| 1. |
- Bredhult, Carolina, et al.
(author)
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Effects of chlorinated biphenyls and metabolites on human uterine myocyte proliferation
- 2007
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In: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 26:10, s. 801-809
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Journal article (peer-reviewed)abstract
- Uterine myometrial cells are responsive to sex steroids, which could make them susceptible to actions of endocrine disrupting environmental contaminants such as some PCBs. The aim of this investigation was to identify possible effects of some chlorinated biphenyls (CBs) and their metabolites on myometrial cell proliferation. Myometrial cells obtained from women in both phases of the menstrual cycle and from pregnant women were grown in vitro and exposed to CB 101, CB 118, 3'-MeSO2-CB 101, 4'-MeSO2-CB 101, 4-OH-CB 107, 17 beta-estradiol, progesterone, ethinylestradiol or levonorgestrel. The proliferative activity was studied by a BrdU assay. Myometrial cell cultures originating from pregnant women exhibited decreased proliferation in response to 3'-MeSO2-CB 101, 4'-MeSO2-CB 101 and 4-OH-CB 107. Estradiol, a combination of 1 nM 17 beta-estradiol and 10 nM progesterone, ethinylestradiol and levonorgestrel also reduced the proliferation of the myometrial cells, regardless of whether the cells were collected from either of the menstrual cycle phases or from pregnant women. To our knowledge this study is the first to demonstrate that some CBs affect the proliferative activity of human uterine myocytes.
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| 2. |
- Ernstgard, L, et al.
(author)
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Acute effects of exposure to vapours of dioxane in humans
- 2006
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In: Human & experimental toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 25:12, s. 723-729
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Journal article (peer-reviewed)abstract
- Information on the acute effects associated with the handling of 1,4-dioxane is sparse. Our aim was to evaluate the acute effects of 1,4-dioxane vapours. In a screening study, six healthy volunteers rated symptoms on a visual analogue scale (VAS), while exposed to stepwise increasing levels of 1,4-dioxane, from 1 to 20 ppm. The initial study indicated no increased ratings at any of the exposure levels; we decided to use 20 ppm (72 mg/m3) as a tentative no observed adverse effect level (NOAEL). In the main study, six female and six male healthy volunteers were exposed to 0 (control exposure) and 20 ppm 1,4-dioxane vapour, for 2 hours at rest. The volunteers rated 10 symptoms on VAS before, during, and after the exposure. Blink frequency was monitored during exposure. Pulmonary function, and nasal swelling, was measured before, and at 0 and 3 hours after exposure. Inflammatory markers in plasma (C-reactive protein, and interleukin-6) were measured before and at 3 hours after exposure. In conclusion, exposure to 20 ppm 1,4-dioxane for 2 hours did not significantly affect symptom ratings, blink frequency, pulmonary function, nasal swelling, or inflammatory markers in the plasma of the 12 volunteers in our study.
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| 3. |
- Forsby, Anna, et al.
(author)
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Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity.
- 2007
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In: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 26:4, s. 333-338
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Journal article (peer-reviewed)abstract
- Risk assessment of neurotoxicity is mainly based on in vivo exposure, followed by tests on behaviour, physiology and pathology. In this study, an attempt to estimate lowest observed neurotoxic doses after single or repeated dose exposure was performed. Differentiated human neuroblastoma SH-SY5Y cells were exposed to acrylamide, lindane, parathion, paraoxon, phenytoin, diazepam or caffeine for 72 hours. The effects on protein synthesis and intracellular free Ca2+ concentration were studied as physiological endpoints. Voltage operated Ca2+ channel function, acetylcholine receptor function and neurite degenerative effects were investigated as neurospecific endpoints for excitability, cholinergic signal transduction and axonopathy, respectively. The general cytotoxicity, determined as the total cellular protein levels after the 72 hours exposure period, was used for comparison to the specific endpoints and for estimation of acute lethality. The lowest concentration that induced 20% effect (EC20) obtained for each compound, was used as a surrogate for the lowest neurotoxic level (LOEL) at the target site in vivo. The LOELs were integrated with data on adsorption, distribution, metabolism and excretion of the compounds in physiologically-based biokinetic (PBBK) models of the rat and the lowest observed effective doses (LOEDs) were estimated for the test compounds. A good correlation was observed between the estimated LOEDs and experimental LOEDs found in literature for rat for all test compounds, except for diazepam. However, when using in vitro data from the literature on diazepam's effect on gamma-amino butyric acid (GABA)A receptor function for the estimation of LOED, the correlation between the estimated and experimental LOEDs was improved from a 10,000-fold to a 10-fold difference. Our results indicate that it is possible to estimate LOEDs by integrating in vitro toxicity data as surrogates for lowest observed target tissue levels with PBBK models, provided that some knowledge about toxic mechanisms is known.
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| 4. |
- Hansson, Sven Ove
(author)
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Ethical principles for hormesis policies
- 2008
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In: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 28, s. 609-612
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Journal article (peer-reviewed)abstract
- At least two major choices have to be made in the ethical analysis of hormesis policies. The first is where to put the burden of proof when it is uncertain whether a particular hormesis effect exists or not. It is argued that the burden of proof will have to fall primarily on those who claim the existence of such an effect. The second issue arises when (positive) hormesis effects of a substance are weighed against negative effects of the same substance. A decision must then be made whether negative effects affecting one person can be outweighed by positive effects on another person or only by positive effects on that person herself. It is argued that risk-weighing for hormesis effects should be individualistic. This would mean that benefits for one person do not automatically outweigh negative effects on another person.
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| 5. |
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| 6. |
- Jones, A Wayne, 1945-, et al.
(author)
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Relation between blood- and urine-amphetamine concentrations in impaired drivers as influenced by urinary pH and creatinine
- 2005
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In: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 24:12, s. 615-622
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Journal article (peer-reviewed)abstract
- Amphetamine undergoes extensive renal excretion and significant amounts are present in urine as the unchanged parent drug. This prompted us to investigate whether a quantitative relationship existed between blood and urine concentrations of amphetamine in the body fluids of drug-impaired drivers apprehended in Sweden, where this stimulant is the major drug of abuse. The relationship between blood and urine concentrations of amphetamine was determined by multivariate analysis with urinary pH and creatinine as predictor variables. Amphetamine was determined in blood and urine by gas chromatography-mass spectrometry with deuterium-labelled internal standards. The concentration of amphetamine in urine was about 200 times greater than the concentration in blood, the mean and median urine/blood ratios were 214 and 160, respectively, with large individual variations. The Pearson correlation coefficient between urine (y) and blood (x) amphetamine was r= 0.53, n=48, which was statistically highly significant (P < 0.001), although the residual standard deviation (SD) was large (±181 mg/L). The correlation coefficient increased (r=0.60) when the concentration of amphetamine in urine was normalized for dilution by dividing with the creatinine content. When urinary pH and creatinine were both included as predictor variables, the correlation coefficient was even higher (r=0.69), now explaining 48% (r 2=0.48) of the variation in urine-amphetamine concentration. However, the partial regression coefficient for creatinine (53±28.7) was not statistically significant (t=1.85, P >0.05), whereas the corresponding regression coefficient for pH was highly significant and had a negative sign (-102±32.6, t= -3.12, P
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| 7. |
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| 8. |
- Rahi, M., et al.
(author)
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Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta
- 2008
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In: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 27:1, s. 65-71
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Journal article (peer-reviewed)abstract
- BACKGROUND: The ATP-dependent drug-efflux pump, P-glycoprotein (P-gp) encoded by ABCB1 (MDR1), plays a crucial role in several tissues forming blood-tissue barriers. Absence of a normally functioning P-gp can lead to a highly increased tissue penetration of a number of clinically important drugs. METHODS: We have studied the dose-response effect of exogenous ATP on the placental transfer of the well-established P-gp substrate saquinavir in 17 dually perfused human term placentas. We have also studied the influence of the ABCB1 polymorphisms 2677G>T/A and 3435C>T on placental P-gp expression (n = 44) and the transfer (n = 16) of saquinavir. RESULTS: The present results indicate that the addition of exogenous ATP to the perfusion medium does not affect the function of P-gp as measured by saquinavir transfer across the human placenta. The variant allele 3435T was associated with significantly higher placental P-gp expression than the wild-type alleles. However, neither polymorphism affected placental transfer of saquinavir nor there was any correlation between P-gp expression and saquinavir transfer. CONCLUSIONS: Our results indicate that addition of exogenous ATP is not required for ATP-dependent transporter function in a dually perfused human placenta. Although the ABCB1 polymorphism 3435C>T altered the expression levels of P-gp in the human placenta, this did not have any consequences on P-gp-mediated placental transfer of saquinavir.
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| 9. |
- Rignell-Hydbom, Anna, et al.
(author)
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Exposure to persistent organochlorine pollutants and type 2 diabetes mellitus.
- 2007
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In: Human & Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 26:5, s. 447-452
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Journal article (peer-reviewed)abstract
- Persistent organochlorine pollutants (POPs), such aspolychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), dichloro diphenyl trichloroethane (DDT) and its major metabolite 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p' -DDE) have been associated with type 2 diabetes mellitus (T2DM) in recent epidemiological studies. We have analysed 2,2',4,4',5,5' -hexachlorobiphenyl (CB-153) and p,p'-DDE in 544 serum-samples from Swedish women with a median age of 50 years. The participants were asked if they had diabetesand if so, what type of diabetes, years since diagnosis and what kind of treatment they had. Associations between exposure and T2DM were analysed by logistic regression. Moreover, trends of T2DM prevalence were tested with Jonckheere-Terpstra' test. Sixteen of the 544 women (3%) had diabetes, of which15 were classified as T2DM. There was a significant associationwith T2DM for both CB-153 (an increase of 100ng/glipid corresponded to an odds ratio [OR] of 1. 6, 95% confidenceinterval [CI] 1. 0, 2. 7) and p,p9-DDE (OR 1. 3, 95%CI 1. 1, 1. 6). In addition, significant positive trends betweenquartiles of CB-153 and T2DM (P 5 0. 004) and p,p9-DDEand T2DM (P 5 0. 002) were observed. The study showsan association between POP serum concentrations andan increased prevalence of T2DM.
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| 10. |
- Sandin, Per
(author)
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The ethics of hormesis - no fuss?
- 2008
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In: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 27:8, s. 643-646
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Journal article (peer-reviewed)abstract
- It has been argued that the phenomenon of hormesis should prompt us to revise current regulatory policy in order to take beneficial effects of small doses of various agents into account. I argue that three problems - the comparative smallness of hormetic effects, the fine-tuning problem, and the problem of aggregated actions - should lead us not to overemphasize the importance of hormesis for policy, and that they, if anything, points towards a non-consequentialist approach to the ethics of risk.
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