Human & Experimental Toxicology

Ionizing radiation (IR) causes damage to DNA that is apparently proportional to absorbed dose. The incidence of radiation-induced cancer in humans unequivocally rises with the value of absorbed doses above about 300 mGy, in a seemingly linear fashion. Extrapolation of this linear correlation down to zero-dose constitutes the linear-no-threshold (LNT) hypothesis of radiation-induced cancer incidence. The corresponding dose-risk correlation, however, is questionable at doses lower than 300 mGy. Non-radiation induced DNA damage and, in consequence, oncogenic transformation in non-irradiated cells arises from a variety of sources, mainly from weak endogenous carcinogens such as reactive oxygen species (ROS) as well as from micronutrient deficiencies and environmental toxins. In order to relate the low probability of radiation-induced cancer to the relatively high incidence of non-radiation carcinogenesis, especially at low-dose irradiation, the quantitative and qualitative differences between the DNA damages from non-radiation and radiation sources need to be addressed and put into context of physiological mechanisms of cellular protection.

This paper summarizes a co-operative approach by the authors to answer the questions on the quantitative and qualitative DNA damages from non-radiation sources, largely endogenous ROS, and following exposure to low doses of IR. The analysis relies on published data and justified assumptions and considers the physiological capacity of mammalian cells to protect themselves constantly by preventing and repairing DNA damage. Furthermore, damaged cells are susceptible to removal by apoptosis or the immune system. The results suggest that the various forms of non-radiation DNA damage in tissues far outweigh corresponding DNA damage from low-dose radiation exposure at the level of, and well above, background radiation.

These data are examined within the context of low-dose radiation induction of cellular signaling that may stimulate cellular protection systems over hours to weeks against accumulation of DNA damage. The particular focus is the hypothesis that these enhanced and persisting protective responses reduce the steady state level of nonradiation DNA damage, thereby reducing deleterious outcomes such as cancer and aging.

The emerging model urgently needs rigorous experimental testing, since it suggests, importantly, that the LNT hypothesis is invalid for complex adaptive systems such as mammalian organisms.

The article by Pollycove and Feinendegen raises important issues regarding the relative contributions of endogenous and radiation-induced DNA damage to the overall DNA damage burden following low level radiation exposures. Clearly, resolution of the issues raised in their article will have important implications regarding regulatory philosophy. Dose-limiting studies of DNA damage measured on a cell-by-cell basis was used to analyze available data in the context of the proposed model. If one proposes that significant numbers of oxidative DNA lesions are present in cells at a steady state level at any give time, then such damage will be included in the background measure of any DNA damage dependent parameter that is sensitive to these classes of DNA damage. Then the expected number of lesions per cell was compared, prior to X- or γ-ray exposure, at the dose that gives the minimum statistically significant difference from background, at the dose where the DNA damage dependent parameter is twice background (i.e., the doubling dose). The lesion frequencies predicted from the model by Pollycove and Feinendegen are reasonable for the micronucleus assay and the inhibition of DNA supercoil rewinding, but appear to be inconsistent with results from the comet assay. Possible explanations for the inconsistency between the comet assay dose) response data and the predicted levels of DNA damage predicted by the model are discussed, suggesting that the estimates of the radiation induced damage are too low and those for endogenous damage are too high. The goal in introducing these issues is not to be negative to the article but to present a basis for future discussions and more importantly future experimental work, by which the important issues raised can be resolved.

Quantitative comparison of ROS-induced endogenous DNA damage with DNA damage induced by ionizing radiation at environmental level, presented by Pollycove and Feinedegen, is timely and provides basic data for establishing a a sound rule for radiation protection. Main point added to their estimation is quantitative data on oxidative damage to DNA precursormolecules, such as oxo dGTP and their cellular decomposition efficiency. If the precursor damages are taken into account, the amount of initial endogenous DNA damage would be increased by a factor of 100 ^/ 10 000

The premises underlying the article by Pollycove and Feinendegen are unlikely to generate disagreement among most scientists. The authors do a good job of reviewing the scientific literature on the importnat topic of radiation-induced versus endogenous DNA damage, and they use the available data to calculate numerical estimates and comparisons of DNA damages induced by radiation versus metabolic processes. However, these numbers should in no way be confused with proof or disproof of the involvement of specific biological mechanisms. Many important questions for low-dose radiobiology remain unanswered, and there is no substitute for experimental demonstration.

Sudden infant death syndrome (SIDS) has been associated with the volatilization of arsenic, antimony or phosphorus compounds from infants' bedding material by micro-organisms, the so-called ‘toxic gas hypothesis’. The volatilization of arsenic by aerobic micro-organisms isolated from new sheepskin bedding material, as well as on material used by a healthy infant and by an infant who perished of SIDS, was examined. Three fungi were isolated from a piece of sheepskin bedding material on which an infant perished of SIDS, which methylated arsenic to form trimethylarsenic(V) species, precursors to volatile trimethylarsine. These three fungi were identified as Scopulariopsis koningii, Fomitopsis pinicola and Penicillium gladioli by their 26S-ribosomal RNA polymerase chain reaction products. These fungi were not previously known to methylate arsenic. The volatilization of arsenic by these three fungi was then examined. Only P. gladioli volatilized arsenic and only under conditions such that the production of sufficient trimethylarsine to be acutely toxic to an infant is unlikely. S. brevicaulis grew on the sheepskin bedding material and evolved a trace amount of trimethylarsine. Known human pathogens such as Mycobacterium neoaurum and Acinetobacter junii were isolated from used bedding.

Ochratoxin A (OTA) is a mycotoxin produced by several fungi. Many foods can be contaminated by OTA, which is consequently found in the blood of humans and animals. It is known that OTA accumulates in the brain. The aim of this study was to investigate the effects of OTA on the brain. For this purpose, the effect of OTA on N-methyl-Daspartate (NMDA) receptor subunits 2A (NR2A) and 2B (NR2B) in the hippocampus and the protective effect of melatonin were investigated. Three groups of eight rats were used: controls, OTA-treated rats (OTA dose 289 mg/ kg per day) and OTA-melatonin-treated rats (melatonin dose 10 mg/kg per day). After four weeks of treatment, electrophoretic examinations were performed using SDSpolyacrylamide gel electrophoresis and Western blotting of hippocampal homogenates of the different groups. The concentrations of NR2A and NR2B in the OTA group were significantly lower than in the control group. The concentration of NR2B was significantly increased when melatonin was co-administered with OTA compared with OTA only. There was also a significant increase in NR2A levels when melatonin was co-administered with OTA. As a result, subchronic administration of OTA reduced hippocampal NMDA receptor subunits 2A and 2B concentrations in rats. It was thought that this alteration might affect cognitive functions because hippocampal NMDA receptors are involved in the memory and learning processes. Melatonin exhibited a partially protective effect on NR2A and NR2B against OTA.

Acute pancreatitis secondary to organophosphate intoxication is a rare and generally well-course condition, but it is important to be aware of this complication for appropriate clinical management. There are a few reports about this subject in the literature, but it is believed that there are more cases than are reported for this condition. Because symptoms of toxicity can mask this severe complication, we report two cases of acute pancreatitis due to organophosphate intoxication for alerting this condition.

Deliberate self-injection of metallic mercury into subcutaneous tissue is uncommon. A 41-year-old lady with a history of schizophrenia was admitted to our hospital after deliberate injection of metallic mercury into her right wrist and antecubital fossa. Physical examination was unremarkable except for the injection marks over right antecubital fossa and wrist. The presence of subcutaneous mercury deposits in her right elbow and wrist was confirmed by X-rays and ultrasound scan. Three days later, erythema, swelling, induration and tenderness were seen over the injection sites. At the operation on day 9, mercury streaks were seen within the brachialis muscle belly, surrounded by friable necrotic tissues along the tract. A similar picture was noted in her right wrist. The necrotic tissues and mercury streaks were removed. The patient had been unco-operative and she only received incomplete treatment with dimercaprol and 2,3-dimercaptosuccinic acid. Her total blood mercury level (normal B < 50 nmol/L) decreased from 101-151 nmol/L in the first two weeks to 42 nmol/L 3 months later. Her 24-hour urinary mercury excretion (normal B < 10 nmol) changed from 55.7-209.5 nmol in the first 7 weeks to 125.4 nmol 3 months later. This case illustrates that soft tissue metallic mercury can produce local necrosis and may allow continuous absorption with persistent elevations in blood and urinary mercury levels. Therefore, early surgical removal of subcutaneous mercury deposits is required to prevent local complications and minimize the risk of systemic absorption and toxicity.