Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Pesticides--How Research Has Succeeded and Failed in Informing Policy:
DDT and the Link with Breast Cancer
Mary S. Wolff
Department of Community Medicine, Environmental and Occupational Medicine,
Mount Sinai School of Medicine, New York, New York
Abstract
Investigation of chemical exposures as possible etiologic factors for
breast cancer has not been a research priority in the United States, which
is surprising given the evidence from animal studies that environmental
chemicals cause cancer and reproductive dysfunction. Study of environmental
chemicals has also been indicated by the failure of traditional epidemiologic
methods to account for significant proportions of breast cancer incidence
with other risk factors. The fact that breast cancer risk is strongly associated
with reproductive hormones is a further clue that environmental chemicals
should be investigated. In addition to cancer, specific outcomes that need
to be explored are reproductive dysfunction, immunotoxicity and 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 toxicology should 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 at an early age. Better understanding of
breast cancer etiology, and especially its environmental components, may
lead us toward that goal. -- Environ Health Perspect 103(Suppl 6):87-91
(1995)
Key words: Breast cancer, DDT, estrogenicity, epidemiology, methods,
exposure
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
Address correspondence to Dr. Mary S. Wolff, Department
of Community Medicine, Environmental and Occupational Medicine, Box 1057,
1 Gustave L. Levy Place, Mount Sinai School of Medicine, New York, NY 10029.
Telephone (212) 241-6183. Fax (212) 996-0407.
Pesticides such as DDT have been regulated in the United
States for more than two decades. The ban of DDT followed observation of
adverse reproductive effects in wildlife along with evidence of carcinogenicity
in animals and biological persistence in animals and humans. DDT belongs
to a class of organochlorines that includes a number of other pesticides--chlordane,
hexachlorobenzene, benzene hexachloride (aka lindane), for example--and
halogenated biphenyls (polychlorinated biphenyls or PCBs). Many organochlorines,
including DDT and PCBs, were banned in the 1970s. Chlordane was regulated
more recently, and lindane remains in limited pharmaceutical use.
In some ways, the policy to ban organochlorines has worked. From the
U.S. Environemtnal Protection Agency's (U.S. EPA) National Human Adipose
Tissue monitoring program, data clearly show that levels of DDT in adipose
tissue in the U.S. population have steadily declined since 1972 (Figure
1) (1). PCB levels are also going down, albeit more slowly (2).
In addition, control of DDT established a precedent that has probably facilitated
regulation of other organochlorine pesticides (e.g., chlordane) and persistent
halogenated hydrocarbons. An example would be polybrominated biphenyls (PBBs)
that were used as a fire retardant until a disastrous contamination of cattle
feed in Michigan in 1973 and 1974. Control of pesticide usage has also stimulated
a search for less toxic, more readily biodegradable pesticides. Registration
of pesticides is now mandatory for new products, which must satisfy requirements
of safety and toxicity.
Figure 1. Levels
of DDT in adipose tissue in the U.S. population. Data from Kutz et al. (1).
An unfortunate consequence of regulatory policy is that policy makers
may take the view that banning solves the problem. It seems obvious that
the efficacy of regulatory policy should be supported by scientific evaluation
and systematic followup. Thus, with DDT, potential for exposure still exists
even 20 years after its ban, and organochlorines continue to pervade the
environment. Regulation may have halted deliberate discharge into the ecosystem
in the United Sates, but its continued use in developing countries allows
DDT to cross international borders in food produce and in the air and water.
Only recently has the United States decided to restrict exports of a number
of pesticides including DDT (3).
Continuing environmental contamination by organochlorines has resulted
in sustained low-level exposure among wildlife and concomitant reproductive
dysfunction (4). Body burdens of DDT in humans are still significant
in the United States and worldwide. International studies frequently report
detectable levels of DDT residues, with special concern directed toward
those ubiquitous levels in human milk that often exceed exposure guidelines
recommended to protect against cancer (5). Human milk is now the
major source of infant exposure to DDT in the United States. Ironically
lactation is the most efficient means of reducing a woman's body burden
of organochlorines.
Status of Research on DDT and Human Health Effects
After 1972, little further attention was paid to research directed specifically
to identify human health effects from DDT. This complacent attitude may
be attributed to the absence of overt, prominent human health effects due
to DDT exposure, in spite of overwhelming evidence of tumorigenicity and
reproductive failure in animals. Indeed some researchers concluded that
DDT was quite safe for humans.
In view of the extensive animal data on reproductive dysfunction, the
scientific literature has remarkably few studies on human reproduction related
to DDT exposure. Moreover, existing studies are limited with respect to
numbers of subjects as well as overall design sophistication. Only four
human reproductive studies are cited by IARC, two focusing on prenatal effects
and two on preterm abortion (6).
Attempts to determine cancer risk associated with DDT exposure have been
somewhat more extensive, but the data are nevertheless quite inconclusive.
Human studies have looked for elevated rates of any kind of cancer death
among industrially exposed persons. Some have focused on potential risks
for lung cancer, liver cancer, lymphoma, soft-tissue sarcoma, and leukemia
in case-control studies. However, few of these studies had adequate exposure
assessment, which lessens the power to detect an effect. In many reports,
there were no adequate controls for exposures other than DDT, and most studies
did not start out specifically to investigate DDT cancer risk (6).
Nevertheless, hematopoietic cancer and lung cancer risk continues to be
weakly associated with DDT exposure estimates in more recent studies.
As a result, existing research efforts have led to the conclusion that
DDT is a possible human carcinogen, although it is designated as carcinogenic
to animals (6). Evidence for reproductive toxicity is considered
scant, whereas in animals clear impairment is recognized. An exception is
the reported observation in 1986 that suggested a hormonal effect of DDT;
this was the finding that women with higher body burdens of DDE reported
shorter duration of lactation (7). A second study recently confirmed
these findings (8). This research originated at the National Institute
of Environmental Health Sciences (NIEHS), an agency whose intramural program
has supported an innovative approach to human exposure and to experimental
studies on hormonally active substances. Indeed, since these were the first
strong human data of the kind, the observation relating high DDE levels
to curtailed lactation led us to examine the relationship of persistent
organochlorines to breast cancer risk that will be described below.
In view of this evidence, the policy that banned DDT has failed to influence
our national research agenda. Not enough effort has been made to target
environmental research in the area of hormonally related cancers. To some
extent, this failure is now being redressed by current NIEHS/NCI (National
Cancer Institute) initiatives. In defense of current policy, it could be
said that animal carcinogenicity studies on organochlorines led researchers
to look at the wrong outcomes, because these relatively high-dose studies
found mainly liver tumors, a relatively rare tumor in humans in the United
States. However, the animal data also indicate that organochlorines are
estrogenic and may be tumor promoters, and therefore specific study designs
should have been investigated to assess this role for DDT and comparable
organochlorines in both animals and humans. (One such report exists in the
animal literature.) No particular attention has yet been paid to the potential
environmental link with ovarian, colon, endometrial, testicular, prostate,
and breast cancer. In view of the unexplained risk and rising rates for
breast cancer and prostate cancer, environmental etiology for these tumors
is an important line of research that should be vigorously pursued.
Environmental links to cancer immediately afford a means of prevention.
The failure to make this a research priority has been criticized in characterizing
the narrow approach to cancer research since declaration of the war on cancer
(9). These past 20 years have seen an increase, rather than a reduction,
in overall cancer rates. Critics maintain that our national approach has
"neglected research aimed at prevention in favor of the search for
cures" (10). Even among those researchers who subscribe to the
environmental thesis, many maintain that increased rates of cancer can be
attributed to diet and smoking and not industrial carcinogens. Meanwhile,
environmental areas that have been explored as means of cancer prevention
include viruses, vitamins, diet, tamoxifen, smoking, occupational exposures,
radiation, but not pollution or ambient chemical exposures (10).
Breast Cancer and DDT
Breast cancer research has been cited as an example of setting poor research
priorities in that no attempts were made to pursue a connection between
cancer and exposure to carcinogenic chemicals in the food chain, even in
the context of an otherwise enormous investment in studying links between
diet and cancer (10). There were five studies on breast cancer and
DDT exposure before 1985, and only one of these was in the United States.
Yet, other risk factors have not been able to fully explain the dramatic
increase in breast cancer rates in the United Sates during 1970 to 1990,
and only some of the increase is attributable to enhanced screening.
Environmental factors have long been invoked as an explanation for breast
cancer, but environmental chemicals per se have not been widely accepted
as risk factors for breast cancer. Rather, epidemiologic studies have implicated
the diet, alcohol consumption, drug use, and radiation as risk factors for
breast cancer that might account for the environmental evidence. Unfortunately,
the identification of these risk factors has not gone very far in providing
us with an explanation for a major proportion of breast cancer incidence
nor have these studies given us much hope for preventing a significant amount
of the disease. Investigation of chemical exposures as possible etiologic
factors for breast cancer has not been a priority, which is surprising given
the several animal models that use chemical carcinogens [e.g., polycyclic
aromatic hydrocarbons (PAH), methylnitrosourea (MNU)].
In the past few years, evidence has emerged that supports a possible
relationship between breast cancer and exposure to organochlorines in the
environment, whence exposure occurs predominantly through the diet. There
have been four recent case-control studies linking environmental organochlorine
exposures to breast cancer risk (Table 1). The relative risks reported in
these studies are in the range of 2 to 10. If the data are confirmed in
future research, these will rank among the higher risks observed for breast
cancer in the epidemiologic literature. However, the studies were relatively
small and require extensive confirmation before this association becomes
an established risk factor for breast cancer.
In the late 1980s, the first of these studies in Connecticut found approximately
50% higher levels of DDE [bis(4-chlorophenyl)-1,1dichloroethene]*(*DDE
is the major residue of DDT in the environment, and it is usually found
in humans at higher levels and more frequently than any other organochlorine.
), DDT [bis(4-chlorophenyl)-1,1,1-trichloroethane], and higher chlorinated
PCBs in mammary adipose among 20 breast cancer cases compared with 20 controls
(11). The risk for DDT was not statistically significant. There was
approximately a 3-fold increased risk for the highest versus the lowest
tertile of these chemicals in adipose tissue.
A second study took advantage of a well-designed nested case-control
study in which blood had been collected before diagnosis of breast cancer
(12). Again, levels of DDE and PCBs in serum were higher among breast
cancer cases than among carefully matched controls, but only differences
for DDE were statistically significant. Women with the highest levels of
DDE (upper 10%) had about a 4-fold increased risk compared with levels in
the lowest 10%. There was approximately a 9% increased risk for every one
part per billion (ppb) of DDE in blood serum.
Quite recently, a Canadian study found significantly higher levels of
DDE in estrogen receptor-positive (ER) breast cancer cases compared with
ER-negative cases and with controls (13). For ER-positive breast
cancer, the relative risk was approximately 9 for the highest versus the
lowest tertile of these chemicals in adipose tissue. In support of this
evidence, H. Mussalo-Rauhamaa (14) has more recently reported a correlation
between DDE levels and ER levels in their patients, although the findings
require cautious interpretation since no age adjustment was made.
Similar relative risks for breast cancer were found among the Finnish
women with elevated levels of ß-hexachlorocyclohexane, a lindane-related
residue, although no association was found with other organochlorines including
DDE (15). The relative risks in these four studies are in the same
range as those estimated from the animal data (16,17). The potential
association with ER status is of some interest, given the estrogenic activity
of DDT and the rising rates of ER-positive cancer among older women (18).
Since DDT levels in the U.S. population are gradually receding, this
trend should accompany reduced risk of any disease associated with DDT exposures
in the United States. However, DDT and other organochlorines are still widely
used in developing countries where it may affect public health or it may
cross international borders. Furthermore, besides DDT there are myriad other
potentially estrogenic chemicals in commerce that require our vigilance
(4,19). Many of these new chemicals are not detectable long after
exposure, e.g., atrazine and methoxychlor.
Future Research Priorities
How can our scientific research establishment be more effective in protecting
human health? Whether or not the DDT-breast cancer link is confirmed, these
findings have great potential for teaching us more about breast cancer etiology
and in leading us toward preventive strategies. Several lines of research
can be suggested. In addition to the potential for prevention, much can
be learned about etiology by understanding environmental contributions to
breast cancer (Table 2).
Research Areas to Emphasize in Environmental Research
Recent work on breast cancer, as well as accumulating evidence about
reproductive failure in animals, should encourage vigorous exploration of
chemical factors in the environment. Cancer, reproductive dysfunction, and
neurotoxicity need to be investigated. One prominent researcher in the field
of environmental estrogens has recently suggested that we should design
our research using functional toxicology, i.e., research that defines chemicals
more by their function than by their chemistry (20). One such area
of toxicology that merits research attention in both basic science and epidemiology
is reproductive dysfunction by environmental chemicals (e.g., estrogenicity
or endocrine disruption). In a similar context, toxic equivalent (TEQ) factors
have been developed for dioxin-like activity, which may also parallel antiestrogenic
activity (21). From the available literature, it is possible to construct
estrogenicity or endocrine equivalents (EEQ?) that might be useful in terms
of relative biological activity for regulatory purposes (22,23).
This database can be easily expanded to include a wide range of environmental
contaminants.
Functional toxicology also touches a further field that is of potentially
great relevance to breast carcinogenesis, i.e. the relationship between
P450 activity and exposures to DDT and other organochlorines. Association
of elevated P450 activity with DDT and PCB exposure in humans has been known
for many years (24,25). Organochlorines have been widely studied
for their ability to induce P450 enzymes whose baseline activity is genetically
determined. The cytochrome P450 enzymes are responsible for metabolizing
endogenous, as well as exogenous, chemicals in the body (e.g., estrogen
and PAH). Certain of these metabolites may act as ultimate carcinogens that
bind directly to DNA and cause mutations. The genes for P450 are polymorphic
in humans, and the distributions of the polymorphisms vary between different
ethnic populations. Hormones are also metabolized by these enzymes. However,
while the P450 enzymes have been widely studied, only recently has this
area begun to reach fruition in the study of human cancer (26). Although
no information is currently available on breast cancer, a number of investigations
on breast cancer are now underway.
Methods Development Needs
Research priority should be placed upon improving methods for exposure
assessment and into developing innovative epidemiologic and statistical
methodologies for study design and analysis. Better epidemiologic tools
and improved quantitation will allow us to design epidemiologic studies
to trace putative carcinogenic pathways. Other endpoints besides cancer
are important to study as well. Reproductive and neurotoxic effects may
be important risk outcomes to consider.
Existing methodologies are often inadequate to study complex diseases
like cancer, reproductive dysfunction, and neurotoxicity, especially when
attempting to link subtle biological effects with complex and low-level
exposures. Therefore, research testing of environmental hypotheses would
be greatly facilitated by the availability of better epidemiologic instruments
and sophisticated statistical techniques. Improved methods would enable
us to more adequately evaluate associations between indicators of preclinical
disease, genetic factors, causal agents, and risk.
Techniques are needed for exposure assessment that will provide quantitative
individual measurements. These techniques must be able to detect very low
levels of exposure that are common in environmental circumstances. Internal
biological markers of exposure and disease are usually more sensitive and
specific than estimates using external methods (i.e., air pollution or water
contamination levels). This may be useful for DDT, where cumulative body
burdens persist for many years, reflecting integrated past exposure. However,
many of the newly developed pesticides that have replaced organochlorines
are not persistent, presenting a difficult problem in exposure assessment.
With respect to cancer risk, exposure assessment is even more difficult
because initiating events may have taken place 10 to 30 years before cancer
diagnosis. Similarly, PAH and nitro compounds are potential etiologic agents
for cancer and are not persistent in the body. For this reason, historical
exposure information has often been used; this is another means of external
exposure assessment methods.
Funding Mechanisms
Our scientific research and funding strategies must allow more creative
ideas to be tested. En route to soliciting and establishing new methodology
and to confirming and extending our research on DDT and breast cancer, it
may be necessary to finetune our research review and funding policies. Traditional
funding mechanisms possess a certain rigidity toward new, unconventional
ideas. The National Institutes of Health (NIH) likes to fund a sure thing.
As a result, it is a constant struggle to eke out support appropriate funding
mechanisms for new, untested ideas, especially in the current climate of
tight funding. Multiple reviews or special screening panels for special
projects might be considered. The Request for Application (RFA) mechanism
may also be suitable for circumventing the entrenched review process and
for encouraging scientific flights of fancy. Recently NCI and NIEHS have
issued RFAs that will allow researchers to confirm and expand these findings.
Criticism has been leveled at the U.S. EPA on another front--that of whether
a regulatory agency can successfully undertake and administer a research
program (27). Since the U.S. EPA's budget is a significant proportion
of funding for environmental research, its record of performance in predicting
as well as preventing environmental disease may be a starting point for
examining the structure of this agency.
Relevance to Environmental Health Effects among Children
The example of breast cancer relates to children's environmental health,
especially with respect to the potential for prevention of exposures. Evidence
in animals demonstrates that developing tissues are more sensitive to carcinogenic
exposures. Recent evidence, though limited, suggests that exposure to cigarette
exposure or alcohol at an early age may be associated with increased risk
for breast cancer among young women. Women in the United States have markedly
higher age-specific rates of breast cancer compared with Japanese women,
and the differences are most dramatic among premenopausal women. Part of
the difference may be dietary or environmental factors that alter the onset
of puberty, which occurs much later in Japanese women. Therefore preventive
measures such as dietary intervention may need to be undertaken at an early
age. Prevention of environmental exposures related to breast cancer is also
be an important potential means of prevention that should be vigorously
pursued.
Rates of breast cancer occurrence in the United States have steadily
risen since 1940. During that same period, levels of pesticide and PCB residues
in human adipose tissue in the United States have shown parallel increase,
following their introduction into commerce around the time of World War
II. Since then, despite much research on the question, only three factors
have been generally agreed to be strongly linked to breast cancer: age,
country of birth, and family history. These factors are not readily amenable
to change. Medicine has done its job well in finding new avenues of treatment
and detection. However, the existence of a cure without a cause continues
because no pathways for prevention have been found. Innovative research
should be undertaken to develop better methods and to elucidate potential
mechanisms for environmental exposures and breast cancer.
REFERENCES
1. Kutz FW, Wood PH, Bottimore DP. Organochlorine pesticides
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 ß-benzene hexachloride levels
in the adipose tissue of the U. S. population. Environ Res 53:175-192 (1990).
3. Hanson DJ. Administration seeks tighter curbs on exports
of unregistered pesticides. Chem Eng News 72:16-17 (1994).
4. Colborn T, vom Saal FS, Soto AM. Developmental effects
of endocrine-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 application,
and some pesticides. In: IARC Monographs on the Evaluation 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
dichlorodiphenyldichloroethane (DDE) in human milk: 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 of lactation
in a northern Mexican town. Am J Pub Health (in press).
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 human breast lipids
and their relation to breast cancer. Arch Environ Health 47:143-146 (1992).
12. Wolff MS, Toniolo P, Lee E, Rivera M, Dubin N. Blood
levels of organochlorine residues and risk of breast cancer. J Natl Cancer
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 estrogen receptor
positive breast cancer. J Natl Cancer Inst 86:232-234 (1994).
14. Mussalo-Rauhamaa H. Selenium and DDE in breast fat
of breast cancer patients: their relationship to hormone receptors in breast
tissue. J Natl Cancer Inst 85:1964-1965 (1993).
15. Mussalo-Rauhamaa H, Hasanen E, Pyysalo H, Antervo K,
Kauppila R, Pantzar P. Occurrence of ß-hexachlorocyclohexane in breast
cancer patients. Cancer 66:2125-2128 (1990).
16. Foran JA, Cox M, Croxton D. Sport fish consumption
advisories and projected cancer risks in the Great Lakes basin. Am J Publ
Health 79:322-325 (1989).
17. Silberhorn EM, Glauert HP, Robertson LW. Carcinogenicity
of polyhalogenated biphenyls: PCBs and PBBs. Crit Rev Toxicol 20:440-496
(1990).
18. Glass AG, Hoover RN. Rising incidence of breast cancer:
relationship to state and receptor status. J Natl Cancer Inst 82:693-696
(1990).
19. Davis DL, Bradlow HL, Wolff MS, Woodruff T, Hoel DG,
Anton-Culver H. Medical hypothesis: xeno-estrogens as preventable causes
of breast cancer. Environ Health Perspect 101:372-377 (1993).
20. McLachlan J. Functional toxicology: a new approach
to detect biologically active xenobiotics. Environ Health Perspect 5:386-387
(1993).
21. Krishnan V, Safe S. Polychlorinated biphenyls, dibenzo-p-dioxins,
and dibenzofurans as antiestrogens in MCF-7 human breast cancer cells: quantitative
structure-activity relationships. Toxicol Appl Pharmacol 120:55-61 (1993).
22. Korach KS, Sarver P, Chae K, McLachlan JA, McKinney
JD. Estrogen receptor-binding activity of polychlorinated hydroxybiphenyls:
conformationally restricted structural probes. Mol Pharmacol 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
in drug metabolism in workers exposed to polychlorinated biphenyls. 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 on phenylbutazone and cortisol
metabolism in human subjects. Clin Pharmacol Ther 11:724-732 (1970).
26. Gonzalez FJ, Gelboin HV. Role of human cytochrome P-450s
in risk assessment and susceptibility to environmentally based disease.
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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