Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking.As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA 2 LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (20-45 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma.These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.

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Summary.-The basal concentration of the tryptophan metabolite 3-hydroxyanthranilic acid (30HA), which has carcinogenic properties, was measured with an enzymatic method of determination which allowed separate measurement of free and conjugated 30HA. The concentration of free 30HA in untreated bladder cancer patients was significantly (P < 0.001) higher than in a healthy control group, but after local therapy the concentration was significantly lower than before treatment (P < 0-01). The concentration of conjugated 30HA was nearly constant in the three groups. It was concluded that other factors than a genetic determined abnormality might be operating in bladder cancer patients which could lead to an abnormal concentration of 30HA in their urine.'rHE role of tryptophan metabolites in the aetiology of human urinary bladder cancer has been the subject of numerous investigations. Twenty-two years ago a relationship was suggested by Dunning, Curtis and Maun (1950), who showed that a high incidence of bladder tumours resulted when rats were fed 2-acetylaminofluorene combined with DL-tryptophan. Several primary aromatic amine tryptophan metabolites, with a structure similar to known environmental human bladder carcinogens, are present in human urine (Brown and Price, 1956). Direct application to the mouse bladder of these metabolites by the " pellet technique " confirmed the carcinogenic activity of several of them (Bryan, 1971). Recently, Radomski, Glass and Deichmann (1971) have given evidence supporting the role of tryptophan in bladder carcinogenesis by feeding 7 times the normal daily intake of DL-tryptophan to beagle dogs for periods of 3 5 months to 7 years. Marked local hyperplasia of the transitional bladder epithelium was observed in all cases.Several clinical studies of the metabolism of tryptophan have been carried out in patients with bladder cancer (Brown et al., 1960;Price and Brown, 1962;Benassi, Perissinotto and Allegri, 1963;Kochen and Hochberg, 1970). In these investigations one or more metabolites were determined in samples of 24-hour urine. In most of the studies, loading with an oral dose of L-tryptophan was necessary because the analytical methods are working at lower limits of detection and sensitivity when used on basal urines. Because of the differences in method, it is difficult to compare the results obtained in the different laboratories. An abnormal metabolism was often observed in patients with spontaneous bladder cancer, but in other pathological conditions an abnormal excretion pattern was also found (Rose,.Moreover, the excretion of metabolites is related to tryptophan intake, hormonal regulation of the pathway, intake levels of pyridoxine and metabolic individualitv (Albanese et al., 1972). In a pilot study

Metabolites of the amino acid tryptophan have been suspected of being involved in the genesis of human urinary bladder cancer. It was suggested that a neoplastic change could result from increased urinary excretion of tryptophan metabolites. From studies i n which the excretion of metabolites was assessed after loading the patients with L-tryptophan it was concluded that abnormalities i n tryptophan metabolism are causing the elevation o f metabolite excretion. The present study however, which measured basal excretion of metabolites, demonstrates that the presence of tumor i n the urinary tract must be considered as causative for elevations of metabolite excretion. A n improved method for determining the spontaneous metabolite excretion i s described. The metabolites kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid and 3-hydroxyanthranilic acid were determined i n 165 urine samples obtained from bladder cancer patients, renal cancer patients, patients cured of bladder cancer and control subjects. Thirty six percent of the bladder cancer patients and 67% of the renal carcinoma patients excreted abnormally high amounts of a t least one of the metabolites. It was observed that i n bladder cancer an elevated excretion of metabolites OCcurred principally i n patients with obstruction t o the outflow of urine from the kidneys. Ureteral obstruction, probably a direct consequence of the presence of tumor in the urinary tract, causes an alteration in renal function which is reflected in urea and creatinine retention. The high incidence of abnormal excretion of tryptophan metabolites i n renal cancer also points t o alterations i n renal function caused by the presence of tumor.In the past, several lines of evidence have led to the suggestion that metabolites of the amino acid tryptophan are involved in the etiology of cancer of the urinary bladder in man. Dunning et at. (1950) reported that a substantially higher incidence of bladder cancer was observed in rats fed tryptophan with acetylaminofluorene than in rats fed acetylaminofluorene alone. Several metabolites of the tryptophan-kynurenine pathway produced a significant incidence of bladder carcinoma when implanted into the bladder of mice (Bryan, 1971). Furthermore, certain structural similarities of tryptophan metabolites to metabolites of known industrial bladder carcinogens strengthened the idea that these metabolites might be human bladder carcinogens. Small amounts of these metabolites are present in urine samples of healthy human subjects, but it has been shown by several investigators (Boyland and Williams, 1956; Quagliariello et a[., 1961; Benassi et al., 1963) that elevated amounts are excreted by certain patients suffering from cancer of the bladder. It was hypothesized that metabolites of tryptophan, increasingly generated by faulty metabolism, may be the etiological agents in non-industrial bladder cancer. That an abnormal metabolism of tryptophan occurs in certain patients with bladder cancer was concluded from studies in which the funct...