Several. Navigational instruments were very primitive at best. Maps of any area outside Europe were often inaccurate and more often, simply unavailable. Local populations were often hostile and inland expeditions in many cases ended in death or decimation. Ships were small and overcrowded and disease was rampant on most of them, scurvy being a prominent cause of death.
Food could not be kept for any period of time, leading to either malnourishment or to the necessity of hazardous landing operations. One good storm could blow the rigging and the masts overboard, condemning the crew to death by starvation - or it could overturn the whole ship; hundreds of them perished in that way every year. A 16th century explorer returning with about 30 -40% of the crew he had started out with was considered to have done a good job.
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