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SCIENCE ; ~ S Richard S. Nicholson • : -in-Chiet: Daniel E. Koshtand Jr. .r: cIbs Rubinstein .:wnaging Editor: Monica M. Bradford peputy Editors: Philip H. Abelson (Engineering and Ap- }n,ro Suences); John i. Brauman (Physical Sciences); Thomas R. Cech (Biological Sciences) Editorial Staff Assistant Managing Editor: Dawn Bennett Senior Editors: Eleanore Butz. R. Brooks Hanson. Barbara Jasny. Katrina L Kelner. David Lindley, Linda J. Miller, PhiNip D. Szuromi, David F. Voss Assooiate Editors: Gilbert J. Chin, Pamela J. Hines, Paula ; Kiberstis• Suki Parks• L Bryan Ray .: aers: Christine Gilbert, EdNor Steven S. Lapham : Reviews: Katherine Livingston, Editor; Susan zoioh. Editorfal Assistant Contributing Editor. Lawrence I. Grossman Editing: Valerie Jablow, Cara Tate, Senior Copy Editors; Douglas 8. Casey. Harry Jach, Erik G. Morris• Christine M. Pearce Copy Desk: Ellen E. Murphy. Supendsor Joi S. Granger, Daniel T. Helgerman, Beverly Shields, Melissa O. Rosen. 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Jennifer Hodgin Telephone: 202-326-6500: FAX: 202-371-9227; Internet Address: science newsf3aaas.org Art & Production Staff Production: James Landry, Director, Wendy K. Shank, Manager; Lizabeth A. Harman, Assistant Manager; Laura A. Creveiing, Scherraine B. Mack, Linda C. Owens, Associates, Leslie Biizard, Assistant Art: Amy Decker Henry, Director; C. Faber Smith. Asso- r.ate Director; Katharine Sutliff, Sciendtic Illustrator: Holly B:« ;!~. Graphics Associate; Elizabeth CarroN, Graphics A: ,.r Europe Office Editorial: Richard B. Gallagher. Office Head and Senior Editor. Stella M. Hurtley. Jeffrey Williams. Associate Ed'~- tors: Belinda Holden. Editorial Associate News: Daniel Ctery, Editor• Peter Akihous. Conespondent Patricia Kahn, Contributing Correspondenf (Heidelberg) Administrativa Support: Janet Mumford: Anna Riches Address: 14 George IV Street. Cambridge. UK C621HH Telephone: (44) 0223 302067; FAX: (44) 0223 302066 Science Editorial Baard C~ar:°s J. Amtzen F. Clark Howell - ' °j"'more Paul A. Marks - -c:shop Yasutomi Nishizuka - • r:. Er.nxman Helen M. Ranney Bengt Samuelsson P'erre GJles de G1ennes Robert M. Solow Joseoh L. Goldstein Edward C. Stone Ltary L. Good James D. Watson Harry B. Gray Richard N. Zan3 John J. Hoofield EDITORIAL i Risk Assessments, of Low-Level. Exposures In cancer-risk assessments employed by the U.S: Environmental Protection Agency assump- tions are made that exaggerate risks by large factors. Among these is an important but un- proven hypothesis that results obtained by administering huge doses of substances are predic- tive of effects of minuscule doses. To calculate effects of small dos,:s, a linear extrapolation from large doses to zero is employed. The routine use of this procedure implies that pathways of metabolism of large doses and small doses are identical. It implies that mammals have no defense against effects that injure DNA. It implies that no dose, however small, is safe. Examples of instances in which these assumptions are invalid are becoming numerous. Linear extrapolation of effects frc m high to lower doses is often not valid. In a third or more of instances in which a maximum tolerated dose elicited extra tumors in rodents, one- half that dose did not. Bruce Ames and others have pointed out that huge doses of non- genotoxic substances are accompanied by toxicity, cell death, and cell replacements. This creates conditions favorable for growth of rumors. At doses in which cellular death does not occur, tumors would not be produced by non-genotoxic substances. The majority of chemi- cals are not genotoxic, nor does metabolism of them give rise to genotoxic intermediates. Thus the linear extrapolation is not applicable to the majority of chemicals. Recently, short-term experimen s have measured extent of damage to linear DNA caused by different levels of doses of tes: substances. In one example, 11 chemicals known to cause cancer at high doses were administered at low levels. With 8 of 11 substances, the minimum amounts of damaged DNA were found not in controls but in the animals that received an amount intermediate between zero and a high dose. Instead of damaging the DNA of the rodents' livers, the low doses were apparently beneficial to them. In another study, female rats administered 0.001 Ft;/kg per day of dioxin had fewer breast, uterine, pitu- itary, and liver tumors and fewer tumor; overall than did controls. When doses of 0.01 }tg/kg per day were administered, the incide nce of liver tumors exceeded that of controls, but breast, uterine, pituitary, and total twnors, were markedly fewer than in controls. In the above instances, safe (diminished canc er) levels of exposure exist for substances known to cause cancer at higher doses. The use of linear extrapolation from huge doses to zero implies that "one molecule can cause cancer." That assertion disregaris the fact of natural large-scale repair of damaged DNA. Natural chemical and physical Lesions of DNA are caused by thermal and oxidative insults. Metabolic processes employ re,tctive oxygen species including peroxides and OH.* Natural kinds of injury to DNA include depurination, depyrimidination, deamination, single-strand breaks, double-strand breaks, base modification, and protein-DNA crosslinks. Mammalian cells on average undergo about 10,000 measurable DNA modification events per cell per hour. Adult humans are inrernally exposed to about 500 g per day of oxygen-a relentless known destroyer of DNA. In contrast, hypothetical insults from anthropogenic sources are usually from substances pre:;ent in microgram quantities. Creatures ranging from micro-or„anistns to mammals could not survive if they did not have mechanisms to respond to challenges from their environments. During exposure to a somewhat elevated temperature, living forms synthesize a host of different proteins that en- able them to endure even higher temperatures. This phenomenon has been noted in experi- ments with cadmium, mercury, copper, zinc, polychlorinated biphenyls, and insecticides. Studies using x-rays show that a large total instantaneous dose is fatal while the same total dose spread over time is not. Repair of DNA occurs. Studies have shown that DNA-damag- ing agents induce a substantial number of responses, including production of proteases, DNA repair agents, oncogenes, and chromat.n changes.* The current mode of extrapolating high-dose to low-dose effects is erroneous for both chemicals and radiation. Safe levels of exposure exist. The public has been needlessly fright- ened and deceived, and hundreds of billions of dollars wasted. A hard-headed, rapid exami- nation of phenomena occurring at low exposures should have a high priority. 89273274 * BELLE Newsletters. University of Massachusctts; telephone 413-545-1239. SCIENCE • VOL. 265 • 9 SEPTEMBER 1994 Philip H. Abelson 1507