The induction of non-targeted stressful effects in cell populations exposed to low fluences of high charge (Z) and high energy (E) particles is relevant to estimates of the outcome of hadron therapy and the long term health risks of space radiation. To gain greater knowledge of HZE-particle-induced non-targeted effects, we investigated the regulation of stress markers in confluent normal human fibroblast cultures exposed to 1000 MeV/u iron ions (linear energy transfer (LET) ~151 keV/μm) or 600 MeV/u silicon ions (LET ~50 keV/μm) at mean absorbed doses as low as 0.2 cGy, wherein 1-3 % of the cells were targeted through the nucleus by a primary particle. Within 24 h post-irradiation, significant increases in the levels of phospho-TP53 (S15), p21Waf1, HDM2, phospho-ERK1/2, protein carbonylation and lipid peroxidation were detected, which suggested participation in the stress response of cells not targeted by primary particles. This was supported by in situ studies that indicated greater increases in 53BP1 foci formation, a marker of DNA damage, than expected from the number of primary particle traversals. The effect was expressed as early as 15 min after exposure, peaked at 1 h, and decreased by 24 h. A similar tendency occurred after exposure of the cell cultures to 0.2 cGy of 3.7 MeV α particles (LET ~109 keV/μm) that targets ~1.6 % of nuclei, but not after 0.2 cGy from 290 MeV/u carbon ions (LET ~13 keV/μm) by which, on average, ~13 % of the nuclei were hit, which highlights the importance of radiation quality in the induced effect. Together, the above data suggested participation of bystander cells in the observed responses. To investigate whether secondary particles are a factor in expression of the apparent HZE-particle-induced bystander effects, the tracks of the secondaries were simulated with the multi-particle transport code FLUKA and absorbed doses received by the monolayer of cells adjacent to the targeted cells were assessed. The simulations revealed that fragmentation products, other than electrons, in cell cultures exposed to HZE particles comprise <1 % of the absorbed dose. Further, the radial spread of dose due to secondary heavy ion fragments is confined to approximately 10-20 µm. Thus, the latter are unlikely to significantly contribute to stressful effects in cells not targeted by primary HZE particles. In contrast, electrons contributed up to 40 % of the total dose. Benchmarking the FLUKA code with the MCNPX code is expected to generate rather consistent results for the neutron dose.