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Synergy, Antagonism, and Scientific Process, EHP August 1997

  Environmental Health Perspectives Volume 105, Number 8, August 1997
                   Synergy, Antagonism, and Scientific Process
                                                            Make haste slowly.
                                                    Baltisar Morales y Gracian
  In the July 25 issue of the journal Science, John A. McLachlan of the
  Tulane-Xavier Center for Bioenvironmental Research, Tulane University, New
  Orleans, Louisiana, withdrew a previously published paper in which the
  authors had reported marked synergistic effects of several environmental
  chemicals on the activation of the estrogen receptor in a yeast reporter
  system (1). The possibility of synergistic interactions between weakly
  estrogenic chemicals found in the environment has very important mechanistic
  and public health implications.
  In their Science paper McLachlan and colleagues reported that combinations
  of chemicals could activate the estrogen receptor to a degree several orders
  of magnitude above that produced by the individual chemicals (2). The
  biological effects of estrogen are mediated by high-affinity receptor
  proteins located in target cells. The consequences of estrogen receptor
  activation are far reaching because of its regulation of estrogen-responsive
  genes and because many industrial chemicals can interact with estrogen
  receptors, thereby disrupting normal endocrine functions. Disruption of
  normal endocrine functions through chemical interactions with the estrogen
  receptor could possibly be, in part, responsible for infertility,
  endometriosis, and cancers of the breast, uterus, and prostate.
  Laboratories at Texas A&M University, Duke University, NIEHS, and the
  Chemical Industry Institute of Toxicology, tried to repeat the experiments
  of Arnold et al. (2), but without success. These laboratories expressed
  their concerns in a combined technical note published in the January 1997
  issue of Science (3). This was followed by two other papers, which looked at
  several estrogen-receptor assays, and again synergism between weakly
  estrogenic chemicals was not detected (4,5). McLachlan and colleagues were
  unable to confirm their own data and, finally, their original Science paper
  was withdrawn. Withdrawal of their paper received the attention of major
  national newspapers and news services. Following the announcement of
  withdrawal, some inquiries have been made to this office regarding the
  standing of several recent articles published in Environmental Health
  Perspectives by the McLachlan group. These questions have ranged from
  expressions of environmental concern to direct statements regarding
  reliability of published data.
  Three papers have been published in Environmental Health Perspectives by the
  McLachlan group that referenced their now-withdrawn Science paper. The first
  paper subsequent to the Science paper was a commentary that directly
  addressed synergistic interactions with estrogen receptors (6). The
  commentary reviewed and discussed the synergistic activation of the estrogen
  receptor by environmental chemicals, but considered the data presented in
  the Science article simply as confirmatory of synergistic action. The
  article was a commentary in which some degree of speculation is permissable
  and no new data were presented. Two other papers published in Environmental
  Health Perspectives by McLachlan and colleagues that simply referenced the
  withdrawn Science paper are not affected by the withdrawal (7,8), and EHP is
  confident that the data in those papers should be in the scientific
  literature as they represent important contributions to our understanding of
  chemical interactions with the estrogen receptor.
  The history of science includes investigators who have clung to untenable
  positions maintaining their delusions to the bitter end, and most
  withdrawals were forced only after evidence had been offered suggesting some
  form of misconduct. The voluntary withdrawal of a scientific paper because
  the data cannot be substantiated is a rare event. While these actions have
  been very painful for all involved, they are an essential part of the
  process that makes science a unique human enterprise. In science, the
  fallibility of human involvement is minimized over time by observing and
  reobserving, testing and retesting. Data that do not support the consensual
  reality of science are replaced or quickly forgotten. In facilitating this
  process by withdrawing their paper, McLachlan and his colleagues have served
  science appropriately and well.
  These recent circumstances surrounding synergy in yeast have distracted us
  from the larger issues. We know from our experiences with PCBs and several
  pesticide formulations that synergy and antagonism may occur in
  circumstances of multiple chemical exposures. However, the scientific and
  regulatory communities have not developed credible strategies for designing
  mixture studies, in vitro or in vivo, to adequately address the issues of
  synergy, antagonism, or additivity. Moreover, we do not know how to best
  analyze the available data or how to package the information for use in risk
  assessment. These deficiencies must be addressed if we expect to properly
  evaluate health effects arising not only from environmental estrogens but
  chemical mixtures in general.
                                         Gary E. R. Hook and George W. Lucier
                                                         Editors-in-Chief, EHP
  1. McLachlan JA. Synergistic effect of environmental estrogens: report
  withdrawn. Science 277:459Ð463 (1997).
  2. Arnold SF, Klotz DM, Collins BM, Vonier PM, Guillette LJ Jr, McLachlan
  JA. Synergistic activation of estrogen receptor with combinations of
  environmental chemicals. Science 272:1489Ð1492 (1996).
  3. Ramamoorthy K, Wang F, Chen I-C, Safe S, Norris JD, McDonnell DP, Gaido
  KW, Bocchinfuso WP, Korach KS. Potency of combined estrogenic pesticides.
  Science 275:406 (1997).
  4. Gaido KW, McDonnell DP, Korach KS, Safe SH. Estrogenic activity of
  chemical mixtures: is there synergism? CIIT Activities. 17(2):1Ð7 (1997).
  5. Ramamoorthy K, Wang F, Chen I-C, Norris JD, McDonnell DP, Leonard LS,
  Gaido KW, Bocchinfuso WP, Korach KS, Safe S. Estrogenic activity of a
  dieldrin/toxaphene mixture in the mouse uterus, MCF-7 human breast cancer
  cells, and yeast-based estrogen receptor assays: no apparent synergism.
  Endocrinology 188:1520Ð1527 (1997).
  6. Arnold SF, McLachlan JA. Synergistic signals in the environment. Environ
  Health Perspect 104:1020Ð1023 (1996).
  7. Vonier PM, Crain DA, McLachlan JA, Guillette LJ Jr, Arnold SF.
  Interaction of environmental chemicals with the estrogen and progesterone
  receptors from the oviduct of the American alligator. Environ Health
  Perspect. 104:1318Ð1322 (1996).
  8. Arnold SF, Vonier PM, Collins BM, Klotz DM, Guillette LJ Jr, McLachlan
  JA. In vitro synergistic interaction of alligator and human estrogen
  receptors with combinations of environmental chemicals. Environ Health
  Perspect 105(suppl 3):615Ð618 (1997).
  [Table of Contents]
  Last Update: August 28, 1997
  Jackie Hunt Christensen
  Food Safety Project Director
  Institute for Agriculture and Trade Policy
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  e-mail: <jchristensen@igc.apc.org>
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