General principles in the assessment of toxicity of chemical mixtures.

A toxicological interaction may be defined as a condition in which exposure to two or more chemicals results in a qualitatively or quantitatively altered biological response relative to that predicted from the action of a single chemical. Such multiple-chemical exposures may be simultaneous or sequential in time and the altered response may be greater or smaller in magnitude (1,2). The question of how the risk to health of exposure to a combination of chemicals compares to the estimated risk from exposure to each alone may be approached in several ways. The existing literature may be searched for laboratory, clinical or epidemiological studies that deal specifically with exposures to the combinations of chemicals in question. Laboratory and/or epidemiological studies may be initiated to specifically test for interactive effects of specific combinations of chemicals when and if concern for a specific joint exposure arises. Knowledge of the toxicokinetic and toxicodynamic characteristics of individual chemicals may be used to make judgements of the potential for altered health risk arising from specific combined exposure situations. All three of these have several limitations in any problem area dealing with potential exposures to numerous and diverse chemicals. The number of possible combinations of exposures is multiplicative as the list of individual chemicals of concern grows. Furthermore, the permutation of time considerations (that is; simultaneous, separate but close in time or far in time, repeated or single exposures to multiple chemicals) greatly complicates the design of studies for assessment of interactions. As for the first approach, that of literature search for interaction data, there are few reports of