Nonlinearity in biology, toxicology, medicine最新文献

Metallothioneins (MTs) are a group of intracellular metal-binding and cysteine-enriched proteins and are highly inducible in many tissues in response to various types of stress. Although it mainly acts as a regulator of metal homeostasis such as zinc and copper in tissues, MT also acts as a potent antioxidant and adaptive (or stress) protein to protect cells and tissues from oxidative stress. Diabetes affects many Americans and other populations, and its development and toxic effect on various organs have been attributed to increased oxidative stress. Studies showed that zinc-induced or genetically enhanced pancreatic MT synthesis prevented diabetes induced by chemicals such as streptozotocin and alloxan, and zinc pretreatment also prevented spontaneously developed diabetes. Since diabetic complications are the consequences of organ damage caused by diabetic hyperglycemia and hyperlipidemia through oxidative stress, whether MT in nonpancreatic organs also provides a preventive effect on diabetic toxicity has been recently investigated. We demonstrated that overexpression of cardiac MT significantly prevented diabetes-induced cardiomyopathy. Likewise, overexpression of renal MT also prevented diabetes-induced renal toxicity. In addition, we also found that MT as an adaptive protein is overexpressed in several organs in response to diabetes. Therefore, the biological importance of diabetes-induced MT in diabetic complications and subsequent other pathogenesis was further explored. We found that diabetes-induced hepatic and renal MT synthesis was accompanied by a significant prevention of endotoxin-induced hepatic toxicity and cisplatin-induced renal toxicity. These studies suggest that MT as an adaptive protein can prevent both diabetes development and its complications or subsequent suffered other pathogenic injury.

From our recent work on the three-dimensional structure of epoxide hydrolases we theoretically deduced the likelihood of a two-step catalytic mechanism that we and others have subsequently experimentally confirmed. Analysis of the rate of the two steps by us and by others show that the first step-responsible for removal of the reactive epoxide from the system-works extraordinarily fast (typically three orders of magnitude faster than the second step), sucking up the epoxide like a sponge. Regeneration of the free enzyme (the second step of the catalytic mechanism) is slow. This becomes a toxicological problem only at doses of the epoxide that titrate the enzyme out. Our genotoxicity work shows that indeed this generates a practical threshold below which no genotoxicity is observed. This shows that-contrary to old dogma-practical thresholds exist for definable genotoxic carcinogens.

Cancer and noncancer health effects have traditionally been handled differently in quantitative risk assessment. A threshold (i.e., safe exposure) has been assumed for noncancer health effects, and low-dose linearity without a threshold has been assumed for cancer. "Harmonization" attempts to reconcile these contrasting assumptions under one paradigm. Recent regulatory initiatives suggest that the U.S. Environmental Protection Agency may be leaning toward a harmonized, probabilistic/linear approach for noncancer health effects. Proponents of this approach cite variability in human susceptibility as an argument against thresholds (i.e., some individuals may be exquisitely sensitive at exposures well below threshold levels). They also cite the results of epidemiological models that suggest low-dose linearity for noncancer health effects. We will discuss the implications of these arguments and compare them to what is known about human biological variability in general. We will also touch on the regulatory implications of hormesis within this framework.

Extrapolation from studies of chemical carcinogenicity in rodents, at high doses, to humans, at the typically low doses to which we are exposed, has been one of the most controversial issues in toxicology. Many chemical carcinogenesis experiments currently are evaluated on a linear scale for dose. Log dose has been the standard for decades in pharmacology and toxicology for noncancer toxicities and there is no reason to think that it should not apply to chemical carcinogenesis. Furthermore, log dose is consistent with fundamental principles of chemistry. Direct comparisons of linear and logarithmic scales for dose illustrate the deceptive nature of linear plots for dose; low doses, which is where our interest lies in comparing human exposures, are compressed beyond evaluation by a linear scale. Unequivocal thresholds for carcinogenicity are shown when the dose-response curves for animal studies done at high doses are evaluated on a log scale for dose. This observation now raises the issue of the relevance to human exposures of these high-dose experiments in animals. Studies analyzed by this log dose to linear response procedure demonstrate that the thresholds from animal experiments can be used to calculate safety factors for human exposure and that humans are more resistant than animals to carcinogenesis from chemicals.

A two-stage, clonal-expansion model of liver tumor risk in mice was developed by Kodell et al. (Food Addit Contam 18:237-253, 2001) based on the hypothesis that fumonisin B(1), a naturally occurring mycotoxin in corn, is not genotoxic, but rather causes cancer through the disruption of sphingolipid metabolism. This disruption is assumed to cause an increase in apoptosis, in response to which cells proliferate to compensate for reduced tissue mass. The resulting differential increase in the number of pre-neoplastic cells at risk of mutation during cell division is assumed to lead to an increase in the incidence of tumors. Two-year liver tumor incidences predicted by the model using data on organ weight, cell proliferation, and sphingolipid metabolism provided a reasonable match to the actual 2-year observed incidences in a study conducted at the National Center for Toxicological Research. The predictions indicated no risk at low doses (even a possible hormetic effect) and high risk at high doses in females, as well as a complete absence of a dose response (or perhaps, a hormetic effect) in males. This paper provides a commentary on the risk-assessment implications of the modeling results, pointing out that the model's low-dose predictions provide scientific support and justification for the U.S. Food and Drug Administration's low-ppm guidance levels in corn products. These guidance levels are significantly higher than would be obtained using linear extrapolation, the method most often used for genotoxic carcinogens and other carcinogens for which low-dose linearity cannot be ruled out.

The effect of amyloid beta-peptide (betaAP), which can have both neurotrophic or neurotoxic effects on neurons and has been implicated in the pathogenesis of Alzheimer's disease (AD), was studied on astrocytes using primary cultures and astrocyte cell lines (rat C6 glioma, human 1321NI astrocytoma cells). The cultures were exposed to 0.0005-50 mug/ml) betaAP fragments 1-40, 25-35, 31-35, or 40-41 (control) for 24 hr. Some of the fragments were maintained at 37 degrees C for 48 hr to induce aggregation and some of the cell cultures were pretreated with the differentiating agent dBcAMP before the experiments. The astrocyte responses were evaluated for lysosome activity (neutral red assay) and levels of structural proteins, glial fibrillary acidic protein, vimentin, and S-100, which are altered in the dystrophic plaques with associated astrogliosis in AD. The cells frequently responded with biphasic responses, with initial (low-dose) activation-type responses (i.e., increases of indicator compared to controls), before reductions with altered morphology (increased branching of cells) at higher concentrations. However, cell death (with EC(50) values) was not observed, even at the maximum concentrations of betaAP fragments. The findings suggest that the astrocytes have a relatively high resistance against the betaAP toxicity.

Some have suggested a threshold mechanism for the carcinogenicity of exposure to hexavalent chromium, Cr(VI). We evaluated the nature of the exposure-response relationship between occupational exposure to Cr(VI) and respiratory cancer based on results of two recently published epidemiological cohort studies. The combined cohort comprised a total of 2,849 workers employed at two U.S. chromate production plants between 1940 and 1974. Standardized mortality ratios (SMRs) for lung cancer in relation to cumulative Cr(VI) exposure categories were reported using regional mortality rates. Linear additive and multiplicative relative risk regression models were fit to the SMRs of the individual and combined studies. Both models fit the data from the individual studies reasonably well; however, the fit was somewhat less adequate for the pooled data. Meta-analysis of the slope estimates obtained from the multiplicative relative risk model showed substantial heterogeneity between the two epidemiological studies. In conclusion, these data indicate that a linear dose response describes the relationship between Cr(VI) and lung cancer reasonably well, and therefore these analyses do not necessarily support the threshold hypothesis for the lung carcinogenicity of Cr(VI). However, these results must be interpreted with recognition of the limitations of the use of epidemiological data in the evaluation of nonlinear exposure-response patterns.

The New York State Department of Environmental Conservation promulgates ambient water quality standards to protect sources of potable water from contamination by toxic chemicals and other substances. Ambient water quality standards are a state program with U.S. EPA oversight, including a federal Clean Water Act requirement for "triennial review." New York's standards are derived according to procedures in state regulation and in conjunction with the New York Slate Department of Health. Because standards are set at levels much below those that demonstrate effects in laboratory studies, high-to-low dose extrapolations are required. The procedures address both carcinogenic and noncarcinogenic effects. Existing regulations essentially require a linear high-to-low dose extrapolation for carcinogenic effects of a chemical (i.e., there is a finite risk at all doses above zero dose). The regulations also require a nonlinear high-to-low dose extrapolation for the noncarcinogenic effects (uncertainty factor approach) of the chemical (i.e., once below the threshold for the effect, the risk at all doses above zero is zero). New York's ongoing triennial review is addressing both standards and standard-setting procedures. Proposed revisions to the procedures, yet to be formally adopted, would allow greater flexibility and use of a nonlinear uncertainty-factor-based approach for carcinogenic effects of chemicals where warranted. The presentation will focus on the expected revisions to the procedures for carcinogenic effects.

To date there is no single shared property of the various physical and chemical agents that elicit the beta-curve to account for its form, leading to the proposition that hormesis is a consequence of the nonspecificity of adaptive responses. It is argued that adaptive responses to toxic agents may be expected to follow the beta-curve. Four kinds of examples are reviewed (enzyme activity, sequestration and repair, and reproductive and homeostatic responses) that corroborate this proposition. The homeostasis example (incorporating homeorhesis) is considered in more detail, using the author's published hydroid experimental growth data, to show that both the alpha- and beta-curves are satisfactorily explained in this way. Many consider that hormesis is merely due to regulatory overcorrections, but it is proposed that it is a consequence of adaptations of the rate-sensitive growth control mechanism (homeorhesis) to sustained levels of inhibition to which the growth control mechanism adapts. In response to low levels of inhibition, upward adjustment of preferred growth rates confers greater resistance to inhibition, with growth hormesis as a cumulative byproduct.