MW K-19

Nonlinearity of Radiation Health EffectsMyron PollycoveU.S. Nuclear Regulatory Commission, Washington, DC

The prime concern of radiation protection policy since 1959 has been to protect DNA fromdamage. In 1994 the United Nations Scientific Community on the Effects of Atomic Radiationfocused on biosystem response to radiation with its report Adaptive Responses to Radiation ofCells and Organisms. The 1995 National Council on Radiation Protection and Measurementsreport Principles and Application of Collective Dose in Radiation Protection states that because nohuman data provides direct support for the linear nonthreshold hypothesis (LNT), confidence inLNT is based on the biophysical concept that the passage of a single charged particle could causedamage to DNA that would result in cancer. Several statistically significant epidemiologic studiescontradict the validity of this concept by showing risk decrements, i.e., hormesis, of cancermortality and mortality from all causes in populations exposed to low-dose radiation. Unrepairedlow-dose radiation damage to DNA is negligible compared to metabolic damage. The DNAdamage-control biosystem is physiologically operative on both metabolic and radiation damageand effected predominantly by free radicals. The DNA damage-control biosystem is suppressedby high dose and stimulated by low-dose radiation. The hormetic effect of low-dose radiation maybe explained by its increase of biosystem efficiency. Improved DNA damage control reducespersistent mis- or unrepaired DNA damage i.e., the number of mutations that accumulate during alifetime. This progressive accumulation of gene mutations in stem cells is associated withdecreasing DNA damage control, aging, and malignancy. Recognition of the positive health effectsproduced by adaptive responses to low-dose radiation would result in a realistic assessment of theenvironmental risk of radiation. - Environ Health Perspect 106(Suppl 11:363-368 (1998).http://ehpnet1.niehs.nih.gov/1998/Suppl-1/363-368pollycove/abstract.html

Key words: radiation, response, metabolism, oxygen, radicals, health, mortality, cancer,nonlinearity

The best scientific evidence of humanradiation effects initially came from epidemi-ologic studies of atomic bomb survivors inHiroshima and Nagasaki. Although no evi-dence of genetic effects has been found,these studies showed a roughly linear rela-tionship between the induction of cancerand extremely high dose-rate single highdoses of atomic bomb radiation. This wasconsistent with the knowledge that ioniz-ing radiation can damage DNA in linearproportion to high-dose exposures andthus produce gene mutations known to beassociated with cancer. In the absence ofcomparable low-dose effects it was prudentto propose tentatively the no-thresholdhypothesis that extrapolates linearly from

effects observed at high doses to the sameeffects at very low doses. It was accepted in1959 by the International Commission onRadiological Protection (1) then adoptedby national radiation protection organiza-tions to formulate regulations for the pro-tection of occupationally exposed workersand the public (2).

The hypothesis that all radiation isharmful in linear proportion to the dose isthe principle used for collective dose calcu-lations of the number of deaths producedby any radiation, natural or generated, nomatter how small. The National Councilon Radiation Protection and Measurements(NCRP) Report 121, Principles andApplication of Collective Dose in Radiation

This paper is based on a presentation at The Third BELLE Conference on Toxicological Defense Mechanismsand the Shape of Dose-Response Relationships held 12-14 November 1996 in Research Triangle Park, NC.Manuscript received at EHP 1 1 March 1997; accepted 15 October 1997.

Address correspondence to Dr. M. Pollycove, Office of Nuclear Material Safety and Safeguards, U.S.Nuclear Regulatory Commission, MS-TB-F5, 11545 Rockville Pike, Rockville, MD 20852. Telephone: (301) 415-7884. Fax: (301) 415-5369. E-mail: mxp@nrc.gov

Abbreviations used: BEIR, Committee on the Biological Effects of Ionizing Radiation; cGy, centigray; CLL,chronic lymphocytic leukemia; LET, linear energy transfer; LNT, linear nonthreshold hypothesis; mSv, millisiev-erts; NCRP, National Council on Radiation Protection and Measurements; NSWS, nuclear shipyard workerstudy; r, rad; ROS, reactive oxygen species; SMR, standardized mortality ratio; UNSCEAR, United NationsScientific Committee on the Effects of Atomic Radiation.

Protection (3), summarizes the basisfor adherence to linearity of radiationhealth effects:

Taken as a whole, the body of evidencefrom both laboratory animals andhuman studies allows a presumption ofa linear no threshold response at lowdoses and low-dose rates, for both muta-tions and carcinogenesis. Therefore,from the point of view of the scientificbases of collective doses for radiationprotection purposes, it is prudent toassume the effect per unit dose in thelow-dose region following single acuteexposures or low-dose fractions is a lin-ear response. There are exceptions tothis general rule of no threshold, includ-ing the induction of bone tumors inboth laboratory animals and in somehuman studies due to incorporatedradionuclides, where there is clearlyevidence for an apparent threshold.

However, few experimental studies, andessentially no human data, can be saidto prove or even to provide direct sup-port for the concept of collective dosewith its implicit uncertainties of non-threshold linearity and dose-rate inde-pendence with respect to risk. The bestthat can be said is that most [sic] studiesdo not provide quantitative data that,with statistical significance, contradictthe concept of collective dose.

Ultimately, confidence in the linear nothreshold dose-response relationship atlow doses is based on our understandingof the basic mechanisms involved.Genetic effects may result from a genemutation, or a chromosome aberration.The activation of a dominant actingoncogene is frequently associated withleukemias and lymphomas, while the lossof suppressor genes appears to be morefrequently associated with solid tumors. Itis conceptually possible, but with a van-ishing small probability, that any of theseeffects could result from the passage of asingle charged partide, causing damage toDNA that could be expressed as a muta-tion or small deletion. It is a result of thistype of reasoning that a linear nonthresh-old dose-response relationship cannot beexcluded. It is this presumption, based onbiophysical concepts, which provides abasis for the use of collective dose inradiation protection activities (3).

The NCRP report (3) summarizes thatalthough some studies "provide quantita-tive data that, with statistical significance,contradict the concept of collective

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dose....Ultimately, confidence in the linearno threshold dose-response relationship atlow doses [linear nonthreshold hypothesis(LNT)] is based on our understanding of thebasic mechanisms involved." This paper willexamine current understanding of the basicbiologic mechanisms involved in the LNTand present some of the statistically signifi-cant epidemiologic data that contradicts theLNT. Recent biologic data will be exam-ined; they also contradict "the presumption,based on biophysical concepts, which pro-vides a basis for the use of collective dose inradiation protection activities (3)."

Increased longevity and decreasedcancer death rates have been observed inpopulations exposed to high natural back-ground radiation and reported for severaldecades. These observations contradict theLNT, the radiation paradigm that all radia-tion including that of natural backgroundis harmful in linear proportion to the dose.Established radiation authorities considersuch observations spurious or inconclusivebecause of unreliable public health data orundetermined confounding factors such assmoking, income, education, medical care,population density, pollution of air, water,and food, and other socioeconomic vari-ables. Recently, however, the followingstatistically significant controlled epidemio-logic studies (4-13) have demonstratedthat exposure to low or intermediate levelsof radiation are associated with positivehealth effects.

In his current review of hormesis (4)Z. Jaworowski, past chairman of the UnitedNations Scientific Community on theEffects of Atomic Radiation (UNSCEAR),cites recent data showing hormetic effectsin humans from the former Soviet Union.After high radiation exposure from a ther-mal explosion in 1957, 7852 persons livingin 22 villages in the Eastern Ural moun-tains were divided into three exposuregroups averaging 49.6, 12.0, and 4.0 cGyand followed for 30 years. Tumor-relatedmortality was 28, 39, and 27% lower inthe 49.6, 12.0, and 4.0 cGy groups, respec-tively, than in the nonirradiated controlpopulation in the same region. In the 49.6and 12.0 cGy groups the difference fromthe controls was statistically significant(Figure 1). Epidemiologic studies showingbeneficial effects of low doses of radiationin atomic bomb survivors and otherpopulations were reviewed by S. Kondo(Figure 2) (5). Induded in Kondo's revieware the apparently beneficial effects of lowdoses of external y-rays on the life span ofradium-dial painters and the significantly

lower mortality from cancers at all sites ofresidents of Misasa, Japan an urban areawith radon spas, than of residents of thesuburbs of Misasa (Figure 3).

These beneficial effects are consistentwith findings of B.L. Cohen (6), whichrelate the incidence of lung cancer to radonexposure in nearly 90% of the populationof the United States. The 1601 countiesselected for adequate permanence of resi-dence provide a high-power statisticalanalysis. After applying the Committee onthe Biological Effects of Ionizing Radiation(BEIR) IV 1988 report (7) correction forvariations in smoking frequency, the

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Figure 1. Standardized cancer mortality ratio in threeexposure groups followed for 30 years after a thermalexplosion. Adapted from Jaworowski (4).

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Cohen study (6) shows a strong tendencyfor lung cancer mortality to decrease withincreasing mean radon level in homes. Thisfinding is in sharp contrast to the BEIR IVtheoretical increased mortality derived bylinear nonthreshold extrapolation of effectsin uranium miners exposed to high radonconcentrations (7). The discrepancybetween theoretical and measured slopes is20 SD (Figure 4). Rigorous statisticalanalysis of 54 socioeconomic, 7 altitudeand weather, and multiple geographic vari-ables as possible confounding factors bothsingly and in combination demonstrates nosignificant decrease in the discrepancy. The

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Figure 3. Standardized mortality ratios of populationscontinually exposed to high (Misasa radium springs)and low (control area) air concentrations of radon.Adapted from Kondo (5).

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Figure Z The higher death rate after 55 years old (dot-ted line) corresponds to the people living in Nagasakiwho were not exposed to the atomic bomb. Lowerdeath rate after 55 years old (solid line) corresponds toatomic bomb survivors. Adapted from Mine et al. (30).

2 3 4 5 6 7Mean radon level, pCi/liter

Figure 4. Lung cancer mortality rates corrected for smok-ing compared with mean home radon levels by U.S.county and comparison with BEIR IV linear model (7).Observed mortality risk is 1.00 at 1.7 pCi/liter, the aver-age U.S. residential radon level. Adapted from Cohen (6).

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multiple independent requirements that apossible unknown confounding factormust make its existence highly improbable.A reasonable explanation is that stimu-lated biologic mechanisms more thancompensate for the radiation insult andare protective against cancer in a low-dose,low-dose-rate range.

The 13-year U.S. Nuclear ShipyardWorkers Study (NSWS) of the health effectsof low-dose radiation was performed byMatanoski (8) and reported in UNSCEAR1994 (9). A.C. Upton, who concurrentlychaired the National Academy of SciencesBEIR V Committee on Health Effects of

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Exposure to Low Levels ofIonizing Radiation(10), chaired the technical advisory panelthat advised on the research and reviewedresults of the NSWS.

The results of the NSWS (9) contradictthe conclusions of the BEIR V report (10)that small amounts of radiation have risk(the LNT). From the database of almost700,000 shipyard workers, including about108,000 nudear workers, three study groupswere selected: a) 28,542 nuclear workerswith working lifetime doses . 5 mSv (manyof them received doses well in excess of50 mSv); b) 10,462 nuclear workers withdoses < 5 mSv; and (c) 33,352 nonnuclear

Laukemia Lymphatic and hemopoietic cancers

Figure 5. Standardized mortality ratios for selected causes of death among shipyard workers in the United States.Nuclear worker cumulative dose: 0.5 to > 4OcSv (rem). Adapted from Matanoski (8).

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Figure 6. Cancer mortality among nuclear industry workers in three countries. Adapted from Cardis et al. (12). Datafrom D,, D3, D4, and D6 were excluded (86 of 119 deaths). Data from D2, D5, and D7 were included (33 of 119 deaths).

workers. Deaths in each of the groups wereclassified as attributable to leukemia, lym-phatic and hematopoietic cancers, mesothe-lioma, lung cancer, or all causes. The resultsdemonstrated a statistically significantdecrease in the standardized mortality ratio(SMR) for the two groups of nudear work-ers for death from all causes compared withthe nonnuclear workers. For the . 5 mSvgroup of nuclear workers, the highly signifi-cant risk decrease to 0.76 of the SMR fordeath from all causes, 16 SD below 1.00, isinconsistent with and not explained by thehealthy worker effect (Figure 5) (9). TheSMR of these nudear workers for leukemiaand lymphatic and hematopoietic cancerswere also decreased, but not statistically sig-nificant. The nonnudear and nudear work-ers were similarly selected for employment,were afforded the same health care there-after, performed the same type of workexcept for exposure to 60Co y-radiation,and had a similar median age of entry intoemployment of approximately 34 years. Thisprovides high statistical evidence that lowlevels of ionizing radiation are associatedwith risk decrements.

Upton (11) considers the three-countrylow-dose radiation and cancer study ofCardis et al. (12) the best occupationalstudy of nudear workers (Figure 6). Cardiset al. (12) concluded "There was no evi-dence of an association between radiationdose and mortality from all causes or fromall cancers. Mortality from leukemia,excluding chronic lymphocytic leukemia(CLL) ... was significantly associated withcumulative external radiation dose (one-sided p-value = 0.046: 119 deaths)." In refer-ence to the statistical methods used, theauthors stated: "As there was no reason tosuspect that exposure to radiation would beassociated with a decrease in risk of any spe-cific type of cancer, one sided tests are pre-sented throughout" (12). The authors'analysis of the 1 19 deaths from all leukemiasexcept CLL excluded 86 deaths in dose cate-gories 1, 3, 4, and 6, in which there werefewer deaths than expected. Trend analysisof the remaining 33 deaths in dose cate-gories 2, 5, and 7 for estimated p= 0.046was obtained "using computer simulationsbased on 5000 samples, rather than thenormal approximation" (12) (Figure 6).

The Canadian breast cancer fluoroscopystudy reported the observations of the mor-tality from breast cancer in a cohort of31,710 women who had been examined bymultiple fluoroscopy between 1930 and1952 (13). The observed rates of mortalityare related to breast radiation doses and

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* Nuclear radiation workers, 29,000a Nonnuclear radiation workers, 33,000I 95% Confidence limits

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presented only in tabular form. Miller etal. (13) compared linear and linear-qua-dratic dose-response models fit to the dataand conclude "that the most appropriateform of dose-risponse relations is a simplelinear one, with different slopes for NovaScotia and the other provinces." On thebasis of this linear model, which excludesthe data with the highest confidence limits(Figure 7), the authors predicted the life-time excess risk of death from breastcancer after a single exposure to 1 cGy (1r) at age 30 to be approximately 60 per 1million women or 900 per 1 million womenexposed to 15 cGy. The observed data,however, demonstrate with high statisticalconfidence a reduction of the relative riskof breast cancer to 0.66 (p= 0.05) at 15 rand 0.85 (p = 0.32) at 25 r. The study pre-dicted that a dose of 0.15 Gy would beassociated with 7000 fewer deaths in these1 million women. L.S. Taylor, past presi-dent of the NCRP, considered applicationof LNT for calculations of collective doseas "deeply immoral uses of our scientificheritage" (14).

During the past decade rapid advancesin our knowledge of molecular biologyand cell function have enabled us tounderstand why low-dose, low-dose-rateradiation is associated with positive healtheffects despite the carcinogenic effect ofhigh-dose, high-dose-rate radiation. Ourunderstanding is based on three cellularmolecular biology observations:* The high background of intrinsic

potential mutations (DNA alterations,106/cell/day) produced by reactive oxy-gen species (ROS): free radicals andreactive oxygen metabolites and thermalinstability compared to 20 potentialmutations produced predominantly bythe, free radicals generated by 1 cGy oflow linear energy transfer (LET) radia-tion (15-17). In addition, because offundamental limitations on the accuracyof DNA replication and repair, everyclass of genes is likely to undergo400,000 mutations/day in each person(18). The comparatively rare mutations(persistent mis- or unrepaired DNAalterations) produced by low-LET low-dose radiation (averaging 10-7/cell/dayfor 0.1 cGy/year background) are similarto the 1/cell/day intrinsic mutationsoccurring in an environment free ofmutagens (Figure 8) (17).

* The presence of an active DNA damagecontrol biosystem that, until decliningwith age, effectively prevents (antioxidantdetoxification of ROS and cell cycle

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Figure 7. Canadian breast fluoroscopy study. Adapted from Miller et al. (13). Abbreviations: A-P, anterior to pos-terior exposure; MLS, multipolynomial least squares; L-QM, linear-quadratic model; P-A, posterior to anteriorexposure; RR, relative risk.

Figure 8. The DNA damage-control biosystem. Adapted from Pollycove and Feinendegen (17). Quantities in paren-theses are fractions of metabolic DNA damage from low-LET background 0.1 cGy/year radiation DNA damage.GSH, glutathione reductase.

control), repairs (DNA repair enzymes),and removes (cell cycle control, apoptosis[self-programmed cell death], necrosis,differentiation, and immune system)intrinsic and environmental DNA alter-ations, as documented in UNSCEAR (9)(Figure 8) (17,19-29).The activity of the DNA damage controlbiosystem is decreased by high-dose(e.g., > 1 Gy), high-dose-rate (e.g., . 20cGy/min) radiation, but adaptivelyresponds with increased activity to

low-dose (e.g., <20 cGy) low-dose-rate(e.g. < 1 cGy/min) radiation. Thisactivity is documented in UNSCEAR(9) [Figure 9; (22)].The theoretical presumption that each

mutation produced by ionizing radiationis associated with a linear increase in theincidence of cancer focuses on the negli-gible number of mutations produced byradiation. Emphasis is placed on the diffi-culty of repairing relatively rare doublestrand breaks [0.4/cell/cGy low-LET

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NONLINEARITY OF RADIATION HEALTH EFFECTS

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radiation (16)] and if unrepaired,ignoring their removal each day togetherwith trillions of other intrinsic andenvironmental unrepaired DNA defectsby the adaptive responses of the DNAdamage-control biosystem. The highnumber of intrinsic mutations are disre-garded, as are the adaptive responses toradiation that until diminished with ageeffectively prevent, repair, and removeboth intrinsic and environmental DNAalterations. Contrary to the increased risksassociated with their suppression by high-dose radiation, these adaptive responsesare stimulated by low-dose radiation tofunction even more effectively anddecrease the risks of mortality and cancer(Figures 9, 10) (9,17,22). "In a lifetime,every single gene is likely to have under-gone mutation on about 1010 separateoccasions in any individual humanbeing"(18). These observations of funda-mental biologic cellular functions contra-dict the theoretical presumption based onbiophysical concepts and exclude an LNTdose-response relationship.

Recognition of the positive healtheffects produced by adaptive responses tolow-level radiation would result in a real-istic assessment of the environmental riskof radiation. There is no statistically sig-nificant human low-dose radiation datathat supports the LNT hypothesis (1).Instead of adhering to nonscientific influ-ences on radiation protection standardsand practice (14) that impair health careand research and waste many billions ofdollars annually for protection againsthypothetical risks of low-level radiationexposure, this resource could be used pro-ductively for effective health measures andmany other benefits.

REFERENCES

1. ICRP. Recommendations of the International Commission onRadiological Protection. International Commission onRadiological Protection Publ 1. London:Pergamon Press,1959.

2. ICRP. Principles for Limiting Exposure of the Public to NaturalSources of Radiation. Statement from the 1983 WashingtonMeeting of the ICRP. International Commission onRadiological Protection Publ 39. Oxford:Pergamon Press, 1984.

3. NCRP. Principles and Application of Collective Dose inRadiation Protection. NCRP Rpt No 121. Bethesda,MD:National Council on Radiation Protection andMeasurements, 1995;45.

4. Jawarowski Z. Beneficial radiation. Nukleonika 40:3-12 (1995).5. Kondo S. Health Effects of Low-Level Radiation. Osaka,

Japan/Madison, WI:Kinki University Press/Medical Physics,1993.

6. Cohen BL. Test of the linear no-threshold theory of radiationcarcinogenesis in the low dose, low dose rate region. HealthPhys 68:157-174 (1995).

7. National Academy of Sciences. Committee on BiologicalEffects of Ionizing Radiation. Health Risks of Radon andOther Internally Deposited Alpha Emitters (BEIR IV).Washington:National Acaemy Press, 1988.

8. Matanoski GM. Health effects of low-level radiation in ship-yard workers final report. Rpt No DOE DE-AC02-79EV10095. Washington:U.S. Department of Energy, 1991.

9. United Nations Scientific Committee on the Effects of AtomicRadiation. Annex B. In: Sources and Effects of Ionizing Radiation;UNSCEAR 1994 Report to the General Assembly, with ScientificAnnexes. New York:United Nations, 1994;185-272.

10. National Academy of Sciences. Committee on BiologicalEffects of Ionizing Radiation. Health Effect of Exposure to

Environmental Health Perspectives * Vol 106, Supplement 1 * February 1998 367

M. POLLYCOVE

Low Levels of Ionizing Radiation (BEIR V). Washington:National Acaemy Press, 1990.

11. Upton AC. Radiation Carcinogenesis: Issues in RiskAssessment. Washington:The Brookings Institution, 1966.

12. Cardis E, Gilbert GS, Carpenter L, Howe G, Kato I,Armstrong BK, Beral V, Cowper G, Douglas A, Fix J et al.Effects of ow doses and low dose rates of external ionizing radi-ation: cancer mortality among nuclear industry workers inthree countries. Radiat Res 142:117-132 (1995).

13. Miller AB, Howe GR, Sherman GJ, Lindsay JP, Yaffe MJ,Dinner PJ, Risch HA, Preston DL. Mortality from breastcancer after irradiation during fluoroscopic examination inpatients being treated for tuberculosis. N Engl J Med321:1285-1289 (1989).

14. Taylor LS. Some non-scientific influences on radiation protec-tion standards and practice. Health Phys 39:851-874 (1980).

15. Billen D. Spontaneous DNA damage and its significance forthe "negligible dose" controversy in radiation protection.Radiat Res 124:242-245 (1990).

16. Ward JF. Radiation chemical methods of cell death. In:Proceedings of the 8th International Congress of RadiationResearch, 1986. Vol II (Fielden EM, Fowler JF, Hendry JH,Scott D, eds). London:Taylor & Francis, 1987;162-168.

17. Pollycove M, Feinendegen L. Unpublished data.18. Bishop JM, Cairns J, Ellman R, Land H, Ponder B. Cancer. In:

Molecular Biology of the Cell (Alberts B, Bra D, Lewis J, RaffM, Roberts K, Watson JD, eds). New York:Garland, 1989;1187-1218.

19. Varmus H, Weinberg RA. Genes and the Biology of Cancer.New York:Scientific American Library, 1993;1 53.

20. Ames BN, Gold LS, Willet WC. The causes and prevention ofcancer. Proc Nati Acad Sci USA 92:5258-5265 (1995).

21. Yamaoka K. Increased SOD activities and decreased lipid per-oxide in rat organs induced by low X-irradiation. Free RadicBiol Med 11:3-7 (1991).

22. Makinodan T, James SJ. T cell potentiation by low dose ioniz-ing radiation: possible mechanisms. Health Phys 59(1):29-34(1990).

23. Anderson RE. Effects of low-dose radiation on the immuneresponse. In: Biological Effects of Low Level Exposures: Dose-Response Relationships (Calabrese EJ, ed). Chelsea, MI:Lewis,1992;95-112.

24. Sohal RS, Weindruch R. Oxidative stress, caloric restriction,and aging. Science 273:59-63 (1996).

25. Lithgow GJ, Kirkwood TBL. Mechanisms and evolution ofaging. Science 273:80 (1996).

26. Wei Q, Matanoski GM, Farmer ER, Hedayati MA, GrossmanL. DNA repair and aging in basal cell carcinoma: a molecularepidemiology study. Proc Natl Acad Sci USA 90:1614-1618(1993).

27. Miller RA. The aging immune system: primer and prospectus.Science 273:70-74 (1996).

28. Ross DW. Biology of aging. Arch Pathol Lab Med 120:1148(1996).

29. Duke RC, Ojcius DM, Young JD-E. Cell suicide in health anddisease. Sci Am Dec:80-87 (1996).

30. Mine M, Nakamura T, Mori H, Kondo H, Okajima S. Thecurrent mortality rates of A-bomb survivors in Nagasaki City[in Japanese with English abstract]. Jpn J Public Health28:337-342 (1981).

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