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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was withdrawn.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
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
2105 1st Avenue South
Minneapolis, MN 55404
612-870-3424 (direct line)
IATP's Endocrine Disrupter Resource Center: http://www.sustain.org/edrc