(CANCER RESEARCH 49, 1045-1048, February 15, 1989]

Analgesics, Cigarette Smoking, and Other Risk Factors for Cancer of the RenalPelvis and Ureter1

Ronald K. Ross,2 Annlia Paganini-Hill, Joseph Landolph, Vibeke Gerkins, and Brian E. Henderson

Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033

ABSTRACT

Results from a population-based case-control study of cancer of therenal pelvis and ureter are reported. Telephone interviews were conductedwith 187 residents of Los Angeles County diagnosed with cancer of therenal pelvis and ureter over a 4-year period ending December 31, 1982,and with individually sex-, age- and race-matched neighborhood controls.The major risk factor identified for cancer of the renal pelvis and ureterwas cigarette smoking. Subjects who smoked more than 25 years had arelative risk of 4.5 of developing these tumors, compared to nonsmokers(P < 0.0001). Heavy use of over-the-counter analgesics was also associated with a significant increase in risk; it appears that an elevated riskwas conveyed by all the major active constituents of those compoundscurrently marketed in the United States, aspirin, caffeine, and acetaminophen. Persons who had used these drugs for 30 consecutive days at anytime in their life preceding diagnosis had twice the risk of developingcancer of the renal pelvis or ureter compared to persons not reportingsuch use (/' < 0.01). Heavy coffee drinkers (>7 cups/day) had a 1.8-fold

increase in risk compared to nondrinkers. Although risk tended to increase with increasing consumption, this result was not statisticallysignificant. The risk associated with heavy coffee consumption wasreduced to 1.3 after adjusting for smoking. Nine cases compared to nocontrols reported a first degree relative with kidney cancer. A history ofkidney stones was associated with an increased risk of cancer of theureter (relative risk = 2.5) that was not, however, statistically significant.

INTRODUCTION

Approximately 20-25% of epithelial cancers of the kidney inthe United States occur in the renal pelvis. In 1965 a reportfrom Sweden indicated that in a series of 106 patients withcancer of the renal pelvis, six had a history of papillary necrosisassociated with heavy usage of phenacetin-containing analgesics(1). Three years later, Bengtsson et al. (2) reported that 8 of104 patients with chronic pyelonephritis following extensive an-algesicusedevelopedtransitionalcellcarcinomasoftherenal pelviscompared to none of 88 patients with chronic pyelonephritisfrom other causes. During the next 5 years, case reports of cancer of the renal pelvis occurring in heavy analgesic users camefrom Denmark (3), Canada (4), Australia (5), and Sweden (6).

This association has biological plausibility. Phenacetin, aspirin (acetylsalicylic acid), caffeine, and acetaminophen havebeen the major active ingredients of the most commonly usedover-the-counter analgesics in the United States over the pastseveral decades. Phenacetin is carcinogenic in mice and rats,inducing tumors of the kidney and lower urinary tract (7, 8).There is no definitive experimental evidence that aspirin is acarcinogen, but it can induce more severe nephrotoxic effectsin rats than does phenacetin (9). Caffeine is linked to bladdercancer by some epidemiológica! studies (10, 11). Although dataare conflicting on the potential of acetaminophen as an experimental carcinogen (12-14), it may be a human carcinogen

Received 3/11/88; revised 10/4/88; accepted 10/12/88.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

' Supported by Grants CA 25669, CA41277, and CA 17054 from the NationalCancer Institute, Bethesda, MI).

2To whom requests for reprints should be addressed, at USC School of

Medicine, Morris Cancer Hospital & Research Institute, P.O. Box 33800, 1441Eastlake Ave., Room 803, Los Angeles, CA 90033-0804.

primarily because 70% of ingested phenacetin is metabolizedin the liver to acetaminophen, which is conjugated and thenexcreted in the urine (15). In the laboratory, we have shownthat both phenacetin and acetaminophen, but not aspirin, induce low but concentration-dependent numbers of type II morphologically transformed foci in cultured C3H/10T'/2 clone 18mouse embryo cells.3

Most, but not all of several case-control studies which evaluated the relationship between analgesic use and developmentof cancer of the renal pelvis (16-18,19), found some associationwith long-term use. These studies have been limited, either bythe size of the study sample, by the use of surrogate respondents,or by their ability to characterize adequately this relationship,and have been inconsistent in their evaluation by analgesicformulation. In the only United States study, McLaughlin etal. in Minnesota (18), reported a relative risk of 3.9 in malesand 3.7 in females for regular long-term (>36 months) users ofphenacetin- or acetaminophen-containing drugs compared tononusers, but neither result was statistically significant. Fifty% of the patients in this study were deceased and next of kinwere interviewed.

We report here the results of the largest case-control studyof cancer of the renal pelvis and ureter to date. All subjects inthis study were interviewed directly. Details of analgesic use aswell as of other potential etiological agents were collected.

MATERIALS AND METHODS

Cases were drawn from incident cases of cancer of the renal pelvisand ureter diagnosed in Los Angeles County residents under age 75between January 1, 1978 and December 31, 1982, and were identifiedthrough the Cancer Surveillance Program, a population-based tumorregistry of Los Angeles County (20). During this period 314 such caseswere identified, but 61 had died before we were able to contact them.Twenty cases refused to be interviewed, and the physicians of 30 othersrefused on their patient's behalf. Interviews were completed with the

remaining 203 cases, but we were unable to locate a suitable controlfor 16 of these. The remaining 187 case-control pairs constituted thestudy sample. Of these cases 121 had primary tumors of the renal pelvis(80 men) and 66 of the ureter (47 men).

Neighborhood controls were identified by walking a predeterminedalgorithm, through an obligatory sequence of houses beginning at aresidence bearing a specific relationship to the residence of the case atdiagnosis. Controls were individually matched to cases on date of birth(±5years), sex, and race. The control identification procedure continued until an appropriate person had been identified or until 40 housingunits had been approached. We attempted to account for all personsnot at home during our initial "walk" by repeat mailings and telephone

contact. We interviewed controls for 187 of the interviewed cases. Onaverage, we contacted 22 household units to identify a consentingmatched neighborhood control and had one household with an incomplete roster of residents per completed control interview.Two % of eligible controls refused participation, and the next eligibleperson in the walk sequence was selected.

Data were collected via telephone interviews conducted with casesand controls by one nurse epidemiologist (V. G.). Questionnaires werestructured with the use of a verbatim script, including appropriate

3 S. R. Patierno, W. Lehman, B. E. Henderson, and J. L. Landolph. Study of

the ability of phenacetin, acetominophen, and aspirin to induce cytotoxicity,mutation, and morphological transformation in C3H/10T'/2 Clone 8 mouseembryo cells, Cancer Res., 49: 1038-1044, 1989.

1045

on July 30, 2021. © 1989 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

RISK FACTORS FOR CANCER OF RENAL PELVIS AND URETER

introductory and transitional statements between ordered questions.The questionnaire asked a lifetime occupational history, a medicalhistory focusing on conditions for which analgesics might be indicated(e.g., headaches, arthritis, back pain), use of tobacco, alcohol, andcoffee, and family cancer history. The analgesic history was obtainedseparately for prescription and for nonprescription compounds, butfocused on the latter. Study participants were asked whether they hadused any of 13 different nonprescription medications for more than 30days in a single year, and the years of first and last use of such anamount. To determine more concentrated use of these compounds,participants were asked the number of months in their lifetime theyhad taken each medication at least daily (i.e.. 30 consecutive days). Foreach medication, participants were also asked the usual highest dailydose (as determined by number of pills) and the major reason for takingeach medication. Study participants were also asked about any use of19 prescription medications.

We calculated the cumulative number of person months of use of allaspirin-, caffeine-, phenacetin-, and acetaminophen-containing compounds from over-the-counter medications. Because acetaminophen isa major metabolite of phenacetin and because the frequency of use ofthe latter was low, we combined phenacetin- and acetaminophen-containing analgesics for some analyses.

For every variable examined, the exposure history for the case-control pair was presumed to end at the diagnosis date of the case.Unless otherwise indicated, we maintained the matched pairs design inthe statistical analyses (21). For dicho to inmis variables, we usedMcNemer's x2 test and computed point estimates of RR.4 For contin

uous variables and those with multiple levels, we used conditionallogistic regression methods to estimate the relative risk. For ordinalvariables, a trend test was used to determine whether there was a dose-related increase or decrease in risk. All reported P values are 2-sided.

RESULTS

Table 1 presents results for the major potential risk factorsevaluated in this study. Among those variables studied, cigarettesmoking was most strongly associated with an increased risk ofcancer of the renal pelvis and ureter. Persons with a history ofregular cigarette smoking had 3.6 times the risk of lifetimenonsmokers. Compared to nonsmokers, the relative risk forcurrent cigarette smokers was considerably higher (RR = 5.2)than for past smokers (RR = 2.5). Risk increased with increasing duration of smoking; smokers of more than 25 years had4.5 times the risk of developing a cancer of the renal pelvis andureter compared to lifetime nonsmokers.

Coffee consumption was weakly associated with increasedrisk. Participants who reported drinking 7 or more cups ofcoffee daily had 1.8 times the risk of noncoffee drinkers. Risktended to increase with increasing consumption, but this trendwas not statistically significant (P = 0.11).

Results for analgesic use by major categories (aspirin-, acetaminophen-, phenacetin-, caffeine-containing) are also shownin Table 1. The relative risks were elevated somewhat for eachof these categories and were statistically significant for aspirin-and caffeine-containing analgesics (RR = 1.9, P = 0.01, andRR = 2.1, P = 0.01, respectively). The relative risk estimatesfor more concentrated use of these compounds (i.e., greaterthan use for 30 consecutive days) were comparable to thoseobserved for use for greater than 30 days per year. The resultsfor aspirin- and caffeine-containing analgesics were again statistically significant (P = 0.01 and P = 0.04, respectively) andwere nearly so for acetaminophen-containing compounds (RR= 2.0, P = 0.08).

Results for several other potential risk factors for cancer ofthe renal pelvis and ureter are shown in Table 2. A self-reportedfamily history of kidney cancer, but not of any other cancers

Table I Matched relative risks for cancer of the renal pelvis and ureter bycigarette smoking, coffee consumption, and use of over-the-counter analgesics

No.ofRisk

factorCigarette

smokingNeverPastCurrentYr

of cigaretteuse0<2526+No.

of cigarettes/day (currentsmokersonly*)<20>20Colice

drinking(cups/day)None1-23-45-67+Analgesics

(>30 days/yr) containingCaffeineAspirinAcetaminophenPhenacetinAcetaminophen/phenacetinAny

ofaboveAnalgesics

(>30consecutivedays)containingCaffeineAspirinAcetaminophenPhenacetinAcetaminophen/phenacetinAny

of aboveCases265510626311302481295159232548873611428826492272455Controls726748724174939356454191527642910347013291151531Relative

risk1.02.55.21.01.94.53.83.21.00.91.31.31.82.1.9.3.1.3.62.01.92.01.41.72.1P<0.0001°<0.0001°<0.0001°0.11°0.010.010.340.830.310.040.040.010.080.560.130.003

* Test for trend.* Referent category is never/past smokers.

Table 2 Matched relative risks for cancer of the renal pelvis and ureter by otherselected risk factors

RiskfactorFamily

history of cancerofKidneyBladderProstateCervixBody

massindexLowMediumHighAlcohol

(drinks'/day)None«12+Urinary

tractstonesUrinary

tractinfectionsPelvic

X-raysNone1-45+NoCases"94111068586070308724521382325.ofControls"0791059646384337016451323716Relative

risk000.61.20.91.00.80.81.01.11.51.61.21.00.51.5P<0.0010.370.650.810.570.180.170.420.04

" Number of cases and controls does not always total 187 due to missing

values.* 12 oz beer, 4 oz wine, 1 oz liquor.

4The abbreviation used is: RR, relative risk.

specifically evaluated, was strongly associated with risk. Ninecases versus no controls reported an affected first degree relative(6 siblings and 3 parents). No attempt was made to validatethese cases by review of medical records or death certificates.

1046

on July 30, 2021. © 1989 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

RISK FACTORS FOR CANCER OF RENAL PELVIS AND URETER

There was no consistent relationship between weight, height,or body mass index and risk, although more cases than controlswere at the upper extreme of weight (14 cases and 5 controlsreported a prediagnosis weight of 220 pounds or more). Ahistory of urinary tract stones was weakly associated with risk(RR = 1.6, P = 0.17). Alcohol consumption, either overall orby specific categories of consumption (beer, wine, or hardliquor), was not strongly related to risk of cancer of the renalpelvis and ureter. Risk was increased 1.5 times for individualsreporting 5 or more X-rays to the pelvic region, compared tothe risk of those reporting none. These X-rays were for a varietyof different indications (pelvis or hip fractures, kidney stones,and lower back problems were the most common).

Tables 3 and 4 show details of the association between cancerof the renal pelvis and ureter and use of analgesics for at least30 consecutive days. Even though the risk estimates are imprecise due to few exposed individuals in several categories, theassociation between analgesic use and risk is more apparent innon- or short-duration smokers (Table 3). To separate out thoseformulations responsible for any increased risk, we evaluatedthe risk of combinations of the three major categories of analgesic use (Table 4). These results demonstrate an elevation inrisk for each combination of categories evaluated. No data wereavailable on exposure to caffeine-containing analgesics whichdo not also contain aspirin.

Frequency of use of most of the prescription analgesicsstudied was low, but the observed relative risks for individualcompounds were generally compatible with those observed fornonprescription compounds. The most frequently used prescription analgesics included one containing a combination ofaspirin, caffeine, and phenacetin (Fiorinal; 6 exposed cases and4 exposed controls, RR = 1.7), one containing caffeine andphenacetin (Soma; 7 exposed cases and 6 exposed controls, RR= 1.2), and one containing none of the constituents beingevaluated by this study (Darvon; 27 exposed cases and 16exposed controls, RR = 1.9).

Reported concentrated use of over-the-counter analgesics wasgenerally of short duration, and there was no strong evidencethat risk from such use was duration related. Six cases (versus2 controls) reported more than 5 years of daily use of acetamin-ophen/phenacetin-containing analgesics; 5 cases (versus 3 controls) reported such use of caffeine-containing analgesics; and12 cases (versus 10 controls) reported this level of use of aspirin-containing analgesics (8 cases versus 5 controls reported morethan 10 years of use).

The relative risks for the major potential risk factors evaluated in this study by sex and primary site (ureter versus renalpelvis) are summarized in Table 5. Long duration cigarettesmoking is the major risk factor identified in this study for bothcancer of the renal pelvis and cancer of the ureter. Six of the 9individuals reporting a first degree relative with kidney cancerhad their primary site in the renal pelvis. A history of lowerurinary tract stones appears to be a stronger risk factor forcancer of the ureter (RR = 2.5, both sexes combined) than forcancer of the renal pelvis (RR .= 1.2, both sexes combined).

Although the number of exposed individuals is small for manyof the analgesic variables shown, the relative risks tend to behigher for women than for men, especially for cancer of therenal pelvis.

Logistic regression was used to examine the simultaneouseffect of several risk factors identified in the univariate analysis.The variables included duration of smoking (<25, 26+ years);daily cups of coffee (0-2, 3+); family history of kidney cancer;history of urinary tract stones; and greater than 30 days ofconsecutive use of any major category of analgesic. The risk forgreater than 2 cups of coffee consumption was reduced from1.5 to 1.1 and that for a history of urinary tract stones from 1.9to 1.5. The relative risk for a family history of kidney cancerremained unchanged and that for greater than 30 consecutivedays of over-the-counter analgesic use was reduced slightly,from 2.1 to 2.0, respectively. The risk for long duration (26+years) cigarette smoking increased from 3.4 to 3.8, comparedto lesser or no use.

DISCUSSION

Our data on the relationship between cigarette smoking andcancer of the renal pelvis and ureter are consistent with the 5previous case-control studies reporting on this association (16-19, 22). As a group these studies have suggested a strongassociation with cigarette smoking, with the highest risk in theheaviest smokers (for summary, see Ref. 11). Our study isnearly as large as these 5 previous studies combined and allowsmore precise risk estimates for smoking by duration of use, inboth men and women.

We are aware of only 3 previous studies which evaluated theassociation between coffee drinking and cancer of the renalpelvis. The results of these studies have been inconsistent. Onefound no association (19), a second only a weak association(restricted to men) (18), and the third a strong association(based, however, on the coffee drinking habits of just 28 persons) (22). Our data are consistent with a weak associationbetween risk and amount of coffee consumed daily, but thisrelationship is explicable largely by the strong association withcigarette smoking.

The first case-control study to evaluate the association between analgesic use and cancer of the renal pelvis was negative(19). However, the study was small (33 cases) and used hospitalcontrols who may be unrepresentative of the general populationin terms of frequency of analgesic use. Subsequent case-controlstudies have all found evidence of an association, but of varyingstrength. Two studies conducted by McCredie et al. in NewSouth Wales (16, 17) suggested a strong association between"regular" use of analgesics and cancer of the renal pelvis in

both sexes. The second study suggested that in women thisstrong association was limited mainly to phenacetin-containingcompounds.

In a study of 74 cases of cancer of the renal pelvis and 697population controls in Minnesota, McLaughlin et al. ( 18) founda 3.9-fold and 3.7-fold excess risk in men and women, respec-

Table 3 Unmatched relative risks" for use of over-the-counter analgesics for more than 30 consecutive days, by smoking duration

Nonsmokers Smoking duration

fi25yr 26+ yr

Analgesic category Cases Controls RR Cases Controls RR Cases Controls

1Referent category for each RR is "no use for more than 30 consecutive days" in that smoking category.

1047

RR

CaffeineAspirinAcetaminophen/phenacetin21021835.95.01.96641729.61.22.91833281114100.91.51.0

on July 30, 2021. © 1989 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

RISK FACTORS FOR CANCER OF RENAL PELVIS AND URETER

Table 4 Matched relative risks for use of over-the-counter analgesics for morethan 30 consecutive days by combinations of major active ingredients

Exposure status"

Aspirin —¿� —¿� + +Caffeine + - +

No. of cases 138 0 23No. of controls 158 0 16Relative risk 1.0 - 1.795% confidence interval 0.8-3.3

Acetaminophen/phenacetin —¿� —¿� +Caffeine +

No. of cases 152 11 9No. of controls 170 2 4Relative risk 1.0 5.5 2.895% confidence interval 1.2-25 0.7-10

Acetaminophen/phenacetin —¿� - +Aspirin —¿� + —¿�

No. of cases 132 31 6No. of controls 156 16 2Relative risk 1.0 2.3 4.095% confidence interval 1.2-4.3 0.8-2.1

26132.2

1.1-4.2

++

1511

1.40.6-3.1

1813

1.70.8-3.7

" —¿�,nonexposed; +, exposed.

Table 5 Matched relative risks for selected variables by site and sex (number ofcasesIcontrols given in parentheses)

RenalpelvisVariableYr

of cigarette useNone<25yr

26+Coffee

(cups/day)None1-2

3+Family

history of kidney cancerMale(n

-80)1.0(8/21)

1.3(14/25)4.3(58/34)1.0(4/16)

0.8(18/25)1.3(48/39)°°

(4/0)Female

(1 =41)1.0(10/25)

1.9(7/6)3.6(24/10)1.0(8/9)

0.9(11/14)1.4(22/18)»

(2/0)UreterMale

(n =47)1.0(3/14)

2.8 (6/8)5.1(28/25)1.0(5/6)

1.1 (13/14)1.3(29/27)»

(3/0)Female

(n =19)1.0(5/12)

7.1 (4/2)8.5(10/5)1.0(2/4)

2.0(9/11)5.1(8/4)(0/0)

Urinary tract stones 1.1(11/10) 2.0(2/1)

Analgesics: >30 daysconsecutive usecontaining

CaffeineAspirinPhenacetin/acet-

aminophenAny of above2.2(11/5)

1.1 (18/17)1.3(9/7)1.1

(19/17)7.7(8/1)

7.1 (15/3)3.4(7/2)7.7(18/4)0.8

(4/5)2.3 (12/7)1.3(6/5)2.5

(14/8)1.5(3/2)

2.0 (4/2)2.0(2/1)2.0

(4/2)

lively, who were regular long-term (>36 months) users ofphenacetin- or acetaminophen-containing drugs, comparedwith nonusers. However, neither result was statistically significant.

Our study provides some limited support for these previousobservations, suggesting that out of the ordinary use of over-the-counter analgesics increases risk of cancer of the renal pelvisand ureter.

A number of issues must be considered in evaluating thelikelihood that these modest observed associations are causal.Recall bias is one possible explanation for the increased risksobserved for the various combinations of analgesic use. Inaddition to over-the-counter analgesics, we asked about use ofseveral other commonly used drugs for which we had no apriori etiological hypothesis. The relative risks for most of thesewere at or near 1.0; these included thyroid hormone supplementation (22 exposed cases, 23 exposed controls, RR = 1.0;Milk of Magnesia (14 exposed cases, 14 exposed controls, RR= 1.0), and Butazolidin (5 exposed cases, 7 exposed controls,RR = 0.7). One exception was Metamucil (12 exposed cases, 5exposed controls, RR = 2.4, P = 0.09).

It is unlikely that the indications for these medications are

associated with increased risk rather than the drugs per se. Weobserved comparable risk estimates for analgesic use across avariety of medical conditions (e.g., arthritis, back or musclepain, headaches, and bursitis). Use of these drugs to treat earlysymptoms of the disease does not explain the observed associations since high risks were observed for use beginning severaldecades earlier; no use in cases began in the year precedingdiagnosis.

This study suggests that heavy use of over-the-counter analgesics is associated with an increased risk of cancer of the renalpelvis and ureter, and that the elevated risk extends acrossformulations containing all the major active ingredients of over-the-counter analgesics currently used in the United States. Ifrisk is limited to one or several preparations or ingredients, ourstudy was not sufficiently sensitive to determine this. A tendency to use multiple over-the-counter analgesics containingvarious formulations interchangebaly complicates attempts toproduce more exact risk estimates, as does the rarity of thesetumors and the relatively modest increase in risk associatedwith analgesic use.

REFERENCES1. Hultengren, N., Lagergren, ('., and Ljungqvist, A. Carcinoma of the renal

pelvis in renal papillary necrosis. Acta Chir. Scant]., lì:314-320, 1965.2. Bengtsson, I '.. Angervall, I... Elman, II.. and Lechmann, L. Transitional cell

tumors of the renal pelvis in analgesic abusers. Scant). J. Urol. Nephrol., 2:145-150,1968.

3. Hoybye, G., and Nielson, O. E. Renal pelvic carcinoma in phenacetin abusers.Scand. J. Urol. Nephrol., 5: 190-192, 1971.

4. Liu, T., Smith, G. W., and Rankin, J. T. Renal pelvic tumor associated withanalgesic abuse. Can. Med. Assoc. J., 107: 768-771, 1972.

5. Adam, W. R., Dawborn, J. K., Price, C. J., Pierce, C. G., Riddell, J., andStory, H. Anaplastic transitional-cell carcinoma of the renal pelvis in association with analgesic abuse. Med. J. Aust., l: 1108-1109, 1970.

6. Angersall, L., Bengtsson, U., Zetterlund, C. G., and Zsingmund, M. Renalpelvic carcinoma in a Swedish district with abuse of a phenacet in -contain ingdrug. Br. J. Urol., 41:401-405, 1969.

7. Nakanishi, K., Kurata, Y., Oshima, M., Fukushima, S., and Ito, N. Carcin-ogenicity of phenacetin: long-term feeding study in B6C3Fi mice. Int. J.Cancer, 29:434-444, 1982.

8. Isaka, H., Yoshii, H., Otsuji, A., Koike, M., Nagai, T., (Count. M., Sugiyasu,K., and Kanabayashi, T. Tumors of Sprague-Dawley rats induced by long-term feeding of phenacetin. Gann, 70: 29-36, 1979.

9. Calder, I. C., Funder, C. C., Green, C. R., Harn, K. N., and Tange, J. D.Comparative nephrotoxicity of aspirin and phenacetin derivatives. Br. Med.J., * 518-521, 1971.

10. Kuhlmann, W., Fromme, H. G., Heege, E. M., and Ostertag, W. Themutagenic action of caffeine in higher organisms. Cancer Res., 28: 2375-2389, 1968.

11. Ross, R. K., Paganini-Hill, A., and Henderson, B. Epidemiology of bladdercancer. In: D. Skinner and G. Lieskovsky (eds), Genitourinary Cancer, pp.23-31. Philadelphia: W. B. Saunders, 1988.

12. Hinson, J. A. Biochemical toxicology of acetaminophen. In: E. Hodgson, R.R. Bend, and R. M. Philpot (eds). Reviews in Biochemical Toxicology, Vol.2, pp. 103-129. New York: Elsevier, 1980.

13. Flaks. A., and Flaks, F. Induction of liver cell tumors in IF mice by paracetamol. Carcinogenesis (Lond.), 4: 363-368, 1983.

14. Hiraga, K., and Fujii. T. Carcinogenicity testing of acetaminophen in F344rats. Gann, 76:79-89, 1985.

15. Hagiwara, A., and Ward, J. M. The chronic hepatoxic, tumor-promoting andcarcinogenic effects of acetaminophen in male B6C3F1 mice. Fundam. Appi.Toxicol., 7:376-386, 1986.

16. McCredie, M., Ford, J. M., Taylor, J. S., and Stewart, J. H. Analgesics andcancer of the renal pelvis in New South Wales. Cancer (Phila.) 49: 2617-2625, 1982.

17. McCredie, M., Stewart, J. H., Ford, J. M., and MacLennan, R. A. Phenac-etin-containing analgesics and cancer of the bladder or renal pelvis in women.Br. J. Urol., 55: 220-224, 1983.

18. McLaughlin, J. K., Blot, W. J., Mandel, J. S., Schuman, L. M., Mehl, E. S.,and Fraumeni, J. F. Etiology of cancer of the renal pelvis. J. Nati. CáncerInst., 71: 287-291,1983.

19. Armstrong, B., Garrod, A., and Doll, R. A retrospective study of renal cancerwith special reference to coffee and animal protein consumption. Br. J.Cancer, 33: 127-136, 1976.

20. Mack, T. M. Cancer Surveillance Program in Los Angeles County. Nati.Cancer Inst. Monogr., 47: 99-101, 1977.

21. Breslow, N. E., and Day, N. E. Statistical Methods in Cancer Research, Vol.1. IARC Scientific Publication No. 32. Lyon, France: International Agencyfor Research on Cancer, 1980.

22. Schmauz, R., and Cole, P. Epidemiology of cancer of the renal pelvis andureter. Nati. Cancer Inst., 52: 1431-1434, 1974.

1048

on July 30, 2021. © 1989 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

1989;49:1045-1048. Cancer Res   Ronald K. Ross, Annlia Paganini-Hill, Joseph Landolph, et al.   Cancer of the Renal Pelvis and UreterAnalgesics, Cigarette Smoking, and Other Risk Factors for

  Updated version

  http://cancerres.aacrjournals.org/content/49/4/1045

Access the most recent version of this article at:

   

   

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/49/4/1045To request permission to re-use all or part of this article, use this link

on July 30, 2021. © 1989 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from