others 1997) might result in adaptation through the same mechanisms.
The recent microarray expression studies (Yin and others 2003) that demonstrated downregulation of the large HSPs 30 min after irradiating the mouse brain with 100 mGy may support these conjectures. Also, the radiation-induced downregulation of CDC16, which belongs to the anaphasepromoting complex, was enhanced by an adaptive dose of 20 mGy (Zhou and Rigaud 2001). In fact, regulation of repair and cell cycle progression may be achieved by differential complex formation (Eckardt-Schupp and Klaus 1999). For instance, PCNA (proliferating cell nuclear antigen) expression, which is modulated by p53 in response to radiation, may play an important role in regulating and coordinating cell cycle progression, DNA replication, translesion synthesis, and DNA excision repair, depending on its partner proteins. Within minutes after ionizing radiation, the immediate-response genes transcription factors such as c-jun, c-fos, and NF-kB are turned on, possibly thwarting the general downregulation of transcription after irradiation and allowing privileged transcription of special genes. The sensors for these fast responses are in membranes, and they initiate signal transduction by several cascades of protein kinases (Eckardt-Schupp and Klaus 1999) that may involve reactive oxygen intermediates (Mohan and Meltz 1994; Hoshi and others 1997). Therefore, adaptation in mammalian cells probably involves induction of signal transduction pathways (Stecca and Gerber 1998) rather than induction of DNA repair enzymes.
There is much variability and heterogeneity in the ability to induce adaptive responses that usually require a priming dose of 10–200 mGy and a large challenge dose of 1–2 Gy. Challenge doses of this magnitude probably have little relevance to risk assessment for low radiation doses of 1–100 mGy. Furthermore, the molecular pathways associated with the phenomenon have not been delineated. Available data indicate that the adaptive response results from DNA damage that can be induced by 3HTdR (triliated thymidine) incorporated into DNA, by H2O2, and by restriction enzymes (Wolff 1992b; Sasaki 1995; Belyaev and Harms-Ringdahl 1996). The ability to induce an adaptive response appears to depend on the genotype (Wojcik and others 1992), which may relate to genetic variation reported for radiation-induced transcriptional changes (Correa and Cheung 2004). In fact, the effect of the genotype on the adaptive response has been demonstrated most conclusively in Drosophila melanogaster (Schappi-Bushi 1994).
A priming dose has been reported to reduce chromosomal damage in some chromosomes and increase it in others (Broome and others 1999). Data are needed, particularly at the molecular level, on adaptation induced when both priming and challenging doses are in the low-dose range <100 mGy; relevant end points should include not only chromosomal aberrations and mutations but also genomic instability and, if possible, tumor induction. In vitro and in vivo data are needed on delivery of the priming and challenge doses over several weeks or months at very low dose rates or with fractionated exposures.
Finally, we should be concerned about the cumulative effect of multiple low doses of less than 10 mGy. Such data have not yet been obtained, in particular those explaining the molecular and cellular mechanisms of the adaptive response. Therefore, it is concluded that any useful extrapolations for dose-response relationships in humans cannot be made from the adaptive responses observed in human lymphocytes or the other cellular systems mentioned above. In fact, a study (Barquinero and others 1995) reporting that an average occupational exposure of about 2.5 mGy per year over 7–21 years resulted in a variable adaptive response for chromosomal aberrations induced in human lymphocytes by a large challenge dose of 2 Gy also reported that the incidence of spontaneous aberrations was increased significantly by the occupational exposure. Barquinero and colleagues (1995) also cite six reports indicating that basal rates of chromosomal abnormalities are in general higher in exposed human populations; recent papers (Tanaka and others 2000; Tawn and others 2000a, 2004; Burak and others 2001; Liu and others 2002; Maffei and others 2004) present similar information. Therefore, based on current information, the assumption is unwarranted that any stimulatory effects of low doses of ionizing radiation substantially reduce long-term deleterious radiation effects in humans.
A factor that could have a significant effect on the dose-response relationship is the bystander effect that irradiated cells have on nonirradiated cells. Recent comprehensive reviews of bystander effects observed in vitro (Morgan 2003a) and in vivo (Morgan 2003b) emphasized their possible mechanisms, implications, and variability. In addition, reviews have been published recently on the relationship between the bystander effect, genomic instability, and carcinogenesis (Little 2003; Lorimore and others 2003). Observations that irradiated cells or tissues could have deleterious effects on nonirradiated cells or tissues were reported many years ago (Bacq and Alexander 1961) and were termed abscopal effects. As an example of such an effect, plasma from patients who underwent localized radiation therapy induced chromosomal aberrations in lymphocytes from nonirradiated patients (Hollowell and Littlefield 1968; Littlefield and others 1969). A bystander effect has been demonstrated conclusively for cells in culture exposed to high-LET radiation, usually α-particles. Little and colleagues estimated that a single α-particle traversing a cell can induce HPRT mutations (Nagasawa and Little 1999), sister-chromatid exchanges (Nagasawa and Little 1992), upregulation of p21 and p53, and downregulation of cyclin B1, cdc2, and rad51 (Azzam and others 1998) in unirradiated cells. At least for the bystander effect on signal transduction