General considerations of dose-effect and dose-response relationships

2022 ◽  
pp. 299-317
Author(s):  
Daphne B. Moffett ◽  
M. Moiz Mumtaz ◽  
Dexter W. Sullivan ◽  
Margaret H. Whittaker
Keyword(s):  
PEDIATRICS ◽  
1996 ◽  
Vol 98 (1) ◽  
pp. 76-83 ◽  
Author(s):  
Edward Z. Tronick ◽  
Deborah A. Frank ◽  
Howard Cabral ◽  
Mark Mirochnick ◽  
Barry Zuckerman

Objective. To determine in a representative sample of full-term urban newborns of English-speaking mothers whether an immediate or late dose-response effect could be demonstrated between prenatal cocaine exposure and newborn neurobehavioral performance, controlling for confounding factors. Methods. The Neonatal Behavioral Assessment Scale (NBAS) was administered by masked examiners to a total sample of 251 clinically healthy, full-term infants at 2 days and/or 17 days. Three in utero cocaine exposure groups were defined: heavily exposed (n = 44, >75th percentile self-reported days of use during pregnancy and/or >75th percentile of meconium benzoylecognine concentration); lightly exposed (n = 79, less than both 75th percentiles); and unexposed (n = 101, no positive biological or self-report marker). At the 3-week examination there were 38 heavily exposed, 73 lightly exposed, and 94 unexposed infants. Controlling for infant birth weight, gestational age, infant age at the time of examination, mothers' age, perinatal risk, obstetric medication, and alcohol, marijuana, and cigarette use, a regression analysis evaluated the effects of levels of cocaine exposure on NBAS performance. Results. No neurobehavioral effects of exposure on the newborn NBAS cluster scores or on the qualifier scores were found when confounders were controlled for at 2 to 3 days of age. At 3 weeks, after controlling for covariates, a significant dose effect was observed, with heavily exposed infants showing poorer state regulation and greater excitability. Conclusions. These findings demonstrate specific dose-related effects of cocaine on 3-week neurobehavioral performance, particularly for the regulation of arousal, which was not observed in the first few days of life.


2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Jun Yang ◽  
Ming Jing ◽  
Xiaoge Yang

Abstract Steroid treatment has become recognized as an important risk factor for avascular osteonecrosis of the femoral head. However, not all patients who receive long-term, high-dose steroids develop osteonecrosis, indicating that there are individual differences in occurrence. We explored the relationship between polymorphisms and steroid-induced osteonecrosis of the femoral head (SONFH) incidence with variables. We used a multilevel mixed-effects logistic regression model, which is an expansion of logistic regression, for each type of steroid, primary disease, drug dose, applied duration, and single-nucleotide polymorphism (SNP). We also conducted a dose-response meta-analysis to analyze the cumulative dosage and SONFH risk in mutation carriers. There were significant correlations between the ABCB1 rs1045642 mutant and SONFH in the prednisone-use and methylprednisolone/prednisone-use populations. The ABCB1 rs2032582 mutant homozygote had a protective effect in the methylprednisolone/prednisolone renal transplant population. For ApoB rs693, mutation increased the incidence of SONFH in prednisone-use and methylprednisolone/prednisolone-use populations and renal transplant patients. For ApoB rs1042031, mutation increased the risk of SONFH in the prednisone-use population. The PAI-1 rs1799768 mutation had a protective effect on the SONFH risk prednisone-use and renal transplant populations. ABCB1 rs1045642 mutations have a protective effect against SONFH, and ApoB rs693 and rs1042031 increase the SONFH risk. Cumulative dosage and treatment duration had little effect on the results. In addition, there was a dose-effect correlation in ABCB1 rs1045642 and rs2032582 mutation carriers.


2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
F R Gentile ◽  
R Primi ◽  
E Baldi ◽  
S Compagnoni ◽  
C Mare ◽  
...  

Abstract Background Pollution has been suggested as a precipitating factor for cardiovascular diseases via a series of different mechanisms. However, data about the link between the different air pollutants and the risk of out-of-hospital cardiac arrest (OHCA) are limited and controversial. Purpose The primary aim of this study is to examine the impact of short-term exposure to particulate and gaseous pollutants on the incidence of OHCA in a vast metropolitan and rural area that encompasses four provinces of the Po Valley in Northern Italy, one of the most polluted areas in Italy and Europe due to its levels of industrialization and high population density. The secondary aim of this study is to look for a dose-effect curve, which could help predict OHCA incidence based on the concentration of pollutants in a specific area. Methods This is a retrospective analysis of prospectively collected data both in the OHCA registry (Lombardia CARe) and in the database of the regional agency for environmental protection (ARPA) of the Lombardy region. All medical OHCAs and the mean daily concentration of pollutants including fine particulate matter (PM10, PM2.5), benzene (C6H6), carbon monoxide (CO), nitrogen dioxide (NO2), sulphur dioxide (SO2) and ozone (O3) were considered from January 1st to December 31st, 2019 in the southern part of the Lombardy region (provinces of Pavia, Lodi, Cremona and Mantua; 7863 km2; about 155ehab724.2654 inhabitants). Days were divided into high or low incidence of OHCA according to the median daily incidence. A Probit dose-response analysis and both uni- and multivariable logistic regression models were provided for each pollutant. Results The median daily incidence of OHCA was 0.3 cases/100,000 inhabitants. Benzene was the pollutant with the greatest difference between days at high and low incidence of OHCA [0.7 (IQR 0.4–1.2) vs 0.4 (IQR 0.3–0.7), p<0.001], whereas SO2 had the lowest and least significant difference between the two periods [3.2 (IQR 2.8–3.6) vs 3.1 (IQR 2.7–3.5), p=0.046]. O3 showed a countertrend, being significantly higher in the low-incidence period [29.9 (IQR 10.9–61.7) vs 56.1 (IQR 25.5–74.1), p<0.001] as well as temperature [10.1— (IQR 5.2–14.8) vs 15.1 (IQR 8.9–23.3), p<0.001]. By using the Probit regression analysis and after adjusting for temperature, a dose-response relationship was demonstrated for all the tested pollutants. Conclusions Our results clarify the link between pollutants and the acute risk of cardiac arrest suggesting the need of both improving the air quality and integrating pollution data in future models. FUNDunding Acknowledgement Type of funding sources: None.


2018 ◽  
Vol 129 (5) ◽  
pp. 1295-1304 ◽  
Author(s):  
Yanlu Zhang ◽  
Michael Chopp ◽  
Zheng Gang Zhang ◽  
Yi Zhang ◽  
Li Zhang ◽  
...  

OBJECTIVECerebrolysin is a neuropeptide preparation that mimics the properties of neurotrophic factors and has had beneficial effects in the treatment of neurodegenerative diseases, stroke, and traumatic brain injury (TBI). To further evaluate treatment schemes, the authors assessed the dose-response of Cerebrolysin on functional improvement in a rat model of mild TBI (mTBI).METHODSThis dose-response study was a prospective, randomized, blinded, and placebo-controlled preclinical experiment. Male Wistar adult rats, subjected to mTBI induced by a closed head impact, were treated randomly with 0 (saline as placebo), 0.8, 2.5, or 7.5 ml/kg of Cerebrolysin 4 hours after mTBI and daily for a total of 10 consecutive days. A battery of cognitive and sensorimotor functional tests was performed over 90 days.RESULTSThe primary outcome was functional improvement over the 90 days; animal weight and death were the secondary and safety outcomes, respectively. A significant (p < 0.001) dose effect of Cerebrolysin on cognitive recovery 3 months after injury was found. Cerebrolysin at a dose of ≥ 0.8 ml/kg significantly (p < 0.001) improved cognitive outcome. The higher dose (7.5 ml/kg) resulted in significantly better cognitive recovery than the lowest doses (0.8 ml/kg) but not relative to the 2.5-ml/kg dose. Cerebrolysin at a dose of 2.5 or 7.5 ml/kg also caused different onset times of significant improvement in sensorimotor function. No differences in body weight or mortality rate among the groups were found.CONCLUSIONSThis preclinical randomized, placebo-controlled, and blinded study with a clinically relevant treatment scheme revealed that Cerebrolysin at doses of 0.8–7.5 ml/kg, administered 4 hours after mTBI and then once daily for a total of 10 consecutive days, improved functional outcomes 3 months after injury. A dose of 2.5 ml/kg is likely an optimal dose for the treatment of experimental mTBI.


2016 ◽  
Author(s):  
Robert F. M. Herber ◽  
John H. Duffus ◽  
Jytte Molin Christensen ◽  
Erik Olsen ◽  
Milton V. Park
Keyword(s):  

2016 ◽  
Vol 44 ◽  
pp. 1660239
Author(s):  
Demetre Zafiropoulos ◽  
E. Facco ◽  
Lucia Sarchiapone

In case of a radiation accident, it is well known that in the absence of physical dosimetry biological dosimetry based on cytogenetic methods is a unique tool to estimate individual absorbed dose. Moreover, even when physical dosimetry indicates an overexposure, scoring chromosome aberrations (dicentrics and rings) in human peripheral blood lymphocytes (PBLs) at metaphase is presently the most widely used method to confirm dose assessment. The analysis of dicentrics and rings in PBLs after Giemsa staining of metaphase cells is considered the most valid assay for radiation injury. This work shows that applying the fluorescence in situ hybridization (FISH) technique, using telomeric/centromeric peptide nucleic acid (PNA) probes in metaphase chromosomes for radiation dosimetry, could become a fast scoring, reliable and precise method for biological dosimetry after accidental radiation exposures. In both in vitro methods described above, lymphocyte stimulation is needed, and this limits the application in radiation emergency medicine where speed is considered to be a high priority. Using premature chromosome condensation (PCC), irradiated human PBLs (non-stimulated) were fused with mitotic CHO cells, and the yield of excess PCC fragments in Giemsa stained cells was scored. To score dicentrics and rings under PCC conditions, the necessary centromere and telomere detection of the chromosomes was obtained using FISH and specific PNA probes. Of course, a prerequisite for dose assessment in all cases is a dose-effect calibration curve. This work illustrates the various methods used; dose response calibration curves, with 95% confidence limits used to estimate dose uncertainties, have been constructed for conventional metaphase analysis and FISH. We also compare the dose-response curve constructed after scoring of dicentrics and rings using PCC combined with FISH and PNA probes. Also reported are dose response curves showing scored dicentrics and rings per cell, combining PCC of lymphocytes and CHO cells with FISH using PNA probes after 10 h and 24 h after irradiation, and, finally, calibration data of excess PCC fragments (Giemsa) to be used if human blood is available immediately after irradiation or within 24 h.


1985 ◽  
Vol 1 (4) ◽  
pp. 23-41 ◽  
Author(s):  
Michael L. Dourson ◽  
Richard C. Hertzberg ◽  
Rolf Hartung ◽  
Karen Blackburn

This paper describes two general methods for estimating ADIs that circumvent some of the limitations inherent in current approaches. The first method is based on a graphic presentation of toxicity data and is also shown to be useful for estimating acceptable intakes for durations of toxicant exposure other than the entire lifetime. The second method uses dose-response or dose-effect data to calculate lower CLs on the dose rate associated with specified response or effect levels. These approaches should lead to firmer, better established ADIs through increased use of the entire spectrum of toxicity data.


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