Chemicals that cause toxicity though a direct mechanism, such as acetaminophen, covalently bind to a select group of proteins prior to the development of toxicity, and these proteins may be important in the initiation of the events that lead to the hepatotoxicity. Disruption of the cell is measured by release of intracellular proteins such as alanine aminotransferase and occurs late in the time course following a hepatotoxic dose of a direct toxin. Prior to this disruption, there appears to be a large number of proteins covalently modified by a reactive metabolite. There are at least two possible mechanisms that may cause the toxicity. First, some critical protein is a target of the reactive metabolite. Disruption of the enzymatic function (or a critical pathway for a regulatory protein) may lead directly to cell death. With the direct hepatotoxin acetaminophen, there is a decrease in the activity of several of the early target proteins, but how this disruption of critical proteins leads to the toxicity is still unclear. The early targets appear to be proteins with accessible nucleophilic sulfhydryl groups, and usually the target has a high concentration of the protein within the cell. It is possible that the binding to some of these proteins represents a detoxification protecting more critical targets within the cell. A second mechanism for the direct toxicity is that more and more proteins become targets in the time course following administration of a direct toxin, and eventually the cells machinery is overwhelmed. The cell can then no longer function, or there is a disruption the redox balance within the cell due to the decreased function of numerous proteins. In contrast to the direct-acting toxins, the chemical-protein conjugates that initiate toxicity through an activation of the immune system appear to have a limited number of target proteins and are localized within one subcellular fraction. Halothane produces adducts almost exclusively in the microsomal fraction, and these adducts appear to be limited to selective proteins with high concentrations in this fraction. The substitution level is an important factor in the development of an immune response. Halothane hepatitis patients' antibodies primarily recognize proteins with a high substitution level. For halothane and diclofenac, the proteins are accessible to the immune system through exposure on the plasma membrane. Trichloroethylene binds primarily to a 50-kDa microsomal protein, and preliminary evidence has been presented which indicates that a trichloroethylene-protein conjugate is released into the blood following exposure, where contact with the immune system can occur. In order to elicit an immune response the immune system requires multiple exposure to the chemical-protein conjugates. With halothane hepatitis and with diclofenac hepatitis, as well as occupational and environmental exposure to trichloroethylene, there are multiple exposures leading to repeat presentation of the protein adducts to the immune system; this situation is not general...
1. To investigate the effects of trichloroethylene on cytochrome P4502E1 (CYP2E1), an isozyme responsible for its metabolic activation, mice were treated with trichloroethylene and Western blot staining with both anti-dichloroacetyl and anti-CYP2E1 antisera detected a comigrating 50 kDa protein band. There was a dose-dependent increase in the intensity of the 50 kDa protein adduct stained immunochemically with anti-dichloroacetyl. 2. CYP2E1 enzyme activity was decreased from control levels in a dose-dependent manner in mice treated with 250-500 mg/kg TRI. 3. Microsomal incubations with trichloroethylene resulted in covalent binding to several proteins including a 50 kDa adduct, which is in contrast with the selective binding to the 50 kDa protein observed in vivo. 4. CYP2E1 enzyme activity levels were significantly decreased following microsomal incubation with NADPH and trichloroethylene, and additionally there was a time- and NADPH-dependent decrease in enzyme activity indicating that trichloroethylene is a mechanism-based inhibitor of CYP2E1.
Estimates of cancer risk from short-term exposure to carcinogens generally rely on cancer potency values derived from chronic, lifetime-exposure studies and assume that exposures of limited duration are associated with a proportional reduction in cancer risk. The validity of this approach was tested empirically using data from both chronic lifetime and stop-exposure studies of carcinogens conducted by the National Toxicology Program. Eleven compounds were identified as having data sufficient for comparison of relative cancer potencies from short-term versus lifetime exposure. The data were modeled using the chronic data alone, and also using the chronic and the stop-exposure data combined, where stop-exposure doses were adjusted to average lifetime exposure. Maximum likelihood estimates of the dose corresponding to a 1% added cancer risk (ED(01)) were calculated along with their associated 95% upper and lower confidence bounds. Statistical methods were used to evaluate the degree to which adjusted stop-exposures produced risks equal to those estimated from the chronic exposures. For most chemical/cancer endpoint combinations, inclusion of stop-exposure data reduced the ED(01), indicating that the chemical had greater apparent potency under stop-exposure conditions. For most chemicals and endpoints, consistency in potency between continuous and stop-exposure studies was achieved when the stop-exposure doses were averaged over periods of less than a lifetime-in some cases as short as the exposure duration itself. While the typical linear adjustments for less-than-lifetime exposure in cancer risk assessment can theoretically result in under- or overestimation of risks, empirical observations in this analysis suggest that an underestimation of cancer risk from short-term exposures is more likely.
Recently, we and others have proposed the methods of mapping the widely accepted logic underlying evidence-based medicine (EBM) in the field of toxicology. [1][2][3][4][5] The goal of evidence-based toxicology (EBT) is to provide a consistent, objective, and rule-based methodology for evaluating human and animal toxicology data to determine whether a chemical creates a human health risk; that is, whether the chemical is known to cause a specific toxic or adverse health effect in humans. 1,6,7 Early adopters of EBT include scientists and regulatory groups such as the U.S. Food and Drug Administration and the National Academy of Sciences critique of the U.S. Environmental Protection Agency (USEPA). [8][9][10][11] EBT is being evaluated by the USEPA itself at a recent workshop with some evident initial confusion. A report by some presenters 12 miscites the order and contents of originating EBT publications, incorrectly suggests that the systematic reviews are somehow equivalent to EBT rather than just one fundamental step in the process, and would have EBT focus on nonhuman animal studies to the virtual exclusion of human effects. Remarkably, the word ''cause'' or ''causation'' does not appear in the article, even though Hartung, a basic toxicologist initiator of EBT, considers causation of human health effects as one of the four pillars of the ''temple'' of EBT. 5 Recently, two publications discussed alternative, but contradictory, approaches for analyzing animal and human data when trying to reach cause and effect conclusions. 13,14 Here, we discuss some shortcomings of these two contrasting proposals viewed from a perspective of a comprehensive framework for causation, that is, EBT. 1
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