Radiation Exposure and Cancer: A Simpler View of Three Mile Island
The article by Wing et al. (1) introduced the idea of calculating the relative intensity of radioactive fallout between sectors of a circle drawn around the accident at Three Mile Island. The partition derived from wind and weather data allowed a comparison of ratios of radiation exposure between sectors with cancer incidence ratios and bypassed much of the uncertainty involved in calculating actual doses. The results indicated that higher fallout was correlated with higher cancer incidence. Considering that the average levels of radioactivity in each sector were low, this could be interpreted as evidence for a proportional carcinogenic response to low doses of ionizing radiation. There is, however, a simpler way to interpret the same set of data.
Wing et al. (1) reported that some of the people exposed to the fallout from the accident showed signs of acute radiation damage. They also reported that ground measurements of radioactivity were not adequate to show the details of distribution of the fallout or the resulting doses to individuals. We are free to infer that the fallout was patchy, that some of the residents were exposed to high doses of ionizing radiation, and that the data of Wing et al. (1) show a correlation of the frequency of high exposure "hits" on people in each sector with the sector's share of the region's radioactive burden. In this view, increases in cancer incidence were simply correlated with the number of people hit by high doses of ionizing radiation. This interpretation is consistent with the conclusions drawn by Raabe et al. (2) from data on radium dial painters, the data set that offers the most precise readings of both individual radiation doses and carcinogenic effects in humans. It is also consistent with the patchy distribution of radioactive fallout from explosions often observed at the Nevada Proving Grounds.
George G. Berg
University of Rochester School of Medicine
Rochester, New York
References
1. Wing S, Richardson D, Armstrong D, Crawford-Brown D. A reevaluation of cancer incidence near the Three Mile Island nuclear plant: the collision of evidence and assumptions. Environ Health Perspect 105:52-57 (1997).
2. Raabe OG, Book SA, Parks NJ. Bone cancer from radium: canine dose response explains data for mice and humans. Science 208:61-64 (1980).
Consequences of the 1979 Three Mile Island Accident Continued: Further Comment
As principal investigator of the Three Mile Island (TMI) Accident Study funded by the TMI Public Health Fund, I appreciate the space for some observations further to our reply (1) to Wing's reanalysis (2) of our study (3,4). Two far from careful or evenhanded news items (5,6), and your own editorial (7) call for further comment.
My principal colleagues in this study (Jan Beyea, Maureen Hatch, Sylvan Wallenstein) and I are committed to rigor in science as well as to the public health and environmental movements. We applaud your desire to air controversy. But we forsee and fear the ultimate discredit that poor science, together with advocacy parading as science, can bring to epidemiology and the movements of which we are a part. The essential point is that what you label controversy is not controversial in any real sense.
Instead, we have a situation manufactured from misconceptions, misinterpretations, mistaken logic, and simple error. Our results and those of Wing et al. (2) differ in no important respect. Our conclusions do differ: we saw no convincing evidence that cancer incidence was a consequence of the nuclear accident; they claim there is such evidence. We urge you and those of your readers interested in the issue to study our original papers and reports before judging. Your own (5) and other news reports [for instance, The Lancet (4)] ignored our published response to the brouhaha. In that light, we need to expand on some points and make some new ones.
At the heart of the matter, it seems to us, is Wing's assertion that our original interpretation is based on circular reasoning. He makes this charge, he says, because we did not believe in the hypothesis under test. The first of two objections to this charge is that it is untrue. We had no such simplistic belief. At the outset, in the light of the uncertainties about the dose of radiation from the 1979 nuclear accident, and also of a reported cluster of deaths that conceivably pointed to acceleration of cancers already initiated, we accepted the possibility of an effect.
At the same time, given the short postaccident observation period and the putatively low dose, we were doubtful that any but the most radiosensitive cancers could be detected. We did not seek, but were sought out, to investigate on behalf of the TMI Public Health Fund. Our acceptance of the considerable undertaking involved was realistic, with no great expectation of startling results. Public duty at a time when fear and unrest beset the affected communities was a strong motive.
This mistaken allegation about our beliefs is much the lesser of our two objections. The greater objection is to Wing's claim that circular reasoning led to failure to prove an a priori hypothesis we allegedly did not believe. To test an a priori hypothesis, which we did, is of course a procedure specifically designed to preclude circularity. More disturbing is the religious cast of mind this charge displays. To make a prior belief a criterion for judging evidence is the very antithesis of any scientific or logical method, from the inductivist Francis Bacon early in the 17th century to the hypothetico-deductive Karl Popper in the 20th. Whatever we do, we must surely aim for a maximum of rigor and objectivity. One is obliged to attempt disproof no less than verification. In striving toward elusive truth, a priori belief is beside the scientific point. Passionate belief, which characterized Wing, may well be a handicap.
An a priori hypothesis subject to test, by contrast, is a considerable asset regardless of belief. Wing's position amounts to a charge that we are either incapable of understanding our data--on that score let our records speak--or that we obfuscate or lie. In your news report (5), indeed, Wing suggests the latter: he is quoted as ascribing our conclusions to author bias. (In this respect, should there not have been mention of Wing's role, with regard to the accident, as witness for the plaintiff in personal injury litigation against the TMI utilities?)
Wing's more specific case against our report rests mainly on two particular issues, namely, his use of relative rather than absolute dose and the adjustments he made for baseline conditions. Let us take these in turn.
Wing makes much of his use of relative dose as "an alternative logical approach" and seems to reproach us on this score [see Wing et al. (2), page 53, second and third columns]. Although they later note that we in fact used relative dose, in remarks to the press (5) we are again reproved. So we must make clear that all our major analyses and results in fact derived precisely from the use of relative dose.
Relative dose is not an exact or complete description of what we did. In a major and labor-intensive effort, one of us (J. Beyea) carried out detailed topographic and meteorologic mapping of the area to model estimates of the direction and concentration of radiation emissions from the accident, from routine operations of the plant, and from background radiation. To our knowledge, ours was a unique approach to deriving exposure measures in the face of uncertain actual dose. We also divided the local area at risk into 69 census-derived small tracts. We then compared cancer incidence and mortality rates in the tracts most heavily exposed with those less exposed, having taken account of both background radiation and routine plant emissions.
What Wing et al. (2) themselves did about relative dose is not clear to us. In their paper, no description was apparent, nor did we recognize any consideration of background radiation or routine emissions, both strong features of our overall analysis. We assume that they made use of our estimates of radiation distribution from the accident.
In our analysis, we judged observations after the accident to be the critical test in making adjustments for baseline values. We were cautious in adjusting for demographic and other such variables from the situation existing before the accident because of uncertainties in these data. No information was to be had about subsequent migration, and the target population could only be that exposed to the accident and remaining in the district thereafter.
In any case, in the matter of cancers as an outcome, our study sought effects of the accident strictly in one direction. On this ground, there would seem to be reason to adjust for the baseline, but only after a positive effect was observed, and this we did. An apparent effect could always be a consequence merely of the previous distributions of cancer existing in the affected areas. Nonetheless, the data were in the main presented stratified by area for postulated exposure level and by time period. (We see no point in the fuss Wing makes about cancer incidence data from 1975--the first of 5 preaccident years--that we concluded were undercounted. In the absence of detectable geographic bias our decision to include them, and Wing et al's decision to exclude them and adjust their results, are equally justifiable.)
There is neither mystery nor obfuscation in our presentation of the data. We are not sure we can say the same for Wing et al. They charge that we were constrained in our analyses in respect of emissions estimated by the judge's antecedent order. Certainly, we had no direct access to the records of the TMI Utility, but as far as we know, what was available was published. Of course, in using our models Wing et al. (2) operate under exactly the same constraint. We do not see that they find anything of note not reported by us and, indeed, they report rather fewer results than we do and in a less acessible manner.
Contrary to yet another allegation, our recommendation was firm [to the TMI Public Health Fund and also in print (4,8)] that a follow-up was needed, both to allow larger numbers of cases to accumulate in the aftermath of the accident and to collect individual level data on possible exposure and confounding.
In sum, then, Wing et al. (2) make assertions about what they take to be proven effects while we are cautious in accepting them as proven. It is a stretch to rate this difference, which your journal has given such prominence, as a controversy. Can it be said, in truth, that by going into contention Wing et al. have advanced the cause of the community or the environment? As we see it, they have done no more than muddy the waters.
Mervyn Susser
Gertrude H. Sergievsky Center
Columbia University in the City of New York
New York, New York
References
1. Hatch M, Susser M, Beyea J. Comments on "A reevaluation of cancer incidence near the Three Mile Island nuclear plant" [letter]. Environ Health Perspect 105:12 (1997).
2. Wing S, Richardson D, Armstrong D, Crawford-Brown D. A reevaluation of cancer incidence near the Three Mile Island nuclear plant: the collision of evidence and assumptions. Environ Health Perspect 105:52-57 (1997).
3. Hatch MC, Beyea J, Nieves JW, Susser M. Cancer near the Three Mile Island nuclear plant: radiation emissions. Am J Epidemiol 132:397-412 (1990).
4. Hatch M, Susser M. Author's response to "Cancer near nuclear installations" [letter]. Am J Epidemiol 132:416-417 (1990).
5. Revisiting Three Mile Island [news]. Environ Health Perspect 105:22-23 (1997).
6. Rowe P. Three Mile Island cancer linked to radiation [letter]. Lancet 349:625 (1977).
7. Dieter M. Open scientific debate for conflicts in science [editorial]. Environ Health Perspect 105:10 (1997).
8. Susser M, Hatch MC. Cancer near the Three Mile Island Nuclear Plant. Philadelphia:Three Mile Island Public Health Fund, 1988.
Response: Science, Public Health, and Objectivity: Research into the Accident at Three Mile Island
Although controversies over scientific findings are common, the topic of health effects of ionizing radiation has generated an exceptional amount of heat. Despite a century of research since Roentgen's discovery of X rays, fundamental disagreements exist over biophysical mechanisms, dose-response assumptions, analytical strategies, interspecies extrapolations, and the representativeness of studies of select human populations (1-7). In the United States, the last decade has seen revelations about human radiation experimentation (8) and a shift in responsibility for radiation health effects research from the Department of Energy to the Department of Health and Human Services, stimulated by concerns over secrecy and conflict of interest (9,10). These disagreements have been amplified by public and scientific debates over military, energy, and medical applications of nuclear technology (11).
As one of the best known technological failures of the nuclear era, the 1979 accident at the Three Mile Island nuclear power plant has generated its share of controversy, most recently in the pages of Environmental Health Perspectives (12-16). In his letter, Susser raises a number of important issues related to the context and logic of research on health effects from the 1979 nuclear accident at Three Mile Island (TMI) (17). We would like to follow his lead by giving some background regarding our involvement in the study of cancer incidence in the 10-mile area around TMI and also respond to some of his specific points regarding the logic and methods of the original study and our reanalysis.
Susser notes that he and his colleagues did not seek the opportunity to study cancer incidence around TMI, but were asked to investigate the accident "on behalf of the TMI Public Health Fund" (17). The Fund, financed by the nuclear industry as a result of a legal settlement, was governed by the U.S. District Court for the Middle District of Pennsylvania, which imposed requirements regarding the conduct of research and the review and approval of reports by attorneys for the industry (18). We do not suggest that this led Susser and colleagues to alter findings or purposefully construct research to support the industry. However, to the extent that all research is influenced by assumptions and beliefs from the framing of questions to the interpretation of evidence, the context of negotiation with industry representatives is important to understanding the research product.
Like Susser, we did not seek out funding for our reanalysis and, like the original research, our work was conducted in a context that is important to understanding the product. We were asked to review Susser and Hatch's data on cancer incidence by attorneys for approximately 2,000 plaintiffs in a class action suit that was before the same court that administered the TMI Public Health Fund. Civil suits may be a poor way to address public health problems; however, in our society, civil action has played an important role by bringing health issues (including asbestos, tobacco, air and water pollution) to public attention, and has provided some recourse to members of the public seeking protection from powerful industries.
We took a number of measures to reduce the potential for apparent or real conflict of interest in working on research that was related to a lawsuit. Rather than accepting funds directly, we made arrangements for the attorneys to support our reanalysis through a grant from the nonprofit John Snow Institute. The grant was received by our University in the same manner as other grants and covered only the usual salary, computer, communications, and other costs associated with research. We were not paid as consultants, we accepted no conditions about the conduct of our research, and we were free to publish whatever we found to be noteworthy.
Emphasizing his commitment to objectivity and rigor in science, Susser states his concern that our paper is not about controversy (12), but is "a situation manufactured from misconceptions, misinterpretations, mistaken logic and simple error" (17). Here we differ. First, accurate research depends on accurate counting of the data. One error in Hatch et al.'s published research resulted from miscounts of cancer cases, which contributed to their underestimate of the radiation-cancer dose-response association for the postaccident period (15).
Second, it is important to critically examine data for sources of bias. While Susser saw "no point in the fuss Wing makes about cancer incidence data from 1975" (17), we were concerned about the undercount of cancer cases in 1975, one of the years that Susser and Hatch used to establish baseline (preaccident) cancer rates. Two hundred seventy-one incident cases were recorded in the 10-mile area in 1975 versus approximately 500 cases recorded annually in subsequent years. The ratio of incident cases to cancer deaths was 0.97 in 1975 versus approximately 1.6 in subsequent years. Susser and Hatch assumed that undercounted cases were "randomly distributed throughout the study area" (17). Given the available data, we quantitatively assessed the effect of the 1975 data on dose-response estimates. If the undercounted cases were indeed randomly distributed, dose-response associations would be the same regardless of whether 1975 was included. We showed that this was not the case and that, in particular, there was no association between radiation dose estimates and preaccident lung cancer incidence when 1975 data were excluded (15). Failure to exclude the undercounted 1975 data led Hatch et al. (19) to conclude that, "it is apparent from the preaccident gradient that one or more lung cancer risk factors are operating to produce an exposure pattern very similar to the pathway for the radioactive plume."
Third, the choice of disease outcomes is critical. Hatch et al. (19) felt there was sufficient prior evidence to limit their primary hypotheses to leukemias excluding chronic lymphocytic leukemia, lymphoma, and childhood cancer. As we noted in our paper, one consequence of the focus on childhood and specific hematapoetic cancers (rather than all such cancers considered as a larger group) was to reduce the sample size used to evaluate the accident effect. Additionally, their analyses of childhood cancer included children who were not yet conceived at the time of the accident among the exposed. Their choice of specific radiosensitive cancers was based on studies of qualitatively different radiological exposures, medical treatments, and A-bomb radiation, for which inhalation of radioactive gases was not an issue. Given the potential for inhalation of radioactive gases as an exposure route, the large magnitude of some release estimates (20), and consideration of the importance of adequate sample size, we chose to focus on the outcomes all cancers, lung cancer, and leukemia (15).
Fourth, confounding can bias dose- response estimates in either direction. Susser states that their approach was to "adjust for the baseline [cancer rates], but only after a positive effect was observed" (17). The approach of conducting analyses in which confounding is evaluated for positive associations, but not given equal attention as a potential source of bias of negative findings, will obscure positive results. In fact, Hatch et al. (19) reported deficits before the accident in childhood cancer (odds ratio = 0.67) and adult leukemia (odds ratio = 0.59) in areas that were to receive the highest doses from the accident; these deficits could have been examined as a source of potential bias towards the null. This is why we adjusted all analyses for baseline (preaccident) cancer rates (15). With this approach, uncontrolled confounding would imply a distribution of cancer risk factors that appeared only after the accident and that was correlated with the geography of plume travel in the 10-mile area.
Susser (17), as well as academic critics in the popular press (21), have not discussed the evidence upon which our conclusions are based. These results are, we believe, striking for an environmental epidemiology study. Taking lung cancer as an example, consider the ratios of observed to expected incident cases during 1981-1985 in areas ranging from the most upwind to the most downwind: 0.43, 0.68, 1.05, 1.07, 1.22, 1.26, 1.66, 1.69, and 2.34 [our Table 3; 1.0 represents the average for the 10-mile area (15)]. The goodness of fit statistic for this trend (0.082% increase in lung cancer incidence rates per dose unit), interpretable as a chi-squared statistic with one degree of freedom, was 6.58 [our Table 2 (15)]. Readers not familiar with goodness of fit statistics may be interested to learn that this result is associated with a two-tailed p<0.02. The dose-response gradient was stronger in both magnitude (0.103% per dose unit) and goodness of fit (*2 = 8.51; p<0.005) when socioeconomic variables were considered (15). It should be noted that the hypothesis being evaluated is that the accident led to increases in cancer, a one-sided hypothesis, for which p-values should be divided by two. After a hypothesis is stated and a strong design has been chosen that reduces the potential for confounders to explain the phenomenon (in this case, adjustment for preaccident disease rates), such evidence of a dose-response association generally would be considered as support for the hypothesis.
We argued that the previous investigators did not interpret the evidence as supporting the hypothesis because of errors in the analysis (discussed above) and circular reasoning (13,15,16). Susser (17) notes that their "analyses and results ... derived precisely from the use of relative dose"; our concern, however, has been that their interpretation of the findings was largely in terms of absolute dose. Numerous statements in the paper by Hatch et al. (19) indicate that they assumed the absolute doses were too low to produce the effect being investigated. Their prior expectation, "that no excess cancer would be found," was "based on estimated releases and conventional radiobiology" (19). Doses calculated from their assumptions about releases were described as "a fraction of the average U.S. exposure of 0.8-1 mSv from natural background radiation in the course of a year" and "very low, an average of approximately 0.1 mSv, with 1 mSv the projected maximal dose" (19). Their conclusion states, "the possibility that emissions from the Three Mile Island nuclear power plant could have contributed to the observed trends, in lung cancer in particular, must be weighed against . . . the low estimates of radiation exposure" (19 ).
Susser (17) states that to test an a priori hypothesis "precludes circularity" of logic. The problem of circularity, however, arises when a researcher does not accept evidence, collected in the course of research designed to test an alternative hypothesis, as a reason to reject the null hypothesis. It is not "religion" to begin a study with the prior belief that the exposure under study might be a cause of the effect under study; rather it is a necessary part of science. The null hypothesis (that no association exists) must be able to be rejected (that is, one must be able to accept that the exposure could possibly cause the effect), or a study shouldn't be done.
At our introduction to this study, we felt that if the estimated magnitude of the reported doses was correct, any association between radiation and cancer would be too small to observe with the available data. However, plaintiffs in the civil suit, as well as others, questioned whether the doses received by some people may have been much higher than the reported maximal dose of 1 mSv (20,22). This scenario is elaborated in the letter by Berg (23). Their concerns were supported by scientific evidence collected from atmospheric monitoring and plant and animal studies. Furthermore, dozens of local citizens issued sworn affidavits that described erythema, hair loss, nausea, and vomiting (22,24), all symptoms that can occur following acute exposure to high doses of radiation. Aware that such symptoms may arise from other situations and that this event was highly stressful, we reviewed medical literature on mass hysteria to evaluate whether the reported symptoms corresponded to those typically found in outbreaks of unexplained disease that have been ascribed to psychogenic origins (25-30). Our review of the case reports at TMI suggested that they did not correspond to the classical mass hysteria scenario, which involves people in close proximity to each other, predominately female, and not including erythema and hair loss. Since the publication of Susser and Hatch's work, some of those who complained of symptoms have had tests for chromosomal aberrations, which supported their contention that they experienced acute radiation effects (31,32).
We believe that Susser and his colleagues acted in good faith. However, all scientific research takes place within an institutional context that affects the framing of scientific questions and interpretation of evidence. This institutional context, which includes prevailing professional opinion and judgment as well as views about the utility of evidence generated outside professional channels, is critical to the issue of objectivity versus advocacy raised by Susser (17). Over the past few decades, philosophers of science have described the joint influences of the context and internal logic of scientific inquiry (33-35). Recognizing the inevitable connection between knowledge and the context in which it is acquired challenges the conventional view that objectivity requires the removal of all extraneous influences from the scientific product. This more complex view requires us to seek objectivity through explication of our assumptions and values as well as through avoidance of bias in study design, data collection, and analysis (36).
Although our reevaluation of cancer incidence around TMI was based entirely on data collected by Susser and his colleagues, our internal logic, including operational hypotheses and analytical strategy, was influenced by our interpretation of what Susser refers to as "public duty." We considered the possibility that the authorities who controlled the TMI Public Health Fund and government and industry officials who investigated radiation releases and population doses were wrong. We gave attention to residents' reports of acute symptoms, acknowledged the history of secrecy and incomplete disclosure of radiation releases in the nuclear industry (8), and considered other supporting evidence of high level radiation assembled by plaintiffs in the civil suit. Much of this information was not available to Susser and his colleagues.
We do not believe that the cancer incidence study, by itself, constitutes proof of the presence or absence of high radiation doses from TMI. However, we do believe that the study designed by Susser and his colleagues has yielded results that demand serious attention, and that the differences in logic, analysis, and conclusions between the original articles and our reevaluation constitutes more than "brouhaha" (17). It is unfortunate, if not tragic, that so many questions remain 18 years after the accident. At the very least, we hope that the follow-up of cancer incidence beyond 1985, to which Susser refers, will be available soon.
Steve Wing
David Richardson
Department of Epidemiology
School of Public Health
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Donna Armstrong
Department of Epidemiology
School of Public Health,
Rensselaer, New York
References
1. National Research Council. Committee on the Biological Effects of Ionizing Radiation (BEIR V). Health Effects of Exposure to Low Levels of Ionizing Radiation. Washington, DC:National Academy Press, 1990.
2. Caufield C. Multiple Exposures: Chronicles of the Radiation Age. Chicago:University of Chicago Press, 1989.
3. Nussbaum RH, Köhnlein W. Inconsistencies and open questions regarding low-dose health effects of ionizing radiation. Environ Health Perspect 102:656-667 (1994).
4. Gofman JW. Radiation and Human Health. San Francisco:Sierra Club Books, 1981.
5. Gofman JW. Supra-linear dose-response for radiation-induced cancer; no basis for Piepho's doubt (letter). Health Phys 63:236-237 (1992).
6. Stewart AM, Kneale GW. A-bomb radiation and evidence of late effects other than cancer. Health Phys 58:729-735 (1992).
7. Stewart AM, Kneale GW. An overview of the Hanford controversy. Occup Med 6:641-663 (1991).
8. ACHRE. Final Report, Advisory Committee on Human Radiation Experiments. Report No. 061-000-00-848-9. Washington, DC:U.S. Government Printing Office, 1995.
9. SPEERA. Report to the Secretary by the Secretarial Panel for the Evaluation of Epidemiologic Research. Washington, DC:U.S. Department of Energy, 1990.
10. Geiger HJ, Rush D, Michaels D. Dead Reckoning: A Critical Review of the Department of Energy's Epidemiologic Research. Washington, DC:Physicians for Social Responsibility, 1992.
11. Wing S. Limits of epidemiology. Med Global Survival 1:74-86 (1994).
12. Dieter M. Open scientific debate for conflicts in science [editorial]. Environ Health Perspect 105:10 (1997).
13. Revisiting Three Mile Island [news]. Environ Health Perspect 105:22-23 (1997).
14. Hatch M, Susser M, Beyea J. Comments on "A reevaluation of cancer incidence near the Three Mile Island nuclear plant" [letter]. Environ Health Perspect 105:12 (1997).
15. Wing S, Richardson D, Armstrong D, Crawford-Brown D. A reevaluation of cancer incidence near the Three Mile Island nuclear plant: the collision of evidence and assumptions. Environ Health Perspect 105:52-57 (1997).
16. Wing S, Richardson D, Armstrong D. Reply to comments on "A reevaluation of cancer incidence near the Three Mile Island nuclear plant" [letter]. Environ Health Perspect 105:266-268 (1997).
17. Susser S. Consequences of the 1979 Three Mile Island accident continued: further comment. Environ Health Perspect 105:566-567 (1997).
18. Rambo SH. Civil Action No. 79-0432. District Court for the Middle District of Pennsylvania, 15 December 1986.
19. Hatch MC, Beyea J, Nieves JW, Susser M. Cancer near the Three Mile Island nuclear plant: radiation emissions. Am J Epidemiol 132:397-412 (1990).
20. A Review of Dose Assessments at Three Mile Island and Recommendations for Future Research. Philadelphia:Three Mile Island Public Health Fund, 1984.
21. Goldman M. Three Mile Island's impact on regional cancer rates is clear: no ill effects detected. Philadelphia Inquirer, 4 April 1997, A25.
22. Moholdt B. Summary of acute symptoms by TMI area residents during accident. In: Proceedings of the Workshop on Three Mile Island Dosimetry, Vol II. Philadelphia:Academy of Natural Sciences, 1985;A109-A111.
23. Berg GG. Radiation exposure and cancer: a simpler view of Three Mile Island. Environ Health Perspect 105:566 (1997).
24. Aamodt M, Aamodt N. Petitioners vs. United States Nuclear Regulatory Commission. Docket Number 50-289. Washington, DC: Administrative Court, 1984.
25. Small G, Borus J. The influence of newspaper reports on outbreaks of mass hysteria. Psychiatr Q 58:269-278 (1987).
26. Simon G, Katon W, Sparks P. Alergic to life: psychological factors in environmental illness. Am J Psychiatry 147:901-906 (1990).
27. Hefez A. The role of the press and the medical community in the epidemic of "mysterious gas poisoning" in the Jordan West Bank. Am J Psychiatry 142:833-837 (1985).
28. Faust H, Brilliant L. Is the diagnosis of "mass hysteria" an excuse for incomplete investigation of low-level environmental contamination? J Occup Med 23:22-26 (1981).
29. Donnell HD Jr, Bagby JR, Harmon RG, Crellin JR, Chaski HC, Bright MF, Van-Tuinen M, Metzger RW. Report of an illness outbreak at the Harry S. Truman State Office Building. Am J Epidemiol 129:550-558 (1989).
30. Aldous JC, Ellam GA, Murray V, Pike G. An outbreat of illness among schoolchildren in London: toxic poisoning not mass hysteria. J Epidemiol Community Health 48:41-45 (1994).
31. Shevchenko V. Assessment of genetic risk from exposure of human populations to radiation. In: Consequences of the Chernobyl Catastrophe: Human Health (Burlakova E, ed). Moscow: Center for Russian Environmental Policy and Scientific Council on Radiobiology RAS, 1996;46-61.
32. Shevchenko V, Snigiryova GP. Cytogenetic effects of the action of ionizing radiations on human populations. In: Consequences of the Chernobyl Catastrophe: Human Health (Burlakova E, ed). Moscow:Center for Russian Environmental Policy and Scientific Council on Radiobiology RAS, 1996;23-45.
33. Kuhn T. The Structure of Scientific Revolutions, Vol 2. Chicago:University of Chicago Press, 1962.
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Bisphenol A in Food Cans: An Update
The can manufacturing industry and suppliers have followed closely the current research on can coatings and have conducted our own research as it relates to potential exposure to bisphenol A from can coatings. We would like to present new research findings that will amend several conclusions drawn by Nagel et al. (1) in Environmental Health Perspectives.
The paper states that the active level of bisphenol A in rodents was measured at 2 and 20 micrograms per kilogram body weight per day (
g/kg/day) and is "near or within the reported ranges of human exposure." This conclusion appears to be based on human exposure data derived from a paper by Brotons et al. (2) in Environmental Health Perspectives in 1995. New, updated data based on much more definitive analytical methodology supersedes this finding.
In late 1996, our industry's Epoxy Can Coating Work Group of the Interindustry Group on Bisphenol A and Alkylphenols completed a second study on potential human exposure to bisphenol A from epoxy lacquer-coated food cans. The first study from this work group (3), completed in 1995, was referenced by Nagel et al. (1). The second study was undertaken using the improved analytical methodology that minimizes the interferences which were observed in the first study and likely occurred in the study of Brotons et al. (2).
The findings of the 1996 report, "Potential Exposure to Bisphenol A from Epoxy Can Coatings" (4), provide new improved exposure data. This 1996 study with more accurate data was not referenced by Nagel et al. (1). These new data, which have now been provided to the U.S. Food and Drug Administration and the National Academy of Sciences Committee on Hormone-related Toxicants in the Environment, indicate that the estimate of dietary exposure is approximately 0.1 g/kg/day under the most exaggerative conditions. Obviously, this is a level far below the lowest dietary exposure used by Nagel et al. (1). It is therefore quite clear that epoxy lacquer-coated metal food and beverage containers present no public health hazard.
William C. Hoyle
Robert Budway
Can Manufacturers Institute
Washington, D.C.
References
1. Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons W. Relative binding affinity-serum modified access assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect 105:70-76 (1997).
2. Brotons JA, Olea-Serrano MF, Villalobos M, Pedraza V, Olea N. Xenoestrogens released from lacquer coating in food cans. Environ Health Perspect 103:608-612 (1995).
3. Society of the Plastics Industry. Report on Potential Exposures to Bisphenol A from Epoxy Can Coatings. Washington, DC:Society of the Plastics Industry, 1995.
4. Society of the Plastics Industry. Potential Exposure to Bisphenol A from Epoxy Can Coatings. Washington, DC:Society of the Plastics Industry, 1996.
Note: The final report of the Epoxy Can Coating Work Group is available by contacting Susan Howe, Society of the Plastics Industry, 1801 K Street NW, Suite 600K, Washington, D.C., 20006-1301; (202) 974-5223.
Response
In a paper published earlier this year (1), we described biological effects in vivo on the rodent prostate caused by fetal exposure to very low doses of the environmental estrogen bisphenol A. Fetuses were exposed by feeding pregnant female mice bisphenol A at average maternal doses of 2 and 20 g/kg maternal body weight per day (2 and 20 ppb), and these exposure levels produced enlarged prostates [similar to effects seen with low doses of estradiol and diethylstilbestrol (2)] measured in subsequent adulthood. Our conclusion that these doses of bisphenol A were "near or within the reported ranges of human exposure" was based on exposures to bisphenol A following application of some dental sealants as reported by Olea et al. (3), where up to 913 g of bisphenol A were reported released into saliva in the first hour after application of sealant. This 913 g of bisphenol A in a 60 kg human would be equivalent to 913 ÷ 60, or 15 g/kg body weight, well above the lowest dose of 2 g/kg/day at which we observed a biological effect in mice on the developing prostate. In a very recent report, Steinmetz et al. (4) detected biological effects of bisphenol A at a concentration down to 1 nM, or 0.23 g/l.
In their letter addressing several conclusions drawn in our study, Hoyle and Budway noted that the Epoxy Can Coating Work Group's final report "Potential Exposure to Bisphenol A from Epoxy Can Coatings" is now available and that newer methods for measuring bisphenol A minimize interferences and therefore revise downward the estimates of exposure to bisphenol A. However, the revised value in the final report for estimated daily intake (EDI) of bisphenol A extracted from epoxy can linings, using the improved methods, was reduced only 35%, from 9.6 to 6.3 g/person/day, compared to the preliminary report. The final report expressed the EDI as a potential exposure level of 0.105 g/kg/day. However, a limitation to these studies is that solvents were used to simulate the effects of food to extract bisphenol A from the lining of cans, whereas in the study referred to by Hoyle and Budway in their letter, Brotons et al. (5) extracted bisphenol A actually present in the liquid phase of vegetables stored in cans, and values published in this study ranged from nondetectable to 23 g bisphenol A in a can of peas.
For chemicals such as bisphenol A, the FDA calculates an acceptable daily intake (ADI), which is assumed to be safe. To calculate the ADI, safety or uncertainty factors (6) are applied to results from animal studies. Safety factors originate from the realization of uncertainty with regard to extrapolating from animal data to estimation of risk to humans. There are three multiplicative uncertainties that apply here: 1) a 10-fold safety factor is applied when the lowest dose used in the experiment results in an adverse effect (such as prostate enlargement) instead of no adverse effect; 2) another 10-fold safety factor is normally also applied since, in the human population, there is assumed to be a distribution of susceptibility and intake levels; and 3) because of uncertainty in extrapolating from experimental animals to humans, another 10-fold safety factor is standard. Dividing the lowest dose (2 g/kg) in our study (that led to an adverse effect) by a safety factor of 1,000 provides an ADI of 0.002 g/kg using current methods of risk assessment (6). Thus, exposure to bisphenol A at 0.105 g/kg/day is 50-fold higher than the ADI calculated above.
For Hoyle and Budway to support the statement "It is therefore quite clear that epoxy lacquer-coated metal food and beverage containers present no public health hazard," they should have used accepted risk assessment procedures and referenced the estimated daily intake of bisphenol A from cans to an acceptable daily intake level. Instead, they referred to the lowest dose used in our study and indicated that the EDI reported by the Society of the Plastics Industry of 0.105 g/kg/day "is a level far below the lowest dietary exposure used by Nagel et al." It is clear that the estimated daily intake of bisphenol A from cans is actually above the level that would justify the statement regarding public health.
Although the Epoxy Can Coating Work Group's report focused on exposure from cans, bisphenol A exposure may derive from a number of sources in addition to can linings, and published findings demonstrate that these other sources contribute to a higher body burden of this chemical (3). With regard to the public health, exposure to chemicals that act via a common mechanism (such as binding to estrogen receptors) should be viewed in the context of intake from all sources. However, even if one accepts that each source of exposure be viewed independently, based on current risk assessment methods, to support the contention that no public health hazard exists from the use of bisphenol A to coat food and beverage cans, there would have to be a wide (>1,000-fold) margin of safety between the EDI from cans and the lowest adverse effect level in animal studies. Based on the findings of our study as well as of the Steinmetz et al. study (4), this clearly is not the case.
Wade V. Welshons
Department of Veterinary Biomedical Sciences
University of Missouri-Columbia
Columbia, Missouri
Frederick S. vom Saal
Susan C. Nagel
Division of Biological Sciences
University of Missouri-Columbia
Columbia, Missouri
References
1. Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV. Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect 105:70-76 (1997).
2. vom Saal FS, Timms BG, Montano MM, Polanza P, Thayer KA, Nagel SC, Dhar MD, Ganjam VK, Parmigiani S, Welshons WV. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci USA 94:2056-2061 (1997).
3. Olea N, Pulgar R, Perez P, Olea-Serrano F, Rivas A, Novillo-Fertrell A, Pedraza V, Soto AM, Sonnenschein C. Estrogenicity of resin-based composites and sealants used in dentistry. Environ Health Perspect 104: 298-305 (1996).
4. Steinmetz R, Brown NG, Allen DL, Bigsby RM, Ben-Jonathan N. The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology 138:1780-1786 (1997).
5. Brotons JA, Olea-Serrano MF, Villalobos M, Pedraza V, Olea N. Xenoestrogens released from lacquer coating in food cans. Environ Health Perspect 103:608-612 (1995).
6. Beck BD, Rudel R, Calabrese EJ. The use of toxicology in the regulatory process. In: Principles and Methods of Toxicology (Hayes AW, ed). 3rd ed. New York:Raven Press, 1994;19-58.
Last Update: June 24, 1997
