Thyroid function and thyroid tumors in toxaphene-treated rats

Historically, a direct and irreversible genotoxic reaction of a xenobiotic with DNA has been considered to be a universal and obligatory initiating event in the etiology of neoplasia, and it was assumed therefore that (1) there was no threshold other than zero exposure for cancer initiation, and (2) like radiation, exposure was additive over a lifetime. Human exposure to xenobiotics causing neoplasia in laboratory rodents has been regulated in many countries on that basis. In the last decade evidence has accumulated indicating that some neoplasia in laboratory rodents may not be caused by a direct and irreversible interaction of xenobiotics with DNA. In addition, it has been found that some neoplasia caused in laboratory rodents by xenobiotics may not be relevant for biochemical/physiological reasons. This has raised the question whether human exposure to these xenobiotics should be regulated by the no-threshold philosophy used for direct-acting genotoxic xenobiotics or whether they can be regulated by the threshold philosophy used for classical xenobiotic-induced toxic effects. In a bioassay carried out by the National Cancer Institute and published in 1979, toxaphene was found to cause an increase in the occurrence of two spontaneously occurring tumors in laboratory rodents that since have been found to have both genotoxic and nongenotoxic etiologies in laboratory rodents. Experiments described in this paper are part of a program to help elucidate whether the increased incidence of these two neoplasms in laboratory rodents could have had a nongenotoxic origin, and thus whether toxaphene could be regulated by a threshold approach. Forty male rats were orally intubated with 100 mg/kg/day technical grade toxaphene in corn oil for 3 days. The dose was reduced to 75 mg/ kg/day on Day 4 due to toxicity. This lower dose was administered daily for 25 days. Another group of 40 male rats was orally gavaged daily with equivalent volumes of corn oil. After 0, 7, 14, and 28 doses, 10 test and 10 vehicle control animals were sacrificed for gross and histopathological examination of thyroid, parathyroid, and pituitary glands. Weights of these endocrine organs, body weights, and brain weights were determined. Prior to sacrifice, a blood sample was obtained from each animal for preparation of serum for analyses of thyroid stimulating hormone (TSH), thyroxine (T4), thyroid hormone (T3), and reverse T3 (rT3). Thyroid glands were evaluated microscopically for follicular cell hypertrophy, hyperplasia, and colloid storage. There were significant time-related increases in serum TSH in the test animals after 7, 14, and 28 doses of toxaphene. The serum levels of T3, T4, rT3, and corrected T3 (CrT3) in the test group were not significantly different from controls at each interval. Thyroid gland weights and thyroid to brain weight ratios were not significantly (p > 0.05) increased in the test group at each sacrifice interval. Pituitary weight, brain weight, and the ratios of these organ weights to body weights were similar in the test and control groups at each sacrifice interval. Thyroid follicular cell hypertrophy and intrafollicular hyperplasia increased and thyroid follicular cell colloid stores decreased with duration of treatment with toxaphene. The hormonal and histopathologic changes seen in the test group were consistent with increased excretion of T3 and/or T4 resulting from cytochrome P450 enzyme induction in the liver. This mechanism for thyroid neoplasia is not known to occur in humans.