Pesticides How Research Has Succeededand Failed in Informing Policy: DDT and theLink with Breast CancerMary S. WolffDepartment of Community Medicine, Environmental and Occupational Medicine, Mount Sinai School ofMedicine, New York, New York

Investigation of chemical exposures as possible etiologic factors for breast cancer has not been a research priority in the United States, which is sur-prising given the evidence from animal studies that environmental chemicals cause cancer and reproductive dysfunction. Study of environmentalchemicals has also been indicated by the failure of traditional epidemiologic methods to account for significant proportions of breast cancer inci-dence with other risk factors. The fact that breast cancer risk is strongly associated with reproductive hormones is a further clue that environmentalchemicals should be investigated. In addition to cancer, specific outcomes that need to be explored are reproductive dysfunction, immunotoxicityand neurotoxicity. Policy guiding our research should encourage toxicologic investigations of exposures to environmental chemicals that use state-of-the-art methods to determine exposure and human health effects. Using the approach suggested by John McLachlan, functional toxicologyshould be used to assess the activity of chemicals with regard to these outcomes. Just as dioxin toxicity can be expressed as toxic equivalents,estrogenic activity, for example, can be characterized in terms of estrogenic equivalents. In addition to the need to undertake this kind of research,needs for methods development and creative research funding mechanisms are discussed. Prevention of breast cancer may require intervention atan early age. Better understanding of breast cancer etiology, and especially its environmental components, may lead us toward that goal. - EnvironHealth Perspect 1 03(Suppl 6):87-91 (1995)

Key words: breast cancer, DDT, estrogenicity, epidemiology, methods, exposure

Pesticides such as DDT have been regu-lated in the United States for more thantwo decades. The ban of DDT followedobservation of adverse reproductive effectsin wildlife along with evidence of carcino-genicity in animals and biological persis-tence in animals and humans. DDTbelongs to a class of organochlorines thatincludes a number of other pesticides-chlordane, hexachlorobenzene, benzenehexachloride (aka lindane), for example-and halogenated biphenyls (polychlorinatedbiphenyls or PCBs). Many organochlorines,including DDT and PCBs, were banned inthe 1 970s. Chlordane was regulated morerecently, and lindane remains in limitedpharmaceutical use.

In some ways, the policy to banorganochlorines has worked. From theU.S. Environmental Protection Agency's(U.S. EPA) National Human Adipose

This paper was presented at the Symposium onPreventing Child Exposures to EnvironmentalHazards: Research and Policy Issues held 18-19March 1994 in Washington, DC. Manuscript received:December 5, 1994; accepted: May 15, 1995.

Address correspondence to Dr. Mary S. Wolff,Department of Community Medicine, Environmentaland Occupational Medicine, Box 1057, 1 Gustave L.Levy Place, Mount Sinai School of Medicine, NewYork, NY 10029. Telephone (212) 241-6183. Fax (212)996-0407.

Tissue monitoring program, data clearlyshow that levels of DDT in adipose tissuein the U.S. population have steadilydeclined since 1972 (Figure 1) (1). PCBlevels are also going down, albeit moreslowly (2). In addition, control of DDTestablished a precedent that has probablyfacilitated regulation of other organochlo-rine pesticides (e.g., chlordane) and persis-tent halogenated hydrocarbons. An examplewould be polybrominated biphenyls (PBBs)that were used as a fire retardant until a dis-astrous contamination of cattle feed inMichigan in 1973 and 1974. Control ofpesticide usage has also stimulated a searchfor less toxic, more readily biodegradablepesticides. Registration of pesticides is nowmandatory for new products, which mustsatisfy requirements of safety and toxicity.

An unfortunate consequence of regula-tory policy is that policymakers may takethe view that banning solves the problem. Itseems obvious that the efficacy of regulatorypolicy should be supported by scientificevaluation and systematic followup. Thus,with DDT, potential for exposure stillexists even 20 years after its ban, andorganochlorines continue to pervade theenvironment. Regulation may have halteddeliberate discharge into the ecosystem inthe United Sates, but its continued use indeveloping countries allows DDT to cross

international borders in food produce andin the air and water. Only recently has theUnited States decided to restrict exports ofa number of pesticides including DDT (3).

Continuing environmental contamina-tion by organochlorines has resulted in sus-tained low-level exposure among wildlifeand concomitant reproductive dysfunction(4). Body burdens of DDT in humans arestill significant in the United States andworldwide. International studies frequentlyreport detectable levels of DDT residues,with special concern directed toward thoseubiquitous levels in human milk that oftenexceed exposure guidelines recommendedto protect against cancer (5). Human milkis now the major source of infant exposureto DDT in the United States. Ironicallylactation is the most efficient means ofreducing a woman's body burden oforganochlorines.

Status of Research on DDTand Human Health EffectsAfter 1972, little further attention was paidto research directed specifically to identifyhuman health effects from DDT. Thiscomplacent attitude may be attributed tothe absence of overt, prominent humanhealth effects due to DDT exposure, inspite of overwhelming evidence of tumori-genicity and reproductive failure in

Environmental Health Perspectives 87

M.S. WOLFF

IL

10 -W

cl.

E 6-m

- 4-

2-

1950 1955 1960 1965 1970 1975 1980 1985

Figure 1. Levels of DDT in adipose tissue in the U.S.population. Data from Kutz et al. ( 1).

animals. Indeed some researchers con-cluded that DDT was quite safe for humans.

In view of the extensive animal data onreproductive dysfunction, the scientific lit-erature has remarkably few studies onhuman reproduction related to DDT expo-sure. Moreover, existing studies are limitedwith respect to numbers of subjects as wellas overall design sophistication. Only fourhuman reproductive studies are cited byIARC, two focusing on prenatal effects andtwo on preterm abortion (6).

Attempts to determine cancer risk asso-ciated with DDT exposure have beensomewhat more extensive, but the data arenevertheless quite inconclusive. Humanstudies have looked for elevated rates ofany kind of cancer death among industri-ally exposed persons. Some have focusedon potential risks for lung cancer, liver can-cer, lymphoma, soft-tissue sarcoma, andleukemia in case-control studies. However,few of these studies had adequate exposureassessment, which lessens the power todetect an effect. In many reports, therewere no adequate controls for exposuresother than DDT, and most studies did notstart out specifically to investigate DDTcancer risk (6). Nevertheless, hematopoi-etic cancer and lung cancer risk continuesto be weakly associated with DDT expo-sure estimates in more recent studies.

As a result, existing research effortshave led to the conclusion that DDT is apossible human carcinogen, although it isdesignated as carcinogenic to animals (6).Evidence for reproductive toxicity is con-sidered scant, whereas in animals clearimpairment is recognized. An exception isthe reported observation in 1986 that sug-gested a hormonal effect of DDT; this wasthe finding that women with higher bodyburdens of DDE reported shorter durationof lactation (7). A second study recentlyconfirmed these findings (8). This researchoriginated at the National Institute ofEnvironmental Health Sciences (NIEHS),an agency whose intramural program has

supported an innovative approach tohuman exposure and to experimental stud-ies on hormonally active substances.Indeed, since these were the first stronghuman data of the kind, the observationrelating high DDE levels to curtailed lacta-tion led us to examine the relationship ofpersistent organochlorines to breast cancerrisk that will be described below.

In view of this evidence, the policy thatbanned DDT has failed to influence ournational research agenda. Not enougheffort has been made to target environmen-tal research in the area of hormonallyrelated cancers. To some extent, this failureis now being redressed by currentNIEHS/NCI (National Cancer Institute)initiatives. In defense of current policy, itcould be said that animal carcinogenicitystudies on organochlorines led researchersto look at the wrong outcomes, becausethese relatively high-dose studies foundmainly liver tumors, a relatively rare tumorin humans in the United States. However,the animal data also indicate that organo-chlorines are estrogenic and may be tumorpromoters, and therefore specific studydesigns should have been investigated toassess this role for DDT and comparableorganochlorines in both animals andhumans. (One such report exists in the ani-mal literature.) No particular attention hasyet been paid to the potential environmen-tal link with ovarian, colon, endometrial,testicular, prostate, and breast cancer. Inview of the unexplained risk and risingrates for breast cancer and prostate cancer,environmental etiology for these tumors isan important line of research that shouldbe vigorously pursued.

Environmental links to cancer immedi-ately afford a means of prevention. Thefailure to make this a research priority hasbeen criticized in characterizing the narrowapproach to cancer research since declara-tion of the war on cancer (9). These past20 years have seen an increase, rather than areduction, in overall cancer rates. Criticsmaintain that our national approach has"neglected research aimed at prevention infavor of the search for cures" (10). Evenamong those researchers who subscribe tothe environmental thesis, many maintainthat increased rates of cancer can be attrib-uted to diet and smoking and not industrialcarcinogens. Meanwhile, environmentalareas that have been explored as means ofcancer prevention include viruses, vitamins,diet, tamoxifen, smoking, occupationalexposures, radiation, but not pollution orambient chemical exposures (10).

Breast Cancer and DDT

Breast cancer research has been cited as an

example of setting poor research prioritiesin that no attempts were made to pursue a

connection between cancer and exposure

to carcinogenic chemicals in the foodchain, even in the context of an otherwiseenormous investment in studying linksbetween diet and cancer (10). There were

five studies on breast cancer and DDTexposure before 1985, and only one ofthese was in the United States. Yet, otherrisk factors have not been able to fullyexplain the dramatic increase in breast can-

cer rates in the United Sates during 1970to 1990, and only some of the increase isattributable to enhanced screening.

Environmental factors have long beeninvoked as an explanation for breastcancer, but environmental chemicals per se

have not been widely accepted as risk fac-tors for breast cancer. Rather, epidemio-logic studies have implicated the diet,alcohol consumption, drug use, and radia-tion as risk factors for breast cancer thatmight account for the environmental evi-dence. Unfortunately, the identification ofthese risk factors has not gone very far inproviding us with an explanation for a

major proportion of breast cancer inci-dence nor have these studies given us muchhope for preventing a significant amount

of the disease. Investigation of chemicalexposures as possible etiologic factors forbreast cancer has not been a priority, whichis surprising given the several animal mod-els that use chemical carcinogens [e.g.,polycyclic aromatic hydrocarbons (PAH),methylnitrosourea (MNU)].

In the past few years, evidence hasemerged that supports a possible relation-ship between breast cancer and exposure to

organochlorines in the environment,whence exposure occurs predominantlythrough the diet. There have been fourrecent case-control studies linking envi-ronmental organochlorine exposures to

breast cancer risk (Table 1). The relativerisks reported in these studies are in therange of 2 to 10. If the data are confirmedin future research, these will rank among

the higher risks observed for breast cancer

in the epidemiologic literature. However,the studies were relatively small and requireextensive confirmation before this associa-tion becomes an established risk factor forbreast cancer.

In the late 1980s, the first of these stud-ies in Connecticut found approximately50% higher levels of DDE [bis(4-

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POLICYIMPLICATIONS OFRESEARCH ONDDTAND BREASTCANCER

Table 1. Recent case-control studies of breast cancer and DDT exposure.

References Cases Controls Relative risk

Mussalo-Rauhamaa et al. (16) 44 33 a(correlation DDE-ER)Falck et al. (12) 20 20 -3 (67 > 33 percentile)Wolff et al. (13) 58 171 -4 (10-90 percentile)Dewailly et al. (14) 18 17 ER+: -9 (67>33 percentile)

"Relative risk of 10 for highest BHC (hexachlorocyclohexane) exposures.

chlorophenyl)- 1,1 dichloroethene]*, DDT[bis(4-chlorophenyl)-- ,1,1-trichloroethane],and higher chlorinated PCBs in mammaryadipose among 20 breast cancer cases com-pared with 20 controls (11). The risk forDDT was not statistically significant. Therewas approximately a 3-fold increased risk forthe highest versus the lowest tertile of thesechemicals in adipose tissue.A second study took advantage of a

well-designed nested case-control study inwhich blood had been collected beforediagnosis of breast cancer (12). Again, lev-els of DDE and PCBs in serum werehigher among breast cancer cases thanamong carefully matched controls, butonly differences for DDE were statisticallysignificant. Women with the highest levelsof DDE (upper 10%) had about a 4-foldincreased risk compared with levels in thelowest 10%. There was approximately a9% increased risk for every one part perbillion (ppb) ofDDE in blood serum.

Quite recently, a Canadian study foundsignificantly higher levels of DDE in estro-gen receptor-positive (ER) breast cancercases compared with ER-negative cases andwith controls (13). For ER-positive breastcancer, the relative risk was approximately9 for the highest versus the lowest tertile ofthese chemicals in adipose tissue. In sup-port of this evidence, H. Mussalo-Rauhamaa (14) has more recently reporteda correlation between DDE levels and ERlevels in their patients, although the find-ings require cautious interpretation sinceno age adjustment was made.

Similar relative risks for breast cancerwere found among the Finnish womenwith elevated levels of P-hexachlorocyclo-hexane, a lindane-related residue, althoughno association was found with otherorganochlorines including DDE (15). Therelative risks in these four studies are in thesame range as those estimated from theanimal data (16,17). The potential associa-tion with ER status is of some interest,

given the estrogenic activity of DDT andthe rising rates of ER-positive canceramong older women (18).

Since DDT levels in the U.S. popula-tion are gradually receding, this trendshould accompany reduced risk of any dis-ease associated with DDT exposures in theUnited States. However, DDT and otherorganochlorines are still widely used indeveloping countries where it may affectpublic health or it may cross internationalborders. Furthermore, besides DDT thereare myriad other potentially estrogenicchemicals in commerce that require ourvigilance (4,19). Many of these new chem-icals are not detectable long after exposure,e.g., atrazine and methoxychlor.

Future Research PrioritiesHow can our scientific research establish-ment be more effective in protectinghuman health? Whether or not the DDT-breast cancer link is confirmed, these find-ings have great potential for teaching usmore about breast cancer etiology and inleading us toward preventive strategies.Several lines of research can be suggested.In addition to the potential for prevention,much can be learned about etiology byunderstanding environmental contributionsto breast cancer (Table 2).

Research Areas to Emphasize inEnvironmental ResearchRecent work on breast cancer, as well asaccumulating evidence about reproductivefailure in animals, should encourage vigor-ous exploration of chemical factors in theenvironment. Cancer, reproductive dys-function, and neurotoxicity need to beinvestigated. One prominent researcher inthe field of environmental estrogens hasrecently suggested that we should designour research using functional toxicology,i.e., research that defines chemicals moreby their function than by their chemistry(20). One such area of toxicology thatmerits research attention in both basicscience and epidemiology is reproductivedysfunction by environmental chemicals(e.g., estrogenicity or endocrine disrup-tion). In a similar context, toxic equivalent

Table 2. Research priorities in human environmentaltoxicology.

Cancer, reproductive dysfunction, neurotoxicityFunctional toxicology: relative toxicity using equivalents

* Dioxin toxic equivalency (TED)* Estrogenicity (EEQ?)* Neurotoxicity (NEQ?)

Methods for epidemiology and statistics* Study design strategies* Data analysis techniques

Methods for exposure assessment* Individual biological markers* Markers/indices for short-lived chemical exposures

Funding mechanisms* Solicited proposals by NIH for testing unusualhypotheses

* Special review process

(TEQ) factors have been developed fordioxin-like activity, which may also parallelantiestrogenic activity (21). From theavailable literature, it is possible to con-struct estrogenicity or endocrine equiva-lents (EEQ?) that might be useful in termsof relative biological activity for regulatorypurposes (22,23). This database can beeasily expanded to include a wide range ofenvironmental contaminants.

Functional toxicology also touches afurther field that is of potentially great rele-vance to breast carcinogenesis, i.e. the rela-tionship between P450 activity andexposures to DDT and other organochlo-rines. Association of elevated P450 activitywith DDT and PCB exposure in humanshas been known for many years (24,25).Organochlorines have been widely studiedfor their ability to induce P450 enzymeswhose baseline activity is genetically deter-mined. The cytochrome P450 enzymes areresponsible for metabolizing endogenous,as well as exogenous, chemicals in the body(e.g., estrogen and PAH). Certain of thesemetabolites may act as ultimate carcino-gens that bind directly to DNA and causemutations. The genes for P450 are poly-morphic in humans, and the distributionsof the polymorphisms vary between differ-ent ethnic populations. Hormones are alsometabolized by these enzymes. However,while the P450 enzymes have been widelystudied, only recently has this area begunto reach fruition in the study of humancancer (26). Although no information iscurrently available on breast cancer, anumber of investigations on breast cancerare now underway.

Methods Development NeedsResearch priority should be placed uponimproving methods for exposure assessmentand into developing innovative epidemio-

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*DDE is the major residue of DDT in the environ-ment, and it is usually found in humans at higherlevels and more frequently than any other organo-chlorine.

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logic and statistical methodologies forstudy design and analysis. Better epidemio-logic tools and improved quantitation willallow us to design epidemiologic studies totrace putative carcinogenic pathways.Other endpoints besides cancer are impor-tant to study as well. Reproductive andneurotoxic effects may be important riskoutcomes to consider.

Existing methodologies are often inade-quate to study complex diseases like cancer,reproductive dysfunction, and neurotoxic-ity, especially when attempting to link sub-tle biological effects with complex andlow-level exposures. Therefore, researchtesting of environmental hypotheses wouldbe greatly facilitated by the availability ofbetter epidemiologic instruments andsophisticated statistical techniques.Improved methods would enable us tomore adequately evaluate associationsbetween indicators of preclinical disease,genetic factors, causal agents, and risk.

Techniques are needed for exposureassessment that will provide quantitativeindividual measurements. These tech-niques must be able to detect very low lev-els of exposure that are common inenvironmental circumstances. Internal bio-logical markers of exposure and disease areusually more sensitive and specific thanestimates using external methods (i.e., airpollution or water contamination levels).This may be useful for DDT, where cumu-lative body burdens persist for many years,reflecting integrated past exposure.However, many of the newly developedpesticides that have replaced organochlo-rines are not persistent, presenting a diffi-cult problem in exposure assessment. Withrespect to cancer risk, exposure assessmentis even more difficult because initiatingevents may have taken place 10 to 30 yearsbefore cancer diagnosis. Similarly, PAHand nitro compounds are potential etio-logic agents for cancer and are not persis-

tent in the body. For this reason, historicalexposure information has often been used;this is another means of external exposureassessment methods.

Funding MechanismsOur scientific research and funding strate-gies must allow more creative ideas to betested. En route to soliciting and establish-ing new methodology and to confirmingand extending our research on DDT andbreast cancer, it may be necessary to fine-tune our research review and funding poli-cies. Traditional funding mechanismspossess a certain rigidity toward new,unconventional ideas. The NationalInstitutes of Health (NIH) likes to fund asure thing. As a result, it is a constantstruggle to eke out support appropriatefunding mechanisms for new, untestedideas, especially in the current climate oftight funding. Multiple reviews or specialscreening panels for special projects mightbe considered. The Request for Application(RFA) mechanism may also be suitable forcircumventing the entrenched reviewprocess and for encouraging scientificflights of fancy. Recently NCI and NIEHShave issued RFAs that will allowresearchers to confirm and expand thesefindings. Criticism has been leveled at theU.S. EPA on another front-that ofwhethera regulatory agency can successfully under-take and administer a research program(27). Since the U.S. EPA's budget is a sig-nificant proportion of funding for environ-mental research, its record of performancein predicting as well as preventing environ-mental disease may be a starting point forexamining the structure of this agency.

Relevance to EnvironmentalHealth Effects among ChildrenThe example of breast cancer relates tochildren's environmental health, especiallywith respect to the potential for prevention

of exposures. Evidence in animals demon-strates that developing tissues are more sen-sitive to carcinogenic exposures. Recentevidence, though limited, suggests thatexposure to cigarette exposure or alcohol atan early age may be associated withincreased risk for breast cancer amongyoung women. Women in the UnitedStates have markedly higher age-specificrates of breast cancer compared withJapanese women, and the differences aremost dramatic among premenopausalwomen. Part of the difference may bedietary or environmental factors that alterthe onset of puberty, which occurs muchlater in Japanese women. Therefore pre-ventive measures such as dietary interven-tion may need to be undertaken at an earlyage. Prevention of environmental expo-sures related to breast cancer is also be animportant potential means of preventionthat should be vigorously pursued.

Rates of breast cancer occurrence in theUnited States have steadily risen since1940. During that same period, levels ofpesticide and PCB residues in human adi-pose tissue in the United States haveshown parallel increase, following theirintroduction into commerce around thetime of World War II. Since then, despitemuch research on the question, only threefactors have been generally agreed to bestrongly linked to breast cancer: age, coun-try of birth, and family history. These fac-tors are not readily amenable to change.Medicine has done its job well in findingnew avenues of treatment and detection.However, the existence of a cure without acause continues because no pathways forprevention have been found. Innovativeresearch should be undertaken to developbetter methods and to elucidate potentialmechanisms for environmental exposuresand breast cancer.

REFERENCES

1. Kutz FW, Wood PH, Bottimore DP. Organochlorine pesti-cides and polychlorinated biphenyls in human adipose tissue.Rev Environ Contam Toxicol 120:1-82 (1991).

2. Robinson PE, Mack GA, Remmers J, Levy R, Mohadjer L.Trends of PCB, hexachlorobenzene, and P-benzene hexachlo-ride levels in the adipose tissue of the U. S. population. EnvironRes 53:175-192 (1990).

3. Hanson DJ. Administration seeks tighter curbs on exports ofunregistered pesticides. Chem Eng News 72:16-17 (1994).

4. Colborn T, vom Saal FS, Soto AM. Developmental effects ofendocrine-disrupting chemicals in wildlife and humans.Environ Health Perspect 101:378-385 (1993).

5. Wolff MS. Occupationally derived chemicals in breast milk.

Am J Industr Med 4:259-281 (1983).6. WHO, IARC. Occupational exposures in insecticide applica-

tion, and some pesticides. In: IARC Monographs on theEvaluation of Carcinogenic Risks to Humans, Vol 53. Lyon:International Agency for Research on Cancer, 1991; 179-249.

7. Rogan WJ, Gladen BC, McKinney JD, Carreras N, Hardy P,Thullen J. Tingelstad J, Tully M. Polychlorinated biphenyls(PCBs) and dic lorodiphenyldichloroethane (DDE) in humanmilk: effects on growth, morbidity, and duration of lactation.Am J Pub Health 77:1294-1297 (1987).

8. Gladen BC, Rogan WJ. DDE and shortened duration oflactation in a northern Mexican town. Am J Pub Health (inpress).

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9. Beardsley T. A war not won. Sci Am 270:130-138 (1994).10. Epstein S. Environmental and occupational pollutants are

avoidable causes of breast cancer. Int J Health Serv 24:145-150(1994).

11. Falck FY, Ricci A Jr, Wolff MS, Godbold J, Deckers J.Pesticides and polychlorinated biphenyl residues in humanbreast lids and their relation to breast cancer. Arch EnvironHealth 47:143-146 (1992).

12. Wolff MS, Toniolo P, Lee E, Rivera M, Dubin N. Blood levelsof organochlorine residues and risk of breast cancer. J NatlCancer Inst 85:648-652 (1993).

13. Dewailly E, Dodin S, Verreault R, Ayotte P, Sauve L, Morin J.High organochlorine body burden in women with estrogenreceptor positive breast cancer. J Natd Cancer Inst 86:232-234(1994).

14. Mussalo-Rauhamaa H. Selenium and DDE in breast fat ofbreast cancer patients: their relationship to hormone receptorsin breast tissue. J Natd Cancer Inst 85:1964-1965 (1993).

15. Mussalo-Rauhamaa H, Hasanen E, Pyysalo H, Antervo K,Kauppila R, Pantzar P. Occurrence of P-hexachlorocyclohexanein breast cancer patients. Cancer 66:2125-2128 (1990).

16. Foran JA, Cox M, Croxton D. Sport fish consumption advi-sories and projected cancer risks in the Great Lakes basin. Am JPubl Health 79:322-325 (1989).

17. Silberhorn EM, Glauert HP, Robertson LW. Carcinogenicityof polyhalogenated biphenyls: PCBs and PBBs. Crit RevToxicol 20:440-496 (1990).

18. Glass AG, Hoover RN. Rising incidence of breast cancer: rela-tionship to state and receptor status. J Natl Cancer Inst82:693-696 (1990).

19. Davis DL, Bradlow HL, Wolff MS, Woodruff T, Hoel DG,Anton-Culver H. Medical hypothesis: xeno-estrogens as pre-

ventable causes of breast cancer. Environ Health Perspect101:372-377 (1993).

20. McLachlan J. Functional toxicology: a new approach to detectbiologically active xenobiotics. Environ Health Perspect5:386-387 (1993).

21. Krishnan V, Safe S. Polychlorinated biphenyls, dibenzo--diox-ins, and dibenzofurans as antiestrogens in MCF-7 humanbreast cancer cells: quantitative structure-activity relationships.Toxicol Appi Pharmacol 120:55-61 (1993).

22. Korach KS, Sarver P, Chae K, McLachlan JA, McKinney JD.Estrogen receptor-binding activity of polychlorinated hydroxy-biphenyls: conformationally restricted structural probes. MolPharmacol 33:120-126 (1988).

23. Soto AM, Lin T-M, Justicia H, Silvia RM, Sonnenschein C.An in-culture bioassay to assess the estrogenicity of xenobiotics.In: Chemically Induced Alterations in Sexual Development:The Wildlife/Human Connection (Colborn T, Clement CR,eds). Princeton, NJ:Princeton Scientific Publishing Co,1992;295-309.

24. Alvares A, Fischbein A, Anderson KE, Kappas A. Alterations indrug metabolism in workers exposed to polychlorinatedbiphenyls. Clin Pharmacol Ther 22:140-146 (1977).

25. Poland A, Smith D, Kuntzman R, Jacobson M, Conney AH.Effect of intensive occupational exposure to DDT onphenylbutazone and cortisol metabolism in human subjects.Clin Pharmacol Ther 11:724-732 (1970).

26. Gonzalez FJ, Gelboin HV. Role of human cytochrome P-450sin risk assessment and susceptibility to environmentally baseddisease. J Toxicol Environ Health 40:289-308 (1993).

27. Stone R. Can Carol Browner reform EPA? Science 263:312-315(1994).

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