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In contrast to inorganic mercury pregnancy massage order cheap fosamax on line, 90% of the methylmercury is eliminated from the body in the feces menopause zaps fosamax 70mg on line, and less than 10% is in the urine menstrual art fosamax 70mg generic, with a half-life of 45­70 days (Clarkson menstrual blood art purchase fosamax 35 mg with amex, 2002; Risher et al. The major differences include that the conversion to inorganic mercury in the body is much faster for ethylmercury, which can result in renal injury. The mercury concentrations in brain are lower for ethylmercury than methylmercury. The half-life for ethylmecury is only 15­20% of that for methylmercury (Clarkson et al. A Dose­Response Simulation of Estimated Methylmercury Body Burden and the Onset and Frequency of Symptoms from Iraq Epidemic Poisoning in 1970s. Ataxia Dysarthria Deafness Death Toxicity Mercury Vapor Inhalation of mercury vapor at extremely high concentrations may produce an acute, corrosive bronchitis and interstitial pneumonitis and, if not fatal, may be associated with central nervous system effects such as tremor or increased excitability. With chronic exposure to mercury vapor, the major effects are on the central nervous system. Early signs are nonspecific, and this condition has been termed the asthenic-vegetative syndrome or micromercurialism. Identification of the syndrome requires neurasthenic symptoms and three or more of the following clinical findings: tremor, enlargement of the thyroid, increased uptake of radioiodine in the thyroid, labile pulse, tachycardia, dermographism, gingivitis, hematologic changes, or increased excretion of mercury in urine. The triad of tremors, gingivitis, and erethism (memory loss, increased excitability, insomnia, depression, and shyness) has been recognized historically as the major manifestation of mercury poisoning from inhalation of mercury vapor. Sporadic instances of proteinuria and even nephrotic syndrome may occur in persons with exposure to mercury vapor, particularly with chronic occupational exposure. Mercury vapor release from amalgam is in general too low to cause significant toxicity (Clarkson et al. Although a high dose of mercuric chloride is directly toxic to renal tubular cells, chronic low-dose exposure to mercury salts may induce an immunologic glomerular disease (Bigazzi, 1999). Exposed persons may develop proteinuria that is reversible after they are removed from exposure. Experimental studies have shown that the pathogenesis has two phases including an early phase characterized by an anti-basement membrane glomerulonephritis, followed by a superimposed immune-complex glomerulonephritis with transiently raised concentrations of circulating immune complexes (Henry et al. The pathogenesis of the nephropathy in humans appears similar, although antigens have not been characterized. In humans, the early glomerular nephritis may progress to interstitial immune-complex nephritis (Pelletier and Druet, 1995; Bigazzi, 1999). Methylmercury the major human health effect from exposure to methylmercury is neurotoxicity. Clinical manifestations of neurotoxicity include paresthesia (a numbness and tingling sensation around the mouth, lips) and ataxia, manifested as a clumsy, stumbling gait, and difficulty in swallowing and articulating words. Other signs include neurasthenia (a generalized sensation of weakness), vision and hearing loss, and spasticity and tremor. Neuropathological observations have shown that the cortex of the cerebrum and cerebellum are selectively involved with focal necrosis of neurons, lysis, and phagocytosis, and replacement by glial cells. These changes are most prominent in the deeper fissures (sulci), as in the visual cortex and insula. The overall acute effect is cerebral edema, but with prolonged destruction of gray matter and subsequent gliosis, cerebral atrophy results (Takeuchi, 1977). Mechanism of Toxicity High-affinity binding of divalent mercury to sulfhydryl groups of proteins in the cells is an important mechanism for producing nonspecific cell injury or even cell death. Mercury causes overexpression of metallothionein and glutathione system-related genes in rat tissues (Brambila et al. Sensitive Sub-populations Early life stages are particularly vulnerable to mercury intoxication (Counter and Buchanan, 2004). In Minamata, Japan, pregnant women who consumed fish contaminated with methylmercury, manifested mild or minimal symptoms, but gave birth to infants with severe developmental disabilities, raising initial concerns for mercury as a developmental toxicant. Prenatal methylmercury exposure at high levels can induce widespread damage to the fetal brain.

Thyroid Tumors in Humans Thyroid carcinomas are the most common endocrine neoplasms in humans pregnancy 6 weeks symptoms purchase fosamax from india, affecting approximately 1% of the population (Sherman menstrual 10 days order cheap fosamax line, 2003) women's health center elmhurst hospital cheap 70 mg fosamax free shipping. Roughly 95% of all thyroid tumors are of thyroid follicular epithelial cell origin womens health resource center lebanon nh order fosamax master card, including papillary, follicular, and anaplastic thyroid carcinomas. The subclassification of thyroid cancers into these four categories is clinically significant. Papillary thyroid carcinomas metastasize via lymphatics to local lymph nodes in an estimated 50% of cases but have the most favorable prognosis, with a 98% 10-year survival rate. Follicular thyroid carcinomas are more prevalent in areas of dietary iodine deficiency, metastasize hematogenously, and are less likely than papillary thyroid carcinomas to take up radioactive iodide for imaging and therapeutic ablation. However, the 10-year survival rate for follicular thyroid carcinomas is still high at 92%. Anaplastic thyroid carcinomas are almost invariably fatal due to rapid invasion of critical structures in the neck, distant metastases, and a failure to take up radioactive iodide. Medullary carcinomas frequently metastasize via the bloodstream, in addition to lymphatic spread, and are treated with surgical resection and/or external beam radiation. In contrast to follicular origin thyroid tumors, C-cells and tumors arising from them do not have the ability to take up radioactive iodide. Genetic Events in Thyroid Tumors of Follicular Cell Origin Thyroid follicular cells are responsible for iodide uptake and thyroid hormone synthesis and can undergo neoplastic transformation to carcinomas of three histotypes: papillary, follicular, and anaplastic. It is well known that papillary thyroid carcinomas can occur secondary to ionizing radiation exposure, particularly in children (Sherman, 2003; Boice, 2005). After the Chernobyl nuclear reactor accident in 1986, the incidence of thyroid carcinomas in children in affected areas of Belarus increased from less than one per million to more than 90 per million (Cardis et al. Ret protooncogene is a receptor tyrosine kinase normally involved in the glialderived neurotropic factor signaling pathway in neuroendocrine and neural cells. Sporadic papillary thyroid carcinomas unrelated to radiation exposure make up more than two-thirds of all cases, and several genetic events have been identified as important in their tumorigenesis (Nikiforov, 2004). Genetically Engineered Mouse Models of Thyroid Cancer Genetically engineered mouse models of thyroid cancer facilitate analysis of the roles of specific genetic mutations in thyroid tumorigenesis (Jhiang et al. Because thyroid cancer truly encompasses several diseases with different etiologies and relevant genetic mutations, no single transgenic mouse model of thyroid cancer can fully recapitulate the full spectrum of disease. However, several models have successfully reproduced various aspects and have offered insight into genetic mutations underlying thyroid tumorigenesis. These mouse models of thyroid cancer offer examples of positive genotype­phenotype correlation (Knostman et al. Over the past decade, several genetically engineered mouse models of thyroid cancer have been utilized to replicate variants of the human disease (Table 21-3). In some cases, tumor suppressor gene knockout mice have been created and cross-bred with transgenic mice expressing thyroid-specific oncogenes, resulting in increased tumorigenesis and/or an aggressive phenotype. However, even with a p53 knock-out, no model has been able to demonstrate significant tumor dedifferentiation or metastasis (LaPerle et al. Primordial cells arising from neural crest migrate ventrally during embryonic life to become incorporated in the last (ultimobranchial) pharyngeal pouch. The ultimobranchial body fuses with primordia of the thyroid and distributes C-cells to varying degrees throughout the mammalian thyroid gland. A tissue-specific p53 knockout would help to eliminate this problem and allow the mice to live long enough to potentially develop more advanced thyroid cancer (Knostman et al. The limitation of this model is the presence of hyperthyroidism and thyroid hormone resistance, which is not typical of the human disease. However, rodents are notoriously susceptible to thyroid neoplasia due to perturbations of the pituitary­ thyroid axis (Capen, 1997, 2001). Many of the mouse models of thyroid follicular cell neoplasia fail to reproduce the normal hormonal milieu present in humans with thyroid cancer. Rapid onset of dysplasia or neoplasia replacing the majority of the normal thyroid tissue, especially in neonatal and juvenile mice, often results in significant hypothyroidism unless thyroid hormone supplementation is instituted. In addition, human thyroid neoplasms are more than twofold more common in women than in men, suggesting that estrogen plays a role in tumorigenesis, while no sex predilection has been achieved in the current mouse models.

The myc family (c-myc pregnancy qa buy generic fosamax on-line, N-myc menopause not sleeping 35mg fosamax, and L-myc) encodes for transcription factors that are found activated in a number of tumor types (Marcu et al menstruation on the pill order fosamax 35 mg mastercard. Tumor Suppressor Genes Retinoblastoma (Rb) Gene In contrast to oncogenes womens health group columbia tn order genuine fosamax on line, the proteins encoded by most tumor suppressor genes act as inhibitors of cell proliferation or cell survival (Table 8-17). The prototype tumor suppressor gene, Rb, was identified by studies of inheritance of retinoblastoma. Loss or mutational inactivation of Rb contributes to the development of a wide variety of human cancers. In addition, the Rb­E2F complex acts as a transcriptional repressor for many of these same genes (Chellappan et al. Rb phosphorylation is initiated by an active Cdk4­cyclin D complex, and is completed by other cyclin-dependent kinases (Sherr, 1993; Weinberg, 1995). Most tumors contain an oncogenic mutation of one of the genes in this pathway, such that cells enter the S phase of the cell cycle in the absence of the proper extracellular growth signals that regulate Cdk activity. In addition, Rb is bound and inactivated by the E1A protein of the adenoviruses (Whyte et al. Phosphorylation of p53 by these and other kinases results in stabilization of p53 and an increase in cell content of this protein (Finlay et al. A missense point mutation in one p53 of the two alleles in a cell can abrogate almost all p53 activity, because virtually all the oligomers will contain at least one defective subunit, and such oligomers cannot function as a transcription factor. Oncogenic p53 mutations thus act as "dominant negatives," in contrast to tumor-suppressor genes such as Rb (Levine et al. The transcription of cyclin-kinase inhibitor p21, which binds to and inhibits mammalian G1 Cdk­cyclin complexes, is induced by p53. In most cells, accumulation of p53 also leads to induction of proteins that promote apoptosis, and therefore would prevent proliferation of cells that are likely to accumulate multiple mutations. Proteins that interact with and regulate p53 are also altered in many human tumors. For example, benzo(a)pyrene produces inactivating mutations at codons 175, 248, and 273 of the p53 gene in cultured cells; these same positions are mutational hot spots in human lung cancer (Nakayama et al. However, no mutations have been observed in sporadic breast cancers (Futreal et al. Mutations, especially deletions of the p16 gene, that inactivate the ability of p16 to inhibit cyclin D-dependent kinase activity are common in several human cancers including a high percentage of melanomas (Kamb et al. Loss of p16 would mimic cyclin D1 overexpression, leading to Rb hyperphosphorylation and release of active E2F transcription factor. Hormesis and Carcinogenesis Hormesis is defined as a dose­response curve in which a U, J, or inverted U-shaped dose­response is observed; with low-dose exposures often resulting in beneficial rather than harmful effects (Calabrese, 2002). One of the first reports establishing an hormetic response was observed with ionizing radiation, in which it was hypothesized to be due to adaptation to background radiation exposure, as well as enhanced metabolism and Response Stimulation Inhibition Dose Figure 8-27. Numerous examples exist that provide evidence for U- and J-shape dose relationships to different biomarkers of carcinogenesis, both for initiating and promoting carcinogens. For example, low-dose styrene treatment resulted in a decrease of chromosomal aberrations (Camurri et al. Several chronic bioassays for carcinogenicity in rats and mice have demonstrated a negative correlation between proliferative hepatocellular lesions and lymphomas at low and medium dose levels (Young and Gries, 1984). Evidence for a U-shaped dose­response curve has also been demonstrated for phenobarbital (Kitano et al. These investigators have shown that phenobarbital promoted the growth of diethylnitrosamine-induced hepatic lesions at doses between 60 and 500 ppm, while doses between 1 and 7. Adaptive responses have been proposed to explain the hormetic effects observed by chemical carcinogens. When experimental an- imals are exposed to chemicals, the initial response is an adaptive response to maintain homeostasis (Calabrese, 2002). Adaptive responses usually involve actions of the chemical on cellular signaling pathways that lead to changes in gene expression, resulting in enhanced detoxification and excretion of the chemical, as well as preserving the cell cycle and programmed cell death. It has been proposed that following very low doses of chemicals, the upregulation of these mechanisms overcompensates for cell injury such that a reduction in tumor promotion and/or tumor development is seen, and would explain the U- or J-shaped response curves obtained following carcinogen exposure. A common feature of chemical carcinogens for which hormetic effects have been proposed is the formation of reactive oxygen species and the induction of cytochrome P450 isoenzymes.

Critical to the effectiveness of such surveillance by manufacturers and government regulatory agencies is the ability to detect a "signal women's health kindle discount 35mg fosamax amex," such as that related to life-threatening idiosyncratic hematotoxicity pregnancy gingivitis buy cheap fosamax 70mg on line. Over the past 5 years women's health center dickson tn purchase genuine fosamax on line, regulatory agencies and drug monitoring centers have been developing computerized data mining methods to better identify reporting relationships in spontaneous reporting databases that have enabled and optimized such signal detection (Almenoff et al women's health tips for losing weight buy fosamax 70mg with amex. Such tools provide an objective and unprecedented systematic and simultaneous view of these large databases and alert government and manufacturers to critically important new safety signals that inform the toxicologist. Arneborn P, Palmblad J: Drug-induced neutropenia-a survey for Stockholm 1973­1978. The total blood, circulating and marginal granulocyte pools and the granulocyte turnover rate in normal subjects. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Brugnara C: Reticulocyte cellular indices: A new approach in the diagnosis of anemias and monitoring of erythropoietic function. Capsoni F, Sarzi-Puttini P, Zanella A: Primary and secondary autoimmune neutropenia. Caramori G, Adcock I: Anti-inflammatory mechanisms of glucocorticoids targeting granulocytes. Deckmyn H, Vanhoorelbeke K, Peerlinck K: Inhibitory and activating human antiplatelet antibodies. Deldar A: Drug-induced blood disorders: Review of pathogenetic mechanisms and utilization of bone marrow cell culture technology as an investigative approach. Girard D: Activation of human polymorphonuclear neutrophils by environmental contaminants. Guevara A, Labarca J, Gonzalez-Martin G: Heparin-induced transaminase elevations: A prospective study. Kumar S, Bandyopadhyay U: Free heme toxicity and its detoxification systems in human. Matzdorff A: Platelet function tests and flow cytometry to monitor antiplatelet therapy. Pessina A, Malerba I, Gribaldo L: Hematotoxicity testing by cell clonogenic assay in drug development and preclinical trials. Ponka P: Tissue-specific regulation of iron metabolism and heme synthesis: Distinct control mechanisms in erythroid cells. Rader M: Granulocyte colony-stimulating factor use in patients with chemotherapy-induced neutropenia: Clinical and economic benefits. Sundman-Engberg B, Tidefelt U, Paul C: Toxicity of cytostatic drugs to normal bone marrow cells in vitro. Uetrecht J: Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions. Voog E, Morschhauser F, Solal-Celigny P: Neutropenia in patients treated with rituximab. Studies in animals and humans have indicated that the immune system comprises potential target organs, and that damage to this system can be associated with morbidity and even mortality. Indeed, in some instances, the immune system has been shown to be compromised (decreased lymphoid cellularity, alterations in lymphocyte subpopulations, decreased host resistance, and altered specific immune function responses) in the absence of observed toxicity in other organ systems. These studies coupled with tremendous advances made in immunology and molecular biology have led to a steady and exponential growth in our understanding of immunotoxicology during the past 25 years. Recognition by regulatory agencies that the immune system is an important, as well as sensitive, target organ for chemicaland drug-induced toxicity (as described in greater detail later in this chapter) is another indication of the growth of this subdiscipline of toxicology. With the availability of sensitive, reproducible, and predictive tests, it is now apparent that the inclusion of immunotoxicity testing represents a significant adjunct to routine safety evaluations for therapeutic agents, biological agents, and chemicals now in development. Understanding the impact of toxic responses on the immune system requires an appreciation of its role, which may be stated succinctly as the preservation of integrity. It is a series of delicately balanced, complex, multicellular, and physiological mechanisms that allow an individual to distinguish foreign material. Examples of nonself are a variety of opportunistic pathogens, including bacteria and viruses, and transformed cells or tissues. The immune system is characterized by a virtually infinite repertoire of specificities, highly specialized effectors, complex regulatory mechanisms, and an ability to travel throughout the body. The great complexity of the mammalian immune system is an indication of the importance, as well as the difficulty, of its role. If the immune system fails to recognize as nonself an infec- tious entity or neoantigens expressed by a newly arisen tumor, then the host is in danger of rapidly succumbing to the unopposed invasion.

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