Proposed PBPK model to predict infant exposure to toxic chemicals in breast milk. (Correspondence).

In the mini-monograph, "Pharmacokinetics of Toxic Chemicals in Breast Milk: Use of PBPK Models to Predict Infant Exposure," published in the June issue of Environmental Health Perspectives, Clewell and Gearhart (2002) described a model schematic-developed in rats for the lactational transfer of perchlorate and iodide from the mother to the neonate. They used this physiologically based pharmacokinetic (PBPK) model to predict the distribution of perchlorate and iodide in lactating mothers and in infants in humans.

It is thought that because of its similarity in ionic size to iodide, the perchlorate ion is a competitive inhibitor of iodide at the sodium iodide symporter (NIS), the plasma membrane protein that catalyzes the accumulation of iodide into thyroid cells (Wolff 1998). The perchlorate ion blocks the binding of iodide to the NIS and is not internalized by the NIS into the thyroid cell (De La Vieja et al. 2000). Perchloate can accumulate in the thyroid but does not seem m accumulate in the thyrocytes (Eskandari et al. 1997). Perchlorate is excreted intact in the urine and has a half-life in humans of about 6-8 hr. Approximately 95% is recovered in the urine over 72 hr (Eichler 1929). Perchlorate is excreted quickly and is not stored, but enough iodine is stored in humans for about 6 weeks.

The PBPK model described by Clewell and Gearhart (2002) is a "schematic of the lactation model for the rat and human." The rat model was included in the March 2002 external review draft in preparation for the U.S. Environmental Protection Agency Toxicological Review and Draft Risk Characterization meeting held 5-6 March 2002 in Sacramento, California. At the meeting Nancy Carrasco, whose team sequenced and cloned the NIS (Dai et al. 1996), repeatedly claimed that perchlorate is not internalized by the thyroid cells. Additionally, NIS sites have not been found in human skin (Ajjan et al. 1998; Vayre et al. 1999).

Perchlorate has been in medical use since the 1950s, primarily for the treatment of hyperthyroidism; it is still in clinical use today mainly for diagnostic purposes. The toxicity of perchlorate in humans is known, as is its dose response in humans who have been exposed therapeutically, occupationally, in clinical studies, or environmentally via drinking water (Soldin et al. 2001). Iodide inhibition will not cause adverse effects on humans if thyroid hormone levels remain normal. Assuming a daily intake of 2 L water/day, the highest known level of perchlorate in drinking water (24 [micro]g/L) would yield a daily exposure of less than 50 [micro]g/day. This seems a large range of safety, being 10-fold 16wer than the 500 [micro]g/day level that Greer et al. (2002) considered to be the no-effect level in humans for the inhibition by perchlorate of iodine uptake by the thyroid, the mode-of-action held to be the initial and essential pharmacologic effect of perchlorate. It is also a thousand-fold lower than the 50 mg/day level at which an effect on thyroid hormone levels in humans may be expected. The absence of an observed effect on neonatal thyroid, thyroidal diseases, or thyroidal cancer in areas with higher detected perchlorate levels is epidemiologically consistent with the human toxicologic and pharmacologic observations.

Offie Porat Soldin
Soldin Research and Consultants Inc.
Bethesda, Maryland
and Motherisk, Clinical Pharmacology
The Hospital for Sick Children
Toronto, Canada
E-mail: [e-mail]

REFERENCES

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