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A major objective of combination toxicology is to establish whether a mixture of chemicals will result in an effect similar to that expected on the basis of additivity. This requires understanding of the basic concepts of the combined toxicological action of the compounds of the mixture: simple similar action (dose addition), simple dissimilar action (effect or response addition), and interaction (synergism, potentiation, antagonism). The number of possible combinations of chemicals is innumerable, and in vivo testing of these mixtures is unattainable from an ethical, economical, or pragmatic perspective. Prediction of the effect of a mixture based on the knowledge of each of the constituents requires detailed information on the composition of the mixture, exposure level, mechanism of action, and receptor of the individual compounds. Often, such information is not or is only partially available and additional studies are needed. Research strategies and methods to assess joint action or interaction of chemicals in mixtures such as whole mixture testing, physiologically based toxicokinetic modeling and isobologram and dose response surface analyses are discussed. Guidance is given for risk assessment of both simple and complex mixtures. We hypothesize that, as a rule, exposure to mixtures of chemicals at (low) non-toxic doses of the individual constituents is of no health concern. To verify the hypothesis is a challenge; to timely detect exceptions to the rule is the real challenge of major practical importance.

The combined effects on the nasal epithelium of mixtures of ozone and formaldehyde at cytotoxic and noncytotoxic concentrations were examined. Male Wistar rats were exposed by inhalation during 22 h/d for 3 consecutive days to 0.3, 1.0, or 3.0 ppm formaldehyde, or to 0.2, 0.4, or 0.8 ppm ozone, or to mixtures of 0.4 ppm ozone and 0.3, 1.0, or 3.0 ppm formaldehyde, or to 1.0 ppm formaldehyde and 0.2, 0.4, or 0.8 ppm ozone, or they were sham-exposed to clean air. The noses were examined for pathological changes at six standard cross levels by light microscopy and for epithelial cell proliferation by counting [3H-methyl]thymidine-labeled cells at cross levels II and III. Ozone at 0.4 ppm or 0.8 ppm or formaldehyde at 3 ppm enhanced cell proliferation at cross level II at all locations, except for the epithelium of the septum, which was not affected by ozone. At cross level III ozone alone did not induce cell proliferation, but formaldehyde at 0.3 and 1 ppm tended to reduce cell proliferation while at 3 ppm proliferation was slightly stimulated. The combined exposure to 0.4 ppm ozone and 0.3 ppm formaldehyde induced less cell proliferation at cross levels II and III when compared with that of 0.4 ppm ozone alone. Less cell proliferation was also seen at cross level II when animals were exposed to 0.4 or 0.8 ppm ozone in combination with 1 ppm formaldehyde than when exposed to these ozone concentrations alone. A more than additive increase in cell proliferation was found at cross level II after exposure to 0.4 ppm ozone in combination with 3 ppm formaldehyde, and at cross level III in animals exposed to 0.4 ppm ozone and 1 or 3 ppm formaldehyde. Treatment-related histopathological nasal changes, such as disarrangement, loss of cilia, and hyper/metaplasia of the epithelium were seen at 0.2, 0.4, and 0.8 ppm ozone and at 3 ppm formaldehyde. Simultaneous exposure to both materials did not noticeably affect type, degree, and size of the microscopic nasal lesions.

The subacute inhalation toxicity of acetaldehyde was examined with four groups of 20 hamsters each, exposed repeatedly to acetaldehyde vapor at concentrations of 0, 390, 1,340, and 4,560 ppm (six hr day, five days/week) for a 90-day period. The highest level induced growth retardation, ocular and nasal irritation, increased numbers of erythrocytes, increased weights of heart and kidneys, and severe histopathological changes in the respiratory tract that mainly consisted of necrosis, inflammatory changes, and hyper- and metaplasia of the epithelium. The upper segments of the respiratory tract were much more severely injured than the lower parts. At 1,340 ppm treatment-releated changes included increased kidney weights in males and slight hyper- and metaplastic changes of the tracheal epithelium; 390 ppm was considered a no toxic effect level.