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Archives of Toxicology (v.83, #3)

Low-dose extrapolation in toxicology: an old controversy revisited by Hermann M. Bolt; Rosemarie Marchan; Jan G. Hengstler (pp. 197-198).

Some thoughts on the use of replacement alternatives for toxicity testing and risk assessment by Robert D. Combes (pp. 199-201).

The road to linearity: why linearity at low doses became the basis for carcinogen risk assessment by Edward J. Calabrese (pp. 203-225).

This article assesses the historical foundations of how linearity at low dose became accepted by the scientific/regulatory communities. While the threshold model was used in the 1920s/1930s in establishing radiation health standards, its foundations were challenged by the genetics community who argued that radiation induced mutations in reproductive cells followed a linear response, were cumulative and deleterious. Scientific foundations of linearity for gonadal mutations were based on non-conclusive evidence as well as not being conducted at low doses. Following years of debate, leaders in the genetics community participated in the U.S. National Academy of Sciences (NAS) (1956) Biological Effects of Atomic Radiation (BEAR) BEAR I Committee, getting their perspectives accepted, incorporating linearity for radiation-induced mutational effects in risk assessment. Overtime the concept of linearity was generalized to include somatic effects induced by radiation based on a protectionist philosophy. This affected the course of radiation-induced and later chemically-induced carcinogen risk assessment. Acceptance of linearity at low dose from chemical carcinogens was strongly influenced by the NAS Safe Drinking Water Committee report of 1977 which provided the critical guidance to the U.S. EPA to adopt linear at low dose modeling for risk assessment for chemical carcinogens with little supportive data, much of which has been either discredited or seriously weakened over the past 3 decades. Nonetheless, there has been little practical change of regulatory policy concerning carcinogen risk assessment. These observations suggest that while scientific disciplines are self correcting, that regulatory ‘science’ fails to display the same self-correcting mechanism despite contradictory data.

Keywords: Threshold; Dose response; Risk assessment; Carcinogen; Mutagen; Mutation; Linearity; Somatic mutation hypothesis

Getting the dose–response wrong: why hormesis became marginalized and the threshold model accepted by Edward J. Calabrese (pp. 227-247).

The dose–response relationship is central to the biological and biomedical sciences. During the early decades of the twentieth century consensus emerged that the most fundamental dose–response relationship was the threshold model, upon which scientific, health and medical research/clinical practices have been based. This paper documents that the scientific community made a fundamental error on the nature of the dose response in accepting the threshold model and in rejecting the hormetic-biphasic model, principally due to conflicts with homeopathy. Not only does this paper detail the underlying factors leading to this dose response decision, but it reveals that the scientific community never validated the threshold model throughout the twentieth century. Recent findings indicate that the threshold model poorly predicts responses in the low dose zone whereas its dose response “rival”, the hormesis model, has performed very well. This analysis challenges a key foundation upon which biological, biomedical and clinical science rest.

Keywords: Hormesis; Hormetic; Threshold; Biphasic; U-shaped; J-shaped

Low levels of methylmercury induce DNA damage in rats: protective effects of selenium by Denise Grotto; Gustavo R. M. Barcelos; Juliana Valentini; Lusânia M. G. Antunes; José Pedro F. Angeli; Solange C. Garcia; Fernando Barbosa Jr (pp. 249-254).

In this study we examined the possible antigenotoxic effect of selenium (Se) in rats chronically exposed to low levels of methylmercury (MeHg) and the association between glutathione peroxidase (GSH-Px) activity and DNA lesions (via comet assay) in the same exposed animals. Rats were divided into six groups as follows: (Group I) received water; (Group II) received MeHg (100 μg/day); (Group III) received Se (2 mg/L drinking water); (Group IV) received Se (6 mg/L drinking water); (Group V) received MeHg (100 μg/day) and Se (2 mg/L drinking water); (Group VI) received MeHg (100 μg/day) and Se (6 mg/L drinking water). Total treatment time was 100 days. GSH-Px activity was determined spectrophotometrically and DNA damage was determined by comet assay. Mean GSH-Px activity in groups I, II, III, IV, V and VI were, respectively: 40.19 ± 17.21; 23.63 ± 6.04; 42.64 ± 5.70; 38.50 ± 7.15; 34.54 ± 6.18 and 41.39 ± 11.67 nmolNADPH/min/gHb. DNA damage was represented by a mean score from 0 to 300; the results for groups I, II, III, IV, V and VI were, respectively: 6.87 ± 3.27; 124.12 ± 13.74; 10.62 ± 3.81; 13.25 ± 1.76; 86.87 ± 11.95 and 76.25 ± 7.48. There was a significant inhibition of GSH-Px activity in group II compared with group I (P < 0.05). Groups V and VI did not show a difference in enzyme activity compared with groups III and IV, showing the possible protective action of Se. Comet assay presented a significant difference in DNA migration between group II and group I (P < 0.0001). Groups V and VI showed a significant reduction in MeHg-induced genotoxicity (P < 0.001) when compared with group II. A negative correlation (r = −0.559, P < 0.05) was found between GSH-Px activity and DNA lesion, showing that the greater the DNA damage, the lower the GSH-Px activity. Our findings demonstrated the oxidative and genotoxic properties of MeHg, even at low doses. Moreover, Se co-administration reestablished GSH-Px activity and reduced DNA damage.

Keywords: Methylmercury; Selenium; Comet assay; Glutathione peroxidase; Antigenotoxicity

Fluorescence study on site-specific binding of perfluoroalkyl acids to human serum albumin by Yan-Min Chen; Liang-Hong Guo (pp. 255-261).

Binding of five perfluoroalkyl acids with human serum albumin (HSA) was investigated by site-specific fluorescence. Intrinsic fluorescence of tryptophan-214 in HSA was monitored upon addition of the chemicals. Although perfluorobutyl acid (PFBA) and perfluorobutane sulfonate (PFBS) did not cause fluorescence change, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorododecanoic acid (PFDoA) induced fluorescence quenching, from which binding constant of 2.7 × 10⁵ M⁻¹ for PFOA and 2.2 × 10⁴ M⁻¹ for PFOS was calculated. Two fluorescent probes, dansylamide (DA) and dansyl-l-proline (DP), were employed in fluorescence displacement measurements to study the interaction at two Sudlow’s binding sites. At Site I, both PFBA and PFBS displaced DA with binding constants of 1.0 × 10⁶ M⁻¹ and 2.2 × 10⁶ M⁻¹. At Site II, PFBS and PFDoA displaced DP with binding constants of 6.5 × 10⁶ M⁻¹ and 1.2 × 10⁶ M⁻¹, whereas PFBA did not bind. The data were compared with fatty acids to evaluate the potential toxicological effect of these environmental chemicals.

Keywords: Albumin; PFOS; PFOA; Fluorescence; Fatty acid

Hormetic acute response and chronic effect of ethanol on adenine nucleotide hydrolysis in rat platelets by Glaecir R. Mundstock Dias; Maria Rosa Chitolina Schetinger; Roselia Spanevello; Cinthia Melazzo Mazzanti; Roberta Schmatz; Vânia Lúcia Loro; Vera Maria Morsch (pp. 263-269).

The objective of this study was to verify the acute and chronic effects of ethanol on platelet NTPDase and 5′-nucleotidase activities. These enzymes modulate platelet function by regulating adenine nucleotide bioavailability and adenosine production. In the acute treatment, doses of 0.8, 2.0, 4.0, 6.0 and 8.0 g/kg ethanol were administered via orogastric tube, and induced a biphasic or hormetic effect on ATP, ADP and AMP platelet hydrolysis. Ethanol at a dose of 0.8 and 2.0 g/kg increased NTPDase activity (44 and 35%, P < 0.0001) with ATP as substrate, whereas when ADP was used there was only a tendency for NTPDase activity to increase. ATP and ADP hydrolysis decreased by 31–77% (P < 0.0001) in 4.0, 6.0 and 8.0 g/kg of ethanol compared to the control. AMP hydrolysis showed a tendency to increase at ethanol doses of 0.8 and 2.0 g/kg, but was inhibited by 45–100% (P < 0.0001) at the higher doses. Chronic treatment consisted of the oral administration of 20% ethanol solution during 31 weeks as the only source of liquid and inhibited NTPDase activity (15 and 20%, P < 0.05) with ATP and ADP as substrate, respectively. However, AMP hydrolysis by 5′-nucleotidase increased by 40% (P < 0.05). Thus, we speculate that the effects of ethanol on NTPDase and 5′-nucleotidase activities could be related with the platelets alterations commonly observed in alcohol users.

Keywords: NTPDase; 5′-nucleotidase; Ethanol; Platelet; Hormesis

Colombistatin: a disintegrin isolated from the venom of the South American snake (Bothrops colombiensis) that effectively inhibits platelet aggregation and SK-Mel-28 cell adhesion by Elda E. Sánchez; Alexis Rodríguez-Acosta; Rene Palomar; Sara E. Lucena; Sajid Bashir; Julio G. Soto; John C. Pérez (pp. 271-279).

Snake venoms are complex mixtures of proteins, which affect the vital biologic systems of prey, as well as humans. Envenomation leads to immobilization by paralysis, cardiac, and circulatory failure. These same venom proteins that cause havoc in the physiologic system could be used as therapeutic agents. Disintegrins and disintegrin-like proteins are molecules found in the venom of four snake families (Atractaspididae, Elapidae, Viperidae, and Colubridae). The disintegrins are non-enzymatic proteins that inhibit cell–cell interactions, cell–matrix interactions, and signal transduction. These proteins may have potential in the treatment of strokes, heart attacks, cancers, osteoporosis, and diabetes. The present study describes the isolation and characterization of a disintegrin (colombistatin) found in the venom of the Venezuelan snake mapanare (Bothrops colombiensis). Colombistatin was purified by a two-step high-performance liquid chromatography procedure, which included reverse phase C18 and size exclusion protein Pak 60. Colombistatin inhibited ADP-induced platelet aggregation, human urinary (T24) and skin melanoma (SK-Mel-28) cancer cell adhesion to fibronectin, and cell migration. Colombistatin contained 72 amino acids with a mass of 7.778 kDa as determined by mass spectrometry. Colombistatin could be used as a therapeutic tool in the treatment of melanoma cancers and also thrombotic diseases.

Keywords: Disintegrin, Venom, Mapanare; Bothrops colombiensis ; T24 cells; SK-Mel-28; Platelet aggregation; Cell migration

Effects of bisphenol A on breast cancer and its risk factors by Mihi Yang; Jae-Ha Ryu; Raok Jeon; Daehee Kang; Keun-Young Yoo (pp. 281-285).

The incidence of breast cancer in Korea has been increasing for the last two decades (1983–2005), and now, breast cancer is ranked the leading cause of cancer in Korean women. Along with other endocrine disrupting chemicals (EDCs), bisphenol A (BPA) has been suspected as a potential risk factor for breast cancer. We studied potential associations between BPA exposure and breast cancer risks in Korean women by performing biomonitoring of BPA among breast cancer patients and controls (N = 167). Blood samples were collected between 1994 and 1997 and kept over 10 years in a freezer under well controlled conditions. The blood BPA levels determined by HPLC/FD, ranged between LOD (0.012 µg/L) and 13.87 µg/L (mean ± SD, 1.69 ± 2.57 µg/L; median, 0.043 µg/L). In age-matched subjects (N = 152), there were some associations between BPA levels and risks of breast cancer, such as age at first birth and null parity. However, there were no significant differences in blood BPA levels between the cases and the controls (P = 0.42). Considering interactions between BPA exposure and risks of breast cancer, we suggest further enlarged biomonitoring studies of BPA to provide effective prevention against breast cancer.

Keywords: Endocrine disruptor; Bisphenol A; Breast cancer; Biomonitoring

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Archives of Toxicology (v.83, #3)