Nonlinearity in biology, toxicology, medicine最新文献

Numerous studies of populations living in areas with good air quality have reported correlations between daily average levels of ambient particulate matter (PM) and daily mortality rates. These associations persist at PM levels below current air quality standards and are difficult to reconcile with the toxicology of PM chemical constituents. The unusual level of lethality per unit PM mass predicted by these associations may result from confounding by unmeasured societal, behavioral, or stress factors. Daily average ambient PM levels may be expected to correlate with societal activity level, because a working population increases PM emissions through increased manufacture, power utilization, construction, demolition, farming, and travel. Also, people's perceived and actual health depend on societal and psychological factors. A stress such as anger strongly increases the risk of death due to heart attack. Societal factors modify mortality as shown by calendar-related changes in mortality that are unrelated to air quality. Cardiovascular and respiratory mortality are correlated to day of the week, end of the month, and to the first week of the year. There is likely a role of such nontoxicologic variables in the PM associations, and without vigorously testing if other variables correlate as well as PM, we may erroneously conclude that reducing already low levels of PM will yield real public health benefits.

The National Toxicology Program (NTP) dose-ranging studies typically employ five dosages and a concurrent control and are conducted for 2- and 13-week exposure periods. Because five doses are employed it suggested the possibilities of the occurrence of sub-NOAEL doses in many of these bioassays and of evaluating the occurrence of hormesis within the NTP bioassay. As a result, 59 environmentally relevant agents in the NTP toxicity database were assessed for their capacity to affect hormetic dose responses for growth as measured by change in weight gain. Hormetic effects were observed with 51 (88%) of the 58 agents evaluated. When considered by species, hormetic effects were observed in 48% (98/205) of bioassays involving mice and 14% (29/204) of bioassays involving rats. Hormetic effects were seen in a comparable fashion between males and females of both mice (i.e., 47 male and 51 female) and rats (13 male and 16 female rats). These observations represent a new finding within the NTP bioassay database that have potential implications for issues relating to study design and endpoint measured, as well as underlying biological mechanisms that affect efficiency of nutrient utilization under conditions of low-level toxicant exposure.

Our attempts to confirm reports of low-dose/hormetic effects in rodent endocrine toxicity studies are reviewed. It is concluded that our present failure to confirm any such effects is due, in large part, to a general lack of understanding of confounding influences and the failure of most investigators to confirm their findings before publication. The major potential confounding factor is suggested to be variability of the parameters under study within control groups, a factor that assumes increased importance when attempting to demonstrate weak low-dose effects. This is illustrated by our studies with bisphenol A in the mouse uterotrophic assay and of finasteride in the Hershberger antiandrogenicity assay. In both of these cases our ability to demonstrate a low-dose effect is dependent on whether concurrent or recent control values are used.

To investigate the possibility of the involvement of an oxidative stress induction in the mechanism of the cytotoxic effect of quinolone antibiotics, we examined the viability of human fibroblast cells exposed to ciprofloxacin (CPFX), and measured the levels of lipid peroxidation (LP), glutathione (GSH), and the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX). The data showed that the effect of CPFX on the viability of cells, as determined by neutral red uptake assay, was time-dependent, and the dose-response relation was biphasic. Cytotoxicity was not observed in the concentration range 5-150 mg/l CPFX when the cells were incubated for 24 h. In contrast, lower concentrations (5 and 12.5 mg/l) of CPFX increased the cell growth in all incubation periods tested. Marked decreases in the viability of fibroblasts were observed at concentrations 50 and 75 mg/l, and >/=50 mg/l, following 48 and 72 h exposure, respectively (p < 0.05). However, when the cells were exposed to > 75 mg/l CPFX for 48 h, no cytotoxicity was observed. By exposing fibroblast cultures to 75 mg/l CPFX for 48 h, an induction of LP enhancement and a marked decrease in intracellular GSH were observed. Vitamin E pretreatment of the cells lowered the level of LP, increased the total GSH content, and provided significant protection against CPFX-induced cytotoxicity. The biphasic effect of CPFX possibly resulted from the complex dose-dependent relationships between reactive oxygen species (ROS), cell proliferation, and cell viability. It was previously reported, in fact, for several cell models that ROS exert a biphasic effect on cell growth. Furthermore, cultured fibroblasts release their own free radicals, and the inhibition of endogenous ROS inhibits the fibroblast cell proliferation, whereas the effect of exogenous ROS is biphasic.

Wistar rats were divided into six groups, which were given La (NO(3))(3) at 20.0, 10.0, 2.0, 0.2, and 0.1 mg/kg, and the control group, which was given physiological saline, respectively, for six months. Pathological changes of liver were observed via light microscopy and transmission electron microscopy. Glutamic-oxalacetic transaminase, glutamic-pyruvic transitanase, gamma-glutamyl transferase, and alkline phosphatase activities in the serum were measured. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde of liver were determined. The metabolic accumulation of lanthanum in rat liver was investigated via inductively coupled plasma mass spectrometry. Results showed no abnormal biochemical changes. In the group of 20.0 mg/kg La(NO(3))(3), there were loss of weight, decrease of glycogen in the hepatocytes, denser matrix of the mitochondria, and deformation of the nuclei of some hepatocytes with different degrees and infiltration of inflammatory cells in the portal area. The higher was the dose, the higher was the number of bodies contain high electronic dense gravel-like granules, and secondary lysosomes with dense bodies were observed. In the group fed 0.1 mg/kg La(NO(3))(3), intracellular glycogen showed an increasing tendency, particularly increased animal growth and increased activities of SOD and GSH-Px. The content of La in the liver increased regularly with increase in dose and time of administration. The results further proved that low-dose La(NO(3))(3) produced some specific biologic effects. This study illustrated the influence of La(NO(3))(3) on rat liver at cellular and subcellular levels and it provides an experimental basis for the purpose of setting a reasonable standard for safely utilizing rare earth elements.

Hormesis is a dose-response phenomenon that has received little recognition, credibility and acceptance as evidenced by its absence from major toxicological/risk assessment texts, governmental regulatory dose-response modeling for risk assessment, and non-visibility in major professional toxicological society national meetings. This paper traces the historical evolution of the hormetic dose-response hypothesis, why this model is not only credible but also more common than the widely accepted threshold model in direct comparative evaluation, and how the toxicological community made a critical error in rejecting hormesis, a rejection sustained over 70 years.

Spectroscopic strategies that substantiate periodic oscillations in low rates of NADH oxidation exhibited by ECTO-NOX proteins at the animal and plant cell surface are described. Both continuous display and discontinuous rate determinations exhibit the oscillations but continuous displays lack sufficient resolution to discern details. A procedure is documented where rates are determined by least squares analyses of traces recorded over 1 min at intervals of 1.5 min. These traces recapitulate the continuous displays but offer an opportunity to reliably estimate changes in reaction rates over short time intervals not afforded by the continuous traces. Results from previously used rate determination over 5 min intervals are included for comparison. Turbidity is identified as the major contributor to losses in resolution. Even highly purified NOX preparations tend to aggregate to form turbid suspensions. With turbid suspensions, double beam or dual wavelength instrumentation where the sample is placed immediately adjacent to the photomultiplier tube are required to reduce losses in resolution from turbidity. Also required are high levels of synchronous ECTO-NOX function. Blue or red (plants) light, small molecules (i.e., melatonin) and autosynchrony alone or in combination were used to synchronize the oscillations. Special problems posed by preparations containing more than one ECTO-NOX form and where the different ECTO-NOX forms do not cross entrain are discussed.

Many drug concentration-effect relationships are described by nonlinear sigmoid models. The 4-parameter Hill model, which belongs to this class, is commonly used. An experimental design is essential to accurately estimate the parameters of the model. In this report we investigate properties of D-optimal designs. D-optimal designs minimize the volume of the confidence region for the parameter estimates or, equivalently, minimize the determinant of the variance-covariance matrix of the estimated parameters. It is assumed that the variance of the random error is proportional to some power of the response. To generate D-optimal designs one needs to assume the values of the parameters. Even when these preliminary guesses about the parameter values are appreciably different from the true values of the parameters, the D-optimal designs produce satisfactory results. This property of D-optimal designs is called robustness. It can be quantified by using D-efficiency. A five-point design consisting of four D-optimal points and an extra fifth point is introduced with the goals to increase robustness and to better characterize the middle part of the Hill curve. Four-point D-optimal designs are then compared to five-point designs and to log-spread designs, both theoretically and practically with laboratory experiments.D-optimal designs proved themselves to be practical and useful when the true underlying model is known, when good prior knowledge of parameters is available, and when experimental units are dear. The goal of this report is to give the practitioner a better understanding for D-optimal designs as a useful tool for the routine planning of laboratory experiments.