Health risks from combined exposures: mechanistic considerations on deviations from additivity

Living organisms are exposed every day to a multitude of physical, chemical and biological agents. However, assessments of possible deleterious outcomes from these exposures concentrate on single agents and neglect the potential for combined effects, i.e., synergisms or antagonisms. Biomechanistic considerations based on multistep processes such as carcinogenesis indicate the potential for highly detrimental interactions, if two or more consecutive rate limiting steps are specifically effected by different agents. However, this depends on the specificity of the individual agents for well defined molecular structures or DNA sequences. Low specificity towards molecular structure or DNA-sequence-and therefore exchangeability-of many genotoxic agents indicate little functional specificity of most agents and therefore little vulnerability towards synergism at most occupational and non-occupational exposure situations. In addition, the relative insignificance of combined actions for those common exposure situations where highly non-linear dose effect relationships for non-genotoxic acting agents are involved is also evident. However, an experimental proof of the quantitative assessment of the contribution of synergistic interactions to the total detriment from natural and man-made toxicants is remote. Surprises therefore cannot be excluded.