Use of Generalized Additive Model to Detect the Threshold of δ-Aminolevulinic Acid Dehydratase Activity Reduced by Lead Exposure.

BACKGROUND: Lead inhibits the enzymes in heme biosynthesis, mainly reducing δ-aminolevulinic acid dehydratase (ALAD) activity, which could be an available biomarker. The aim of this study was to detect the threshold of δ-aminolevulinic acid dehydratase activity reduced by lead exposure. METHODS: We collected data on 121 lead workers and 117 non-exposed workers when annual health examinations were performed. ALAD activity was determined by the standardized method of the European Community. ALAD G177C (rs1800435) genotyping was conducted using the polymerase chain reaction and restricted fragment length polymorphism (PCR-RFLP) method. In order to find a threshold effect, we used generalized additive models (GAMs) and scatter plots with smoothing curves, in addition to multiple regression methods. RESULTS: There were 229 ALAD1-1 homozygotes and 9 ALAD1-2 heterozygotes identified, and no ALAD2-2 homozygotes. Lead workers had significantly lower ALAD activity than non-exposed workers (41.6 ± 22.1 vs. 63.3 ± 14.0 U/L, p < 0.001). The results of multiple regressions showed that the blood lead level (BLL) was an important factor inversely associated with ALAD activity. The possible threshold of BLL affecting ALAD activity was around 5 µg/dL. CONCLUSIONS: ALAD activity was inhibited by blood lead at a possible threshold of 5 µg/dL, which suggests that ALAD activity could be used as an indicator for lead exposure regulation.

Smelting Remains a Public Health Risk Nearly a Century Later: A Case Study in Pueblo, Colorado, USA.

Pueblo, Colorado has a long history of smelting activities, and recent studies raised concerns about lead exposure. This study tested 240 children in Pueblo for blood lead levels (BLLs) and found a significant association between distance from old smelters and children BLLs. Around 7.5% of Pueblo children had BLLs above the Centers for Disease Control and Prevention reference level of 5 µg/dL for elevated BLL, and 18.3% had BLLs between 3.3⁻4.9 µg/dL. Out of the 36 children who lived near former smelters, 13.9% had BLLs above 5 µg/dL vs. 6.37% for children living away from old smelters. The proportion of Pueblo children with elevated BLL was nearly three times the 2007⁻2010 United States national average (7.5% vs. 2.6%), and this was higher in the immediate vicinity of old smelters (13.9% vs. 2.6%). Genetic polymorphisms for ALAD-1 or ALAD-2 alleles, which play a role in susceptibility to lead toxicity, were not associated with children BBLs. Around 38.5% of houses sampled near the smelters had topsoil lead levels higher than the Environmental Protection Agency’s benchmark of 400 mg/kg. Our study resulted in the addition of areas of Pueblo to the EPA Superfund National Priorities List in December 2014, and cleanup is currently underway to minimize the public health risks.

Genetic modification of ALAD and VDR on lead-induced impairment of hearing in children.

Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) genes may modify lead metabolism and neurotoxicity. Two cohorts of children were examined for hearing [pure-tone audiometry (PTA), brain stem auditory evoked potentials (BAEP)], acoustic otoemission (transient emission evoked by a click) and blood-lead concentrations (B-Pb). The children were genotyped for polymorphisms in ALAD and VDR. The median B-Pbs were 55 and 36µg/L in the two cohorts (merged cohort 45µg/L). B-Pb was significantly associated with impaired hearing when tested with PTA (correlation coefficient rS=0.12; P<0.01), BAEP (rS=0.18; P<0.001) and otoemission (rS=-0.24; P<0.001). VDR significantly modified the lead-induced effects on PTA. Carriers of the VDR alleles BsmI B, VDR TaqI t and VDR FokI F showed greater toxic effects on PTA, compared to BsmI bb, VDR TaqI TT and VDR FokI ff carriers. No significant interaction was found for ALAD. Lead impairs hearing functions in the route from the cochlea to the brain stem at low-level exposure, and polymorphisms in VDR significantly modify these effects.

Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA).

BACKGROUND AND OBJECTIVE: Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh. METHODS: Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected to determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA). RESULTS: The mean BPb level was 9.7 µg/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1 carriers. CONCLUSION: This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys.