G1 arrest has been a focus for therapeutic treatment. Irradiation of a tissue induces a response in both irradiated and non-irridiated cells. It was found that even cells up to 50–75 cell diameters distant from irradiated cells exhibit a phenotype of enhanced genetic instability such as micronucleation. This suggests an effect on cell-to-cell communication such as paracrine and juxtacrine signaling. Normal cells do not lose their DNA repair mechanism whereas cancer cells often lose it during radiotherapy. However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of carcinogenesis. This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation. Molecular targeting of the DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA double-strand breaks. Direct inhibitors target proteins (PARP family) and kinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as EGFR and insulin growth factor. The effective therapeutic index can be affected by targeting, in which the therapeutic agent is concentrated in its area of effect. For example, in radiation therapy for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as in peptide receptor radionuclide therapy for neuroendocrine tumors and in chemoembolization or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity. Safety ratio Sometimes the term safety ratio is used, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use. In such cases, the effective dose is the amount and frequency that produces the desired effect, which can vary, and can be greater or less than the therapeutically effective dose. The Certain Safety Factor, also referred to as the Margin of Safety (MOS), is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population