Development of a benchmark dose for lead-exposure based on its induction of micronuclei, telomere length changes and hematological toxicity

Abstract

Background: Excessive lead exposure is associated with adverse health effects. However, there is a lack of systematic investigation using large populations to ascertain acceptable exposure limits.

Objectives: Our study was aimed to identify human exposure-response relationships between lead exposure and health-related outcomes, and to determine a benchmark dose (BMD).

Methods: A total of 1896 participants from a lead-acid battery plant were recruited. Blood lead levels (BLLs) were detected for all participants. Hematological parameters (n = 1896), micronuclei (MN) frequencies (n = 934), and relative telomere length (rTL) (n = 757) were also determined. Multivariate linear/Poisson regression analyses were performed to examine associations between BLLs and these health outcomes. Restricted cubic splines were used to identify dose-response relationships. Three BMD approaches were used to calculate BMD and its 95% lower confidence limit (BMDL).

Results: Among all participants, BLLs show a right-skewed distribution (median, 185.40 μg/L; 25th - 75th percentile, 104.63-271.70 μg/L). There existed significant differences for red blood cell (RBC), hemoglobin (Hb), MN and rTL among different BLL dose groups. After adjusting for possible confounders, all indicators were significantly associated with BLLs. Restricted cubic splines show that there were linear dose-response relationships for RBC and Hb with BLLs, while non-linear for MN and rTL. Results from the three BMD approaches indicate that the dichotomous models were better than continuous models to calculate BMD and BMDL of BLLs. The conservative BMDL obtained from RBC data was 135 for total, 104 for male and 175 μg/L for female. The corresponding BMDL obtained from Hb data was 105 for total, 116 for male and 70 μg/L for female. As for MN data, the BMDL estimate was 66 for total, 69 for male and 64 μg/L for female. Finally, the BMDL from rTL data was 35 for total, 32 for male and 43 μg/L for female.

Conclusions: Our data show significant dose-response relationships between lead exposure and expressions of hematological toxicity and genotoxicity. The new BMDLs of 135 and 105 μg/L based on RBC and Hb, and even more strict level of 66 and 35 μg/L based on MN and rTL are lower than current exposure limits in China. Therefore, the four values can be considered as novel exposure limits. In addition, sex effect should be taken into account when setting occupational health standard. Considering that different biomarkers have different sensitivities, better understanding their relationships will certainly improve the current emphasis on precision health risk assessment.

Keywords: Benchmark dose; Hematological parameter; Lead exposure; Micronuclei; Restricted cubic splines; Telomere length.