**1. Introduction**

#### **1.1 Actual thyroid disease demographics**

Thyroid diseases increase in a ubiquitous global phenomenon suspected to further rise in the upcoming decades (Dua et al. 2008). Thyroid cancer is the most common endocrine malignancy, representing 2% of all malignancies. A rapid global rise in its incidence has been seen in recent decades, especially concerning the papillary type, which has been increasing in several countries (Liu et al. 2001; Reynolds et al. 2005; Davies and Welch 2006; Enewold et al. 2009; Kilfoy, Devesa et al. 2009; Kilfoy, Zheng et al. 2009). An estimated 44,670 new cases of thyroid cancer are expected to be diagnosed in the United States of America in 2010, with three out of four cases occurring in women. The incidence rate of thyroid cancer has been increasing sharply since the mid-1990s, and it is the fastest growing cancer in both men and women, as well as the ninth most common human malignancy in the USA (American Cancer Society: Cancer Facts and Figures 2010).

The reasons for the increase in occurrences of this type of cancer are still unclear and controversial. Earlier studies suspected that the upward trend was caused by the widespread use of radiation therapy for benign conditions of the head and neck among children and adolescents from the early 1920s to the late 1950s (Weiss 1979; Pottern et al. 1980). Other studies suggested that this trend could be associated with atmospheric nuclear fallouts (Catelinois et al. 2004; Gilbert et al. 1998; Kazakov, Demidchik, and Astakhova 1992; Kerber et al. 1993; Takahashi et al. 2003) or constant diagnostic X-ray exposures (Prokop 2001; Ron et al. 1995) suffered especially by children (Brenner et al. 2001; Golding and Shrimpton 2002; Maitino et al. 2003). More recent studies suggested that the prevalence of thyroid nodules depends on the screening method and population evaluated according to geographic regions and racial groups, indicating that the widespread use of ultrasonography and socioeconomic indicators of health care access could be the major players in this new demography of the thyroid cancer (Morris and Myssiorek 2010; Sprague, Warren Andersen, and Trentham-Dietz 2008).

The steep increase in thyroid cancer is certainly related to better cancer detection by ultrasonography and other imaging techniques in a population growing older, as well as a larger and easier access to health care and robust laboratory diagnostic tools such as TSH and thyroid antibody dosages (Davies and Welch 2006; Ward and Graf 2008). However,

Thyroid Disruptors: How They Act and How We React 5

and an increased risk of thyroid cancer (Mushkacheva et al. 2006; Pottern et al. 1990; Ron et al. 1995; Ron et al. 1989; Schneider et al. 1993; Shore et al. 1993; Shore et al. 2003; Yoshimoto et al. 1995); however, risks from internally deposited radioactive iodine were not well studied until recently (Zablotska et al. 2011; Kazakov, Demidchik, and Astakhova 1992;

Well-documented examples include medical therapeutic external beam radiation and accidental exposure to c-radiation and radioiodine as a result of nuclear weapon explosions

Both radiations (Ostroumova et al. 2009) and thyroid benign nodules (Lyon et al. 2006; Brent

The growing incidence of thyroid cancer over the last decades is entirely due to papillary carcinomas, whereas the incidence of other thyroid cancer types, including the follicular type, remains unchanged or is decreasing (Nikiforov 2010). A better understanding of the biology and etiologic factors responsible for the development of papillary carcinomas is particularly important for unraveling the reasons behind the general increase in thyroid

Mahoney et al (Mahoney et al. 2004) have described that marked increases in the incidence of thyroid cancer after the Chernobyl incident have occurred in all areas of the Republic of Belarus and among all age groups. However, the greatest increases have occurred in children, suggesting that a high prevalence of pre-existing iodine deficiency in combination with unique susceptibility among younger people might have contributed to potential

Ron et al. (Ron et al. 1995) presented a pooled analysis of five cohort and two case-control studies concerning external radiation and thyroid cancer. The study reported a statistically significant excess relative risk per Gy for individuals exposed before 15 years of age. There was no evidence of increased thyroid cancer risk for individuals exposed at older ages. More recent analyses of atomic bomb survivors confirmed a strong inverse association between ERR/Gy and age at exposure, but suggested that adult exposure is associated with a small increase in thyroid cancer risk (Preston et al. 2007). In 2011, Schonfeld et al. (Schonfeld, Lee, and Berrington de Gonzalez 2011) presented an overview of the use of radiation for medical purposes and its significance for thyroid cancer, especially among children, who seem to be more susceptible to the effects of ionizing radiation. In their study, Schonfeld et al analyzed data concerning x-ray use for dental purposes and did not find significant differences among patients that were more exposed to that type of radiation. In what concerns nuclear medicine, there are no data relating that segment to thyroid cancer, and the authors link that to the fact that kids are hardly ever exposed to those types of exams. To analyze data on diagnostic computed tomography, Schonfeld et al used Analytica software for the calculations to estimate means and 95% uncertainty limits. Using this methodology, they calculated that about 1000 future thyroid cancers could be related to computed tomography

There are also some reports on the effects of radiotherapy for cancers and development of thyroid cancer. Thyroid cancer is one of the most common second cancers after radiotherapy during childhood for Hodgkin lymphoma, and significant increased risks of thyroid cancer have been observed from 5 to more than 40 years after childhood radiotherapy (Ng et al. 2010). In addition to cancer treatment, radiotherapy for the treatment of benign conditions,

scans conducted in the United States of America during the year 2007.

Shibata et al. 2001; Takahashi et al. 2003; Dobyns et al. 1974).

or nuclear reactor accidents (Ron et al. 1995).

2010) are related to autoimmune processes.

**2.2 Radiation and thyroid nodules** 

carcinogenic exposures to the thyroid.

cancer incidence.

there are strong indicators that other causes may be involved. Better techniques and larger access to health care cannot be held responsible for the increasing incidence rates of larger tumors, which have been similar to papillary microcarcinoma (Hughes et al. 2011).

In addition, an epidemiological study of thyroid cancer cases in a highly radiated territory in Poland – i.e. in the province of Opole after 1986 – indicate a significant increase in thyroid cancer incidence in males and females during the period 1995-2002, when comparing with the years 1987-1994. The data comprises all the thyroid cancer cases registered in Opole province in the years 1987-2002, originated from the Provincial Cancer Registry in Opole (Tukiendorf, Miszczyk, and McEwan 2010). Finally, the proportion of local staged thyroid cancer increased by 24% in the Black group, 14.4% in the Hispanic white group, 14.3% in the non-Hispanic white group, and only 4.0% in the Asian group between the periods 1992–1996 and 2000–2004. Five-year survival rates of patients with papillary tumor were approximately 95%; however, that of anaplastic tumor ranged from 5.6% to 11.4% among REGs (Race/Ethnicity Groups) (Yu et al. 2010).

Autoimmune thyroid disorders, comprising Graves' disease and Hashimoto's thyroiditis, are considered polygenic, multifactorial diseases characterized by an abnormal activation of the immune system as a result of interactions between genetic predisposition and environmental factors, the former accountant for approximately 70 – 80% of liability to develop autoimmune thyroid disorders (Wiersinga 1999). Accumulating data confirm that the burden of autoimmune diseases is rising as well, affecting 5 to 10% of the world population. They are a significant cause of morbidity and mortality accounting for soaring health care costs, comparable to those of cancer and heart disease (Cooper, Bynum, and Somers 2009; Eaton et al. 2007; Shoenfeld et al. 2008).

Hashimoto's disease and Graves' disease are the two most common forms of autoimmune thyroiditis, the archetypal organ-specific autoimmune disease in humans. Both are characterized by lymphocytic infiltrate and autoreactivity against thyroid autoantigens (Michels and Eisenbarth 2010; Rapoport and McLachlan 2001; Zenewicz et al. 2010). There are strong evidences for a major role of heredity in Graves' disease, as demonstrated with a population-based study of two Danish twin cohorts (Brix et al. 2001). This study indicated that 21% of the causes involved in Graves' disease development can be attributed to environmental factors (Brix et al. 2001; Prummel, Strieder, and Wiersinga 2004). However, recent analysis of thyroid disease demographics indicate that environmental factors probably have been playing an important role in the observed rise in thyroid disease incidence all over the world (Morris and Myssiorek 2010). Among these environmental causes, viral infections have been repeatedly demonstrated related to type 1 diabetes mellitus and multiple sclerosis (Cabrera-Rode et al. 2003; Dahlquist et al. 1995; Hiltunen et al. 1997; Hyoty and Taylor 2002; Lonnrot, Korpela et al. 2000; Lonnrot, Salminen et al. 2000).

In addition, other factors including ionizing radiation, dietary iodine intake, reproductive factors like estrogens, and cigarette smoking might be considered as thyroid disruptors, working as triggers for thyroid disease.
