Assessment of carcinogenic hazard of chemical mixtures through analysis of binary chemical interaction data.

Assessment of the potential health hazard of environmental complex chemical mixtures is one of the most difficult and challenging problems in toxicology. In this article, we describe the development of an innovative computerized system for ranking and predicting potential cancer hazard of chemical mixtures. We take into consideration both the additive risk of individual carcinogens present and the projected overall interaction effect of the mixture based on analyzing and integrating the possible interaction effects of all binary pairs of individual constituents of the mixture. Using this system, it can be predicted that a number of mixtures of polycyclic aromatic hydrocarbons should have a carcinogenic risk lower than that calculated by the simple additivity model, whereas the reverse is true for a number of other mixtures. The system can be very useful in hazard ranking and priority setting in dealing with mixture problems such as cleanup of hazardous waste.

Effects of biosolubility on pulmonary uptake and disposition of gases and vapors of lipophilic chemicals.

Since statistical analysis proved the intercorrelation of tissue-gas partition coefficients of chemicals with similar chemical structures, bioavailability is controlled by one parameter dependent on the physicochemical properties of the chemicals and two constants distinguishing the tissues. Oil-gas partition coefficients are suggested to describe the biosolubility of volatile halogenated aliphatic chemicals. Tissue-gas partition coefficients derived from oil-gas partition coefficients were substituted in a pharmacokinetic model in order to study the effect of biosolubility on uptake, distribution, and elimination of inhaled chemicals. The simulation was focused on occupational exposures (8 h/day, 5 days/wk). Desaturation curves for all tissues show three exponential decays. The analysis of the simulation data indicates three patterns in behavior of inhaled vapors and gases in the body. Tissue uptake of poorly soluble chemicals (oil-gas partition coefficient less than 10) is flow limited at the beginning of exposure, but the partial pressures of such chemicals in the body equilibrate very rapidly with ambient air. Increased pulmonary uptake compensates for metabolic clearance. The rapid response of tissue concentrations to changes in exposure concentrations indicates that the toxic effect can easily be induced by short-term increase of exposure concentration, and that emergence from the reversible effect is rapid when exposure ceases. Tissue uptake of chemicals with oil-gas partition coefficients between 10 and 10(4) is flow limited during the entire 8-h exposure. Tissue concentrations increase slowly. Pulmonary uptake, being restricted by alveolar ventilation, compensates at steady state only for the amount of chemical removed by metabolic clearance. Therefore, tissue concentrations at steady state are lower than biosolubility. Accumulation during occupational exposure is obvious. Dumping of inhaled chemicals in adipose tissue protects the target organ from the occasional short-term increases in the exposure concentration. Tissue uptake of highly soluble chemicals (oil-gas partition coefficients greater than 10(4)) is limited by alveolar ventilation and exposure concentration. The rising and declining of tissue concentrations is very slow, half-times being in the magnitude of months and years. Metabolism reduces the half-time significantly. A lagging acute toxic effect can develop as the chemical accumulates in the body; the effect is most likely to persist long after the termination of the exposure.(ABSTRACT TRUNCATED AT 400 WORDS)