Assessment of the genotoxicity of tert-butyl alcohol in an in vivo thyroid comet assay.

Chronic exposure to high (20,000 ppm) concentrations of tert-butyl alcohol (TBA) in drinking water, equivalent to ~2100 mg/kg bodyweight per day, is associated with slight increases in the incidence of thyroid follicular cell adenomas and carcinomas in mice, with no other indications of carcinogenicity. In a recent toxicological review of TBA, the U.S. EPA determined that the genotoxic potential of TBA was inconclusive, largely based on non-standard studies such as in vitro comet assays. As such, the potential role of genotoxicity in the mode of action of thyroid tumors and therefore human relevance was considered uncertain. To address the potential role of genotoxicity in TBA-associated thyroid tumor formation, CD-1 mice were exposed up to a maximum tolerated dose of 1500 mg/kg-day via oral gavage for two consecutive days and DNA damage was assessed with the comet assay in the thyroid. Blood TBA levels were analyzed by headspace GC-MS to confirm systemic tissue exposure. At study termination, no significant increases (DNA breakage) or decreases (DNA crosslinks) in %DNA tail were observed in TBA exposed mice. In contrast, oral gavage of the positive control ethyl methanesulfonate significantly increased %DNA tail in the thyroid. These findings are consistent with most genotoxicity studies on TBA and provide mechanistic support for non-linear, threshold toxicity criteria for TBA. While the mode of action for the thyroid tumors remains unclear, linear low dose extrapolation methods for TBA appear more a matter of policy than science.

Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review.

The broadening application of glucagon-like peptide (GLP)-1 receptor agonists, specifically semaglutide (Ozempic) for the management of diabetes and obesity brings a critical need to evaluate its safety profile, considering estimates of up to 20 million prescriptions per year in the US until 2035. This systematic review aims to assess the incidence of thyroid cancer and detail the spectrum of adverse events associated with semaglutide, focusing on its implications for patient care. Through a systematic search of PubMed, Scopus, and Embase databases up to December 2023, ten randomized controlled trials (RCTs) involving 14,550 participants, with 7830 receiving semaglutide, were analyzed, with an additional number of 18 studies that were separately discussed because they reported data from the same RCTs. The review focused on thyroid cancer incidence, gastrointestinal symptoms, and other significant adverse events attributed to semaglutide. The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk. Adverse events were predominantly gastrointestinal, including nausea (2.05% to 19.95%) and diarrhea (1.4% to 13%). Nasopharyngitis and vomiting were also notable, with mean prevalences of 8.23% and 5.97%, respectively. Other adverse events included increased lipase levels (mean of 6.5%), headaches (mean prevalence of 7.92%), decreased appetite (reported consistently at 7%), influenza symptoms (mean prevalence of 5.23%), dyspepsia (mean prevalence of 5.18%), and constipation (mean prevalence of 6.91%). Serious adverse events varied from 7% to 25.2%, highlighting the need for vigilant patient monitoring. These findings underscore the gastrointestinal nature of semaglutide's adverse events, which, while prevalent, did not significantly deter from its clinical benefits in the treatment landscape. This systematic review provides a comprehensive assessment of semaglutide's safety profile, with a focus on gastrointestinal adverse events and a low incidence of thyroid cancer. Despite the prevalence of gastrointestinal symptoms, semaglutide remains an efficacious option for managing diabetes and obesity. The detailed characterization of adverse events underscores the importance of monitoring and managing these effects in clinical practice, excluding the hypothesis of carcinogenesis.

Assessment of five typical environmental endocrine disruptors and thyroid cancer risk: a meta-analysis.

Introduction: There are conflicting reports on the association between environmental endocrine disruptors (EEDs) and thyroid cancer. This meta-analysis aimed to elucidate the relationship between EEDs and thyroid cancer. Methods: We searched for epidemiological studies on EEDs and thyroid cancer published in PubMed and Web of Science up to December 2022. We then screened the articles that could extract data on EEDs concentration levels in both thyroid cancer patients and healthy controls. We excluded articles that could not calculate effect sizes, focused on other thyroid diseases, or lacked controls. Standardized mean difference (SMD) was calculated to analyze the association between EEDs and thyroid cancer. We measured the heterogeneity among the included studies using I2, assessed publication bias by Egger's and Begg's test, and evaluated article quality using the Newcastle-Ottawa Quality Score (NOS). In the end, fifteen eligible case-control studies were included. Results: Our comprehensive analysis revealed that polychlorinated biphenyls (PCBs) were negatively associated with thyroid cancer{ SMD = -0.03, 95% confidence interval (CI) = (-0.05, -0.00), P = 0.03}, while polybrominated diphenyl ethers (PBDEs), phthalates (PAEs), and heavy metals were positively associated with thyroid cancer{PBDEs: SMD = 0.14, 95%CI = (0.04, 0.23), P = 0.007; PAEs: SMD = 0.30, 95%CI = (0.02, 0.58), P = 0.04; heavy metals: SMD = 0.21, 95%CI = (0.11, 0.32), P < 0.001}. We did not find a statistically significant relationship between bisphenol A (BPA) and thyroid cancer. Most of the included studies did not show publication bias, except for those on PCBs. Discussion: Our results indicate that exposure to certain EEDs, such as PBDEs, PAEs, and heavy metals, increases the risk of thyroid cancer. However, further large-scale epidemiological studies and mechanism studies are needed to verify these potential relationships and understand the underlying biological mechanisms.

Uncertainties in Radiation Doses for a Case-control Study of Thyroid Cancer among Persons Exposed in Childhood to 131 I from Chernobyl Fallout.

Uncertainties in thyroid doses due to I intake were evaluated for 2,239 subjects in a case-control study of thyroid cancer following exposure to Chernobyl fallout during childhood and adolescence carried out in contaminated regions of Belarus and Russia. Using new methodological developments that became available recently, a Monte Carlo simulation procedure was applied to calculate 1,000 alternative vectors of thyroid doses due to I intake for the study population of 2,239 subjects accounting for sources of shared and unshared errors. An overall arithmetic mean of the stochastic thyroid doses in the study was estimated to be 0.43 Gy and median dose of 0.16 Gy. The arithmetic mean and median of deterministic doses estimated previously for 1,615 of 2,239 study subjects were 0.48 Gy and 0.20 Gy, respectively. The geometric standard deviation of individual stochastic doses varied from 1.59 to 3.61 with an arithmetic mean of 1.94 and a geometric mean of 1.89 over all subjects of the study. These multiple sets of thyroid doses were used to update radiation-related thyroid cancer risks in the study population exposed to I after the Chernobyl accident.

Evidence-based dose-response assessment for thyroid tumorigenesis from acrylamide.

Acrylamide is commonly found in various foods. Cancer studies in rats have reported increases in tumors of the thyroid, mammary tissues, tunica vaginalis of the testis, and sometimes tumors at other sites. We review relevant studies on acrylamide's DNA toxicity, tumor formation and the manner of its tumor formation. We find, as do others, that glycidamide (a metabolite of acrylamide) causes point mutations, but acrylamide does not. We also find that thyroid tumors are most consistently sensitive in rats, being evoked in each of four long-term experiments. We evaluate the common manners of this tumor formation in the thyroid, including both mutagenicity and thyroid growth-stimulation. Consistent with the overall weight of the evidence, we conclude that both of these manners or modes of action may be occurring. We conservatively assume that the mutagenic mode of action determines the low-dose-response and we conclude that growth stimulation likely dominates the response at higher doses. Following US EPA guidelines, we determined that the probit model best reflects the overall data set; this model is also preferred because it better reflects the underlying "decoupled" biology of contributions from potentially two modes of action. We use the probit model to identify a health-protective, linear cancer slope factor (SF) of 0.030 (mg/kg-day)(-1) for the low area of the dose-response curve associated with possible mutagenicity. We also identify a Reference Dose (RfD) in the range of 0.05-0.02 mg/kg-day for the high area of the dose-response curve associated with the growth stimulation. This latter value can be used to determine the upper range of risk. This dose-response assessment is briefly summarized in light of other related work.

Acute toxicity and cancer risk assessment values for tert-butyl acetate.

tert-Butyl acetate (TBAc) is an industrial chemical with potential uses as a degreaser and in architectural coatings. Limited chronic toxicity data exist for TBAc. However, acute inhalation exposure data are available for TBAc. Additionally, TBAc has been demonstrated to be substantially metabolized to tert-butanol (TBA) in rats, and a positive TBA genotoxicity study suggests that TBA may cause oxidative DNA damage. TBA has been shown to induce tumors in both rats and mice, and the Office of Environmental Health Hazard Assessment has calculated an oral cancer potency factor (CSF) for TBA of 3 x 10(-3)(mg/kg-day)(-1). Therefore, TBAc should be considered to pose a potential cancer risk to humans because of the metabolic conversion to TBA. An acute 1-h reference exposure level of 1 mg/m3 can be calculated from the extrapolated no observed adverse effect level of 50 mg/m3. A CSF of 0.002(mg/kg-day)(-1) can be derived for TBAc, assuming 100% metabolism of TBAc to TBA. An inhalation unit risk value for TBAc of 4 x 10(-7)(microg/m(3))(-1) can then be derived from the CSF value for TBAc by assuming a human breathing rate of 20 m3/day, 70% fractional absorption, and an average human body weight of 70 kg.

Order-restricted dose-related trend tests.

Methods of isotonic regression are proposed to increase the power of common trend tests in situations where a monotonicity constraint is imposed upon the dose-response function. Isotonic versions of Cochran-Armitage type trend tests for binary response data are developed, and the bootstrap method is used in finding the empirical distributions of the test statistics and their critical values. The isotonic likelihood ratio test with a survival adjustment is also proposed. This survival adjustment can be applied to the likelihood ratio test for either the order-restricted or unrestricted parameter cases. To achieve the isotonic modifications, an amalgamation algorithm is applied when the observed dose-response is non-monotonic. A Monte Carlo simulation study comparing these trend tests shows the advantages of the isotonic modifications and survival adjustment. By applying the proposed methods to data from a toxicology and carcinogenesis study conducted as part of the National Toxicology Program, the effect of CI Pigment Red 23 is investigated.

Risk assessment of thyroid follicular cell tumors.

Thyroid follicular cell tumors arise in rodents from mutations, perturbations of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only known human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1) chemically induced rodent thyroid tumors are presumed to be relevant to humans; 2) when interspecies information is lacking, the default is to assume comparable carcinogenic sensitivity in rodents and humans; 3) adverse rodent noncancer thyroid effects due to chemically induced thyroid-pituitary disruption are presumed to be relevant to humans; 4) linear dose-response considerations are applied to thyroid cancer induced by chemical substances that either do not disrupt thyroid functioning or lack mode of action information; 5) 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; and 6) nonlinear considerations may be applied in thyroid cancer dose-response assessments on a case-by-case basis for chemicals that disrupt thyroid-pituitary functioning and demonstrate some mutagenic activity. Required data for risk assessment purposes is mode of action information on mutagenicity, increases in follicular cell growth (cell size and number) and thyroid gland weight, thyroid-pituitary hormones, site of action, correlations between doses producing thyroid effects and cancer, and reversibility of effects when dosing ceases.

Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment.

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 disposition. There are important species differences in thyroid gland physiology between rodents and humans that may 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 function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plasma membrane surface of the follicular cell has receptors for TSH and other growth factors. Small organic molecules are not known to be direct TSH receptor agonists or antagonists; however, various antibodies found in autoimmune disease such as Graves' disease can directly stimulate or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby increase or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chemicals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dysfunction produced by a chemical would present a significant toxicological problem before such exposure would increase the risk for neoplasia in humans.