TABLE 6-3 One-Year Chronic Toxicity Study in Cynomolgus Monkeys

Dose Groups

  • Six of each sex in each group at 0 (control), low, middle, upper middle, and high dose; dose selection based on findings of 3-month dose-range finding study

  • Ammonium perchlorate administered daily in drinking water for 12 months

Observations

  • General observations for morbidity and mortality, body weight, food consumption

Thyroid Function Assessment

  • Serum T3, T4, and TSH should be measured before dosing, on day 1, at weeks 1, 2, 4, monthly thereafter through 12 months

  • Thyroid 123I uptake should be measured at appropriate time points

Clinical Test Measures

  • Comprehensive hematology and clinical chemistry before dosing and periodically during study

Pharmacokinetic Measures

  • Appropriate pharmacokinetic measures

Necropsy and Histopathology

  • Full necropsy, macroscopic examination, histopathologic examination of many tissues, including the thyroid and pituitary glands

  • Modify models to incorporate dietary iodide measurements from biomonitoring studies in pregnant or lactating women, such as the studies of Soldin et al. (2003) and Hollowell et al. (1998).

By conducting a sensitivity analysis of their PBPK models, Clewell et al. (2003a,b), Merrill (2001), and Merrill et al. (2003) also identified several measures or biochemical processes that affect simulations of perchlorate and iodide disposition and target-tissue dosimetry in sensitive populations, including

  • Clearance of perchlorate and iodide in urine.

  • Rates of uptake and clearance of perchlorate and iodide in other tissues that contain NIS, such as skin, placenta, and mammary tissue.

  • Protein binding of perchlorate in rat and human plasma at different life stages (adult, pregnant, neonate, and fetus).



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