[CANCER RESEARCH 49. 5736-5747. October 15. 1989)

Screening Prescription Drugs for Possible Carcinogenicity: Eleven to Fifteen Yearsof Follow-up1

Joseph V. Selby,2 Gary D. Friedman, and Bruce H. Fireman

From the Division of Research, Kaiser Permanente Medical Care Program, Oakland, California 94611

ABSTRACT

Using computerized pharmacy records from 1969 to 1973 for a cohortof 143,574 members of the Kaiser Permanente Medical Care Program,we have been testing associations of 215 drugs or drug groups withsubsequent incidence of cancer at 56 sites. This paper presents findingswith follow-up through 1984. There were 227 statistically significant (P< 0.05, two-tailed) associations: 170 positive, 57 negative. Some wereundoubtedly chance findings; others were likely due to confounding byunmeasured covariables. However, several associations suggested hypotheses for further studies and/or the need for continued observation.Most notable among findings not previously reported were associationsof several antibiotics, both oral and topical, with lung cancer. Theseassociations could not be explained by indications for drug use or bydifferences in smoking habits between users and nonusers, and suggest apossible link between the occurrence of bacterial infections and risk forcancer.

In general, our results continue to suggest that most medications usedduring that period did not affect cancer incidence substantially. However,for less frequently prescribed medications, our power to detect moderateincreases in cancer risk was quite low.

INTRODUCTION

Extended postmarketing surveillance is essential for detectingpossible carcinogenicity of medications. For chemicals thatpromote growth of previously initiated cancer cells, the intervalbetween exposure and an increase in cancer incidence shouldbe relatively short. For those that initiate the process in normalcells, more than 20 years may elapse before an effect on cancerincidence is noted (1). Detection of such varied effects byepidemiological means requires observation over a period oftwo decades or more following initial exposure.

We have been following a cohort of 143,574 members ofKPMCP1 of Northern California for whom computerized in

formation on prescriptions was obtained during the years 1969-1973. Beginning with follow-up data through 1976, we haveconducted biennial screening analyses for incidence of cancerat 54 specific sites and two combinations of sites in personsexposed to each of 215 drugs or drug groups (see "AppendixA" for a complete listing of cancer sites and drugs screened).

In previous reports we presented results of screening analyseswith follow-up through 1976 (2) and 1978 (3). This reportupdates screening results through 1984.

This study was conceived as a hypothesis-generating investigation for detecting unsuspected drug-cancer associations.Many of the statistically significant associations, both positiveand negative, will be due to chance, given the very large numberof associations considered. However, other associations willsuggest the need for more detailed studies with control for

Received 3/21/89; revised 7/18/89; accepted 7/21/89.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.

1This work supported by National Cancer Institute Grant R37-CA-19939.2To whom requests for reprints should be addressed, at the Division of

Research. Kaiser Permanente Medical Care Program. 3451 Piedmont Avenue.Oakland. CA 94611.

' The abbreviations used are: KPMCP. Kaiser Permanente Medical CenterCare Program; SMR, standardized morbidity ratio: MHC. multiphasic healthcheckup.

potential confounders. For many drugs, these represent theonly available data on carcinogenicity in humans. We thereforeconsider it important to make this information available toscientists interested in drug safety and carcinogenesis.

SUBJECTS AND METHODS

Descriptionof Data Sources

Between 1969 and 1973, all prescriptions filled at the outpatientpharmacy for the San Francisco KPMCP facility were computer-stored.This facility served an ethnically and economically diverse population,numbering approximately 120,000 persons at any given time. A totalof 1,307,767 dispensings to 143,574 members were recorded. Meanage at initial prescription was 31 years; 54% of the cohort was female.Attrition from KPMCP membership in this cohort, including deaths,has averaged approximately 4% per year since 1972 with higher attrition rates in the first few years of follow-up and among younger cohortmembers. As of December 1984, 1,370,000 person-years of follow-uphad been accumulated and 68,695 persons (48% of the original cohort)remained active KPMCP members.

Occurrence of cancer was ascertained from the California Resourcefor Cancer Epidemiology, the tumor registry for the five counties ofthe San Francisco Bay Area, and from KPMCP hospital dischargeabstracts. For each tumor identified, the patient's medical record is

reviewed by a trained medical record analyst to verify diagnosis date,anatomic site and histológica! type. Through 1984, 6,809 incidentcancers have been verified in 6,382 cohort members.

Incident cancers are not detected for persons after they leave theHealth Plan. We have been concerned that risk estimates could bebiased if cancer risk differs between persons remaining in the HealthPlan and those who leave. Since the last report, we examined thispossibility in two ways. We ascertained mortality through 1980 for allcohort members using the California Automated Mortality System (6).In all, 9,771 deaths were confirmed, 4,408 due to cancer. Selected drug-cancer screenings were conducted on this mortality data and findingswere generally quite similar to those from our incidence data. We alsocompared our incident cancer cases through 1982 in a 10% sample ofthe cohort with those detected by the California Resource for CancerEpidemiology (7). Our surveillance missed 15% of cancers, largelythose that occurred in cohort members who had left KPMCP butremained in the area. The distribution of missing cancers appearedcomparable to that of those we detected. Because the gains in sensitivityfrom adding the overlooked cancers were relatively small (7) and costsof identifying these cases very high, we have not pursued this additionalcase ascertainment for our routine screening analyses.

Identification and Reporting of "Significant" Associations. Details ofour screening analysis methods have been described previously (2-4).Briefly, the number of new cases of each cancer observed in users of adrug is compared to the number expected. Expected numbers areobtained by calculating standard incidence density rates for each cancerin the entire cohort (by sex and 10-year age interval) and applying theserates to the age- and sex-specific distribution of follow-up for users ofeach drug. For the standard rates, follow-up begins at issuance of anyprescription and continues until diagnosis of the cancer, terminationfrom the Health Plan, or the end of 1984, whichever occurs first.Follow-up for a specific drug begins at first prescription of that drug.A SMR (observed/expected) is calculated to assess the strength of eachdrug-cancer association. The departure of the observed from expectednumber of cases is then tested for statistical significance assuming thatthe observed number follows a Poisson distribution.

The choice of method for reporting findings from these screening

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SCREENING DRUGS FOR CARC1NOGENICITY

analyses is difficult. Presenting results of all 12,040 tests is not practical.Listing a portion of the results in rank order by P value or SMR mayunduly favor the commonly used drugs and more frequently occurringcancers (P value ranking) or the less commonly prescribed drugs andrarer cancers (SMR ranking). A Bayesian approach is unappealingbecause little prior information is available for most associations andthe primary' purpose of these analyses is to detect previously unsus

pected relationships.In our opinion, no alternative offers a clear advantage over the

method we have used previously, which was to present all associationswith P values below 0.05, two tailed. However, as follow-up has continued, the number of associations with P values below this cutoff hasincreased to 227, 170 of which were positive. Because of this very largenumber of "significant" associations and the preponderance of positive

associations, this report will focus on those positive associations significant at P < 0.01, two-tailed. A list of positive associations with Pvalues between 0.05 and 0.01 is presented in "Appendix B." We

continue to report the smaller number of negative associations significant at P < 0.05, two-tailed. As in our previous reports, positiveassociations based on only one case are not included.

Control for Possible Confounding of Associations. Many of the observed drug-cancer associations are likely the result of confouding.Cancer-causing behaviors, in particular cigarette smoking, are relatedto use of a variety of medications in this cohort (8). In other instances,the indication for drug use may itself be associated with an increasedcancer risk (e.g., bronchodilators prescribed for chronic obstructivepulmonary disease leads to an apparent association of these drugs with

lung cancer). A drug may even be prescribed for early symptoms of anas-yet-undiagnosed cancer. Neither smoking status nor alcohol consumption is available for the entire cohort. However, this informationis available for a subset of 56,228 cohort members who also took atleast one MHC (5) at a KPMCP facility between 1964 and 1973. MHCdata have been used to explore possibilities of confounding by smokingin the association of antibiotics with lung cancer and the inverseassociation of bronchodilators with uterine cancer (see below). A secondcomputerized database containing records of all outpatient diagnosesat the San Francisco facility for the same years covered by the pharmacydata was used to establish presumptive indications for drug prescriptionin the investigation of the antibiotic-lung cancer and vitamin E-all

cancer associations (see below).All significant associations are reexamined after removing the 1 year

and 2 years of observation immediately following the first recordedprescription for the drug to eliminate associations due to drug use forearly symptoms of cancer. Associations are reported in this paper onlyif statistical significance persisted (P < 0.05) in the 2-year lag analysis,or alternatively, if the SMR was not reduced with lag analysis by morethan one-third of its original deviation from 1.0.

RESULTS

Table 1 is an alphabetical listing of drugs with at least onesignificant (/>< 0.01) positive association in follow-up through1984. For each drug, all significant associations are showntogether with findings for all cancers combined. Using a similar

Table 1 Drugs with at least one significant (P < 0.01) positive association, follow-up through 1984To be included in this table, the significance must persist in the 2-year lag analysis (P < 0.05). or the decrease in SMR (toward 1

the original difference from 1.0.0) must be less than one-third of

DrugAmpicillinAntacidsAspirin

withcodeineBelladonnaNo.

ofusers6,7063,05421.15816,072Cancer

typeorsiteLungAll

cancerEsophagusAll

cancerLungMouth

floorAllcancerStomachAll

cancerNumber

ofcasesObserved48168122291761388153750Expected27.3158.73.0201.1141.85.2848.028.3741.5SMR°1.761.064.031.141.242.491.041.871.01PValue<0.002<0.002<0.01<0.01<0.002Firstyear

when P <0.0519841980198419761984

Bronchodilators. systemic

Cyproheptadine

Dexchlorpheniramine maléate

Dicyclomine

Digitalis group

Diphcnylhydantoin

Erythromycin

Estrogens

Folie acid

Furosemide

5,329 Lung 68 32.7 2.08 <0.002 1976All cancer 247 218.4 1.13

883 Larynx 3 0.2 12.06 <0.01 1978All cancer 18 24.0 0.75

372 Nose, ear 2 0.1 24.10 <0.01 1978All cancer 26 26.7 0.98

2,115 Thyroid 6 1.4 4.23 <0.01 1976All cancer 71 68.5 1.04

2,466 Lung 56 34.0 1.65 <0.002 1976All cancer 261 211.5 1.23 <0.002

954 Brain 7 0.9 8.18 <0.002 1976All cancer 61 52.6 1.16

13.941 Lung 86 59.5 1.44 <0.002 1984Myeloma 14 5.1 2.72 <0.002 1980All cancer 454 425.8 1.07

5,965 Uterus 117 58.0 2.02 <0.002 1976All cancer 575 519.1 1.11 <0.05 1978

248 Oropharynx 2 0.1 26.01 <0.01 1980Hypophrynx 2 0.0 46.45 <0.002 1982All cancer 30 11.5 2.60 <0.002 1978

2,302 Pharynx, unspecified 2 0.1 19.80 <0.01 1976Lung 50 25.4 1.97 <0.002 1976All cancer 233 164.5 1.42 <0.002 1978

Continues

5737

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SCREENING DRUGS FOR CARCINOGENICITY

Table 1—Continued

Drug-,

BenzenehexachlorideMagaldrateMethyprylonMultivitaminsOral

contraceptivesPentazocinePentobarbitalPhenylbutazonePolymyxin-neomycin

(topical)Progestérones

& progestagensNo.

ofusers1,1483532491.88115,2081,6732,1563,6438,6822,850Cancer

typeorsiteHodgkinsAll

cancerUnspecified

leukemiaAllcancerLymphosarcomaAll

cancerEsophagusMouth

floorMouthunspecifiedHypopharynxAll

cancerCervix

uteriAllcancerPharynx

unspecifiedLungAll

cancerLungThyroidAll

cancerRectumAll

cancerBreastAll

cancerEndocrineAll

cancerNumber

ofcasesObserved324219420744413119344332512551621225296814883124Expected0.319.70.124.00.520.12.00.60.50.5111.5146.0385.60.113.394.324.11.4167.214.0305.057.8421.40.2125.8SMR"9.051.2237.270.798.730.973.446.517.717.741.171.321.1535.731.891.332.124.181.271.790.971.401.1614.900.99P

Value<0.01«cO.Ol<0.01<0.01<0.01<0.01<0.01<0.002<0.01<0.002<0.01<0.01<0.002<0.01<0.002<0.01<0.01<0.02<0.01Firstyear

when P <0.051984197819801976198219781976197619761976197619761976197619761980198019801984

Propantheline 1,600

Secobarbital 2,884

Senna 355

Spironolactone 1,475

Sulfathiazole-sulfacetamide-sulfabenzamide-urea 1,229(topical)

All cancer

Small intestineAll cancer

ThyroidAll cancer

Pharynx unspecifiedAll cancer

All cancer

121

4236

326

2155

64

90.8

0.7209.7

0.319.9

0.1127.4

36.8

1.33

6.021.13

11.541.30

20.541.22

1.74

<0.01

<0.01

<0.01

<0.01<0.05

<0.002

1984

19841980

1978

19761976

1982

Tetracycline

Trihexyphenidyl hydrochloride

22,810

177

LungAll cancer

Kidney, urinaryAll cancer

212980

316

163.9924.0

0.315.3

1.291.06

11.001.05

<0.002

<0.01

1982

1978

°SMR, standardized morbidity ratio, or observed cases divided by expected cases.

format, the 57 significant (P < 0.05) negative associations arepresented in Table 2. Because we have conducted three biennialanalyses since the last publication, the follow-up year in whichthe association first became statistically significant (at P< 0.05)is also shown.

DISCUSSIONThe number of "significant" associations, both positive and

negative, was well below the 600 that might be naively expectedby chance alone (12,040 hypothesis tests x 0.05). However, forboth positive and negative associations, the highest possible"significant" P value (at 0.05, two tailed) was generally well

below 0.05 because of the small size of expected values formany tests and the discrete nature of observed values. We mayestimate the actual number of associations that would be expected to fall below this cutoff by chance in these data bycalculating the average highest possible significant one-tailed P

value (i.e., P < 0.025 for each tail) among the 12,040 tests. Forpositive associations, across the 12,040 tests the average highestpossible P value below 0.025 was 0.010, yielding 120 associations. For protective associations, if the expected number ofcases was less than 3.69, even zero observed cases would not bestatistically significant. Through 1984, only 1,873 associationshad an expected number of 3.69 or more. For these, the averagehighest possible P value below 0.025 was 0.016, yielding 30additional associations. Combining these, only 150 of 12,040tests would be expected to be significant by chance at P < 0.05,two-tailed. That the observed number, 227, is substantiallyhigher than this suggests that some associations are due eitherto confounding or to a causal relationship.

Comments on Positive Associations (Table 1)

Most positive associations that were noted in follow-upthrough 1976 and 1978 have been discussed previously (2, 3)and are not reconsidered here.

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SCREENING DRUGS FOR CARCINOGENICITY

Table 2 Drugs with at least one significant (P < 0.05) negative association, follow-up through 1984To be included in this table, the significance must persist in the 2-year lag analysis, or the increase in the SMR (toward 1.0) must be less than one-third of the

original difference from 1.0.

DrugAmphetaminesAspirin

withcodeine/j-Methasone

(topical)Bronchodilators,

systemicCarbamide

peroxide(topical)ChlordiazepoxideDiazepamEphedrine

sulfateEstrogensFluocinolone

(topical)Glyceryl

guaiacolateHydrocortisone

(topical)Hydrocortisone,

propanediol diacetate. & acetic acid(topical)HydroxyzineMeclizineMeprobamateMethocarbamolMethylphenidate

hydrochlorideNapha/oline

(topical)Nicotinic

acidPenicillinPhcnformin

hydrochloridePhénobarbitalPhenylbutazonePhenylephrineNo.

ofusers3,30821,1584,1225,3293406,23912,9283745.9652,9898,0094,6507842,5172,1785,6215,4535291,4652.37830.2164545,8343.64311.981Cancer

typeorsiteSkinAll

cancerSalivaryAll

cancerPancreasAll

cancerUterusAll

cancerAll

cancerCervix

uteriKidney,urinaryAllcancerLarge

intestineHodgkinsAll

cancerAll

cancerCervix

uteriAllcancerSkinProstateBladderAll

cancerCervix

uteriAllcancerKidney,

urinaryAllcancerProstateAll

cancerBreastAll

cancerPancreasLungAll

cancerRectumThyroidAll

cancerOvaryAll

cancerAll

cancerSkinAll

lympho-mas/leukemiasAll

cancerEsophagusAll

cancerLipAll

cancerLarge

intestineAllcancerLarge

intestineBladderAll

cancerBladderAll

cancerSkinProstateAll

cancerContinues5739Number

ofcasesObserved017708812270124761214105708071145750521641334702480431011111718810044813601503101025507600463684365296633544Expected4.1170.54.3848.07.4256.710.0218.413.624.16.2415.379.94.7784.05.631.8519.14.914.17.4178.726.5350.23.9243.74.946.619.0121.86.228.1219.018.84.5445.86.9350.432.74.29.9124.93.8259.73.8766.14.836.450.118.0433.613.8305.018.549.8596.5SMR0.001.040.001.040.271.050.101.130.440.500.160.990.710.001.030.180.441.110.000.360.270.920.490.990.001.020.000.920.530.910.160.610.860.530.001.000.141.030.460.000.300.810.000.980.000.990.001.260.720.441.010.360.970.320.660.91P

Value<0.05<0.05<0.05<0.002<0.05<0.05<0.05<0.01<0.05<0.05<0.002<0.05<0.05<0.05<0.05<0.01<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.002<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.002<0.05<0.05Firstyear

when P <0.0519841980198419781984198219801980198219841976198419781984197619841982198419801982198019801982198019781984198419781982198219801982198419801982198219801980

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Table 2—Continued

DrugPolymyxin-neomycin

(topical)PotassiumPrednisolone.

injectedPrednisoneProgestérones

&progestagensPromethazine

expectorantPropoxypheneQuinine

sulfateRauwolfiaSimethiconeSulfacetamide

(topical)SulfisoxazoleTolnaftate

(topical)Triamcinolone

(topical)Trimethobenzamide

hydrochlorideTriprolidineNo.

ofusers8.6821,9761,9245.3982,85018.47717.9369524,2271,3387,81811,6592,34115,29081814,881Cancer

typeorsiteBrain

AllcancerProstate

AllcancerBreast

AllcancerCervix

uteriAllcancerAll

lympho-mas/leukemiasAllcancerSkin

AllcancerSkin

UterusAllcancerBladder

AllcancerBladder

AllcancerRectum

AllcancerProstate

AllcancerRectum

AllcancerLarge

intestineAllcancerStomach

BrainAllcancerBreast

AllcancerStomach

RectumAll cancerNumber

ofcasesObserved2

488S128i:14792851

12418

1,04019

461,1740106124640

9332

48411

56349516

67X61309

11469Expected7.5

421.511.9

117.122.0

170.919.3277.17.3

125.829.9

996.936.5

62.51.164.13.9

110.021.2463.24.190.146.2

494.720.4

538.111.1

108.226.0

13.1787.15.7

32.017.5

20.15 13.6SMR0.27

1.160.42

1.090.54

0.860.47

1.030.14

0.990.60

1.040.52

0.741.010.00

0.960.57

1.000.00

1.030.69

0.980.54

1.050.36

0.880.61

0.461.000.17

0.940.51

0.550.91P

Value<0.05

<0.002<0.05<0.05<0.05<0.05<0.05<0.01

<0.05<0.05<0.05<0.05<0.05<0.05<0.05<0.05

<0.05<0.05<0.05

<0.05<0.05First

yearwhen P <0.05198019841978

19761978198219761976

1980198419801982

1982197619781980

19801976

198219821984

19841980

*SMR. standardized morbidity ratio, or observed cases divided by expected cases.

Antibiotics and Lung Cancer. Ampicillin, tetracycline, anderythromycin use were each significantly (P < 0.01) associatedwith an increased risk for lung cancer; three other antibioticswere also associated with lung cancer with P values between0.01 and 0.05: cephalexin (9 observed, 3.3 expected, P = 0.01),cloxacillin (7 observed, 2.7 expected, P = 0.04), and sulfameth-oxazole (23 observed, 14.5 expected, P = 0.05). Except forcephalexin, these six associations first became significant withfollow-up through 1982 or later. Lag analyses (1- and 2-year)did not diminish any of the associations substantially. Risk wasalso increased slightly among 30,216 users of penicillin (118observed, 102.8 expected, P = 0.15). For three other antibiotics,sulfisoxazole, doxycycline, and clindamycin, SMRs were 1.0 orslightly below.

We hypothesized that antibiotic use for respiratory infectionsrelated to cigarette smoking and chronic obstructive pulmonarydisease could explain this cluster of associations. However,when indications for antibiotic prescriptions were obtained bylinking to the outpatient diagnosis file, confounding by indication for use did not explain the association. Risk was as highor higher for each antibiotic when prescribed for nonsmoking-related indications (e.g., urethritis, cystitis, evilulitis) as for

indications related to smoking (e.g., acute and chronic bronchitis, emphysema, cough, pneumonia). We also conducted longitudinal analyses in the 30,567 adult pharmacy cohort members who took at least one MHC using Cox proportional hazards models to control for cigarette smoking status (scored asnever-, ex-, or current smoker of <1, 1-2, or >2 packs per day).Relative hazards for use of five of the six antibiotics wereincreased somewhat after adjustment. Thus, the associationsare not the result of excess cigarette smoking among antibioticusers. Although chance could explain these findings, the pos-siblity that susceptibility to bacterial infection may reflect anincreased susceptibility to cancer as well as has been raised (9)and should be investigated further.

Antacids and Cancer of the Esophagus. The association ofantacid use with esophageal cancer was diminished only slightlyin the 2-year lag analysis, suggesting that antacid use for earlysymptoms of esophageal cancer is not the principal explanationfor this association. In the United States, 80 to 90% of allesophageal cancer has been attributed to the combined effectsof alcohol and cigarette smoking (10). The antacids-esophagealcancer association may therefore reflect use of antacids forother smoking and alcohol-related illnesses such as peptic ulcer

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disease and gastritis. An excess of stomach cancer was alsonoted among antacid users (18 observed, 7.3 expected, P =0.001), but this association was almost completely eliminatedin the 2-year lag analysis (7 observed, 6.0 expected).

Aspirin with Codeine and Cancer of the Lung. Aspirin withcodeine, a frequently used narcotic analgesic, was associatedwith a slight increase in risk of lung cancer with follow-upthrough 1984. An increase in cancer of the floor of the mouthhas been present since the initial analyses (follow-up through1976). This, together with increases in both lung and pharyngealcancer among recipients of pentazocine (Table 1) suggests thatusers of narcotic analgesics may more frequently be cigarettesmokers, and at increased risk for a variety of cancers becauseof this behavior.

Belladonna and Cancer of the Stomach. An excess of stomachcancer was noted among users of belladonna preparations infollow-up through 1984. Risk was confined to the 91% ofbelladonna users who received oral rather than topical preparations. These preparations were almost exclusively antispas-modic combinations used to treat acute or chronic gastrointestinal symptoms. Risk declined in the 2-year lag analysis (fromSMR = 1.93 to SMR = 1.67), suggesting that the drug wassometimes used for treatment of early cancer symptoms.

Phénobarbitalwas often combined with belladonna in thesepreparations. We have previously reported increased risks forseveral cancers (not including stomach cancer) among barbiturate users in this dataset (2,3, 11, 12). Risk was lower (SMR= 1.47) among 1,402 persons receiving belladonna preparationswithout phénobarbitalthan in the much larger group of 13,229persons who also received phénobarbital(SMR = 1.96). Moreover, the SMR declined to 1.00 in the 2-year lag analysis in theformer group, but remained elevated in those receiving phénobarbital (SMR = 1.76, 31 observed, 17.6 expected, P = 0.005).Risk for stomach cancer was not increased among recipients ofphénobarbitalprescriptions (5 observed, 5.23 expected) in follow-up through 1984. Thus, our data do not provide consistentevidence for an association of either belladonna or phénobarbital with stomach cancer.

Folie Acid and Cancers of the Oropharynx, Hypopharynx, andAll Cancer. Folie acid has been associated with an increasedincidence of all cancer since its first analysis with follow-upthrough 1978 (3). The cancers occurring in excess have beenlargely smoking and/or alcohol-related and we have previouslynoted that most folie acid recipients have a diagnosis of alcoholism in their medical records. Thus, alcohol and cigarettes inthis group is the likely explanation for their excess of cancers.

Erythromycin and Multiple Myeloma. An association betweenerythromycin and multiple myeloma was first noted in follow-up through 1980. We are unaware of other reports of possiblecarcinogenic effects of erythromycin. However, erythromycinis known to inhibit hepatic enzymes responsible for metabolismof at least two drugs, theophylline (13) and cyclosporine (14).Erythromycin could alter metabolism of potentially carcinogenic compounds as well, resulting in excessive or prolongedexposure to such agents.

Duration or intensity of exposure to erythromycin did notdiffer between the 14 erythromycin users who developed multiple myeloma and 28 randomly selected age-, sex-matchedcontrols who had also used erythromycin but did not developmyeloma. Nor did indications for erythromycin use differ tosuggest possible confounding factors. The age distribution atdiagnosis (mean age, 68 years) was not unusual for multiplemyeloma. Thus we find no supporting evidence for either acausal association or a confounded relationship and suspectthat chance may have produced this finding. Other antibiotics

were not, in general, associated with an increased risk formyeloma.

Methyprylon and Lymphosarcoma. Four cases of lymphomaoccurred among 249 users of methyprylon compared to 0.5cases expected. The date of diagnosis ranged from 15 monthsto 8 years following the first recorded methyprylon prescription.Three cases were diffuse histiocytic lymphomas; two arose inthe stomach, and the extent of disease could not be defined inthe third. The fourth case was a polymorphous lymphocyticlymphoma arising in the base of the tongue. Methyprylon, likebarbiturates (see below), induces hepatic microsomal enzymes(15), which may alter the metabolism of other potential carcinogens. Methyprylon has been associated anecdotally with bothneutropenia and thrombocytopenia, but we were unable toidentify previous reports of associations with cancer at any site.Thus, at present we are inclined to attribute this finding tochance variation.

Nonprenatal Multivitamins and Various Cancers. Associationsof multivitamin use with cancers of the hypopharynx and esophagus have been noted since 1976, with cancers of the mouthsince 1978, with cancer of the tongue since 1980, with cancerof the floor of the mouth since 1982, and with all cancer since1984. These associations are likely due to a higher prevalenceof alcoholism and increased cigarette smoking among personsprescribed multivitamins. Among the 4,676 recipients of prenatal vitamins there was no significant increase in cancer at anysite and an SMR of 0.95 for all cancers combined.

Phenylbutazone and Cancer of the Rectum. A significant excess of cancer of the rectum was first noted among users of thisnonsteroidal antiinflarnmatory agent in follow-up through 1980and has persisted with continuing follow-up. No other cancersoccurred to a significant excess in phenylbutazone users. Inanimals studies, phenylbutazone does not appear to act as eithera primary carcinogen or as a promoter of tumor development(16). In humans, the drug has been associated with leukemiaand lymphatic malignancies in case reports. We did not find anassociation in a large case-control study of leukemia and lymphoma (17). We are unaware of any reports linking phenylbutazone to cancers outside the lymphatic/hematopoetic systemand suspect that the association noted here is a chance finding.

Propantheline and All Cancer. The incidence of all cancer wasincreased among users of this anticholinergic medication whichis frequently used to treat peptic ulcer disease and other gastrointestinal symptoms. No single cancer occurred in significantexcess. Small increases were noted in the incidence of stomach,pancreas, espohagus, and large intestine cancers, but thesedeclined substantially in the lag analyses suggesting use forearly symptoms of the cancers. Other cancers occurring in slightexcess included lung, melanoma, uterine corpus and cervix, andurinary bladder. That most of these are smoking-related cancerssuggests that cigarette smoking could have led to both pepticulcer disease (with propantheline use) and subsequently tocancer

Secobarbital and Cancer of the Small Intestine. The association of secobarbital use with cancer of the small intestine is oneof several positive associations we have noted for users of threecommonly prescribed barbiturate preparations (2, 3, 11, 12).Incidence of this cancer was not increased among 5,834 phénobarbital users or 2,156 pentobarbital users through 1984.Incidence of lung cancer among users of each preparation hasbeen significantly increased over expected in each analysis since1976, although for phénobarbitalthis association was no longerstatistically significant in follow-up through 1984 (71 observed,58 expected, P = 0.12). Animal studies (18-20) provide biological plausibility for a tumor-promoting role of barbiturates, but

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SCREENING DRUGS FOR CARC1NOGENICITY

epidemiological evidence is inconclusive (20). The question of and Hodgkin's disease, magaldrate and unspecified leukemia,

potential carcinogenic effects of barbiturates in humans remains senna and thyroid cancer, and trihexylphenidyl hydrochlorideunsettled and deserves further investigation.

Polymyxin B-Neomycin Preparations and All Cancer. Topicalpreparations containing polymyxin B and neomycin sulfatewere associated with a significantly increased total cancer incidence. Increased incidence of breast cancer (81 observed, 57.8expected, SMR = 1.40, P = 0.005) and lung cancer (84 observed, 65.3 expected, SMR = 1.29, P = 0.03) accounted formost of the excess. Five other topical medications containingneomycin including preparations intended for ophthalmic, nasal, skin and vaginal application, were also screened, includingdexamethasone phosphate and neomycin (718 users), dexa-methasone, neomycin, and polymix (371 users), flurandrenolideand neomycin (398 users), gramicidin-neomycin-nystatin-triamcinolone (5,364 users) and hydrocortisone-neomycin (325users). For each of these, breast cancer incidence was greaterthan expected, though differences were not significant (P >0.05).

The SMR for breast cancer was 1.3 (P = 0.007) for allneomycin users combined, with some evidence of a dose-response effect. The SMR was 1.28 (94 observed, 73.6 expected)in 9,715 members who received only one neomycin prescription, and 1.75 (13 observed, 7.4 expected) for 912 users of twoor more prescriptions. Lung cancer risk was not consistentlyelevated in each small group of users, but for all users combined,SMRs for lung cancer were similarly elevated: 1.22 for recipients of one neomycin prescription (80 observed, 65.6 expected),and 1.70 (17 observed, 10.0 expected) for those receiving twoor more prescriptions.

These associations were not entirely specific to the neomycincomponent. In 4,697 members receiving a polymyxin B-baci-tracin preparation, incidence of breast cancer was also increased(43 observed, 29.8 expected, SMR = 1.44, P = 0.03), butincidence of lung cancer was slightly less than expected. In 622members who received polymyxin B alone, there was no increase in breast cancer incidence, but the SMR for lung cancerwas increased (11 observed, 6.44 expected, SMR = 1.71, P =0.13). No increases for either lung or breast cancer were notedamong users of bacitracin, gramicidin, or topical steroid preparations without neomycin or polymyxin B, or in 301 users oftopical gentamicin.

Indications for neomycin use among recipients who developed breast cancer were varied and suggested no obvious confounding explanations. These associations remain unexplained,but they could also reflect a factor that increases susceptibilityto both infections and cancer.

Sulfathiazole-sulfacetamide-sulfabenzamide-urea and All Cancer. Incidence of all cancer was increased among users of triplesulfa vaginal preparations, the SMR declining only slightly in2-year lag analysis: from 1.74 (P< 0.0001) to 1.55 (P= 0.005).The excess was based largely on an increased incidence ofcervical cancer (26 observed, 11.3 expected) and breast cancer(18 observed, 9.9 expected). The association with cervical cancer was greatly reduced by the lag analysis (15 observed, 9.5expected, P > 0.05), suggesting use of the medication forsymptoms of early cervical cancer or precursor conditions. Thebreast cancer association, however, persisted (18 observed, 8.9expected, P = 0.01). There is no obvious confounding factor toexplain this association.

Other Positive Associations Based on Two or Three ObservedCases. Positive associations based on two or three observedcases (Table 1) included progesterone and progestogens andendocrine cancers, cyproheptadine and laryngeal cancer, dex-chlorpheniramine and nasal cancer, 7-benzene hexachloride

and cancer of the kidney. Medical records of these 19 caseswere reviewed to look for evidence of prolonged exposure,possible confounding factors, or a specific unusual histológica!type of cancer that might support a causal relationship. Withthe exception of trihexyphenidyl hydrochloride, exposure toeach of these drugs among the cases was limited to one recordedprescription. Medical records did not suggest confounding byindication for drug use except for one man who developedsquamous cell carcinoma of the maxillary antrum after receiving dexchlorpheniramine once for nasal polyps and allergicrhinitis, and one woman who received medroxyprogesteronefor treatment of amenorrhea which proved to be due to apituitary adenoma.

In the three cases of renal cancer, the interval between firstexposure to trihexyphenidyl and cancer diagnosis ranged from5 to 13 years. In two cases, exposure was prolonged but in thethird, exposure lasted less than 3 weeks. Two cancers were renalcell carcinomas, one an incidental finding at autopsy; the thirdwas a clear cell adenocarcinoma.

Positive Associations (P < 0.01) in Follow-up through 1980or 1982, But Not 1984. Five associations were significant at P< 0.01 in either the 1980 or 1982 follow-up analyses or both,

but not in 1984. Sulfamethoxazole was associated with increased occurrence of multiple myeloma in 1980 (5 cases, 0.94expected in 1,709 users, SMR = 5.31, P = 0.006). No additionalcases occurred in this group during the next 4 years, the SMRdeclining to 3.92 (P = 0.02) in 1984. Lesser increases in riskwere also noted in 1984 analyses for cancer of the lung (23observed, 14.5 expected, P = 0.05) and uterine cervix (12observed, 5.9 expected, P = 0.04), and for the combination ofall lymphomas and leukemias (16 observed, 7.6 expected, P =0.01). A slight excess for all cancer (116 observed, 100.5 expected) was not significant. There is no other epidemiologieevidence of carcinogenicity of this drug. Sulfamethoxazole hasbeen reported to produce thyroid tumors in a single study inrats (22). Interestingly, the closely related drug sulfisoxazolewas not associated with an excess of cancer at any site in ourdata.

Pyridoxine and lung cancer were strongly associated in 1980and 1982 analyses (15 observed cases, 4.28 expected in 1980,SMR = 3.27, P < 0.0001). Lag analyses markedly decreasedthe strength of these associations, but significance (at P < 0.05)persisted. In 1984, these associations did not remain significantin the lag analysis. The main indication for pyridoxine use iscoprescription with isoniazid for treatment or chemoprophy-laxis of tuberculosis. Similar associations with lung cancer havebeen noted for isoniazid since the first analysis (3). The sharpdeclines in these associations in lag analyses suggested to usthat in some cases patients may have received antituberculoustherapy for pulmonary lesions that later proved to be cancerous.Chart review of the isoniazid-associated lung cancer cases confirmed that this was the case in seven of 18 patients (3). Excesscigarette smoking among persons who develop tuberculosis andthe known association of lung cancer with tuberculosis (23) arelikely explanations for the associations that remain after laganalyses.

An association of aminoacridine-sulfanilamide-allantoinpreparations with cervical cancer was noted in 1982 (41 casesobserved, 22.8 expected, P< 0.0001). Lag analyses reduced theassociation to nonsignificance in other years, including 1984,suggesting use for treatment of symptoms of early cervicalcancer or, more likely, associated conditions.

A topical antiseptic, triclobisonium, was associated with

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SCREENING DRUGS FOR CARCINOGENICITY

breast cancer in 1982 (28 observed, 15.7 expected, SMR =1.78, P= 0.006). By 1984, this association had declined slightlyto an SMR of 1.60 (P = 0.02). An association of polyvinylalcohol/chlorbutanol preparations (used to soften ear wax) withmale genital cancers based on two cases was significant in 1982(2 observed, 0.03 expected, P < 0.001 ). One case was eliminatedin 2-year lag analysis, and by 1984 the lag analysis was nolonger significant.

Comments on Negative Associations (Table 2)

Most of the negative, or protective, associations (Table 2)involved only a single cancer site with no corresponding deficitin the incidence of all cancer. In the absence of biologicalevidence for a protective effect, we believe that most of theseassociations are the result of chance. Associations that wereparticularly strong, those that included a significantly lowerincidence of all cancer, and those for which biological explanations have been proposed are discussed here.

Bronchodilators and Uterine Cancer. A low incidence of uterine cancer has been observed among users of bronchodilatorssince the 1978 analysis. Two possible confounding factors ofthis protective association are a higher prevalence of smokingamong users of bronchodilators and a higher prevalence ofallergies and asthma in this group. Cigarette smoking has anantiestrogenic effect leading to earlier menopause, less post-menopausal bleeding, and an apparently lower risk for endo-metrial cancer (24, 25). Excess cigarette smoking among usersof bronchodilators was suggested by a significantly increasedincidence of lung cancer in this group since the initial analysisin 1976 (Table 1) and by a slightly higher prevalence of currentcigarette smoking in the 768 women in the MHC subgroupwho had received bronchodilators compared with those whohad not (41 versus 38%). Bronchodilator use is also a markerfor asthma. The allergic state itself has been suggested to protectagainst occurrence of cancer in several studies (26).

Estrogens and Cancer of the Uterine Cervix. The negativeestrogen-cervical cancer association is most likely explained bya higher prevalence of hysterectomy, which precludes subsequent cervical cancer, among women using estrogens. A common indication for estrogen replacement therapy is surgicalmenopause induced by hysterectomy with oophorectomy.

Vitamin E and Lowered Incidence of AH Cancer. An apparentprotective association of vitamin E use with incidence of allcancer (23 observed, 34.6 expected in 476 users, SMR = 0.67,P = 0.05) was noted in the 1982 analysis. By 1984, the SMRhad risen to 0.73, P = 0.10, and the association is therefore notshown in Table 2. However, because vitamin E has been suggested to have preventive effects for cancer (27), we investigatedthis association further. Nearly all of the apparent protectionwas among female users of vitamin E (8 observed, 18.36 expected in 288 users, SMR = 0.44). Largest deficits were forbreast cancer (1 observed, 4.68 expected), lung cancer (3 observed, 5.20 expected) and colon cancer (3 observed, 4.46expected).

There was no evidence of a dose-response effect. Personswho received only one vitamin E prescription appeared to beprotected (9 observed cancers, 22.4 expected), whereas thosereceiving two or more prescriptions had no apparent protection(14 observed, 12.1 expected). The outpatient diagnosis filerevealed that 85.6% of all prescriptions were issued from theotolaryngology clinic, almost all of these by a single physician.Consequently, the major indications for vitamin E use wereENT conditions, including tinnitus, vertigo, and sensorineuralhearing loss. None of these diagnoses were themselves associated with a significantly lowered risk of all cancer in the cohort.

The absence of a dose-response effect and the isolation of theeffect to women do not support a causal protective association.

Diazepam, Colon Cancer, and Hodgkin's Disease. Concernhas been raised regarding the possible carcinogenicity of diaze-

pam in humans on the basis of reports of enhanced growth ofmammary tumors in rats (28). In the 12,928 users of diazepamin this cohort, the incidence of cancer at two sites, large boweland Hodgkin's lymphoma, was significantly (P < 0.05) lowerthan expected. Consistent with results of three recent case-control studies (29-31), the incidence of breast cancer was notsignificantly different than expected (155 observed, 143.8 expected, SMR = 1.08, P = 0.37). No significant positive associations of diazepam use were noted for cancer at any site. Foranother benzodiazepine, chlordiazepoxide, deficits of cervicaland kidney cancer were noted (Table 2). Slight excesses of lungcancer (73 observed, 57.1 expected, SMR = 1.28, P = 0.05)and cancer of the floor of the mouth (6 observed, 2.1 expected,SMR = 2.90, P = 0.04) suggest an association of drug use andcigarette smoking. Our data therefore provide no evidence todate to suggest that these widely used anxiolytics present acarcinogenic risk.

Meclizine and Lowered Incidence of AH Cancer. An apparentprotective effect of meclizine was seen on incidence of all cancer(188 observed, 219.0 expected among 2,105 users, SMR =0.86, P = 0.03). Significant deficits were noted for lung cancer(17 observed, 28.1 expected, SMR = 0.61, P = 0.03) andpancreatic cancer (1 observed, 6.2 expected, SMR = 0.16, P =0.03). No substantial deficits were noted for any other cancersite. The analyses of cancer incidence by indication describedfor vitamin E above showed no association of vertigo, theprinciple indication for the use of meclizine, with loweredcancer incidence. Overlap of this group of meclizine cases withvitamin E users in our database was minimal; less than 2% ofmeclizine users also received vitamin E. That both cancer siteswith reduced incidence are smoking-related suggests that, forsome unknown reason, meclizine users may smoke less thannonusers.

Phenylephine, Triprolidine, and Naphazoline and LoweredIncidence of AH Cancer. These three commonly prescribedgroups of medications were each associated with significantlylowered incidence of all cancer as well as cancer of at least onespecific site. In addition to lowered incidence of skin, prostate,stomach and rectal cancer shown for one or more of thesegroups in Table 2, smaller nonsignificant deficits of lung cancer,pancreatic and bladder cancer were seen in all three groups.Among 3,410 users of pseudoephedrine (without an antihista-mine), incidence of lung, skin, prostate, and pancreatic cancerwere again reduced (though not significantly), as was all cancerincidence (95 observed, 108.3 expected, SMR = 0.08, P =0.21).

The phenylephrine group included both topical (ophthalmic)and oral preparations, often combined with antihistamines.Triprolidine was usually combined with pseudoephedrine, andthe naphazoline group included both ophthalmic and nasalpreparations. Thus it is difficult to isolate individual components or preparations in this group of medications. Each ofthese medications is often used for allergic symptoms, againsuggesting the explanation that the allergic state may be associated with lower cancer incidence (2). Persons with allergiesmay also smoke less, although the cancers showing loweredincidence were not uniformly smoking related.

Drug Cancer Associations Reported Elsewhere. Our data areof interest in relation to some recent reports of drug-cancerassociations. Concern about hydralazine (32) was partially allayed by its lack of association with breast cancer in one study

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SCREENING DRUGS FOR CARCINOGEN1CITY

(33). Our findings to date agree; among 237 female users ofhydralazine, six breast cancers were observed versus 6.3 expected. No other associations were observed among the 400hydralazine users of both sexes.

Follow-up of 954 recipients of diphenylhydantoin does notsupport reports (34, 35) of an association with Hodgkin's andnon-Hodgkin's lymphoma, multiple myeloma, and leukemia.

There were 4 observed and 4.6 expected cases of all lymphomasand leukemias combined with no statistically significant associations noted among the individual histological types. Werecently reported (36) a lack of association with multiple myeloma.

Levodopa has been suspected of enhancing the developmentof malignant melanoma in bening nevi (37). Only 100 personsreceived levodopa in our cohort; none have developed malignantmelanoma.

An association of methyldopa with cancer of the biliary tracthas been suggested (38), but neither Strom et al. (39) nor we(one case observed, 0.8 expected) could confirm this.

Concluding Remarks

Reexamination of our data after 11 to 15 years of follow-upcontinues to provide limited evidence that, with the exceptionof a few known associations, the ordinary clinical use of mostPharmaceuticals commonly prescribed between 1969 and 1973does not pose increased risks for cancer. Caution is requiredbecause the number of users of many of the drugs in our study

was relatively small (see "Appendix A") so that power to detect

modest increases in cancer risk for these drugs is quite low.Furthermore, if a drug acts as a primary carcinogen only aftera latent period of 20 years or more, our 1,370,000 person-yearsof follow-up through 1984 may contribute very little to detecting the association.

As the number of person-years of follow-up accumulates,power to detect a given SMR increases accordingly. However,if a drug acts as a "promoter" of cancer, its effect may be

expected to be relatively prompt and to last for a limited periodafter exposure ceases. Extending follow-up beyond this periodmay allow subsequent cancer incidence in both cases and controls to "wash out" an early effect. Thus, positive associations

noted in our earlier reports (2, 3) should not be discountedsimply because they are no longer statistically significant.

Many drugs now in common use were not available in 1973or earlier. Of the 50 drugs prescribed most commonly withinKPMCP during 1986, 14 were first marketed after 1973. Dataare now being collected within our organization and elsewherethat will, in time, be useful for examining the possible carcin-ogenicity of these recently introduced drugs.

ACKNOWLEDGMENTS

We wish to express our appreciation to Donna Wells for computerprogramming, and to Merril Jackson. Betty Wong, and Betty Jue whoperformed chart reviews.

APPENDIX A

Table A1 List of 56 cancer sites (and combinations) studied

ICDA-8code140141142143144145146147148149ISO151152153154155156157CancerLipTongueSalivary

glandGumMouth

floorMouth,unspecifiedOropharynxNasopharynxHypopharynxPharynx,

unspecifiedEsophagusStomachSmall

intestineLargeintestineRectumLiverGallbladderPancreasICDA-8

code158159160161162163170171172173174180181182183184185186CancerPeritoneumDigestive,

unspecifiedNose,earLarynxLung,

trachea,bronchusOther& unspecifiedrespiratoryBoneConnectiveSkin

melanomaSkinBreastCervix

uteriChorionepitheliomaUterusOvaryFemale

genitalProstateTestisICDA-8

code18718818919019119219319420020120220.1204205206207208209CancerMale

genitalBladderKidney,

urinaryEyeBrainNervous

systemThyroidglandEndocrineglandsLymphosarcomaHodgkinsOther

lymphomaMultiplemyelomaLymphaticleukemiaMyeloidleukemiaMonocyticleukemiaOther

& unspecifiedleukemiaPolycythemiaveraMyelofibrosisAll

lymphomas &leukemiasAllcancers

Table A2 List of 215 medications (or medication groups) studied Table A2—Continued

DrugsNo. ofusers

Systemic drugsAcetaminophenAcetaminophen with codeineAcetazolamideAllopurinolAmantadine hydrochlorideAmitriptylineAmphetaminesAmpicillinAntacidsAspirinAspirin with codeineAspirin-phenacctin-caffeine-butalbitalAspirin, enteric coatedAspirin, phenacetin, & caffeineAtropine

3.2382.612

507491

951,9573,3086.7063,054

38121.158

2.393393718390

Drugs

BelladonnaBenztropine mesylateBisacodylBismuth magma & paregoricBrompheniramineBronchodilators. systemicCarisoprodolCephalexinChloral hydrateChlorambucilChlordiazepoxideChlorpheniramineChlorpromazineChlorzoxazoneClindamycin

Continues

5744

No. ofusers

16,072197503841

6,9645.329

837474

2,290142

6.23913.443

869428343

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Table A2—Continued Table A2—Continued

DrugsClofibrateCloxacillinColchicineColistin

sulfateCyclophosphamideCyproheptadineDexamethasoneDexbrompheniramineDexchlorpheniramine

maléateDiazepamDicyclomineDiethylpropion

hydrochlorideDigitalisgroupDimenhydrinateDioctyl

sodiumsulfosuccinateDiphenhydramineDiphenhydramine

hydrochloride &phenylpropanolamineDiphenoxylateDiphenylhydantoinDoxycyclineEphedrine

&guaifcncsinEphedrinesulfateEpinephrineErgonovineErgotamine

tartrateErythromycinEstrogensEthambutol

hydrochlorideEthinylestradici &methyltestosteroneFluoxymesteroneFlurazepam

hydrochlorideFolieacidFurosemideGlutethimideGlyceryl

guaiacolateGriseofulvinGuanethidine

sulfateHydralazinehydrochlorideHydrocodone

bitartrate & homatropinemethylbromideHydromorphonehydrochlorideHydroxyzineHydroxyzine-ephedrineImipramine

hydrochlorideIndomethacinInsulin

zincsuspensionIron,noprenatalIsoniazidIsophanc

insulinsuspensionIsoproterenolhydrochlorideIsosorbidedinitrateLevodopaMagaldrateMeclizineMeprobamateMethocarbamolMethyldopaMethylphenidate

hydrochlorideMethyprylonMetronidazoleMultivitaminsNicotinic

acidNitrofurantoinNitroglycerinNylidrin

hydrochlorideOralcontraceptivesOxycodoneOxytetracyclinePenicillinPentaerythritol

tetranitratePentazocinePentobarbitalPhenaphen

withcodeinePhenazopyridinePhenformin

hydrochloridePheniraminePhenmetrazine

hydrochloridePhénobarbitalPhenytbutazonePhenylephrinePhenylpropanolaminePotassiumPotassium

iodideNo.

ofusers1456628499242948838741,30237212.9282.1158802.4664352,17110,1054254.2409543444383743893,06677313,9415,9651181681659102482.3023338.0097446064904891992,5172,8073084,867837.9676652763932571003532.1785.6215,4531.4165292492.4601.8812.3781.3051.99917415.2081,07765030,2163001,6732.1563752,2144541.1385065,8343.64311,9811,5581,9761,664Drugs

No. ofusers

Prednisolone, injectedPrednisonePrenatal vitaminsPrimidoneProbenecidProcainamide hydrochlorideProchlorperazineProgestérones& progestagensPromethazine expectorantPromethazine hydrochloridePropanthelinePropoxyphenePropranolol hydrochloridePropylthiouracilPseudoephedrinePS;,Ilium hydrophilic mucilloidPyridoxine hydrochloridePyrrobutamine phosphatePyrvinium pamoateQuinidine gluconate, quinidine sulfateQuinine sulfateRauwolfiaSecobarbitalSecobarbital & amobarbitalSecobarbital, butabarbital, & phénobarbitalSennaSimethiconeSpironolactoneSulfamethoxazoleSulfisoxazoleSulfisoxazole & phenazopyridine hydrochlorideTerpin hydrateTetracyclineThiazidesThioridazineThyroid hormoneTolazamideTolbutamideTrifluoperazine hydrochlorideTrihexyphenidyl hydrochlorideTrimeprazine tartrateTrimethobenzamide hydrochlorideTripelennamine hydrochlorideTriprolidineVitamin B-complex & vitamin CVitamin EWarfarin sodium

Topical drugsAcetic acid & aluminum acetateAminoacridine-sulfanilamide-allantoinBacitracinBenzalkonium chloride & chlordantoinBetamethasoneBismuth resorcin compoundBoric alcohol-hcort-gentian violet ear dropsCalcium propionate & sodium propionateCandicidinCarbacholCarbamide peroxideDexamethasone Na phosphate & neomycin sulfateDexamethasone, neomycin, & polymixinDibucaineDienestrolEchothiophate iodideEpinephryl borateFluocinoloneFluocinonideFluorouracilFlurandrenolideFlurandrenolide & neomycin sulfateFormaldehyde solutionFurazolidone & nifuroxime7-Benzene hexachlorideGentamicin sulfateGramicidin-neomycin-nystatin-triamcinoloneHcortisone. propanediol diacetate, & acetic acidHexylcaine hydrochlorideHydrocortisoneHydrocortisone & neomycinlodochlorhydroxyquin

1,9245,3984,474

91584322

3,4592,850

18,477417

1,60017,936

269107

3.410916606352634671952

4,2272,884

521170355

1,3381,4751.709

11,659438

2.61422,81012,799

2632,752

86719678177689818592

14,881397436633

6563,119

614546

4,122716998400652159340718371374

1,778204184

2,989708355

2,251398557500

1,148301

5,364784310

4,650325

2,068

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Table A2—Continued Table Al—Continued

DrugslodoquinolLevo-epinephrineLidocaineLidocaine

&hydrocortisoneMedrysoneNaphazolineNitrofurazoneNystatinOxymetazolinePhenol,

sodium phcnolate.etc.PilocarpinePolymyxin

BsulfateAPPENDIX

BNo.

ofusers5381347,8683053751,4653176,7531,9803711.020622DrugsPolymyxin-neomycinPolyvinyl

alcohol &chlorobutanolPramoxineSalicylic

acid,2%Salicylicacid,25%Selenium

sulfideSulfacetamideSulfathiazole-sulfacetamide-sulfabenzamide-ureaTetrahydrozoline

hydrochlorideTolnaftateTriamcinoloneTriclobisoniumNo.

ofusers8,6823026226576402,0377,8181,2296672,34115,2903,149Table

Bl Positive drug-cancer associations with P values < 0.05 but 20.01DrugAcetaminophenAcetic

acid and aluminumacetate"AllopurinolAminoacridine-sulfanilamide-allan-toin"AmitriptylineAmpicillinAtropineBelladonnaBetamethasone"BisacodylBismuth,

magma andparegoricBronchodilators.

systemicCarbachol"CarisoprodolCephalexinC'hloral

hydrateChlordiazepoxideChlorpheniramineCloxacillinCyprohepatadineDexamethasone

sodiumphos-phate/neomycinsulfate"Dexchlorpheniramine

maléateDienestrol"

Diethylpropion hydrochlorideDigitalispreparationsDioetyl

sodiumsulfosuccinatcDiphenylhydantoin

Echothiophateiodide"EpinephrineEstrogens

Fluocinolone"Fluocinonide"

Fluorouracil"FluoxymesteroneFlurandrenolide"Flurazepam

hydrochlorideFolieacidFormaldehyde

solution"Furazolidineand nifuroxime"CancerSkin

melanomaEsophagusNose,

earMyelogenous

leukemiaThyroidLiverMyelofibrosisBreastOther

respiratoryThyroidUterusThyroidLarynxKidney,

uretersLargeintestineSkinmelonomaLarynxAll

lymphomas andleu-kemiasLung,

trachea,bronchusFloorofmouthSkin

melanomaFloorofmouthLung,trachea,bronchusBrainMyelomaLung,

trachea,bronchusSkinmelanomaAllcancerLymphosarcomaMyelogenous

leukemiaHodgkin's

ProstateLung

BoneEsophagus

StomachLargeintestineAll

cancerSkinmelanomaUterus

UterusSkinmelanomaHypopharynx

Hodgkin'sMouth,

unspecifiedBladderMyelogenousleukemiaLung,

trachea,bronchusSkin,melanomaAll

cancerObserved/expected1

2/6.13/0.62/0.13/0.57/2.44/1.02/0.28/3.18/3.414/7.422/12.72/0.23/0.54/0.837/24.43/0.53/0.59/3.89/3.33/0.69/3.76/2.173/57.119/11.413/6.67/2.73/0.656/44.33/0.66/1.9

2/0.243/29.020/12.13/0.6

4/1.05/1.6575/519.1

10/4.66/1.7

4/1.02/0.23/0.6

3/0.62/0.2

3/0.52/0.15/1.33/0.421/14.2Drug7-Benzene

hexachloride"Gentamicinsulfate"GlutethimideGlyceryl

guaiacolatcGramicidin-neomycin-nysta-tin-triamcinolone"Guanethidine

sulfateHydroxyzineephedrineInsulin

(zincsuspension)lodochlorhydroxyquin"Iron,

nonprenatalIsoniazidIsoproterenol

hydrochlorideMeclizineMedrysone"MethyldopaMultivitaminsNicotinicacidNitrofurantoinNitroglycerin

PentazocinePhenmetrazinehydrochloridePhénobarbitalPhenylpropanolaminePilocarpine"

Poly mixin-neomycin"Polyvinyl

alcohol/chlorobu-tanol"Potassium

PotassiumiodidePrednisolone.injectedPrednisone

ProcainamidehydrochlorideProchlorperazine

Progesterones/progestogensPromethazine

expectorantPropoxyphenePropranolol

hydrochloridePsylliumhydrophilicmueilloidPyridoxine

hydrochlorideCancerLarynxMyelomaAll

lymphomas andleu-kemiasAll

lymphomas andleu-kemiasSalivary

glandLarynxUterusKidney,

uretersBreastBladderBladderLarge

intestineMyelogenousleukemiaUnspecifiedleukemiaEsophagusLung,

trachea,bronchusThyroidUterusKidney

uretersTongueMouth,

unspecifiedUterinecervixNervoussystemLung,

trachea, bronchusFloor ofmouthLargeintestineGallbladderBoneStomachStomach

Lung, trachea, bronchusUterusStomachLymphocytic

leukemiaBladderKidney,uretersLung,

trachea, bronchusLymphosarcomaBreastSmall

intestineSkinLiverLung,

trachea, bronchusUterinecervixLung,

trachea,bronchusOtherlymphomaUnspecified

leukemiaEsophagusObserved/expected2/0.22/0.24/1.06/2.25/1.56/2.020/12.14/0.97/2.83/0.62/0.112/5.98/3.33/0.43/0.610/4.85/1.45/1.66/2.14/1.04/1.011/5.53/0.642/29.4

3/0.48/2.98/3.23/0.65/1.511/5.484/65.3

29/19.35/1.35/1.2

8/3.37/2.857/40.5

13/6.48/3.43/0.5

5/1.618/10.4194/166.5

89/71.27/2.84/1.02/0.23/0.5Continues5746

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SCREENING DRUGS FOR CARCINOGENICITY

Table Bl—Continued

DrugPyrvinium

pamoateQuinidine(gluconate orsulfate)Quinine

sulfateSeeobarbital.

butabarbital. & phénobarbitalSeleniumSulfide"SennaSpironolactoneSulfacetamide"SulfamethoxazoleCancerProstateHodgkin'sBreastUterusLung,

trachea,bronchusUterusProstateAll

cancerRectumLung,

trachea,bronchusUterinecervixMyelomaObserved/

expected7/2.82/0.113/6.612/5.86/2.19/3.74/1.0155/127.429/19.223/14.512/5.95/1.3DrugSulfathiazole-sulfacetamide-sulfabenzamide-urea"Terpin

hydrateThiazidediureticsThyroidhormoneTolbutamideTriamcinolone"Triclobisonium"Trimeprazine

tartrateTripelennaminehydrochlorideTriprolidineCancerAll

lymphomas andleu-kemiasBreastMyelomaAll

cancerUterusPolycythemia

veraUterusNose,

earBreastUterine

cervixGallbladderThyroidHodgkin'sObserved/

expected16/7.618/9.96/1.91209/1132.928/16.82/0.255/38.03/0.430/18.87/2.32/0.215/7.810/4.2

°Topical preparations.

REFERENCES20

1. Farber, E. Chemical carcinogenesis: a current biological perspective. Carci-nogenesis (Lond.), 5: 1-5, 1984. 21.

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3. Friedman, G. D., and Ury, H. K. Screening for possible drug carcinogenicity:second report of findings. J. Nati. Cancer Inst., 71: 1165-1175, 1983. 23.

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