A broad perturbation of DNA transcription is observed in human cells after exposure to ionizing radiation; it involves the activation of transcription factors, such as NF-kappaB and c-jun/c-fos. After exposure of human lymphoblastoid cells to 5 Gy of radiation, 2–3% of the genes exhibit more than a 50% change in induction or repression (Tusher and others 2001). These genes include several involved in cell cycle control. No genes involved in repair of DNA DSBs generated by ionizing radiation were induced (Tusher and others 2001; Wood and others 2001). It should also be noted that the base-excision repair enzymes involved in the removal of oxidative damage are not induced by low doses of ionizing radiation in human cells (Inoue and others 2004). These studies have provided no support for a general adaptive repair response in human cells to counteract DNA DSB formation that can result in cell death or mutagenesis.

A different type of apparent adaptive response has been well documented for the induction of chromatid-type breaks and mutations in human lymphocytes stimulated to divide. In most studies, a priming or adaptive dose of about 10 mGy significantly reduces the frequency of chromosomal aberrations (Shadley and others 1987; Wolff 1992a, 1996) and mutations (Kelsey and others 1991) induced a few hours later by 1–3 Gy. However, when the priming dose was 10 mGy, the adaptive response for chromosomal aberrations was reduced significantly as the priming dose rate was reduced from 50 mGy/min to 6.4 mGy/min (Shadley and Wiencke 1989). Adaptive responses of this type were reviewed by UNSCEAR (1994).

Although alterations in cell cycle progression have been implicated in the mammalian cell adaptive phenomenon (Aghamohammadi and Savage 1991), carefully controlled studies indicate that the priming dose induces radioresistance for induction of chromosomal aberrations in human lymphocytes (Wolff 1996); priming doses less than 5 mGy, or greater than about 200 mGy, yield very little if any adaptation (Wolff 1992b). The induction and magnitude of the adaptive response in human lymphocytes are highly variable among people (Bose and Olivieri 1989; Sankaranarayanan and others 1989; Shadley and Wiencke 1989; Hain and others 1992; Vijayalaxmi and others 1995; Upton 2000), and the adaptive response could not be induced when lymphocytes were given the priming dose during G0 (Shadley and others 1987). Although inhibitor and electrophoretic studies (Youngblom and others 1989; Wolff 1992b) suggest that alterations in transcribing messenger RNA and synthesis of proteins are involved in the adaptive response in lymphocytes, no specific signal transduction or repair pathways have been identified. Finally, humans exposed occupationally (Barquinero and others 1995) or to iodine-131 (131I) for treatment of thyroid disease (Monsieurs and others 2000) or as children after Chernobyl (Tedeschi and others 1995) varied in their ability to demonstrate an apparent adaptive response for chromosomal aberrations (Padovani and others 1995; Tedeschi and others 1996). This variability may relate to the genetic variation reported for radiation-induced transcriptional changes (Correa and Cheung 2004).

Adaptive responses to radiation observed in other cellular systems for induction of cell lethality, chromosomal aberrations, mutations (Zhou and others 1993; Rigaud and others 1995), and defects in embryonic development provide little information that can be used to suggest that the dose-response curve in the dose range 0–100 mGy will be less steep than that described by the limiting value of α mentioned above. When mouse embryos were exposed to a priming dose of about 10 mGy and evaluated for chromosomal aberrations or defects in development induced by a challenge dose several hours later, the results were highly variable for the induction of an adaptive response (Muller and others 1992; Wojcik and others 1992; Wolff 1996; Wang and others 1998). Studies of radiation-induced mutagenesis also had variable results. Adaptation not only decreases the frequency of mutants induced by a challenge dose but also appears to alter the types of mutants. Adaptation of human lymphoblastoid cells to a challenge dose of 4 Gy 6 h after 20 mGy decreased the proportion of HPRT mutants of the deletion type relative to small point mutations (Rigaud and others 1995). In contrast, adaptation of human-hamster hybrid AL cells to a challenge dose of 3 Gy after a priming dose of 40 mGy increased the proportion of complex unstable mutations (Ueno and others 1996). An extensive study (Sasaki 1995) of chromosomal aberrations, HPRT mutations, and cell killing demonstrated adaptation in quiescent cultured m5S mouse embryonic skin cells preexposed in G1 to 10–50 mGy; cells exposed 4 h later to doses greater than 2 Gy were significantly more resistant than nonadapted cells for all three end points (see Figure 2-2 for cell-killing results). The adaptation phenomenon appeared to involve a protein kinase C signaling pathway. In addition, the lack of an adaptive response in a tumorigenic variant, clone 6110, and restoration of the adaptive response obtained by introducing human chromosome 11 (five other chromosomes had no effect) further suggested that interference of signaling pathways may alter adaptive responses in malignant cells. The observation (Broome and others 2002) that a priming dose as low as 1 mGy induced an adaptive response in a nontransformed human fibroblast cell line for micronuclei induced by a challenge dose of 2 Gy has to be confirmed for other systems and end points, such as mutation induction. Also, the large variation in adaptive response for radiation-induced micronuclei in human lymphoblastoid cell lines must be considered (Sorensen and others 2002). Most important, the adaptive response has to be demonstrated for both priming and challenging doses in the low-dose range <100 mGy, and an understanding of the molecular and cellular mechanisms of the adaptive response is essential if it is to have relevance for risk assessment.

Studies of adaptation for malignant transformation in vitro provide conflicting information and might not be relevant to malignant transformation in vivo. Although the

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