INTRODUCTION: Spaceflight aboard the International Space Station (ISS) involves stays of individual crewmembers for up to 6 mo during which they are exposed to a complex mixture of airborne pollutants. Methods to predict specific health effects from exposure to a mixture of air pollutants are not well developed. Herein, air monitoring data from the ISS are used to demonstrate a new method to estimate a threshold for possible health effects from exposure to mixtures. METHODS: An empirical, additive approach was developed to transform monthly air pollutant data, which had been obtained primarily by gas chromatography-mass spectrometry from samples of ISS air, to threshold (T) values for 16 adverse health effect groups. Spacecraft maximum allowable concentrations (SMACs), available for most spacecraft air pollutants, were used to form target-organ/effect groups, from which group T values were estimated. If T >1 for a group, then there is an unacceptable risk of the toxic effect. RESULTS: Samples of air taken from the ISS in 2010 revealed that all 16 toxicological groups were within safe limits. Highest T values were as follows: mucosal irritants (0.53 +/- 0.44), headache (0.52 +/- 0.06), central nervous system depression (0.25 +/- 0.06), and cardiac sensitization (0.13 +/- 0.04). DISCUSSION: The additive model is supported by limited inhalation data on rats in the literature. Our predictions of no adverse effect on crew health are useful as part of NASA's Lifetime Surveillance of Astronaut Health (LSAH). If one of the 16 levels had exceeded T=1, then standard surveillance could be supplemented to address this potential health risk.