Cancer, human susceptibility

Toxicology is the science that studies the harmful effects chemicals can have on the body. All chemicals affect man to some degree, depending on the time of exposure, concentration, and human susceptibility. One chemical may only cause a slight rash or dizziness while another may result in cancer or death. It is the degree of exposure and toxicity that are of practical concern. 

Tire means by which chemicals enter the body are inhalation (breadiing), ingestion (swallowing), and absorption (skin or living tissue contact). Once in the system these chemicals may produce such symptoms as tissue irritation, rash, dizziness, anxiety, narcosis, headaches, pain, fever, tremors, shortness of breath, birth defects, paralysis, cancer, and death, to mention a few. The amount of chemical diat enters the body is called the "dose." The relationship that defines the body response to the dose given is called the "dose-response curve." The lowest dose causing a detectable response is the "threshold limit." The "limit" is dependent on factors such as particle size of contaminant, solubility, breathing rate, residence time in the system, and human susceptibility. 

The importance of such polymorphisms in human susceptibility to diseases, such as cancer, is now increasingly being recognized. For example, studies in humans with amino biphenyl, a liver and bladder carcinogen, have shown that both the acetylator phenotype and hydroxylator status are important in the formation of adducts (see Chapter 6). 

Petersen SL, Wang L, Yalcin-Chin A et al (2007) Autocrine TNFalpha signaling renders human cancer cells susceptible to smac-mimetic-induced apoptosis. Cancer Cell 12(5) 445-456... 

Experimental animal studies have played a key role in the understanding of the mechanisms of chemical carcinogenesis. The duration of development of a cancer in humans may be several decades, and the development probably includes several steps. Furthermore, individual susceptibility is also important for the disease. Therefore, it has been extremely difficult to make the required observations in exposed individuals. 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Cavalieri, E. Chakravarti, D. Guttenplan, J. Hart, E. Ingle, J. Jankowiak, R. Muti, P Rogan, E. Russo, J. Santen, R. Sutter, T. Catechol estrogen quinones as initiators of breast and other human cancers implications for biomarkers of susceptibility and cancer prevention. Biochim. Biophys. Acta 2006, 1766, 63-78. 

There appears to be an increased risk for the development of cervical cancer among long-term users of oral contraceptives.1 Whether or not this increase in risk can be attributed directly to the use of oral contraceptives is uncertain, however. Data suggest that oral contraceptive users, on average, tend to have more sexual partners and use condoms less frequently, and as a result, this may increase their susceptibility to becoming infected with human papilloma virus (HPV), a known risk factor for cervical cancer. 

Thus, oxygen radical production by leukocytes can be responsible for cancer development. However, the levels of leukocyte oxygen radical generation depend on the type of cancer. For example, PMNs and monocytes from peripheral blood of patients with lung cancer produced a diminished amount of superoxide [169], Timoshenko et al. [170] observed the reduction of superoxide production in bronchial carcinoma patients after the incubation of neutrophils with concanavalin A or human lectin, while neutrophils from breast cancer patients exhibited no change in their activity. Chemotherapy of lung and colorectal carcinoma patients also reduced neutrophil superoxide production. Human ALL and AML cells produced, as a rule, the diminished amounts of superoxide in response to PMA or FMLP [171], On the other hand total SOD activity was enhanced in AML cells but diminished in ALL cells, while MnSOD in AML cells was very low. It has been proposed that decreased superoxide production may be responsible for susceptibility to infections in cancer patients. 

Aflatoxin Bi (AFB) is a mold metabolite which has been observed to be acutely toxic and carcinogenic to a wide variety of animals (5,6) and has been implicated in human primary hepatic carcinoma (7, 8). Diets deficient in protein have been reported to increase the susceptibility of mammals to acute AFB toxicity and the induction of cancer (2, 9, 10, 11, 12, 13). Increased dietary proteins have increased the carcinogenic activity of AFB fed to rats (1 4) and trout (15.). Supportive of this latter finding has been the reported direct relationship between dietary protein content and AFB-DNA adduct formation in vivo in rats (16, 17). 

Risk Assessment. This model successfully described the disposition of chloroform in rats, mice and humans following various exposure scenarios and developed dose surrogates more closely related to toxicity response. With regard to target tissue dosimetry, the Corley model predicts the relative order of susceptibility to chloroform toxicity consequent to binding to macromolecules (MMB) to be mouse > rat > human. Linking the pharmacokinetic parameters of this model to the pharmacodynamic cancer model of Reitz et al. (1990) provides a biologically based risk assessment model for chloroform. 

There are follow-on efforts to the Human Genome Project. In fact, there are several others, including an effort to identify every gene involved in determining susceptibility to cancer. 

Humans, plants, insects, and other animals are all susceptible to viral infection therefore, prevention and control of viral disease carry important health and economic implications. The common cold, acquired immune deficiency syndrome (AIDS), and some cancers are carried by viruses. Viral plant diseases are known to impact fruit trees, tobacco, and many vegetables [1]. Both insects and animals have the ability to transfer viral disease to humans and other animals. The health and economic consequences of viral disease carry enormous consequences, and significant advances have been made toward amelioration of antiviral threats. There is a critical need to identify novel drug classes and new chemical structures, which can be exploited for antiviral drug development. 

Based on a combination of available human case studies and experiments with laboratory animals, the major public health concerns associated with exposure to 1,4-dichlorobenzene are effects on the liver, kidneys, and blood. Some immunological, dermatological, and neurological effects have also been reported in exposed humans. There is information from animal studies which raises the question of whether 1,4-dichlorobenzene can cross the placenta and elicit structural effects on the developing fetus. Data from a study conducted in rats using the intraperitoneal route have demonstrated sperm abnormalities. Cancer of the liver as a result of lifetime exposure to 1,4-dichlorobenzene has been shown in mice, and renal cancer has been reported in male rats. However, recent studies related to the mechanism of renal carcinogenesis in rats suggest that these tumors may not be expected to occur in exposed humans. Issues relevant to children are explicitly discussed in Section 2.6, Children s Susceptibility, and Section 5.6, Exposures of Children. 

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