pressure is multifactorial, the causal contribution of lead is difficult to isolate. A number of biomarkers (blood, tibial, and patella lead), and a variety of populafions differing by age, gender, race, and level of exposure are examined. Systohc and diastolic pressures are assessed separately and may be analyzed both as continuous or dichotomous variables. Kidney function is assessed by the serum creatinine concentration or empirical adjustments of the creatinine to estimate GFR. Large populations are required to achieve statistical significance amidst the noise of the multifactorial causality and the imprecision of outcome measures. Inconsistent results and weak correlations are, therefore, expected as smaller and smaller outcome effects are evaluated. 

Biomarkers of Exposure and Effect. Increased blood and urine lead levels, urinary thioether, urinary phenol, and blood benzene, toluene, pentane, and hexane levels can all be used as biomarkers of... 

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