BACKGROUND Setting Spacecraft Water Exposure Guidelines (SWEGs) for lead (Pb) in spacecraft drinking water has special challenges related to estimating the increase in blood lead levels (PbB) due to the release of lead to systemic circulation via microgravity-induced bone loss. METHODS The effects on the PbB of lead in drinking water (PbW) and lead released from bones, and changes in lead exposure before, during, and after spaceflight, were evaluated using a physiologically based pharmacokinetic model that incorporated environmental lead exposure on Earth and in flight and included temporarily increased rates of osteoporosis during spaceflight. RESULTS The model predicts that in 2030 (the earliest potential launch date for a long-duration mission), the average American astronaut would have a PbB of 1.7 microg x dl(-1) at launch and that, while in microgravity, PbB levels would decrease at PbW values less than about 9 microg L(-1) because of reduced exposure within the spacecraft to environmental lead. Astronauts with high concentrations of lead stored in bones could experience increases in PbB due to microgravity-accelerated release of lead from bones. While the resultant in-flight PbB would depend on their preflight bone lead levels, their PbB will not be significantly further elevated (< 1 microg x dl(-1)) by consuming water with a PbW of < or = 9 microg x dl(-1). Selection of a SWEG that would not result in an increase in blood lead is prudent given uncertainties about health effects at low exposures. CONCLUSIONS A SWEG of 9 microg x L(-1) would protect astronauts on long-duration spaceflights by ensuring that PbB values will not exceed prelaunch levels.