The NAS perchlorate review: adverse effects?

Ginsberg and Rice (2005) argued that the regard dose for perchlorate of 00007 mg/kg for day recommended by the National Academy of Sciences (NAS) Committee to Assess the Health Implications of Perchlorate Ingestion is not adequately protective. As members of the committee, we disagree.

Ginsberg and Rice (2005) based their conclusion upon three points. The first involves the designation of the point of departure as a NOEL (no observ consequence level) versus a LOAEL (lowest observ adverse event level). The committee chose as its point of departure a dose of perchlorate (0007 mg/kg by day) that, when given for 14 days to seven normal subdues did not cause a statistically significant decrease in the cluster mean thyroid iodide uptake (Greet et al. 2002) Accordingly, the committee considered it a NOEL. Ginsberg and Rice (2005) focused upon the fact that only seven subdues were given that dose; they appear to be to say that attention should be paid alone to the results in those controls in whom there was a decrease in thyroid iodide uptake and that the comes in those in whom there was no decrease or an increase should be ignored. They considered the dose to be a LOAEL because of the decrease in uptake in those small in number subjects. It is important to note that a statistically significant decrease of for example, 5% or flat 10% would not be biologically important and, more important, would not be sustained. For example, in another investigation (Braverman et al. 2004), administration of 004 mg/kg for day to normal subjects for 6 month had no event on thyroid iodide uptake when measured at 3 and 6 month and no result on serum thyroid hormone or thyrotropin concentrations measured monthly [Inspection of Figure 5A in salute et al. (2002) suggests that this dose would inhibit thyroid iodide uptake by dint of about 25% if measured at 2 weeks.]

The next to the first issue involves database uncertainty. In clinical studies, perchlorate has been administered prospectively to 68 normal bring under rules for 2 weeks to 6 month In individual study (Brabant et al. 1992) a dose of 92 mg/kg for day for 4 weeks had no event on thyroid function. In occupational studies, doses as high as 05 mg/kg by day had no effect upon thyroid hormone or thyrotropin production in workers. In epidemiologic studies, there were no abnormalities in expansion or thyroid function in children expos life-long to 100-120 [micro]g perchlorate for liter of drinking water, or in pregnant women and newborn infants similarly expos Given the choice of a nonadverse result (inhibition of iodide uptake through the thyroid) as the point of departure and the multiple studies in which doses of perchlorate a great deal of higher than 0.007 mg/kg by day had no effect upon any aspect of thyroid function, the committee did not apply a database uncertainty factor.

Finally, Ginsberg and Rice (2005) argued that inhibition of thyroid iodide uptake is adverse. That conclusion assumes that any acute inhibition would be sustained, for a like reason thyroid hormone production would decrease. That is not the case. There is remarkable compensation for level substantial reductions in thyroid iodide uptake and thyroid hormone production. As noted above, subdues given 0.04 mg/kg per day for 6 month and 92 mg/kg through day for 4 weeks--doses that certainly would inhibit thyroid iodide uptake for a scarcely any weeks--had no decrease in serum thyroid hormone or increase in serum thyrotropin concentrations (the hallmark of level mild hypothyroidism). Short-term inhibition of thyroid iodide uptake is not an adverse effect; it has no adverse results because there is rapid compensation mediated by dint of several independent processes. One of these processe is up-regulation of the thyroid sodium-iodide transport combination of parts to form a whole as a result of intrathyroidal iodide deficiency. The next to the first should there be even a true small decrease in thyroid hormone production, is an increase in thyrotropin secretion, resulting in overall stimulation of the thyroid gland. Analyses of the results of any substance on thyroid function must take these compensatory processe into account, particularly the fact that the issue of any substance that inhibits thyroid function will diminish with time. sole if all of these mechanisms fail will there be hypothyroidism, the first adverse issue in the continuum of issues resulting from perchlorate ingestion. If there is no inhibition of iodide uptake to begin with, there will be no other changes in thyroid function at any time.

We believe that the committee's approveed reference dose of 0.0007 mg/kg for day provides a wide margin of safety for all make subordinates of all ages.

The authors declare they have no competing financial interests.

REFERENCES

Brabant G Bergmann P Kirsch CM Kohrle J Hesch RD yon zur Muhlen A. 1992 Early adaptation of thyrotropin and thyroglobulin secretion to experimentally decreased iodide store in man. Metabolism 4l:1093-1096.

Braverman LE He X Pino s Magnani B, Firek A. 2004 The issue of low dose perchlorate upon thyroid function in normal presents [Abstract]. Thyroid 14:691.