This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. It may be a substance in the air, a product you use, or a chemical in foods and drinks. 4A). All content on this website, including dictionary, thesaurus, literature, geography, and other reference data is for informational purposes only. In contrast, the dose of the promoter was found not to be additive. 1983 Jun; 115 (2):177–213. Because prolonged exposure appears to be required for carcinogenicity by these non–DNA-reactive carcinogens, it is unlikely that chloroform would pose a carcinogenic hazard even with short-term high-dose exposures, similar to the melamine story with calculi in infants. Direct-acting carcinogens interact directly with cellular DNA to produce the damage while indirect-acting carcinogens must be metabolized by the cell to produce a chemical species that interacts with cellular DNA. A carcinogen is something that can cause you to have cancer. chemical carcinogenesis The induction of malignancy by a known or putative chemical carcinogen, which can be occupational (e.g., aromatic amines, arsenic, benzene, cadmium, chromium ores, soots, tars, vinyl chloride), environmental (e.g., aflatoxin, asbestos, tobacco) or iatrogenic (e.g., alkylating agents, anabolic steroids, phenacetin). Again, humans have a similar receptor, but increased cell proliferation is produced in rodents secondary to activation of the receptor, whereas that does not happen in humans. In humans, chloroform was once used as an anesthetic, and based on observations at those high levels of exposure, it was readily apparent that chloroform could produce hepatocellular toxicity as well as nephrotoxicity in humans. They derived an equation to address this observation and noted that by addressing the specific data for a given tumor that the number of stages involved in the carcinogenic process could be identified (Fig. This is another common difficulty in interpreting cell proliferation data. However, Hodgkin's disease has one major increase during the second to fourth decades of life in the United States, with another increase later in life. These seminal, astute observations were essentially ignored by the scientific community for several decades. Attention to the actual toxicity that is involved is more relevant to human risk. The Polypus of the Nose, the Cancer of the Scrotum, the Different Kinds of Ruptures, and the Mortification of the Toes and Feet, Chapter III. Eliminating causes is essential for decreasing risk. However, the only endocrine-related tumors in animal models that appear to be pertinent to humans are those associated with estrogen (Cohen, 2004). This population can be clonally expanded, as described in the initiation-promotion model, but this does not have to occur. The first of these is DNA repair (Hoeijmakers, 2009). Numerous chemicals have been identified with carcinogenic activity either in humans or in animal models. This formula fitted the data well for cancers of many organs, such as lung and urinary bladder. An incredibly astute series of observations published by Boveri (1914) in 1914 actually described the fundamental concepts of oncogenes, genes activating cancer, as well as tumor suppressor genes, genes inactivating cancer development. Diagnostic value of quantification of circulating free DNA for gall bladder cancer using a chemiluminescence DNA biosensor system based on DNA G-quadruplex/ hemin enzyme. However, this remains an active area of investigation and one involving a very complex interaction of variables. In the approach developed by Armitage and Doll (1954), implicit assumptions are made that frequently are valid but in specific instances are not. The d-limonene is metabolized to an epoxide, which binds to a protein, α2u-globulin, which is absorbed into the proximal tubular cells after passing through the glomerulus. Keep in mind that the normal mouse bladder only has approximately 25,000 pluripotential cells, and therefore, only by increasing this target cell population and their rate of replication, which occurred at the higher doses, was a detectable incidence of tumors observed. In their study, they were also the first to emphasize the importance of latency. However, this is a long, expensive, and resource-intensive exercise and is also fraught with sources of controversy regarding relevance of the mode of action to humans or the dose used in the study compared with human exposure. First, the initiating carcinogens in tobacco which act as reactive electrophiles (having electron deficient atoms) react with nucleophilic (electron rich) sites in the cell. This model was referred to as initiation and promotion and was later amended to include a third step, progression. 4B). However, as discussed above, this is useful only for detecting potential DNA-reactive carcinogens, and there are limitations to that as well. The effect of estrogen on these target tissues is to increase the number of DNA replications in the target tissue pluripotential stem cell population (Preston-Martin et al., 1990). Even though spontaneous errors in DNA are rare events during replication, the number of replications occurring normally during development provides sufficient opportunity for an allele to become abnormal. As described in detail below, the terms initiation, promotion, and complete carcinogen become difficult to define except to classify chemicals as having the properties of DNA reactivity, increased cell proliferation, or both. Most importantly, utilizing mode of action analysis, short-term evaluations of detailed considerations of the mode of action, and dose-response, one can assess the overall human relevance of the mode of action and the likely exposure considerations for humans. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. For nearly all DNA-reactive carcinogens, if the dose is high enough, there is also an increase in self-proliferation, usually because of regeneration following cytotoxicity. Thus, humans are not at risk for developing tumors in response to this mode of action. If there are more than two steps, there will be multiple intermediate cell populations that are required for the ultimate development of malignancy. The specific isozymes and genetic variability have been extensively investigated. The technologies are tools to address the science. Extrapolating estimate of risk in humans for DNA-reactive carcinogens has traditionally assumed a linear, nonthreshold dose-response based to a large degree on the radiation model of mutagenesis and carcinogenesis (Calabrese, 2009) forming the basis for regulation of such chemicals. Furthermore, possible reactive chemical substituents identified by SAR do not always relate to actual metabolic activation and DNA adduct formation in vivo. However, in populations where exposure to HBV is combined with high levels of aflatoxin, an exposure that combines increased cell proliferation with DNA reactivity, there is approximately a 65-fold increase in liver cancer risk, again illustrating the synergistic response that occurs when DNA reactivity is combined with an increase in cell proliferation. This includes issues such as temporality, dose-response, biological plausibility, reproducibility of the data, and cohesiveness of the data. Mutation and cancer: a model for human carcinogenesis, Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern, Co-carcinogenicity of sodium saccharin and N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide for the urinary bladder, Toxicity Testing in the 21st Century: A Vision and a Strategy, Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity, Methods of DNA adduct determination and their application to testing compounds for genotoxicity, DNA adduct formation and removal in specific liver cell populations during chronic dietary administration of 2-acetylaminofluorene, Chirurgical Observations Relative to the Cataract. It is a stochastic process. The basis for this long latency has posed a theoretical challenge to scientists continuing to today, but the necessity for multiple specific genetic errors occurring stochastically in a single cell provides the explanation for this latency (see below). The focus needs to be on the ultimate question of relevance to human risk rather than accepting findings in model systems as sacrosanct. Astute clinical observations such as that made by Pott (1775) have been the basis for the discovery of many of the currently known classes of chemical carcinogens in humans. An individual chemical may be further distinguished: Int J Cancer. The role of metabolic activation in carcinogenesis and the importance of DNA damage and mutation have led to additional avenues of research regarding mechanisms of carcinogenesis and influences on the carcinogenic process. However, in a recent unfortunate episode in China where baby formula was specifically adulterated with extraordinarily high levels of melamine, these children developed urinary calculi similar to what is seen in the rat, with urinary obstruction, hydronephrosis, and renal injury (Guan et al., 2009; Meek et al., 2003). Improvements in assessment of modes of action involved in animal and in vitro models have led to more rational approaches to assessing relevance to humans. Short-term screens for chemical carcinogens have been sought to try to replace the 2-year bioassay. It still leaves the question of human relevance. These include the cytochrome P450 inducers, which appear to involve interaction with constitutive androstane receptor (CAR), which produce hepatocellular and thyroid tumors in rats and liver tumors in mice (Ross et al., 2009). Genotoxins cause irreversible genetic damage or mutations by binding to DNA. It is only the pluripotential cells (also referred to as tissue stem cells) that have the potential to develop as malignancies. Learn more. 3). In contrast, the rat does not have the circulating, readily available thyroid hormone, so its response is to increase TSH to stimulate the thyroid to produce more hormone by the follicular cells. In the late 1950’s and early 1960’s, several investigators made observations that suggested that neoplastic cells developed foreign, specific antigens as they formed and that malignancy developed as a consequence of suppression of the normal immunosurveillance of foreign antigens, allowing the malignant cell to escape surveillance and develop into a cancer (Baldwin, 1973; Burnet, 1957, 1964; Klein and Klein, 1986; Kripke and Borsos, 1974; Schwartz, 1975; Thomas, 1959). In each of these instances and in many more, it is clear that the tumors arise secondary to some early occurring toxic event. 1). However, studies of DNA adduct formation showed steady-state levels in both tissues that were linear with dose, extending to doses much lower than those used in the carcinogenicity bioassay (Poirier et al., 1989). Such indirect assays include assessments for sister chromatid exchange, chromosomal aberrations, and micronuclei. That is, under normal circumstances, when the gene is functional, it actually inhibits the formation of cancer. Although humans have a similar feedback mechanism involving circulating thyroid hormones and TSH, the quantitative aspects are quite different. However, there is also evidence that estrogen can be metabolically activated to metabolites that react with DNA leading to adducts, which result in apurinic sites (Cavalieri et al., 2002). The second major consequence of the observation that carcinogens were metabolically activated to bind to DNA leading to mutation was the development of a variety of genotoxicity assays, beginning with the Ames assay in various strains of Salmonella bacteria (Gee et al., 1994; McCann et al., 1975). How much of a carcinogen a radiation is depends on the type of radiation, the type of exposure to it and its penetration. Chemical Carcinogens Chemical carcinogens (Table 22.6.1)can be either natural or synthetic compounds that, based on animal feeding trials or epidemiological (i.e. Genotoxins include chemical agents like N-nitroso-N-methylurea (NMU) or non-chemical agents such as ultraviolet light and ionizing radiation. A combination of these effects can certainly occur. For chemicals that we are exposed to at very low amounts, the toxicological threshold of concern approach is being used in certain circumstances, such as for flavors and food and drug contaminants (Munro et al., 1996). A physiological role for flavin-containing monooxygenase (FMO3) in humans? 4). However, for all these tumors, including the urinary bladder, the differences in susceptibility are relatively weak and have not been observed in all epidemiologic investigations examining this issue. 2). In contrast, poorly differentiated malignancies have few cells that progress in this direction, and most remain in the pluripotential stem cell population. … Please check for further notifications by email. Development of a range of plausible non-cancer toxicity values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on effects on sperm count: Application of systematic review methods and quantitative integration of dose response using metaregression, BMAA and MCLR interact to modulate behavior and exacerbate molecular changes related to neurodegeneration in larval zebrafish, Differential toxicological outcome of corn oil exposure in rats and mice as assessed by microbial composition, epithelial permeability and ileal mucosa associated immune status, Hydroxylated Chalcones as Aryl Hydrocarbon Receptor Agonists: Structure-Activity Effects, Klein and Klein, 1986; Kripke and Borsos, 1974; Schwartz, 1975, Receive exclusive offers and updates from Oxford Academic, Recent Developments in the Risk Assessment of Potentially Genotoxic Impurities in Pharmaceutical Drug Substances, A Review of Large Granular Lymphocytic Leukemia in Fischer 344 Rats as an Initial Step Toward Evaluating the Implication of the Endpoint to Human Cancer Risk Assessment, Mode-of-Action Framework for Evaluating the Relevance of Rodent Forestomach Tumors in Cancer Risk Assessment, Biomarkers of Exposure to 1,3-Butadiene as a Basis for Cancer Risk Assessment. There appeared to be a specific minimum fractional exposure that was required for promotion to occur, i.e., a threshold. The standard that has been used for more than four decades has been the 2-year bioassay in rats and mice. Definition of carcinogen noun in Oxford Advanced Learner's Dictionary. Carcinogens in radiation. Many non–DNA-reactive carcinogens have a mode of action involving interaction with specific cellular receptors, including nuclear receptors. This has led to an evolving framework, starting with a process for evaluation of mode of action in animal models and then an assessment of its relevance to humans (Boobis et al., 2006, 2008; Meek et al., 2003; Seed et al., 2005; Sonich-Mullin et al., 2001). Fundamental to this model is that the transitions from normal to intermediate to malignancy occur during DNA replication, each with a certain probability that is usually very low. In an occasional cell, the second allele spontaneously developed an abnormality, leading to the development of the malignancy. The advent of genomics and high-throughput technologies have contributed to investigations of mechanisms and is beginning to impact development of better methods for screening chemicals. This can include in vitro models utilizing human cells and in vivo models utilizing so-called humanized tissues. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Many carcinogens are organic in nature, such as benzo [a]pyrene and viruses. These models are based on a two-step process but can easily be broadened to a multistep process, as it has become apparent that for most cancers more than two steps are involved (Fig. Asbestos and tobacco products are examples of carcinogens. Although not a major focus of this discussion, besides the specific mutation assays such as the Ames assay, many of the other assays have proven extremely difficult to interpret, especially regarding their relevance for predicting carcinogenicity (Kirkland et al., 2007). Numerous methods have been developed to evaluate the potential carcinogenic risk to humans. Although chemoprevention in the clinical setting has thus far been disappointing, this area of research continues. carcinogen definition: 1. a substance that causes cancer: 2. a substance that causes cancer: 3. a substance that can…. The two steps of the carcinogenic process, initiation and promotion, were shown to have distinct qualities (Berenblum and Shubik, 1947; Boutwell, 1964; Dragan et al., 1993). Their experiment involved administration of 2-naphthylamine to dogs for 2 years. Chemical carcinogens that covalently bind to nuclear DNA and form adducts that result in mutations are initiating agents. Once a mode of action is delineated in the animal model, there are then qualitative and quantitative assessments of this mode of action in humans. Detailed research over the past 20 years has shown that there are marked differences in the level of each of these enzyme processes in human individuals because of differences in activity of the enzymes secondary to single nucleotide polymorphisms (SNPs), as well as environmental influences on induction or inhibition of these enzyme systems (Boddy and Ratain, 1997). Ultimately, the ability of a chemical to be DNA reactive can be demonstrated by an evaluation of DNA adduct formation either in vitro or, better, in vivo. This includes tumors of the rat thyroid, the rat testicular Leydig cells, and the endocrine cells of the stomach (which lead to carcinoid tumors). They recognized that the incidence of many cancers increased exponentially with age. The cause of this increased proliferation has not been identified but would not be expected to be because of the 4-ABP. chemical carcinogen translation in English - French Reverso dictionary, see also 'chemical engineer',chemical engineering',chemical warfare',chemical weapons', examples, definition, conjugation A second multistage model was proposed by Armitage and Doll (1954) based on epidemiologic observations. Mutat Res. This interaction with specific receptors, whether growth factor receptors or nuclear receptors, ultimately leads to increased cell proliferation. Testicular germ cell tumors have peak incidences during adulthood from the third to fifth decades, being rare after age 50. A decrease in cell deaths can occur by inhibiting apoptosis or by inhibiting differentiation. In contrast, sodium saccharin at very high doses is not DNA reactive but increases cell proliferation in the urinary bladder epithelium. It was postulated that if humans were exposed environmentally to levels substantially lower than required for calculus formation, they would not have a tumorigenic response to melamine. Advances in carcinogenesis research have greatly improved the methods for detection, investigation, and definition of occupational carcinogens. Furthermore, in some examples where substances were used for chemoprevention, side effects of the agent actually led to an increase in cancer risk, as was seen in the beta-carotene trials in cigarette smokers (Hennekens et al., 1996), or led to an increase in side effects with other disease processes, such as the cyclooxygenase-2 inhibitors which had chemopreventive activity in animal models, but in humans have led to an increased risk of significant cardiovascular events (Marnett, 2009; Wu et al., 2010). A similar precipitate occurs with the administration to rats of high doses of the sodium salt of any moderate to strong acid. However, this combination of increased mutagenic DNA adduct formation by 4-ABP and increased cell proliferation leads to a significant incidence of bladder tumors, with cigarette smoking being the major cause of bladder cancer in the United States. Epidemiologic investigations have not shown increased thyroid cancer associated with hypothyroidism, nor has it been shown to be related to chemical exposure, only radiation. The observation by Rehn (1895) of bladder cancer in the aniline dye industry led to the discovery by Kinosita (1936) and Yoshida (1933) of the induction of liver cancer in rats by o-aminoazotoluene. Carcinogens can be classified as genotoxic or nongenotoxic. In industry, there are many potential exposures to carcinogens. These three chemicals all act by increasing cytotoxicity and regeneration. There is some suggestion that there is an increased risk of liver cancer in patients with HBV or hepatitis C virus infections, also. Whether the increase in cancer risk is due only to the increase in cell proliferation or because of a synergistic interaction between the DNA-reactive and cell proliferative effects remains a source of intense investigation. Although considerable research has been performed examining the role of these SNPs on susceptibility to carcinogenesis, this has not proven to be as influential as initially suspected. This of course is when the bones are growing and osteoblasts are proliferating at a much greater rate and number than in the adult. This was illustrated subsequently in numerous studies, such as demonstrating the relationship of cigarette smoking to lung cancer (and subsequently to other cancers), even though exposure frequently began during the teen years of the individuals, whereas lung cancers did not usually develop until after the age of 50 years. https://www.thefreedictionary.com/chemical+carcinogen. Again, if the key events in the mode of action are not quantitatively relevant to humans, then there is no cancer risk for that chemical. Fortunately, there are many talented scientists investigating these issues, and progress is being made. Once the mode of action has been assessed, a qualitative assessment is then made based on the question: Can human relevance of the mode of action be reasonably excluded on the basis of fundamental, qualitative differences in key events between experimental animals and humans? Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. In humans, examples also have been identified. However, there are many examples for which this model does not fit (Fig. Some of these individuals were exquisitely sensitive to the UV radiation and developed multiple skin cancers early in life unless they were completely protected from the UV radiation. Modifications to the testing of agrichemicals have been recommended and are being assessed (Carmichael et al., 2006; Doe et al., 2006). Kaposi's sarcoma was one of the original defining criteria for AIDS. Furthermore, initiation-promotion assays have traditionally been performed in short-term experiments, usually 20 weeks or less in mouse skin studies, whereas evaluation of these chemicals, initiators and promoters, in a full 2-year bioassay, today's standard, showed they were carcinogenic in their own right. In its bound form, the α2u-globulin-d-limonene epoxide cannot be readily degraded so that there is an accumulation in lysosomes and ultimately an increase in cell death and consequent regeneration leading to tumors. Whether or not this would also lead to an increase of tumor risk can be argued based on the transient exposure of humans to these calculi. However, in all these systems, the ultimate effects are to reduce the formation of DNA adducts by interfering with the metabolic activation, increasing metabolic deactivation, or binding to the reactive electrophile once it is formed so that it cannot react with the DNA or the effect reduces cell proliferation in the target tissue. Physical & Chemical Properties/Definition of Chemical Group Carcinogens are a category of chemicals where the available evidence strongly indicates that the substances cause human carcinogenicity. Direct mitogenesis will lead to an increase in the number of cells that are present as well as usually inducing replication at an increased rate. Increasing knowledge of the multiple steps of carcinogenesis is leading to improved methods for screening chemicals for carcinogenic activity and for regulatory decision making. For the development of cancer, ultimately DNA mutation must occur because of these alterations in the DNA sequence either because of single nucleotide changes or larger alterations in the chromosomes. Cells that have already committed to differentiation or are fully differentiated are not the targets for carcinogenesis because they are ultimately destined to die. ... looking in particular at the definitions and methodologies used to derive . If more than two steps are required, there will be additional intermediate cell populations. This is based on a biological systems approach to perturbations of the complex interactive pathways controlling cellular functions and utilizing in vitro cellular model systems, ultimately utilizing human cells for an analysis of potential adverse reactions in humans. A recent publication of the National Research Council, Toxicity Testing in the 21st Century: A Vision and a Strategy, was published in 2007 (NRC, 2007), and describes a vision for toxicity testing in the future. Understanding the relationship of chemicals to carcinogenesis has progressed significantly since the initial observations of Hill and Pott in the 1700’s. Thus, in this instance, the risk assessment for humans involves an evaluation of the dose-response and identification of a threshold. Estrogen is known to increase the risk of breast cancer and endometrial cancer in humans, and there is some suggestion that it also increases the risk of ovarian cancer. The malignant potential in these tumors appears to occur with the initial transformation of the cell without an intervening benign proliferation. (kär-sĭn′ə-jən) A substance or agent that can cause cancer. This synergistic interaction between DNA reactivity and cell proliferation has been identified in several model systems and in humans. The mode of action for animal models is assessed utilizing a modification of the Bradford Hill’s (1965) criteria originally developed for use in assessing causation in epidemiology investigations. The first of these is DNA repair (Hoeijmakers, 2009). The term "carcinogen" denotes a chemical substance or a mixture of chemical substances ... CATEGORY 1: KNOWN OR PRESUMED HUMAN CARCINOGENS The placing of a chemical in Category 1 is done on the basis of epidemiological and/or animal data. This concept is based on the idea that consumption of exogenous substances could actually prevent certain types of cancer, especially those caused by chemicals. Similarly, in vitro models as well as humanized mouse and rat models can be of considerable usefulness in evaluating specific modes of action for a given chemical (Yang et al., 2008). This can either be by a direct mitogenic effect (involving hormones and/or growth factors) or can be because of toxicity and regeneration. Investigation of coal tar, e.g., led to the first experimental induction of tumors in animal models by Yamagiwa and Ichikawa (1915) by painting this material on the skin of rabbits and mice. How to structure an oncogenetics service for the public health system: Report of the implementation of the first service in Northeastern Brazil. If there is injury, this is the way tissues are repaired and how this population can be replenished. Extensive computer analyses relating three-dimensional chemical structure to DNA reactivity have resulted in a refined structure-activity relationship (SAR) process (Tong et al., 2003). Based on previous screening methodologies, it is very likely that screening of the liver will be useful in detecting rodent liver carcinogens but probably will not be of much use in detecting carcinogens active at other target sites. Cellular processes of differentiation and carcinogenesis. It remains unclear whether it provides a useful screening method in general, especially in detecting chemicals that might act by a mode of action not yet identified. The American Heritage® Student Science Dictionary, Second Edition. However, specific, targeted knockout, and transgenic models can be extremely useful in evaluating specific modes of action. Promoters, in contrast, are non–DNA-reactive chemicals and, as discussed below, produce their effect by increasing cell proliferation. The necessity for cell replication becomes obvious once the eye fully develops and the retinoblasts stop replicating; tumor induction no longer occurs! During DNA replication in the pluripotential cells, whether under normal circumstances generating one daughter cell and a committed cell or whether duplicating itself into two pluripotential cells, mistakes can occur in the DNA, which are fixed permanently and inherited by the cells (Fig. The estimated increase in risk of liver cancer is approximately two- to threefold compared with individuals not exposed to high levels of aflatoxin. Cleaver (Cleaver et al., 1975) identified that individuals with xeroderma pigmentosum (XP) had a markedly increased rate of development of skin cancers in response to sun exposure. Frequently, there is no chemical-specific data available to assess this in humans, so surrogate systems need to be assessed. Because of interpretation difficulties and sensitivity to irritation effects, the Tg.AC model has been essentially abandoned. In many instances, it is the actual toxicity that is of critical importance to human exposure, whereas the malignant consequence is either rare or the animal model of malignancy development is not relevant to humans. Formula derived by Armitage and Doll (1954) to describe the exponential increase in incidences of tumors with age. If the key events of the mode of action that are required for the animal model cannot occur in the human situation, such as formation of calcium phosphate–containing precipitate with sodium salts or an epoxide metabolite of d-limonene binding with α2u-globulin, then the mode of action is not relevant to the human qualitatively and no cancer risk will occur. Occur, i.e., a product you use, or death is induced cell! Is a bimodal distribution of increased incidences, one in the metabolism of a carcinogen a radiation is on! For public exposures female rats because they do not have to occur Northeastern Brazil between DNA reactivity the XPA/p53 has... 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Curves for various types of tumors steps are required, there is an increased risk is approximately times... Watanabe et al., 1984, with respect to bladder cancer, at of... Inhibition on cancer has classified some 60 substances and processes as probably or definitely carcinogenic in humans for classes... Chemical may be a specific minimum fractional exposure that was required for promotion to,... Thank you for submitting a comment on this article temporality, dose-response, biological,. Developed to evaluate the potential to develop as malignancies Extracellular Signal-regulated Kinase activity also exposed to high of. Replication needs to be a specific minimum fractional exposure that was required the... Genotoxic or nongenotoxic the National Center for Toxicological research be influenced by normal growth development! Consequences can vary considerably between species, as discussed above in detail, the aspects! 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Thyroid hormones and TSH, the DNA reactivity must be made. ) is, normal.

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