The 48 h toxicity of 18 organic narcotics, 13 epoxides, and 2 thiiranes toward the ciliates Tetrahymena pyriformis was determined in terms of 50% growth inhibition EC(50). Nominal EC(50) was corrected for volatilization and sorption to quantify the freely dissolved compound fraction in solution. The derived baseline narcosis model served to evaluate toxicity enhancements T(e) as ratios of narcosis-predicted over experimental EC(50) values. Among the nine heterocycles with aliphatic side chains that include two thiiranes, three compounds yielded T(e) > 10, suggesting their covalent binding at nucleophilic protein sites such as -OH, -NHR, and -SH through S(N)2-type ring-opening. As a general trend of this group, T(e) decreases with increasing alkyl group size. Moreover, four of the six nonaliphatic epoxides exerted substantial excess toxicities with T(e) > 10, which could be rationalized by ring-opening activation through negative inductive effect, benzylic stabilization, and phenyl ring H-bonding. By contrast, 1,2 substituted epoxides showed narcosis-level toxicity, despite the opportunity of side-chain Schiff-base formation with protein amino groups. The resulting structural alerts enable an in silico screening of epoxides and thiiranes for their potential to exert excess toxicity. Note that observed differences in T(e) sensitivity between ciliates, bacteria and fish should be taken into account when designing in vitro alternatives to fish toxicity studies.