Aryl hydrocarbon hydroxylase (AHH) inducibility was determined in a lymphoblast test system in 2,000 consecutive middle-aged male smokers, 304 ex-smokers, and 218 never-smokers in the same birth-year cohorts. Intraindividual, intraobserver, and interobserver, as well as temporal, reproducibility was checked in a special double-blind quadruplet sample series from 20 other consecutive middle-aged men. The results showed a three-modal phenotype distribution of AHH inducibility with high (fold induction 2 3.6), intermediate (2.6-3.6) and low (52.5) levels ranging between 7.6% to 10.51, 38.5% to 43.076, and 46.5% to 53.9%. respectively, in all the smoking categories. The reproducibility of the measurements was excellent, with one-way variance in the order of 0.007 to 0.033. and the applied assay method can therefore be used in large-scale prospective population investigations. Such are required in order to establish a cause-effect association between high AHH inducibility and smoking-related malignancies of the respiratory tract and oral cavity, as has been suggested from earlier retrospective studies in more limited clinical materials of cancers and precanceroses of these varieties. Cancer 56:1988-1994, 1985. H E GENETICALLY DETERMINED intracehlar CytO-T chrome P-450 mixed function oxygenase (MFO) component enzyme system, aryl hydrocarbon hydroxylase (AHH) is a major activator of carcinogens belonging to the polycyclic aromatic hydrocarbon (PAH) group. As recently reviewed by Gelboin,' evidence has now accumulated that suggests, albeit not proves, an important role of the AHH complex in many smoking-related human cancers. After the pioneering study of Kellerman et al. in a clinical series of pulmonary carcinoma,2 we found a similar overrepresentation of cases with high AHH in-ducibility and underrepresentation of low AHH induc-ibility in retrospective materials of laryr~geal~-~ and oral '-lo cancers and precanceroses associated with smoking. In several forthcoming reports of pulmonary carci-noma belonging predominantly to the small-cell and squamous cell varieties,' the observations of Kellerman et al. were also, with a few exceptions, c ~ r r o b o r a t e d , ' ~ ~ ' ~ whereas in pulmonary carcinomas less strongly related to smoking2' in urothelial cancer^,^^*^^ and in cured lung and larynx cancers,24 no significant differences ofthe AHH inducibility in comparison with healthy controls were a p parent. Thus, the findings so far support the concept of AHH as a potential activator of tobacco smoke carcinogens of PAH type mainly when these effect the respiratory tract and/or oral cavity. However, these data all stem fiom retrospective clinical materials and are, therefore, not sufficient to prove a cause-effect relati~nship.'.~' There are several further reasons why prospective studies in sizable population samples have been eagerly req~ested.~' There is an inter-individual heterogeneity of AHH inducibility in humans, first demonstrated by Kellerman ef who proposed an autosomal codominant mode of genetic transmission...
