PBBs metabolism

However, results obtained by Koo et al. (1991) indicate that low to moderate lead exposure (average lifetime PbB level range of 4.9-23.6 pg/dL, geometric mean of 9.8 pg/dL, n=105) in young children with adequate nutritional status, particularly with respect to calcium, phosphorus, and vitamin D, has no effect on vitamin D metabolism, calcium and phosphorus homeostasis, or bone mineral content. The authors attribute the difference in results from those other studies to the fact that the children in their study had lower PbB levels (only 5 children had PbB levels >60 pg/dL and all 105 children had average lifetime PbB levels <45 pg/dL at the time of assessment) and had adequate dietary intakes of calcium, phosphorus, and vitamin D. They concluded that the effects of lead on vitamin D metabolism observed in previous studies may, therefore, only be apparent in children with chronic nutritional deficiency and chronically elevated PbB levels. Similar conclusions were reached by IPCS (1995) after review of the epidemiological data. 

A few studies have reported associations between prenatal lead exposure and changes in heme metabolism. In a study of 294 mother-infant pairs, Haas et al. (1972) reported mean PbB levels of 16.98 pg/dL for mothers and 14.98 pg/dL for newborns. Infant PbB levels and ALA-U were positively correlated. The authors, however, did not report the levels of ALA-secretion in infants and mothers with no lead exposure. In pregnant urban women (Kuhnert et al. 1977), cord erythrocyte lead levels ranged... 

Effects on Vitamin D Metabolism. Lead appears to interfere with the conversion of vitamin D to its hormonal form, 1,25-dihydroxyvitamin D. In children with PbB levels of 33-55 pg/dL, 1,25-dihydroxy-vitamin D levels were reduced to levels comparable to those observed in children with severe renal insufficiency (Rosen et al. 1980). In lead-exposed children with blood lead levels of 33-120 pg/dL,... 

Health effects that have been associated with lead exposures during infancy or childhood include, anemia (Schwartz et al. 1990) (and related disorders of heme synthesis), neurological impairment (e.g., encephalopathy), renal alterations, and colic (Chisolm 1962, 1965 Chisolm and Harrison 1956), and impaired metabolism of vitamin D (Mahaffey et al. 1982 Rosen and Chesney 1983). Death from encephalopathy may occur with PbB levels 125 pg/dL. In addition to the above effects, the following health effects have been associated with lead exposures either in utero, during infancy or during... 

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. 

People are environmentally exposed to PBBs and PBDEs of different congeneric composition than the source commercial mixtures, due to differential partitioning and transformation of the individual congeners in the environment, including transformation in food animals (e.g., dairy cattle in the case of PBBs). Additionally, as discussed in Section 3.4, because PBBs and PBDEs are lipophilic and some congeners are not readily metabolized, they are likely to be retained in the body for long periods of time (years). 

Altered vitamin A homeostasis, primarily manifested as decreased hepatic storage of vitamin A, is another established effect of PBBs in animals. Vitamin A is essential for normal growth and cell differentiation, particularly differentiation of epithelial cells, and some PBB-induced epithelial lesions resemble those produced by vitamin A deficiency. Because it is the primary storage site for vitamin A, the liver has a major role in retinol metabolism. Esterification of dietary vitamin A, hydrolysis of stored vitamin A, mobilization and release into the blood of vitamin A bound to retinol-binding protein, and much of the synthesis of retinol-binding protein occurs in the liver. 

As with the structurally related PCBs (ATSDR 2000), PBBs are rapidly (minutes to hours) cleared from the blood and initially accumulate mainly in the liver, lungs, and muscle (Domino et al. 1982 Matthews et al. 1977). Due to their high affinity for lipid-rich tissues, PBBs are subsequently redistributed to adipose and skin for storage or metabolism in the liver, and a dynamic equilibrium of PBB concentrations is established among all tissues for each PBB homolog (Tuey and Matthews 1980). 

The NADPH-dependent metabolism of a PBB mixture was studied in vitro with liver microsomes of rats induced with PB, PBB, or 3-MC (Dannan et al. 1978a). Of the 12 major components of the mixture, only 2,2, 4,5,5 -pentabromobiphenyl and a hexabromobiphenyl were metabolized by microsomes Ifom PB- or... 

PBB-treated rats. Of seven structurally identified PBB components, only 2,2, 4,5,5 -pentabromobiphenyl had a bromine-lrccpara position. Although 2,2, 4,5,5 -pentabromobiphenyl, 2,3, 4,4, 5-pentabromobi-phenyl, and 2,2, 3,4,4, 5 -hexabromobiphenyl have two adjacent unsubstituted carbons, only 2,2, 4,5,5 -pentabromobiphenyl was metabolized. No significant metabolism occurred when the PBB mixture was incubated with microsomes of control rats or MC-induced rats. When 2,2 - and 4,4 -dibromobiphenyl were incubated with liver microsomes of PB-treated rats, only the 2,2 -congener was metabolized. These results suggest that the presence of a free para position is required for the metabolism of brominated biphenyls and that the bromine content of the molecule is less important in determining metabolism than the position of bromines on the biphenyl nucleus. 

The ability of PBBs to induce hepatic Phase I xenobiotic metabolizing enzymes (cytochrome P-450-dependent monooxygenases) is well documented (Dannan et al. 1978b, 1982a, 1982b, 1983 Ecobichon et al. 1979 Moore et al. 1978, 1979 Parkinson et al. 1983 Robertson et al. 1982 Schramm et al. 1985). PBB mixtures were classified as "mixed-type" inducers of hepatic microsomal monooxygenases and... 

Polybrominated Biphenyls. A recent study has used caffeine as a potential tool to characterize exposure and/or effect of PBBs (Lambert et al. 1990). In this test, caffeine is used as a metabolic probe of cytochrome P-450 isozymes activity from the CYPIA family, which in animals is significantly induced by PBBs (Safe 1984). Tire caffeine breath test (CBT) is primarily useful for detecting induction of CYP1A2 activity in human liver, and for that reason, it also has been used as a marker for exposure to PCBs, CDDs, and CDFs (Lambert et al. 1992). A volunteer population of 50 Michigan subjects with previously high serum PBB levels and 50 with undetectable or low serum levels was compared to a control population not exposed to PBBs (Lambert et al. 1992). Two tests were conducted, the CYP1A2-dependent caffeine... 

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