I am not actually sure about what are you trying to ask in the first part of your question. Maybe in future you will clarify about this more clearly, But for now, surely I can answer the second part of it.
And the answer is yes and no both, it is Yes in the case if that thing really matters for you i.e if you are doing some of the experiments in which the minute changes in mass will affect the whole situation and also in the case if you are working on something big like you are doing an enormously huge workdone on your system.
And the answer which includes No is when you are not working on any experiments which involves extreme amount of workdone, then that won't really matter.
Now let's come on to the reason behind this, the reason is that the term $C$ in the equation $E=mC^2$, is speed of light and that has really a big number! And if you square that then it will become tremendously huge. And if you divide the amount of work you are performing on your system (considering it as a small number) by this huge $C^2$ then that will truly come out to be a very small value for change in mass which will really not affect your experiment. But if the amount of workdone is so huge then you will have to take care of this while performing your experiment.