Species differences in carcinogenicity: the role of metabolism and pharmacokinetics in risk assessment.
Attempts to improve quantitative risk assessments inevitably lead to the use of additional biological data in the risk calculation. The need for more data increases further when differences in response between laboratory animals result in uncertainty in the choice of either the species or the tumour incidence on which to base the risk assessment. Of the many stages of carcinogenesis, the first stage, which involves the uptake and activation of the chemical, is probably the most understood and is by far the easiest to measure experimentally. A review of the use of metabolism and pharmacokinetics in risk assessment reveals how this type of data can explain species differences, the shape of the dose-response curve and even determine the relevance of the animal carcinogenicity data to man. A number of chlorinated hydrocarbons are used to illustrate each of these points.
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ICI Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
D001711:Biotransformation; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism / Q000493:pharmacokinetics; D008752:Methylene Chloride / Q000378:metabolism / Q000493:pharmacokinetics; D009374:Neoplasms, Experimental / Q000139:chemically induced; D012307:Risk Factors; D013045:Species Specificity; D013750:Tetrachloroethylene / Q000378:metabolism / Q000493:pharmacokinetics; D014241:Trichloroethylene / Q000378:metabolism / Q000493:pharmacokinetics
D002273:Carcinogens; D006843:Hydrocarbons, Chlorinated; D014241:Trichloroethylene; D008752:Methylene Chloride; D013750:Tetrachloroethylene