Quantitative evaluation of heme biosynthetic pathway parameters as biomarkers of low-level lead exposure in rats

Erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity, erythrocyte zinc protoporphyrin (ZPP)/heme ratio, and urinary coproporphyrin (UC) concentration have been employed as biological indicators of moderate-to high-level lead exposure, corresponding to blood levels in excess of 50 micrograms/dl, in human subjects. The comparative efficacy of these measures as indicators of lead exposure consistent with sustained lower blood lead levels has not been systematically evaluated. In the present studies, we examined the relative sensitivity and magnitude of response of these three bioindicators in rats during chronic exposure to 0, 100, or 1000 ppm lead as lead acetate in drinking water for up to 10 wk, followed by a 10-wk postexposure period, with weekly assessments, or during subchronic exposure to 0 or 1000 ppm lead as lead acetate in drinking water for 6 d, with daily assessments. Analysis of variance (ANOVA) was used to determine if the lead-treated rats differed from controls and to distinguish between dose groups with respect to the three biochemical indices of lead exposure. The data were normalized by conversion to Z scores in order to compare indicators with regard to magnitude of change in response to lead treatment. The order of sensitivity of each indicator was determined by considering the magnitude of the correlation coefficient (r) between the indicator and the blood lead concentration in each study. The indicators in order of decreasing sensitivity to lead in the chronic study were UC > ZPP/heme > ALAD. The indicators in order of decreasing magnitude of change in response to change in blood lead level were also UC > ZPP/heme > ALAD. None of the heme pathway parameters was judged a satisfactory substitute for direct blood lead measurement as an indicator of low-level lead exposure. However, urinary coproporphyrin appears most useful in this respect owing to highest sensitivity and magnitude of change relative to blood lead content and relatively low variation of mean coproporphyrin levels.