U-shaped Dose-response Relationship Research Articles

Residential Radon in U.S. Counties V Lung Cancer in Women Who Predominantly Never Smoked

Previous studies have found that mean-residential-radon (Rn) levels for U.S. counties are negatively associated with age-adjusted county rates of lung-cancer mortality (LCM), after adjustments for potentially confounding factors. Those results may be due to (a) confounding unaddressable by any county-level (‘ecological’) study design, or (b) county-level factors such as Rn/smoking or age/radon correlations or exposure misclassifications from the use of disparate data sources. Possibilities (b) were addressed by comparing age-specific LCM rates for white women in 2821 U.S. counties who died in 1950–54 at age 40+ (∼11% of whom ever smoked), or at age 60+ (∼% of whom ever smoked), to county Rn levels newly estimated from U.S. Rn, climatic and geological-survey data. Significant negative LCM v Rn trends were found for both age groups, after adjusting for age and subsets of 21 county-level socioeconomic, climatic and other factors. Negative trends were largest for counties with ≤ 100 Bq m−3 Rn (p ≤ 0.00087; 420 analyses). Adjusted relative risk (RRadj) for LCM was significantly elevated (1 150 Bq m−3v 65–100 Bq m−3 Rn, most involving adjustment for climate- and education-related factors likely to have influenced exposure to indoor air contaminants such as Rn and cigarette smoke. Though inconclusive due to potential ecological-fallacy-related confounding that could not be controlled, results from this ecological study are most consistent with a U-shaped dose-response relationship between 1950–54 LCM risk and U.S. residential radon in white women who predominantly never smoked.

Histamine H3-receptor blockade in the rat nucleus basalis magnocellularis improves place recognition memory.

Several lines of evidence have indicated that the central histaminergic system might be involved in learning and memory The aim of the present study was to ascertain the impact on memory processes of putative histaminergic-cholinergic interactions in the nucleus basalis magnocellularis (NBM) of the rat. The effects of thioperamide, a histamine H3-receptor antagonist, were studied on the memory performance of rats in a two-trial, delayed, place-recognition task. The drug was injected into the NBM area 2 min prior to the first trial (1.5, 7.5, and 37.5 ng/0.5 microl; pre-acquisition treatment), within 30 s from the end of the first trial (0.3, 1.5, 7.5, and 37.5 ng/0.5 microl; post-acquisition treatment), or 2 min prior to the second trial (1.5, 7.5, and 37.5 ng/0.5 microl; pre-retrieval treatment). Post-acquisition intra-NBM injections of 1.5 ng and 7.5 ng, but not of 0.3 ng and 37.5 ng thioperamide, significantly enhanced memory retention in treated rats. The histamine H(3)-receptor blocker exerted pro-cognitive effects only when administered post-acquisition, since both pre-acquisition and pre-retrieval treatments were ineffective. The post-acquisition effect of the drug was time dependent and disappeared when the drug was injected 90 min after the end of the first trial. The U-shaped dose-response relationship and the time dependency of the effect of thioperamide indicated that the drug acts on mechanisms involved in memory consolidation. The present findings demonstrate that the pro-cognitive effect of thioperamide is probably due to the modulation of post-acquisition memory processes through an action on the cholinergic basal forebrain. Our results indicate also that H3-antagonists may provide a useful approach for improving spatial recognition memory.

U-Shaped Dose-Response Relationships for Mutation and Cancer

A biologically based mutation model that can be parameterized to reflect U-shaped behavior at low doses of genotoxic substances is derived. The U-shaped behavior results from an efficient, adaptive DNA repair process, by which some endogenous DNA damage that would not be repaired in the absence of the genotoxic substance is repaired when low levels of the substance are present. Hence, the model embodies a type of hormesis. The dose response is U shaped even though the genotoxic mechanism is additive to an existing background mutation process. The risk-assessment implications regarding possible hormetic effects, instead of the generally expected low-dose-linear effects, for agents that are both genotoxic and additive to background are discussed.

U-shaped dose-responses in biology, toxicology, and public health.

The occurrence of U-shaped dose-response relationships (often termed hormesis) has been documented in numerous biological, toxicological, and pharmacological investigations. Many of the endpoints studied are of considerable significance to public health (e.g. body weight, cholesterol levels, ethanol consumption, longevity, cancer incidence, etc). Despite the fact that U-shaped dose-responses are widely and independently observed, little attempt has been made to assess this phenomenon in an integrative manner. This review provides an overview of the historical foundations of hormesis and a discussion of its definition within a mechanistic framework. The occurrence, generalizability, and biological significance of U-shaped dose-response relationships along with the concept of biological optimality are addressed.

Subacute toxicity of α-ergocryptine in Sprague–Dawley rats. 1: general toxicological effects

The dietary subacute toxicity of the ergot alkaloid α-ergocryptine was studied in Sprague–Dawley rats. Rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28–32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). The present study describes the general toxicological effects; the effects on metabolic and hormonal parameters will be reported separately. Body weight, body weight gain, food intake and food efficiency were all decreased with a U-shaped dose–response curve, as in both sexes the ranking severity of effects was in the order 100–20–500 and 4 mg/kg diet. Other changes with a U-shaped dose–response relationship included: hematological parameters (decreased MCV and MCH), serum enzyme activities (slightly increased/decreased ALAT, ASAT, GGT), increased serum urea concentrations, decreased glomular filtration (creatinine and urea clearances), decreased absolute organ weights, increased and decreased relative organ weights, atrophy of thymus and in females atrophy of ovary and uterus with in the mid-dose groups no detectable morphological features of an oestric cycle in the uterus. Other parameters, including increased relative liver, heart and ovarian weights and necrosis of the tail, were influenced in a dose-related manner or only in the high dose group. The U-shaped changes for the parameters mentioned above might be caused by the U-shaped dose–response relationship for food intake, which may be explained by the dopaminergic properties of α-ergocryptine. It is concluded that in rats fed ergocryptine for 28 days the dose–effect curve is rather steep and that the NOAEL is 4 mg/kg diet.

Chronic corticosterone administration dose-dependently modulates Abeta(1-42)- and NMDA-induced neurodegeneration in rat magnocellular nucleus basalis.

The impact of glucocorticoids on beta-amyloid(1-42) (Abeta(1-42)) and NMDA-induced neurodegeneration was investigated in vivo. Abeta(1-42) or NMDA was injected into the cholinergic magnocellular nucleus basalis in adrenalectomized (ADX) rats, ADX rats supplemented with 25%, 100%, 2x100% corticosterone pellets, or sham-ADX controls. Abeta(1-42)- or NMDA-induced damage of cholinergic nucleus basalis neurones was assessed by quantitative acetylcholinesterase histochemistry. Plasma concentrations of corticosterone and cholinergic fibre loss after Abeta(1-42) or NMDA injection showed a clear U-shaped dose-response relationship. ADX and subsequent loss of serum corticosterone potentiated both the Abeta(1-42) and NMDA-induced neurodegeneration. ADX+25% corticosterone resulted in a 10-90 nM plasma corticosterone concentration, which significantly attenuated the Abeta(1-42) and NMDA neurotoxicity. ADX+100% corticosterone (corticosterone concentrations of 110-270 nM) potently decreased both Abeta(1-42)- and NMDA-induced neurotoxic brain damage. In contrast, high corticosterone concentrations of 310-650 nM potentiated Abeta(1-42)- and NMDA-triggered neurodegeneration. In conclusion, chronic low or high corticosterone concentrations increase the vulnerability of cholinergic cells to neurotoxic insult, while slightly elevated corticosterone levels protect against neurotoxic injury. Enhanced neurotoxicity of NMDA in the presence of high concentrations of specific glucocorticoid receptor agonists suggests that the corticosterone effects are mediated by glucocorticoid receptors.

Comments on papers on U-shaped dose-response relationships for carcinogens

Comments on papers on U-shaped dose-response relationships for carcinogens

Comments on papers on U-shaped dose-response relationships for carcinogens

Comments on papers on U-shaped dose-response relationships for carcinogens

A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations.

The development of a comprehensive database of chemical hormetic responses (i.e., U- or inverted U-shaped dose-response relationships) using objective a priori study design, statistical and study replication criteria has recently been reported. An assessment of this database reveals the existence of a wide range of hormetic dose-response relationships including those demonstrating a direct stimulation or an overcompensation response to a disruption of homeostasis. These two broad types of hormetic responses are affected by temporal factors and display unique patterns of dose-range stimulation, magnitude of stimulatory response and relationship of the maximum stimulatory response to the NOAEL. A general classification of U-shaped dose-response relationships is proposed to provide a more organized framework to evaluate the highly distinctive and diverse hormetic responses within the context of establishing underlying biological mechanisms and exploring risk assessment implications.

A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations

A general classification of U-shaped dose-response relationships in toxicology and their mechanistic foundations

Harman-induced changes of extracellular concentrations of neurotransmitters in the nucleus accumbens of rats

Several β-carbolines, including harman, induce voluntary ethanol intake in rats. It is not clear yet which mechanisms cause these effects. One possibility is the stimulation of the mesolimbic reward system. In vivo microdialysis was used to investigate the effects of acute injections of harman (1-methyl-β-carboline) on extraneuronal concentrations of dopamine and 5-hydroxytryptamine in the nucleus accumbens, which is part of the mesolimbic reward system. Administration of harman (2.27 μmol/kg, intraperitoneal application) elicited an increase of the dopamine efflux by 72% which returned to basal levels after approximately 300 min. In contrast, administration of an intermediate dose of harman (13.65 μmol/kg, intraperitoneal application) caused a significant decrease in efflux, to 76% of basal levels. Still higher doses induced again an increased extracellular dopamine concentration. This change was statistically significant in only a subgroup of rats, possibly because individual animals reacted differently to the high doses. Extracellular 5-hydroxytryptamine in the nucleus accumbens was increased during the first 2 h after the administration of high doses (40.94 and 81.93 μmol/kg, intraperitoneal application). These findings indicate that harman affects the activity of mesolimbic dopaminergic neurons following a U-shaped dose-response relationship.

Effects of antimuscarinic antiparkinsonian drugs on brightness discrimination performance in rats

Biperiden (BPR) and trihexyphenidyl (THP), the current antimuscarinic drugs of choice in the management of parkinsonism, have been shown to exert anticonvulsant effects induced by poisoning by the organophosphorus compound soman. The present study was undertaken to evaluate the effects of these drugs on performance of a simple light-intensity discrimination task in rats under a tandem schedule of fixed-ratio (FR) reward/ differential-reinforcement-of-low-rate (DRL) nonreward contingencies, for water reinforcement in 2-h experimental sessions. Both BPR (0.125–2.0 mg/kg, SC) and THP (0.25–8.0 mg/kg, SC) in general decreased overall reinforcement rates in a similar dose dependent and parallel manner, concurrent with increased overall nonreinforced responses in an inverted U-shaped dose-response relationship. Lower doses of BPR (0.125–0.5 mg/kg) and and THP (0.25–2.0 mg/kg) produced a moderate reduction in reinforcement (>−50% of baseline controls), which was correlated well with increases in nonreinforced responses emitted, whereas, higher doses of BPR (> 0.5 mg/kg) and TPH (>−2.0 mg/kg) markedly decreased reinforcements, which mainly resulted from the pausing of responding in the presence of stereotyped behavior. The behavioral disruption induced by BPR was much more rapid than that induced by THP. The ED 50 values (0.6 mg/kg vs. 1.3 mg/kg, respectively) and parallel dose-effect curves suggest that these drugs have similar efficacy, and that BPR is about twice as potent as THP, a ranking that corresponds with their binding affinity at M-1 muscarinic acetylcholine receptors in rat cerebral cortex. Based on the similarity between the anticonvulsant doses of these drugs and the maximal doses that in this study did not disrupt operant responses (0.125 mg/kg vs. 0.25 mg/kg, respectively), it is suggested that both drugs may be useful in protection against seizures produced by the cholinesterase inhibitor soman. Overall, these results suggest that this multiple schedule operant contingency may have promise as a behavioral model to identify the therapeutic or toxic potentials of centrally acting antimuscarinic antiparkinsonian drugs based on their congnitive side effects.

Dose intensity of initial chemotherapy may have an impact on survival in limited small cell lung carcinoma

The analysis of the outcome of 131 patients with limited small cell lung cancer (SCLC) from two consecutive phase II trials which used the same drugs suggested that the intensity of the first course of chemotherapy was a prognostic factor in SCLC. The T3 stage of the TNM classification was the only clinical factor found to be prognostic for overall survival. Irrespective if the T3 stage was controlled or not by multivariate analysis, we found that overall survival rate increased with the dose of cyclophosphamide administered during the first course. A U-shaped dose-response relationship was observed for cisplatinum; survival was ostensibly better for doses ranging from 85 to 105 mg/m 2. When both drugs were taken into account in the analysis, the effect on overall survival remained significant.

Differential effects of centrally injected AVP on heart rate, core temperature, and behavior in rats.

After intracerebroventricular (icv) injection of arginine-vasopressin (AVP; 0.1, 1, 3, 10, 30 and 100 ng) or artificial cerebrospinal fluid (aCSF), heart rate (HR), core temperature (CT), and gross activity were monitored by a wireless telemetry system in rats in the home cage for a 60-min period. In addition, the simultaneous occurrence of various behaviors was recorded by an observer. Also, two structurally related peptides, oxytocin (OXT) and desglycinamide-arginine vasopressin (DGAVP), were tested (10 and 100 ng). Both the time-effect and dose-response relationships of AVP-induced changes in HR and CT were biphasic. Lower doses of AVP produced a tachycardia, whereas injection of higher doses of AVP caused a tachycardia preceded by a significant bradycardia. The concomitant mild rise in CT seen in rats treated with 1 and 3 ng AVP or with aCSF was attenuated in rats given 10 ng AVP; 30 ng AVP resulted in an immediate significant fall in CT, which was restored to control values at 30 min after administration. An inverted U-shaped dose-response relationship was observed for gross activity, locomotion, and rearing behavior, whereas grooming behavior was most marked after the highest dose of AVP. OXT induced a grooming response and cardiac acceleration at the 100-ng dose only, whereas DGAVP produced no effect. To investigate the role of endogenous AVP in the maintenance of tonic ANS activity under resting conditions, rats were treated intracerebroventricularly (icv) with the V1 antagonist d(CH2)5-[Tyr(Me)2]AVP or polyclonal antiserum (W1E) against AVP. During the first 10 min after icv injection of 3 and 10 ng of the antagonist, an increase in HR, CT, and behavioral activation was observed, effects opposite to those produced by the higher dose of AVP. The same variables remained unchanged after administration of 100 ng of the antagonist. W1E injected icv was without effect. In summary, central effects of AVP on autonomic and behavioral activity seem to be mediated by differential neural pathways. In addition, a structure-activity relation seems to exist for the AVP-induced effects. Finally, these results suggest that AVP plays but a minor role in the maintenance of tonic activity of the ANS.

Reciprocal effects between opioid peptides and human polymorphonuclear leukocytes—II: Enhancement of phorbol myristate acetate-induced respiratory burst in human polymorphonuclear leukocyte by opioid peptides previously exposed to activated oxygen species

Activated oxygen species (AOS) have often been shown to promote strong modifications in peptide structures and thus in their biological functions. In the present study, the immunomodulatory effects of Leu-enkephalin, β-endorphin, dynorphin and some fragments are evaluated, before and after exposure of peptides to AOS, by studying their influence on human polymorphonuclear leukocyte (PMN) respiratory burst. None of the tested opioid peptides (modified or not) were shown to affect resting oxidative metabolism in the PMNs. The effects of peptides on phorbol myristate acetate (PMA)-stimulated production of AOS were measured in a lucigenin-enhanced chemiluminescence assay. Before AOS exposure, the opioid peptides suppressed the PMA-stimulated respiratory burst in human PMNs and a U-shaped dose-response relationship, was observed. Conversely, after AOS exposure the opioid peptides enhanced the PMA-stimulated respiratory burst in human PMNs and an inverted U-shaped dose-response relationship was observed. In both cases, the maximal effect was reached at peptide concentrations of 10 −10M-10 −12M.

Fluoxetine seems to widen the nortriptyline antidepressant-like dose range in mice submitted to the tail suspension test (TST)

SummaryThis study was designed to verify whether fluoxetine (FL), a serotonin (5-HT) re-uptake inhibitor, would interfere with nortriptyline (NT), a biphasic U-shaped curvilinear dose-response relationship recently described in our laboratory. We associated 10 mg/kg NT or vehicle to 0, 5, 10, 20 and 40 mg/kg FL, in one group, and 10 mg FL or vehicle to 0, 5, 10, 20 and 40 mg/kg NT, in another group, 30 min before the tail suspension test (TST) in mice. Although we were not able to confirm a synergistic effect between FL and NT, FL-NT association seems to require higher doses of NT to block its own anti-immobility effect at high doses, thus widening NT effective antidepressant-like dose range in mice submitted to TST.

Bombesin-related peptides modulate interleukin-1 production by alveolar macrophages

We have tested the effect of bombesin (BN) and BN-related peptides on the production of interleukin-1 (IL-1) by rat alveolar macrophages. BN incubated with AM alone had no direct effect on IL-1 release. However, at concentrations ranging from 10 −11M to 10 −6M, BN significantly enhanced IL-1 release by AM activated with lipopolysaccharide (LPS). A typically U-shaped dose-response relationship was observed with maximal effect obtained between 10 −9M and 10 −8M. BN also potentiated the stimulatory effects of other IL-1 inducers including muramyl dipeptide (MDP) and granulocyte-macrophage colony stimulating factor (GM-CSF). The 2- to 3-fold enhancement in IL-1 production seen with BN was blocked by the bombesin receptor antagonist [Leu 13, −ψ(CH 2NH)Leu 14]-Bombesin. Furthermore, bombesin-related peptides, gastrin-releasing peptides, (GRP)-27 and GRP-10 also potentiated the stimulatory effects of LPS whereas Neuromedin B (NeB) had no effect. These results suggest that BN-related peptides might play an important role as local modulator(s) of cytokine production and inflammatory reactions in the lung.

Effect of tryptophan on the behavior of nonstressed and stressed mice in Porsolt's swim test

The effect of tryptophan on immobility in Porsolt's swim test was studied in male NIH Swiss mice. Preexposure to a swim or fight-stressor was included in the design. Doses of tryptophan (0, 12.5, 50, 75, 100, 125 and 200 mg/kg) were administered intraperitoneally 60 min prior to the swim test. In the nonstressed mice tryptophan had an U-shaped dose-response relationship: immobility in the water was dose-dependently shortened after doses from 0 to 100 mg/kg, whereas after 125 and 200 mg/kg tryptophan the immobility times did not differ from the values obtained after a saline injection. Preexposure to a swim- or fight-stressor did not make mice more sensitive to the effects of tryptophan. Tryptophan (0–300 mg/kg) had no effect on exploratory behavior or locomotor activity in the holeboard, suggesting that sedation was not a factor in the swim test results. The findings suggest that tryptophan has antidepressant -like properties in Porsolt's swim test.

Characterization of the effects of acute ethanol administration on the release of β-endorphin peptides by the rat hypothalamus

In the present studies the direct effect of ethanol on the release of β-endorphin by the rat hypothalamus was investigated. When various concentrations of ethanol (10–120 mM) were added into the incubation medium, it was noticed that though low concentrations of ethanol (10, 20 and 30 mM) induced a pronounced increase in the release of β-endorphin-like peptides from the hypothalamus, high concentrations of ethanol (40, 60 and 120 mM) induced a less pronounced increase. Exposure of hypothalamus to depolarizing concentrations of potassium chloride (following washing of the ethanol), provoked a significant release of β-endorphin-like peptides, regardless of the ethanol concentration the tissues were exposed prior to the stimulation with the potassium chloride. Chromatographic analysis of the incubation media with Sephadex-G-75 revealed that the hypothalamus released mainly β-endorphin-sized peptides. Analysis of the β-endorphin-sized peptides with reverse-phase high performance liquid chromatography indicated the presence of β-endorphin-(1–31) as well as non-acetyl and acetyl β-endorphin-(1–27). Thus ethanol exerts a biphasic effect on the release of β-endorphin-like peptides by the rat hypothalamus, with low concentrations inducing a dose-dependent increase, reaching maximum at 20 mM ethanol, and with higher concentrations of ethanol inducing a less pronounced increase in the release of β-endorphin-like peptides, leading to an inverted U-shaped dose response relationship of ethanol and release of β-endorphin-like peptides from the rat hypothalamus.

Apparently Beneficial Effect of Low to Intermediate Doses of A-bomb Radiation on Human Lifespan

Among about 100,000 A-bomb survivors registered at Nagasaki University School of Medicine, 290 male subjects exposed to 50-149 cGy showed significantly lower mortality from non-cancerous diseases than age-matched unexposed males. This was deduced from the fitting of a U-shaped dose-response relationship. Reasons for this effect in males, but not in females, are discussed with reference to selection of individuals and to hormesis.