This review paper examines the relationship between chemicals inducing ewessive accumulation of a2u-globulin (ai21g) (CIGA) in hyline droplets inmale rat kidneys and the subsequent development ofnephoit and rnal tubule nopaia in the male rt. This dose-responsive hyaline droplet accumulation distinguishes CIGA carcinogens fromclssical renal carcinogens. CIGA carcinogens also do not appear to react with DNA and are generally negative in short-term tests for genotoxicity. CIGA or their metabolites bind specifically, but reversibly, tomale rat a2,-g The resulting complex appears to be more resistant to hydrolytic degradation in the proximaltubule than native, unbound a2,-g Singlecell necrosis of the tubule epithelium, with associated granular cast formation and papillary mineralization, is followed by sustained regenerative tubule cell prolifertin, foci oftubulehyerl a in the aovoited pronal bules, and renal tubule tumor Although stnrcturally similar proteins have been detected in other species, including hu_ms, renal lesios characteristic Of a2,-g nephropathy have not been observed. Epidemiologic investigation has not specifically examined the CIGA hypothesis for humans. Based on cancer bioassays, hormone manipulation studies, investigations in an ae,-g-deficient strain of rat, and other laboratory data, an increased proliferative response caused by chemically induced cytotoxicity appears to play a role in the development ofrenal tubule tumors in male rats Thus, it is reasonable to suggest that the renal effects induced in male rats by chemicals causing a2.-g accumulation are unlikely to occur in humans.

This paper presents briefly some of the principal results of a mortality analysis of a cohort of workers employed for at least 1 year between 1950 and 1975 at eight oil refineries and approximately 750 distribution centers in the U.K, together with detailed results for kidney cancer and leukemia. Over 99 % of the workers were successfully traced. Their mortality was compared with that of all males in the national population. The mortality from all causes of death is lower than that of the comparison population in both studies, and reduced mortality is also found for many of the major nonmalignant causes of death. In the refinery study, some increased mortality patterns are found for diseases of the arteries, and no healthy worker effect is found in the distribution center study for ischemic heart disease. Mortality from all neoplasms is lower than expected overall in both studies, largely due to a deficit of deaths from malignant neoplasm of the lung. Mortality from malignant neoplasm of the kidney is increased overall in the distribution center study, and in drivers in particular. The mortality from this disease increases with increased time since first exposure. The observed deaths from leukemia are slightly less than expected in the refinery study and slightly more than expected in the distribution center study. One refinery shows increased mortality due to in myeloid leukemia, and mortality is increased among refinery operators. Mortality is also raised in distribution center drivers, particularly for myeloid leukemias, including acute myeloid leukemia.

A meta-analysis of mortality among workers exposed to

To evaluate the hypothesis of increased kidney cancer risk after exposure to hydrocarbons, especially those present in gasoline, we conducted a case-control study in a cohort of approximately 100,000 male refinery workers from five petroleum companies. A review of 18,323 death certificates identified 102 kidney cancer cases, to each of whom four controls were matched by refinery location and decade of birth. Work histories, containing an average of 15.7 job assignments per subject, were found for 98 % of the cases and 94 % of the controls. To each job, industrial hygienists assigned semiquantitative ratings for the intensity and frequency of exposures to three hydrocarbon categories: nonaromatic liquid gasoline distillates, aromatic hydrocarbons, and the more volatile hydrocarbons. Ratings of "present " or "absent " were assigned for seven additional exposures: higher boiling hydrocarbons, polynuclear aromatic hydrocarbons, asbestos, chlorinated solvents, ionizing radiation, and lead. Each exposure had either no association or a weak association with kidney cancer. For the hydrocarbon category of principal a priori interest, thenonaromatic liquid gasoline distillates, the estimated relative risk (RR) for any exposure above refinery background was 1.0 (95 % confidence interval [CII 0.5-1.9). Analyses of cumulative exposures and of exposures in varying time periods before kidney cancer occurrence also produced null or near-null results. In an analysis of the longest job held by each subject (average duration 9.2 years or 40 % of the refinery work history), three groups appeared to be at increased risk:

Agency's (EPA) Risk Assessment Forum recently advised EPA risk assessors against using information on certain male rat renal tubule tumors to assess human risk under conditions specified in a new Forum report. Risk assessment approaches generally assume that chemicals producing tumors in laboratory animals are a potential cancer hazard to humans. For most chemicals, including classical rodent kidney carcinogens such as N-ethyl-N-hydroxyethylnitrosamine, this extrapolation remains appropriate. Some chemicals, however, induce accumulation of ct2,-globulin (%.-g), a low molecular weight protein, in the male rat kidney. The a2.-g accumulation initiates a sequence of events that appears to lead to renal tubule tumor formation. Female rats and other laboratory mammals administered the same chemicals do not accumulate low molecular weight protein in the kidney, and they do not develop renal tubule tumors. Because humans appear to be more like other laboratory animals than like the male rat, in this special situation, the male rat is not a good model for assessing human risk. The Forum report stresses the need for full scrutiny of a substantial set of data to determine when it is reasonable to presume that renal tumors in male rats are linked to a process involving a2ug accumulation and to select appropriate procedures for estimating human risks under such circumstances.

Background. The role of occupational exposure in the aetiology of renal cell cancer is still not dear. In a population-based, case-control study we investigated occupational and smoking history as well as place of residence, marital and socioeconomic status. Method. In a case-control study in Germany, 277 adult cases with incident renal cell cancer and 286 controls frequency-matched to the cases for age and gender have been interviewed. The data were analysed by standard methods using unconditional logistic regression models, to estimate the relative nsk (RR) and the corresponding 95 % confidence interval (95 % Cl). Results. Socioeconomic status was inversely associated (RR = 0.61, 95 % Cl. 0.3-1.2 for highest category) with the risk for renal cell cancer. Heavy smoking gave an increased, but not significant (about twofold) RR in men and women for ex-smokers and current smokers. Employment in metal-related industries (RR = 1.63, 95 % Cl 1 1-2 5) was also identified as a risk factor Additionally, we found an elevated risk associated with exposure to perchloroethylene and tetrachlorocarbonate (RR = 2.52, 95 % Cl • 1.2-5.2) but no time trend could be observed. No associations were found for other occupational exposures, such as working in the chemical industry, transportation or farming nor for exposure to pesticides. Conclusions. The results of our study lead to the suggestion that smoking, occupation and demographic factors probably