Cancer Risk Assessment I
Peter G. Shields in Cancer Risk Assessment, 2005
An agent is a carcinogen if exposure to it causes an increased incidence of malignant neoplasms at one or more anatomic sites in humans, experimental animals, or both. In experimental animal studies, carcinogenicity may also be indicated by increased multiplicity or accelerated appearance of neoplasms. Known human carcinogens include certain infectious agents; all forms of ionizing radiation; and a wide variety of chemical agents and mixtures, some of which occur naturally and some of which are produced by human activities. Carcinogens rarely increase the frequency of tumors at all organ sites, in either humans or experimental animals. Most carcinogens cause tumors at a single site or at a limited number of sites, which in the case of chemicals is largely determined by pathways of metabolism and by the routes of exposure, which affect the dose of active carcinogen delivered to various tissues. Inorganic arsenic, for example, causes human skin cancer when taken in medicinals by ingestion; lung cancer when inhaled under occupational circumstances such as smelting of metal-containing ores; and both of the above plus cancers of the urinary tract and certain other internal organs when present at high concentrations in drinking water (1).
Cancer epidemiology and health policy
Sol Levine, Abraham M. Lilienfeld in Epidemiology and Health Policy, 1987
The process of defining carcinogens remains difficult; controversy prevails on the respective roles of evidence from human epidemiologic studies, animal bioassays, and short-term in vitro tests as a basis for establishment of policies for carcinogen control. Epidemiologic studies, in particular, suffer considerable limitations in their ability to detect modest increases in risk, say of the magnitude of relative risk of 1.3 or below. Many epidemiologists would, in fact, consider 1.3 as the lower limit of relative risk capable of detection even in a large study. One might view risks of this magnitude as the “noise within the system” where one cannot dismiss, beyond reasonable doubt, uncontrolled confounding as a plausible explanation of the observed result. In addition, rarely do the findings of a single epidemiologic study serve as the basis for policy decisions. One of the important criteria in proceeding epidemiologically from association to causation is consistency of the association in different populations and with different methodologies. With the price tag of each individual epidemiologic study of an alleged environmental carcinogen exceeding the $1 million mark, epidemiologic studies in human populations do not seem to serve routinely as the most feasible and cost-efficient route for generating the requisite data base of evidence for regulation of potential environmental carcinogens.
Assessment of Hepatocarcinogenesis by Early Indicators
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
There are two general types of carcinogen, both of which affect the liver: DNA-reactive or genotoxic carcinogens and epigenetic or nongenotoxic carcinogens and epigenetic or nongenotoxic carcinogens (Weisburger and Williams, 1981). Most genotoxic carcinogens are carcinogenic only after biotransformation to highly reactive derivatives or ultimate forms which react with DNA. The liver is the most capable organ in such metabolism of chemicals, although other organs or tissues can generate the ultimate forms in some instances. In the liver, several genotoxic carcinogens have rapidly induced oval cell proliferation (refs., see below) and altered foci (Scherer et al., 1972; Williams and Watanabe, 1978). Some noncarcinogenic pathologic processes induce oval cell proliferation (Lopez and Massanti, 1955; Grisham and Hartroft, 1961) and, therefore this is not a specific effect of carcinogens. In contrast, of diverse chemical carcinogens, those that do not cause hepatocellular carcinoma do not induce altered foci, even after repeated exposures. Likewise, noncarcinogenic noxious agents do not induce foci. Both toxic agents and carcinogens can induce similar nonspecific hepatocellular changes such as focal degeneration and necrosis in the acute phase of their toxic effects. Altered foci, however, do not occur following the acute changes induced by noncarcinogens or carcinogens for other organs than the liver.
Systematic review of the potential respiratory carcinogenicity of metallic nickel in humans
Published in Critical Reviews in Toxicology, 2020
Robyn L. Prueitt, Wenchao Li, Yu-Chi Chang, Paolo Boffetta, Julie E. Goodman
Our analysis of the in vitro mechanistic evidence for metallic nickel carcinogenicity highlights the importance of a systematic evaluation of the literature for mechanistic evidence that considers the quality and RoB, as well as the relevance of each study, and is integrated with the human and experimental animal evidence to support a causal conclusion. Simply noting that a substance can induce certain changes in cells that are consistent with mechanistic pathways associated with carcinogenesis or tumor progression does not provide strong evidence of carcinogenicity. An example of this is IARC's "key characteristics of carcinogens" approach to evaluating mechanistic evidence for carcinogenicity (Smith et al. 2016; Guyton et al. 2018). This approach involves a set of 10 characteristics that are common to known human carcinogens. If a study of a substance has a positive finding for one of these characteristics, one may conclude that it supports some level of evidence for that characteristic. Although metallic nickel has been shown to have some of the 10 characteristics in certain (mostly in vitro) studies (e.g. some types of genotoxicity, induction of oxidative stress), it is not apparent until one evaluates the quality and relevance of these studies, and how they inform what is known from the human and experimental animal evidence (and vice versa), that these positive results do not support metallic nickel as a human carcinogen (Goodman and Lynch 2017).
Cadmium: a new risk factor for endometrial cancer?
Published in Expert Review of Anticancer Therapy, 2019
Jane A. McElroy, Mark I. Hunter
While both of these important risk factors do influence endometrial cancer risk, a recent case control study adjusted the regression model to account for obesity and diabetes mellitus and found a 22% statistically significant increased endometrial cancer risk with cadmium exposure [11]. This suggests cadmium-induced carcinogenicity may be based on multiple distinct mechanisms, some affecting the risk factors and some directly affecting carcinogenicity. More research is needed in this area to support an association as well as explain the pathophysiology. A noteworthy conundrum is the reduced endometrial cancer risk among smokers, yet smoking doubles cadmium exposure. Many hypotheses have been posited to explain the cadmium risk. One hypothesis suggests the double-edged sword of upregulation of metallothioneins by cadmium. Metallothioneins, low molecular weight cysteine-rich proteins sequester this metal. It permit accumulation in the body but also reduces DNA repair activities and suppresses apoptosis. Both of these activities are associated with carcinogenicity. Another hypothesis suggests cadmium acts as a potent metallohormone that mimics the function of steroid hormones [27]. An alternative hypothesis provides evidence of the endometrium as the fourth target tissue for systemic metal deposition, with kidney, liver, and muscle already well-characterized for deposition [28]. Numerous hypotheses are currently being explored to better understand the specific role of this metal on both comorbidities associated with endometrial cancer as well as on endometrial cancer risk [29,30].
Effect of a beta-cypermethrin and emamectin benzoate pesticide mixture on reproductive toxicity in male mice in a greenhouse environment
Published in Toxicology Mechanisms and Methods, 2020
Yuanyuan Zhang, Chang Kong, Huimin Chi, Junxia Li, Jie Xing, Fei Wang, Lijun Shao, Qingfeng Zhai
Pesticides play an important role in the agriculture area, especially as the resistance of pests increases and the use of pesticides becomes more frequent in agricultural production. Studies have shown that workers who have been exposed to pesticides for a long time may experience oxidative damage to their various organs and decreased sperm quality (Latchoumycandane and Mathur 2002; Astiz et al. 2013; Chen et al. 2016; Moralesprieto et al. 2018). According to animal experiments, the International Cancer Research Institute has confirmed that the widely used pesticides have obvious carcinogenicity. It is estimated that the number of pesticide-related cancer patients in the United States accounts for about 50% of the total number of cancer patients in the country, and is higher in China.
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