Neoplastic transformationin vitroinduced by low doses of 232 MeV protons

Abstract

The aim was to define the dose--response curve for high-energy proton-induced neoplastic transformation in vitro. The HeLa x skin fibroblast human hybrid cell assay was used to determine the frequency of neoplastic transformation following doses of 232 MeV protons (mean linear energy transfer, LET=0.44 keV microm(-1)) in the range 5-600 mGy. Proton irradiations were carried out at the Loma Linda University Proton Treatment Facility, CA, USA. The data indicate no evidence for induction of transformation below a dose of 100 mGy. At doses of 5 and 50 mGy, there is evidence for a possible suppression of transformation frequencies below that for spontaneous transformation. The shape of the dose--response curve for high-energy proton-induced transformation of the human hybrid cell line CGL1 does not follow a linear no-threshold model and shows evidence for a threshold as well as for possible suppression of transformation at doses <100 mGy, similar to that seen for other low-LET radiations.

Linear No-Threshold Model vs. Radiation Hormesis

“…Though the use of the linear no-threshold (LNT) extrapolation model has become well established in radiation safety regulations and practices throughout the world in the past several decades, there continues to be a considerable amount of disagreement in the scientific community regarding the appropriateness of its use (Cameron, 1998; Cameron and Moulder, 1998; Cohen, 1998; Mossman, 1998; Strom, 1998; Tubiana, 2005; NRC, 2006; Tubiana et al , 2006; Little et al , 2009; Tubiana et al , 2009). Controlled in-vitro and animal studies have contradicted the LNT model as many of these have shown adaptive response to low dose radiation resulting in reduced mutations and cancers (Hosoi and Sakamoto, 1993; Ishii et al , 1996; Mitchel et al , 1999; Redpath et al , 2003; Elmore et al , 2005; Ina et al , 2005; Day et al , 2007; Moskalev et al , 2011; Phan, 2011; Phan et al , 2012), demonstrating a phenomenon known as radiation hormesis (Luckey, 1980; Luckey, 1991; Calabrese and Baldwin, 2003; Feinendegen, 2005; Jolly and Meyer, 2009; Sanders, 2010). For humans, the effect of radiation on cancer has been inferred by determining the cancer rates of population groups that were exposed to radiation, and comparing these to equivalent population groups not exposed to the radiation.…”

It's Time for a New Low-Dose-Radiation Risk Assessment Paradigm—One that Acknowledges Hormesis

“…Their findings were later confirmed by Redpath et al (2001, 2003). Studies by Dr. Redpath's group also demonstrated the importance of the type of radiation as well as dose rate in radiation hormesis response (Redpath et al 2001, 2003; Ko et al 2004, Elmore et al 2005; Redpath and Elmore 2007). At the encouragement of this author, Day et al (2007) performed the first studies demonstrating radiation post-exposure conditioning hormesis in mice (prostate gland).…”

“…Chromosomal inversions associated with a large radiation dose were completely prevented by a subsequent small radiation dose (mild stress). Now there are many publications related to the indicated classes of radiation-associated hormesis (e.g., Liu et al 1987, 1994; Hosoi and Sakamoto 1993; Cohen 1995; Howe 1995; Khokhryakov et al 1996; Wolff 1996; Jaworowski 1997, 2001; Rossi and Zaider 1997; Hashimoto et al 1999; Tokarskaya et al 1995, 1997, 2002; Redpath et al 2001, 2003; Nyström et al 2002; Wei and Sugahara 2002; Liu 2003, 2004, 2007; Mitchel et al 2003; Pollycove and Feinendegen 2003; Sakai et al 2003; Chen et al 2004, Feinendegen et al 2004; Hooker et al 2004; Ko et al 2004; Mitchel 2004, 2005, 2006, 2007; Scott 2004, 2005a,b, 2007a,b,c; Scott et al 2004; Zaichkina et al 2004; Elmore et al 2005; Ina and Sakai 2005; Tubiana 2005; Tubiana et al 2005; Boreham et al 2006; Mothersill and Seymour 2006; Redpath 2006;…”

“…Here, an approach to regulating radiation exposure is recommended that allows for the existence of a hormetic dose zone just above natural background radiation. The approach relates to the hormetic relative risk (HRR) model previously developed by this author (Scott 2007a,b,c), which is summarized below in a more general form.…”

“…The protective signaling, presumed activated with low doses and dose rates of low-LET radiation, relates to removal of aberrant cells from the body via p53-dependent and independent apoptosis signaling pathways and stimulated immunity (Scott 2007a,b,c; Scott and Di Palma 2007; Scott et al 2007). The protective signaling can also involve DNA repair pathways if a damage threshold is exceeded (Rothkamm and Löbrich 2003).…”