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SCIENCE 244, 755-_757 (May - = Letter / 19, 1989) Pesticides, Riak, and Applesauce The tremendous attention in the media to tlhc growth-re€;ulator Alar raises important issues about &e nation's effort.s to prevent human cancer by regulating chemicals that are carcinogenic in animal studies. Leslie Roberts, in hcr Research News articles "Pes- ticidcs and kids°" (10 Mar., p. 1280) and "Is risk assessment conservativc?" (24 Mar., p. 1553), did noc address several points that we think are important for putting possible risks in perspective. 1) Prsr;cide.,, 99.99% all „arural. Although regulatory cfliorrs are focused on idcncih ing and controlling synthetic chemicals that are estimated to pmc a possible carcino,enic risk to socicry' €;rcater than one in a million (such as Alar), wc are ingesting about 10,000 times more natural than synthetic pesticides (1). All plants produce toxins to protect themseA•es against fungi, insects, and predators such as man (2, 3). Tens of thousands of these natural pesticides have been discovered, and every species of plant contains its own set of different toxins, usually a fc«~ dozen. When plants are stressed or damaged, such as during a pest attack, thev increase their natural pesticide levels manvtold, occasionall}• to levels that are acutely toxic to humans (4). Ven• fetr of these plant toxins have been tested in animal cancer bioassavs, but among those tested, about half (20/42) are carcinogcnic (4, 5). It is probable that• almost every plant product in the supermarket contains natural carcinogens. The following foods contain natural pesticides that cause cancer in rats or mice and are present at levels ranging from a few parts per billion to 4 million parts per billion (ppb) (3, 4): anise, apples, bananas, basil, broccoli, Brussels sprouts, cabbage, cantaloupe, carrots, cauliflower, eelen•, cin- namon, cloves, cocoa, comfrev tea, fenncl, grapefruit juice, honevdew melon, horserad- ish, kale, mushrooms, mustard, nutmeg, or- ange juice, parsley, parsnips, peaches, black pepper, pineapples, radishes, raspberries, tarragon, and turnips. Of the pesticides we cat, 99.99% are all natural, and, like man: made pesticides, most are relativelv new to the modern dict because of the exchange of plant foods among the Americas, Europe, Asia, and Africa within the last 1000 ycars. It is reassuring, however, that the many layers of general defenses in humans and other animals (1, 6, 7) protect against toxins, without distinguishing whether they are svnthetic or natural. 2) Trado-offs. In response to fears about residues of man-made pesticides, plant breeders are active in developing varieties that are naturally pest-resistant. Such varie• ties contain increased amounts of natural pesticides. It should be no surprise, then, that a newly introduced varien• of insect- resistant potato had to be withdrawn from the market, due to acute toxicity to humans caused by much higher levels of the terato- gcns solaninc and chaconine than are nor- mally present in potatoes (8). Similarly, a new varietv of insect-resistant celery recently introduced widely in the United' States is causing outbreaks of dermatitis in produce workers due to a eoncentration of the car- cinogen 8-methdxypsoralcn (and related psoralcns) of 9000 ppb, rather than the usual 900 ppb (9). Many more such cases are likely to crop up: Thus, there is a funda- mental tradc-off bec.vicen nature's pesticides and man-made pesticides. The Environmen- tal Protection Agency (EPA) has strict rcgu- latorn• rcGuircmcnts for ncni• st•nthctic pcsti- eidcs and is stcadih• .reeding out old sub- stances such as Alar that are thought to pose a si;ni6caru hazard; ho«•cvcr, natural pesti- cides arc almost completeh• negleaed. Natu- ral pesticides that are possibly hazardous to humans could casih• be decreased by plant breeding . Given the background of human expo- sures to natural carcinoacns (1-7), the find- ing that about half the chemicals tested in rodents (tivhethcr svntheric or natural) are carcinogenic (1, 5), and the difficulties in risk assessment (discussed below), we have ranked possible hazards on a HERP indcx (dail}• Human Exposure dosdRodent Poten- e}• dose, as a percent) in order to achieve some perspective on human exposure to the plethora of carcinogens (1). Our ranking suggests that carcinogenic hazards from cur- rent levels of pesticide residues or water pollution are likeh• to be minimal relative to the background leveis of natural substances. To put Alar in perspective, we estimate that the possible hazard from UDMH (the carcinogenic breakdown product of Alar) in a daily lifetime glass (6 ounces) of apple juice is HERP = 0.0017% (10). This possi- ble hazard is less than that from the natural carcinogenic hydrazines consumed in one daily mushroom (HERP = 0.1%) (1) or that from aflatoxin in a daily peanut butter sandwich (HERP = 0.03%) (1). It is also less than other possible hazards from natural carcinogens in food, although few have been testcd. These include 8-mcthoxypsora- !en in a daily portion (100 grams) of celery (3, 11), allyl isothioa•anatc in a daily portion of cabbage or Brussels sprouts (3, 12), and alcohol in a daily glass of orange juicc (13). The possible hazard of UDMH in a dailv apple is 1/10 that of a daily glass of apple juice. Other HERP comparisons are shown in (1). Apple juice has becn reportcd to contain 137 natural volatile chemicals (14), of which only five have bccn tested for carcinogcnicitt• (5); three of thcse-bcnzyI acetate, alcohol, and acetaldehyde-have been found to be carcinogenic. The EPA has proposed cancellation hear- ings on Alar, and the Natural Resources Dcfense Council (NRDC) is trying to speed this process up by a year or two. The trade- • offs must bc considcred in efforts to prevent hypothetical carcinogenic risks of 10' or ] 0-S, because the results could be counter- productive if the risks of the alternatives are worse. What risks might we incur by ban- ning Alar? Alar is a growth regulator that delays ripcning of apples so that they do not drop prematurely, and it also delavs ovcr- ripcning in storage. Alar plays a role in reducing pesticide use for some types of applcs, particularly in the Northeast (15). LEITERS 755 756

For exatnp(e, without Alar, the danger of fruit fall from Jcafmincrs is greater, and more pesticides are required to control them. Also, when appla fall prematurely, pests on the apples remain in the orchard to attack the crop the next summer; and more pesticides must bc used. Since A1ar produces firmer apples, and results in fewer falling to the ground, treated fruit may be less susccp- tible to molds. Therefore, it is possible that the amounts and variety of mold toxins present in apple jiuf,ce, for example, parulin (16), will be higher in juice made from untreated apples. The carcinogenicity of pa- tulin has not bcen adequately examincd (17). The EPA should, as NRDC empha- sizes, also take into consideration that chil- dren consume larpe amounts of apple juice. Another trade-off ia that fevver domesticallv grown, fresh appl,cs would be available throughout the y(:a:-, and the price would be higher; thus, co~nsumers might substitute less healthv foods. ' 3) Risk assessme:r. Currently, neither the- ory nor experimental evidence is adequate to guide scientists in eKtrapolating from rodent cancer tests at the maximum tolerated dose (t''rITD)' to human exposures that are thou- sands or millions oi'times lower. Therefore, for prudence's sake, federal regulatory agen- eies routinely make worst-ease assumptions to estimate the upper limit;on risk for low doses; however, the real risks at low doses mav well be zero. Conventional risk assess- ments at the low levels of human exposure thus are rcally quite speculative (1) and should not be viewed as if they were real risks. Accumulatulg; scientific evidence (1, 6, 7, 18) suggests that chemicals administered in animal cancer te:Pts at the MTD are caus- ing cancer in quiescent tissues primarily by increasing cell proliferation, an essential as- peet of earcinogenesis for both mutagcns and nonmutagelu. Because endogenous rates of DNA damage are enormous (6), cell proliferation alonc Ils likely to be tumorigen- ic. Cui proliferation converts DNA adducts (either spontancous or exogenous) to muta- tions or to cpimutations (such as loss of 5- methylC) and exposes single-stranded DNA, a much more sensitive target for mutagcns. It also allows mutant cells to escape from growtlt inhibition signals com- ing from surrounding cells (1, 6, 7). If animal cancer tests are primarily mea- suring cell prolifcration, then the dose-rc- sponse curve should fall off sharply with dose, even for mutagens [as with dicthylni- trosamine (18)] and should have a threshold for nonmutagens. Thus, the hazards at low doses could be niinimal. Furthermore, hu- mans have numerous inducible defense sys- tems against mutagenic carcinogens, such as DNA repair, ando:adant defenses, glutathi- SCIENCE, VOL: 244 one transfcrases, and so forth, which mav make low doses of muragcns protective in some circumstances. Even radiation-thc dassical DNA-damaging agent and carcino- gcn-may be protective in small doses against DNA damage at higher doses, as shown by recent work in human cells (19). Also, recent radiation experiments in mice show a dose threshold for the latency of tumor appearance (20). Thus, low doses of carcinogens appear to be both much more common and less hazardous than is general- ly thought. These scientific questions about mechanisms of carcinogenesis and the pre- ventable causes of human cancer, in anv case, are being resolved by the scientific community as quickly as resources allow. Regulation of lo,w-dose exposures to chemicals based on animal cancer tests may not result in significant reduction of human cancer, because we are exposed to millions of different chemicals-almost all natural- and it is not feasible to test all of them. NIost exposures, with the exception of some occu- pational, medical, or natural pesticide expo- sures, are at low doses. The selection of chemicals to test, a critical issue, should rc8ect human exposures that are at high doses relative to their toxic doses and the numbers of people exposed. Epidemiology has been reasonably successful in identifying risk factors for human cancer, such as smok- ing, hormonal and dietary imbalances, as- bestos, and several occupational chemicals; the data suggest that pesticide residues are unlikely to be a significant risk factor (6, 21). Epidemiology, with molecular approaches, is becoming more sophisticated and will continue to be our main tool in analyzing causes of cancer. In order to minimize can- cer and the other degenerative diseases of aging [which are associated with our con- stantly increasing life expectancy (6, 7)], we need to obtain the knowledge that will come from further basic scientific research. BRUCE N. AMES Department of Bioclumistry, University of Califonua, Berkeley, CA 94720 Lois SwIRSKY GOLD Cell and lYlolecular Biology Division, Lawrence Berkeley l.aboratory, Berkeley, CA 94720 REFERENCES AND NOTES 1. B. N. Ames, R. Magaw, L. S. Gold, Stienct 236, 271(1987); ibid. 237,235 (1987); ibid., p. 1283; B. N. Amcs, L. S. Gold, R Magaw, ibid, p. 1399; B. `. Ames and L. S. Gold, ". 238, 1634 (1987); ibid. 240, 1045 (1998). 2. B. N. Ames, ,3id. 221, 1256 (1983). 3. R. C. Beier, in Revieua,af &vironnurual Curuamnta- tion axd To.dmlopy, G. W. Warc, Ed. (Springcr- Vcrlag, New York, in press). 4. B. :1. Atncs a al., in prcparation. S. L. S. Gold rt a/., Frviroa. Health Pmprrt. 58, 9 (1984); L. S. Gold «al., ibid. 67.161 (1986); L. S. Gold er at., ibid. 74,237 (1987); L. S. Gold rt al., ibid., in press. 19 MAY 1989 6. B. N. Ames, Envvort. .1toL S/utaAa+., in press. 7. in lmponant Adrauts in Ontoloyy 1989, V. T. DeVita, Jr., S. Hcllman, S. A. Roscnberg, Eds. (Lippincott, Philadclphia, PA, 1989), pp. 237-247. 8. S. J. Jadhav, R. P. Sharma. D. K. Salunkhc, CRC Crit. Rev. Tozical. 9, 21 (1981); J. H. Rrnwiek et a1., Teratology 30, 371 (1984). 9. S. F. Berkiey et al., Ann. Intem. :Lted. 105, 351 (1986); P. J. Seligman n aL, Arch. Dematol. 123, 1478 (1987). 10. Envirotunenta! Protection Agency, "Daminozidc special review. Crop 5cld rrials. Supplemental da- minozidc and UDMH residue data for apples, clter- ries, peanuts, pears, and tomatoes," memo from L Cheng to M. Boodfe, 21 Februarv 1989. The HERP is based on a TD.o of 4.83 mykg per day for UDMH. We have not calculated the HERP for Alar (darninozidc), which would be much lower, F. Peren and P. Boffcra 11. .`atl. Cancer Ina. 80, 1282 (1988)1 had reported a HERP for average Alar exposure in apples and apple juice of0.0296, but this value is too high by a factor of 1000 due to an arithmetic error. 11. The HERP is based on a TD,o of 27.3 mg/kg per day for 8-methoxypsoralen. 12. C. H. Van Erten K a/., J. Agric. Food C6rm. 24, 452 (1976); G. R. Fenwick, R. K. Hcanry, W. J. Mtillin, Cdt. Rev. Food Sri. Nutr. 18, 123 (1983); R. K. Heanev and G. R. Fenwick, J. Sri. Food Agdc. 31, 785 (1980); R. F. Mithcr, B. G. Lavis, R. K. Heaney, G. R. Fenwick, Phyrochemisrry 26. 1969 (1987). The HERP is based on a TDoof 96 mg/kg per day for allvl isothiocyanata 13. E. D. Lund, C. L Kirkland, P. E. Shaw, J. Agr'u. Food Chem. 29, 361 (1981). The HERP is based on a TD,o of 9100 mg/kg per day for alcohol. 14. H. ~taux, Ed., Volatile Carnpounds in Food. Quantita- rive Data, vol. 2 (Division for Nutrition and Food Research, TNO-CIVO Food Analysis Institute, Zeist, The Netherlands. 1983). 15. R. J. Prokopy, Fruit Notes 53, 7(Univeniry of Massadtusctcs Cooperative Eztension, Amherst, MA, 1988). 16. C. F. Jclinck A. E. PohLind, G. E. Wood, J. Assoc. ojf. Anal. Chnn. 72, 225 (1989); D. M. Wiison, in .Mycotaxtns and Other Fw,gal Related Food Probknu, J. V. Rodricks, Ed. (American Chemical Socicty, Wsshington, DC, 1976), pp. 90-109; G. M. Ware, C. W. Thorpe, A. E. Pohland, J. Assoc. Ojr Anar. Chent. 57, 1111 (1974); J. L. Wheeler. M. A. Harrison, P. E. Koehler, J. Food Science 52, 479 (1987). 17. International Agency for Resarch on Cancer, lARC :Nono,Qraphs on the Evaluation of the Carcinogenic Risk of ChemitaLs to Hiunans: Some Vaa.rally Ouuning and Synthetic Food Compontnu, Furacmnrvnns a+d L7travio- let Radiation ([ntemational Agency for Research on Cancer, Lyon, France, 1986), vol. 40, pp. 83-98. 18. J. A. Swenberg «al., Environ. Health. Penpact. 76, 57 (1987). 19. S. Woiff, V. AfuL J. K. Wieacke, G. OGvieri, A. Michaeli, Inr. J. Radiat. Biot. 53, 39 (1988); K. Sankarananvanan, A. v. Duvn, M. J. Loos, A. T. Natarajan, Muutt. Res. 211, 7(1989); A. Boai and G. OGvieri, ibid., p. 13. 20. A. Ootsuvuna and H. Tatwoka, RJdi.a. Rcs. 115, 488 (1988). 21. A. H. Smith and M. N. Batcs, in C.rrrinagmiciry and Pcsticidrs, N. N. Ragsdale and R. 11,irnzer, Eds. (American Chcmial S(xietv, Washington, DC, in press); R Pcto, in Assessment of R[s!u from Lo,v-Level Exposure (o Radiation and Chemicals: A Criticat Over- vdeu., A. D. Woodhead, C. J. Shdlabarger, V. Pond, A. Hollacndcr, Eds. (Ptcnum, New York, NY, 1985), pp. 3-16. 22. We thank M. Profa, T. Sbne, and N. Manley for usistatue and criticisms. Supported by NCI Out- standing Investigator grant CA39910 to B.N.A., NIEHS Center grant ES01896, and `'SEHS/DOE Inrengenry Agreement Y01-ES-10066. LETI'ERS 757 2025546162