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Archives of Toxicology (v.84, #6)
The carcinogenicity debate on formaldehyde: How to derive safe exposure limits?
by Hermann M. Bolt; Gisela H. Degen; Jan G. Hengstler (pp. 421-422).
Cancer effects of formaldehyde: a proposal for an indoor air guideline value by Gunnar Damgård Nielsen; Peder Wolkoff (pp. 423-446).
Formaldehyde is a ubiquitous indoor air pollutant that is classified as “Carcinogenic to humans (Group 1)” (IARC, Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropanol-2-ol. IARC monographs on the evaluation of carcinogenic risks to humans, vol 88. World Health Organization, Lyon, pp 39–325, 2006). For nasal cancer in rats, the exposure–response relationship is highly non-linear, supporting a no-observed-adverse-effect level (NOAEL) that allows setting a guideline value. Epidemiological studies reported no increased incidence of nasopharyngeal cancer in humans below a mean level of 1 ppm and peak levels below 4 ppm, consistent with results from rat studies. Rat studies indicate that cytotoxicity-induced cell proliferation (NOAEL at 1 ppm) is a key mechanism in development of nasal cancer. However, the linear unit risk approach that is based on conservative (“worst-case”) considerations is also used for risk characterization of formaldehyde exposures. Lymphohematopoietic malignancies are not observed consistently in animal studies and if caused by formaldehyde in humans, they are high-dose phenomenons with non-linear exposure–response relationships. Apparently, these diseases are not reported in epidemiological studies at peak exposures below 2 ppm and average exposures below 0.5 ppm. At the similar airborne exposure levels in rodents, the nasal cancer effect is much more prominent than lymphohematopoietic malignancies. Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies. Departing from the rat studies, the guideline value of the WHO (Air quality guidelines for Europe, 2nd edn. World Health Organization, Regional Office for Europe, Copenhagen, pp 87–91, 2000), 0.08 ppm (0.1 mg m−3) formaldehyde, is considered preventive of carcinogenic effects in compliance with epidemiological findings.
Keywords: Formaldehyde; Cancer; Risk assessment; Indoor air guideline
Ambient particulate matter and preterm birth or birth weight: a review of the literature by Cristina Bosetti; Mark J. Nieuwenhuijsen; Silvano Gallus; Sonia Cipriani; Carlo La Vecchia; Fabio Parazzini (pp. 447-460).
To review epidemiologic evidence on maternal exposure to particulate matter and adverse pregnancy outcomes, we performed a MEDLINE search of the literature up to June 2009. We considered all original studies published in English including information on total suspended particles (TSP), respirable (PM10) or fine (PM2.5) particles and the risk of preterm birth, low birth weight (LBW) or very low birth weight (VLBW) and small for gestational age (SGA). We identified a total of 30 papers, including 13 with information on preterm birth, 17 on LBW or VLBW, and 4 on SGA. Eight studies on preterm birth, 11 studies on LBW/VLBW and two studies on SGA reported some increased risk (by about 10–20%) in relation to exposure to PM; no meaningful associations was found in the remaining studies. However, even in studies reporting some excess risk, this was inconsistent across exposure levels and pregnancy periods. Epidemiologic studies on maternal exposure to PM during pregnancy thus do not provide convincing evidence of an association with the risk of preterm birth and LBW/VLBW and SGA. The excess risks, if any, are small, and it is unclear whether they are causal, due to misclassification of the exposure or some sources of bias/residual confounding.
Keywords: Air pollution; Birth weight; Particulate matter; Preterm birth; Review
Induction or inhibition of cytochrome P450 2E1 modifies the acute toxicity of acrylonitrile in rats: biochemical evidence by Wang Suhua; Lu Rongzhu; Xu Wenrong; Xing Guangwei; Zhao Xiaowu; Wang Shizhong; Zhang Ye; Han Fangan; Michael Aschner (pp. 461-469).
The present study was designed to examine the effects of the inhibition or induction of CYP2E1 activity on acute acrylonitrile (AN) toxicity in rats. Increased or decreased hepatic CYP2E1 activity was achieved by pretreatment with acetone or trans-1,2-dichloroethylene (DCE), respectively. AN (50 mg/kg) was administered by intraperitoneal injection. Onset of convulsions and death were observed in rats with increased CYP2E1 activity, whereas convulsions and death did not appear in rats within 1 h after treatment with AN alone. Convulsions occurred in all AN-treated animals with increased CYP2E1 activity at approximately 18 min. The levels of cyanide (CN−), a terminal metabolite of AN, were significantly increased in the brains and livers of the AN-treated rats with increased CYP2E1 activity, compared with the levels in rats treated with AN alone, DCE + AN or acetone + DCE + AN. The cytochrome c oxidase (CcOx) activities in the brains and livers of the rats treated with AN or AN + acetone were significantly lower than those in the normal control rats and the rats treated with DCE, whereas the CcOx activities in the brains and livers of rats with decreased CYP2E1 activity were significantly higher than those in AN-treated rats. Brain lipid peroxidation was enhanced, and the antioxidant capacity was significantly compromised in rats with decreased CYP2E1 activity compared with rats with normal or increased CYP2E1 activity. Therefore, inhibition of CYP2E1 and simultaneous antioxidant therapy should be considered as supplementary therapeutic interventions in acute AN intoxication cases with higher CYP2E1 activity, thus a longer window of opportunity would be got to offer further emergency medication.
Keywords: Acrylonitrile; Toxicity; CYP2E1; Cyanide; Cytochrome c oxidase; Oxidative stress
Effects of subchronic perfluorooctane sulfonate exposure of rats on calcium-dependent signaling molecules in the brain tissue by Xiaohui Liu; Wei Liu; Yihe Jin; Wenguang Yu; Li Liu; Hongyao Yu (pp. 471-479).
Perfluorooctane sulfonate (PFOS) is a persistent and bio-accumulative pollutant ubiquitous in wildlife and humans, which receives many concerns on the fate, transport, distribution, and toxicity. Studies have shown that PFOS-induced neurotoxicity in experimental animals; however, little is known about the potential mechanism of PFOS exposure on the central nervous system (CNS). Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα), cAMP-response element binding protein (CREB), c-fos, and c-jun, which are important down-stream molecules of calcium signaling in describing neuron cells structure and function in the CNS, were examined in the paper with the purpose to evaluate the effect of PFOS exposure on brain and approach the molecular mechanisms involved in the neurotoxicity induced by PFOS. Adult male Sprague–Dawley rats were administered with PFOS at dosages of 1.7, 5.0, and 15.0 mg/L in drinking water for 91 consecutive days. LC/MS was used for PFOS analysis in brain tissues, and western blot was employed to determine the expression of CaMKIIα and pCREB in the isolated cortex and hippocampus. The expression of c-fos and c-jun was detected by real-time reverse transcription polymerase chain reaction. The results showed that the expression of CaMKIIα and pCREB exhibits a significant increase in cortex and hippocampus after treatment with PFOS, compared with the control. The transcription factor c-fos was up-regulated in hippocampus, and c-jun was elevated both in cortex and hippocampus in PFOS-treated groups. These results indicated that, at least in part, the neurotoxic effect induced by PFOS is mediated by the Ca2+-dependent molecules in calcium signaling.
Keywords: Perfluorooctane sulfonate; Neurotoxicity; CaMKIIα; CREB
Expression of Neuropathy Target Esterase in mouse embryonic stem cells during differentiation by David Pamies; Juan Antonio Reig; Eugenio Vilanova; Miguel A. Sogorb (pp. 481-491).
Neuropathy Target Esterase (NTE) was initially identified as the primary target esterase of some organophosphorus compounds that cause delayed neuropathy. Some studies in vivo suggest that this protein may also perform a function in embryonic development and therefore also in cell differentiation. The aim of this work was to characterize embryonic stem cells (ESC) as cellular model before to approach to the role of NTE in embryotoxicity processes through mechanistic studies. Mouse D3 ESC in monolayer expressed an NTE activity of 23 nmol phenol/min/mg of protein, while mouse R1 ESC showed a specific NTE activity 3 times higher than D3. An increased expression of gene Pnpla6 (that codifies for NTE) was seen during differentiation in both the D3 cells in monolayer and embryonic bodies (EBS). The maximums of the Pnpla6 expression were reached after 30 h and 5 days of differentiation in monolayer and EBS cultures, respectively. This peak of the Pnpla6 expression correlated with the peak of the NTE enzymatic activity in D3 monolayers. NTE activity and Pnpla6 expression returned to basal levels after 48 h (in monolayer cultures) and 10 days (in EBS) of differentiation, respectively. The changes in the Pnpla6 expression did not correlate with changes noted in the expression of two endoderm, two ectoderm and one neuroectoderm gene markers. In conclusion, this manuscript reports about NTE expression in ESC and its variation during first stages of differentiation. Nevertheless, the role of this activity and the meaning of the variations detected during differentiation must be further studied.
Keywords: NTE; Mouse embryonic stem cell; Differentiation; Embryonic body; Embryonic development
Evaluation of in vivo liver genotoxic potential of Wy-14,643 and piperonyl butoxide in rats subjected to two-week repeated oral administration by Terumasa Suzuki; Meilan Jin; Yasuaki Dewa; Ryohei Ichimura; Yuko Shimada; Sayaka Mizukami; Makoto Shibutani; Kunitoshi Mitsumori (pp. 493-500).
Wy-14,643 (WY), a peroxisome proliferator-activated receptor-alpha agonist, and piperonyl butoxide (PBO), a pesticide synergist, induce oxidative stress and promote hepatocarcinogenesis in the liver of rodents. These chemicals belong to a class of non-genotoxic carcinogens, but DNA damage secondary to the oxidative stress resulting from reactive oxygen species generation is suspected in rodents given these chemicals. To examine whether WY or PBO have DNA-damaging potential in livers of rats subjected to repeated oral administration for 14 days, the in vivo liver comet assay was performed in partially hepatectomized rats, and the expression of some DNA-repair genes was examined. Then, to examine whether they have genotoxic potential, the in vivo liver initiation assay was performed in rats. In the comet assay, positive results were obtained at 3 h after the last treatment of WY, and some DNA-repair genes such as Apex1, Mlh1, Xrcc5, and Gadd45 were up-regulated in the liver. In the liver initiation assay, negative results were obtained for both WY and PBO. The results of the present study suggest that WY, but not PBO, causes some DNA damage in livers of rats, but such DNA damage was repaired by the increased activity of some DNA repair genes and may not lead to a DNA mutation.
Keywords: Wy-14,643; Piperonyl butoxide; Comet assay; Genotoxicity