Damage, chemically-induced

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. 

Rephcation errors, even with a very efficient repair system, lead to the accumulation of mutations. A human has 10 nucleated cells each with 3 X 10 base pairs of DNA. If about 10 cell divisions occur in a lifetime and 10 mutations per base pair per cell generation escape repair, there may evenmaUy be as many as one mutation per 10 bp in the genome. Formnately, most of these will probably occur in DNA that does not encode proteins or will not affect the function of encoded proteins and so are of no consequence. In addition, spontaneous and chemically induced damage to DNA must be repaired. 

F F Chang and F Civan. Practical model for chemically induced formation damage. 7 Petn / Sci Eng, 17(1-2) 123-137, February 1997. 

Immunoenhancement, which, as adverse effect, may lead to immune-mediated diseases such as hypersensitivity reactions and autoimmune diseases. Hypersensitivity reactions are the result of normally beneficial immune responses acting inappropriately, causing inflammatory reactions and tissue damage. The two most frequent manifestation of chemical-induced allergy are contact hypersensitivity and respiratory sensitization, both of which can have a serious impact on quality of life and represent a common occupational health problem. Hypersensitivity reactions are often considered to be increased at such a rate to become a major health problem in relation to environmental chemical exposure. 

As the protective barrier between the body and the external environment, the skin is exposed to potentially damaging chemicals on a daily basis. It has been estimated that approximately 80,000 chemicals are in common use worldwide [5] and new products are being continuously introduced. Chemical production for most countries increased in 2004 with an increase in the total production index for all chemicals of 2.9% in the United States, 4.3% in the United Kingdom, and 6.8% in Canada [6], As new products are being developed and chemical production increases, toxicologists are faced with the need to develop improved methods for evaluating the potential of these chemicals to induce contact dermatitis. 

Dean, B.J. and Danford, N. (1984). Assays for the detection of chemically induced chromosome damage in cultures mammalian cells. In Mutagenicity Testing. A Practical Approach, (Venitt, S. and Parry, J.M., Eds.). IRL Press, Oxford, pp. 187-232. 

Cytotoxicity. The liver is the primary target organ for a variety of drugs and chemicals (Hasemen et ah, 1984 Farland et ah, 1985). The prevalence of drug-and chemical-induced liver injury is of concern because some xenobiotics can produce liver damage at dose levels that are magnitudes below that which causes cell death (Plaa, 1976). Environmental and commercial chemicals can increase this effect by as much as 100-fold (Plaa and Hewitt, 1982 Plaa, 1976). Studies of early cell injury caused by exposure to a toxicant can be undertaken easily in monolayer cultures of hepatocytes, whereas early cell injury is very difficult to assess in vivo. 

Bendy SC, Halsall LC. 1988. GMI ganglioside enhances synaptosomal resistance to chemically induced damage. Neuroscience Letters 84(2) 229-233. 

Chemically-induced testicular damage can be recognized by changes in sperm concentration, sperm motility, and sperm morphology (V robek 1984). Reduced fertility, a highly sensitive biomarker, may... 

Human Lymphoblasts Versatile Indicator Cells for Many Forms of Chemically Induced Genetic Damage... 

Drotman RB, Lawhorn GT. 1978. Serum enzymes as indicators of chemically induced liver damage. Drug Chem Toxicol 1 163-171. 

Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. 

Chemically induced kidney damage is typically seen as acute tubular necrosis (ATN). The cells in the proximal tubule are affected. Reabsorption of water, elec-... 

Casalini, C., Lodovici, M., Briani, C., Paganelli, G., Remy, S., Cheynier, V., and Dolara, P., Effect of complex polyphenols and tannins from red wine (WCPT) on chemically induced oxidative DNA damage in the rat, Eur. J. Nutr., 38, 190, 1999. 

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