Understanding Variation in Atrazine Metabolism in a Nonhuman Primate Model 公开

Brosius, Christina Renaud (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/5x21tf99v?locale=zh
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Abstract

Atrazine is among the most heavily applied pesticides in the United States. Atrazine and a few of its dealkylated and mercapturic acid metabolites have been used as biomarkers of atrazine exposure. This study assessed variation in a biomarker of atrazine exposure, diaminochlorotriazine (DACT), in a nonhuman primate model in serum and urine. The aims of this study were to assess variation in a single individual subject over time and among subjects in one dosing group, to assess variation in the metabolic profile by exposure vehicle, and to perform a comparison of biomonitoring matrices with a look at the elimination of atrazine and its metabolites from plasma and their appearance in urine. A group of six Cynomolgus monkeys were dosed with atrazine via five exposure pathways and doses across five experimental phases. Serum and urine samples were collected at up to 21 time points over seven days. Atrazine, DACT and other atrazine degradates were quantified in serum and urine using solid-phase extraction (SPE) sample preparation and high performance liquid chromatography- tandem mass spectrometry (HPLC-MS/MS) analysis with isotope dilution quantification. Experimentally determined DACT elimination rate constants (Ke) were used to compare atrazine elimination across subjects and exposure pathways and between biological matrices. Curves describing DACT elimination from urine and serum were developed, and DACT half-lives were calculated. Serum DACT half-lives were approximately 11 hours; urine half-lives were approximately 13 hours. Inter-subject and intra-subject variation in Ke were low in both matrices. Elimination rate constants were significantly different (urine p=0.02, serum p=0.006) when identical doses were administered intravenously versus orally, and oral doses administered at varying concentrations produced significantly different estimates of Ke. Elimination of DACT from serum and urine was different. Serum DACT was less abundant, peaked earlier, and dropped below limits of detection earlier. These results can inform planning for future studies that involve biomonitoring of atrazine and its most abundant biomarker.

Table of Contents

I. Introduction.......................................................................................1

II. Methods............................................................................................4

Dosing and sample collection..............................................................4

Sample preparation and analysis.........................................................5

Analysis...........................................................................................7

Variation within subjects............................................................8

Variation among subjects...........................................................8

Variation of the metabolic profile by exposure vehicle....................9

Variation between plasma and urinary metabolite concentrations....9

III. Results............................................................................................9

Variation within subjects....................................................................11

Variation among subjects...................................................................11

Variation of the metabolic profile by exposure vehicle............................12

Variation between plasma and urinary metabolite concentrations............13

IV. Discussion........................................................................................14

V. Conclusions and Recommendations...................................................18

VI. References.......................................................................................19

VII. Tables and Figures..........................................................................21

VIII. Appendix.......................................................................................37

i. List of Tables.................................................................................37

ii. List of Figures...............................................................................37



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