APPENDIX O

Thyroid neoplasia in rodents secondary to goitrogen induced hormone imbalance are not relevant to predicting human risk of thyroid neoplasia

In the absence of adequate human cancer data, it is biologically plausible and prudent to regard agents for which there is sufficient evidence of carcinogenicity in experimental animals as if they presented a carcinogenic risk to humans. However, the possibility that an agent that causes cancer in animals through a mechanism that does not operate in humans must be taken into account. During recent years, evidence has developed that certain neoplasms commonly seen in bioassays for carcinogenicity in rodents can develop thorough such species-specific mechanisms.

When extrapolating from rodents to humans, for all endpoints, it is essential to know more about the similarities and differences across species. Detailed knowledge of molecular mechanisms and cellular and organ system responses can guide us to make better decisions about whether perchlorate or other goitrogens that produce cancers or neurotoxicity in rodents really represent significant risks of doing the same in humans.

There are several species differences in thyroid physiology. Thyroxine-binding globulin (TBG) is the predominant plasma protein in humans and non-human primates that binds and transports thyroid hormone in the blood. This protein has binding affinities 3 and 5 orders of magnitude greater than the other two thyroxine-binding proteins, albumin and pre-albumin, respectively. The lack of TBG in the adult rat is an important difference.4

Major differences are also present in the half-life of thyroxine, 12 hours in the rat versus 5-9 days in humans, and the serum level of TSH which is 25 times higher in the rodent than in humans. The rat also exhibits enhanced thyroid hormone elimination with less efficient enterohepatic recirculation than in humans. Thus, rats require about a 10-fold higher production of thyroxine than do humans4.

The histology of the resting rodent thyroid is similar to that of the stimulated human gland, with small follicles lined by tall follicular cells. Thus, both the physiological parameters and histological appearance indicate that the rodent thyroid gland is more active and operates at a higher level with respect to thyroid hormone turnover as compared to the human gland4.

There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direct carcinogenic effect in the thyroid gland and the other involves chemicals which, through a variety of mechanisms, disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. These secondary mechanisms predominantly involve effects on thyroid hormone synthesis or peripheral hormone disposition3. Perchlorate is non-genotoxic and has been shown to cause thyroid neoplasia in rodents through these secondary mechanisms.

The important species differences in thyroid gland physiology between rodents and humans account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neoplasia, secondary to chemically induced hormone imbalance, is mediated by thyroid-stimulating hormone (TSH) in response to altered thyroid gland function1,2. There would be little if any risk for non-genotoxic chemicals such as perchlorate that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function.

There is convincing evidence that in rodents, thyroid hormone imbalance alone leads to tumor formation based on studies on the effect of iodine deficiency, partial thyroidectomy and transplantation of TSH-secreting tumors. The weight of the evidence suggests that rodents are more sensitive than human subjects to thyroid tumor induction due to hormonal imbalances that cause elevated TSH levels. At least 20 different compounds cause follicular cell neoplasms of the thyroid in rats and/or mice, however, none of these is unequivocally associated with thyroid cancer in humans4.

In a 1999 FDA review of the science behind another goitrogen, sulfamethazine, the authors stated: "The pathogenesis of thyroid tumors in rats and humans is different. There is no evidence for a primary causative role of TSH in thyroid tumor formation in humans; however, TSH at normal levels may play some necessary, but incomplete role in human thyroid tumor development.... Accordingly, there are few examples of thyroid carcinogens in humans. X-irradiation and radioactive iodine are the only clearly known human thyroid carcinogens; there are no other chemicals known to induce thyroid tumors in Humans." 11 The USEPA science policy position is that nonlinear thyroid cancer dose-response considerations are applied to chemicals that reduce thyroid hormone levels, increase TSH and thyroid cell division, and are judged to lack mutagenic activity.12

When human patients have markedly altered changes in thyroid function and elevated TSH levels, as in areas with high incidents of endemic goiter due to iodine deficiency, there is little if any increase in the incidence of thyroid cancer. The relative resistance to the development of thyroid cancer in humans with elevated plasma TSH is in marked contrast to the response of the thyroid gland to chronic TSH stimulation in rats and mice1,2.

Two recent human ecological studies have been conducted comparing populations exposed to perchlorate in drinking water with populations not exposed to perchlorate in drinking water. A study of the prevalence of thyroid cancer among the Medicaid eligible population in Nevada determined that the prevalence of thyroid cancer in 1997-1998 was not elevated in Clark County with 4-24 ppb in drinking water compared to Washoe County and the rest of Nevada where perchlorate is not detectable in the water sources.5 A recent epidemiological study of cancer incidence in the Redlands, California (with low level groundwater contamination with perchlorate) did not identify a generalized cancer excess or thyroid cancer excess in this community .6

In evaluating the question "Does chronic excess TSH stimulation secondary to iodine uptake inhibition at the NIS does cause thyroid cancer in humans?", epidemiological studies among populations with varying exposure to thiocyanate are also relevant to consider. Thiocyanate is known to competitively inhibit iodine uptake at the NIS in the same manner as perchlorate. The primary sources of thiocyanate among western cultures that do not depend upon cassava as a staple in their diet are cigarette smoking and cruciferous vegetables. Three recent epidemiological studies report a significant reduction in thyroid cancer among cigarette smokers. This appears to be valid for males and females and for all cell types of thyroid cancer.7,8,9 It is also dose-dependent with the higher smoking levels corresponding to lower cancer prevalence.7 A pooled analysis of several case-control studies of thyroid cancer concluded that cruciferous vegetables are not positively related to thyroid cancer risk. Their effect does not seem to be substantially different from that of other vegetables, which appear to be protective on this cancer.10

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