A clash of old and new scientific concepts in toxicity, with important implications for public health.
ABSTRACT A core assumption of current toxicologic procedures used to establish health standards for chemical exposures is that testing the safety of chemicals at high doses can be used to predict the effects of low-dose exposures, such as those common in the general population. This assumption is based on the precept that "the dose makes the poison": higher doses will cause greater effects.
We challenge the validity of assuming that high-dose testing can be used to predict low-dose effects for contaminants that behave like hormones. We review data from endocrinology and toxicology that falsify this assumption and summarize current mechanistic understanding of how low doses can lead to effects unpredictable from high-dose experiments.
Falsification of this assumption raises profound issues for regulatory toxicology. Many exposure standards are based on this assumption. Rejecting the assumption will require that these standards be reevaluated and that procedures employed to set health standards be changed. The consequences of these changes may be significant for public health because of the range of health conditions now plausibly linked to exposure to endocrine-disrupting contaminants.
We recommend that procedures to establish acceptable exposure levels for endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose results. Setting acceptable levels of exposure must include testing for health consequences at prevalent levels of human exposure, not extrapolations from the effects observed in high-dose experiments. Scientists trained in endocrinology must be engaged systematically in standard setting for endocrine-disrupting compounds.
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ABSTRACT: Exposure to endocrine disruptors (EDs) during early development might lead to adverse health outcomes later in life. Tributyltin (TBT), a proven ED, is widely used in consumer goods and industrial products. Herein we demonstrate the effects of low doses of tributyltin chloride (TBTCl) on reproduction of male KM mice. Pregnant mice were administered by gavage with 0, 1, 10, or 100 μg TBTCl/kg body weight/day from day 6 of pregnancy through the period of lactation. TBTCl dramatically decreased sperm counts and motility on postnatal days (PNDs) 49 and 152. Meanwhile, a significant increase in sperm abnormality was observed in exposed mice on PND 49, but comparable to that in the control on PND 152. The histopathological analysis of testes of treated animals showed a dose-dependent increase in sloughing of germ cells in seminiferous tubules. Mice treated with 10 μg TBTCl/kg exhibited decreased intratesticular 17β-estradiol (E2) levels on PND 49, and then followed by an obvious recovery on PND 152. While, no significant differences in serum E2, testosterone (T) levels and intratesticular T levels were detectable between control and TBTCl-exposed offspring at the sacrifice. These results suggest that perinatal TBTCl exposure is implicated in causing long lasting alterations in male reproductive system and these changes may persist far into adulthood. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013.Environmental Toxicology 08/2013; · 2.71 Impact Factor
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ABSTRACT: For years, scientists from various disciplines have studied the effects of endocrine disrupting chemicals (EDCs) on the health and wellbeing of humans and wildlife. Some studies have specifically focused on the effects of low doses, i.e. those in the range that are thought to be safe for humans and/or animals. Others have focused on the existence of non-monotonic dose-response curves. These concepts challenge the way that chemical risk assessment is performed for EDCs. Continued discussions have clarified exactly what controversies and challenges remain. We address several of these issues, including why the study and regulation of EDCs should incorporate endocrine principles; what level of consensus there is for low dose effects; challenges to our understanding of non-monotonicity; and whether EDCs have been demonstrated to produce adverse effects. This discussion should result in a better understanding of these issues, and allow for additional dialogue on their impact on risk assessment.Reproductive Toxicology 02/2013; · 3.14 Impact Factor
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ABSTRACT: A World War II defense site at Northway, Alaska, was remediated in the 1990s, leaving complex questions regarding historic exposures to toxic waste. This article describes the context, methods, limitations and findings of the Northway Wild Food and Health Project (NWFHP). The NWFHP comprised 2 pilot studies: the Northway Wild Food Study (NWFS), which investigated contaminants in locally prioritized traditional foods over time, and the Northway Health Study (NHS), which investigated locally suspected links between resource uses and health problems. This research employed mixed methods. The NWFS reviewed remedial documents and existing data. The NHS collected household information regarding resource uses and health conditions by questionnaire and interview. NHS data represent general (yes or no) personal knowledge that was often second hand. Retrospective cohort comparisons were made of the reported prevalence of 7 general health problems between groups based on their reported (yes or no) consumption of particular resources, for 3 data sets (existing, historic and combined) with a two-tailed Fisher's Exact Test in SAS (n=325 individuals in 83 households, 24 of which no longer exist). The NWFS identified historic pathways of exposure to petroleum, pesticides, herbicides, chlorinated byproducts of disinfection and lead from resources that were consumed more frequently decades ago and are not retrospectively quantifiable. The NHS found complex patterns of association between reported resource uses and cancer and thyroid-, reproductive-, metabolic- and cardiac problems. Lack of detail regarding medical conditions, undocumented histories of exposure, time lapsed since the release of pollution and changes to health and health care over the same period make this exploratory research. Rather than demonstrate causation, these results document the legitimacy of local suspicions and warrant additional investigation. This article presents our findings, with discussion of limitations related to study design and limitations that are inherent to such research.International journal of circumpolar health. 01/2013; 72.
volume 117 | number 11 | November 2009 • Environmental Health Perspectives
The very public debate about potential
harmful consequences of exposure to the
plastic monomer bisphenol A (BPA) is a lead-
ing high-profile battleground in a scientific
revolu tion currently under way in toxicology
(Layton 2008; Myers et al. 2009). But much
more is under contention than the health risks
of one chemical. Data emerging from studies
of endocrine-disrupting chemi cals (EDCs),
such as BPA, that mimic or in numerous
ways interfere with hormone action, chal-
lenge the central assumption that has guided
toxicology for centuries, including today’s
regulatory apparatus for assessing chemical
safety. In so doing, they challenge the meth-
ods and the adequacy of chemical exposure
Using High-Dose Testing to
Predict Low-Dose Effects
The core assumption of regulatory toxicol-
ogy is that experiments using high doses will
reveal potential effects of low doses. This is
derived from 16th-century dogma but is still
typically applied today by federal regulators
(White et al. 2009), although it conflicts
directly with well-established principles in
endocrinology regarding hormone action.
The acceptance of this assumption has pro-
found implications for the assessment of risk
to human health posed by EDCs.
The approach of using very high-dose test-
ing to predict consequences of much lower
doses that are typically within the range of
widespread human exposure emerges from a
16th-century observation by Paracelsus that
toxicologists paraphrase as “the dose makes
the poison” (Gallo 1996). Paracelsus’ logic
holds if and only if a chemical’s effects follow
a monotonic dose–response curve, in which
more of the chemical leads to a greater effect.
Monotonicity and non monotonicity refer to
changes in the slope of the curve describing
dose and response. Monotonic curves may
be linear or non linear, but the slope never
reverses from positive to negative or vice versa.
The slope of a non monotonic curve changes
sign, from positive to negative or vice versa.
Biologically relevant non monotonic curves
include “U-shaped” or “inverted-U–shaped”
dose–response relationships. When toxicolo-
gists began to focus on potential health effects
of EDCs, endocrinolo gists raised questions
about the appropriateness of assuming mono-
tonicity as a basis for chemical risk assess-
ments, because non monotonicity is a general
charac teristic of endogenous hormones, hor-
monally active drugs, and environmental
chemicals with hormonal activity.
Indeed, Paracelsus’ assumption is directly
contradicted by decades of research in endo-
crinology and clinical medicine showing that
hormonally active compounds have dose–
response curves in which low doses can cause
effects opposite to those at high doses. This
issue is so central to hormone action that it
is a critical component of determining the
dose required for hormonally active drugs.
Two well-known examples are Lupron [used
to treat reproductive disorders in women and
men (Garner 1994)] and tamoxifen [used to
treat breast cancer (Mortimer et al. 2001)],
in which low doses stimulate whereas high
doses inhibit disease. Specifically, for both of
these drugs, a phenomenon known as low-
dose “flare” occurs, during which there is
stimulation of the response that the drug
inhibits when the blood level of the drug
reaches the high clinically effective dose range
(e.g., for Lupron, testosterone secretion in
men with prostate cancer; and for tamoxifen,
prolifera tion of mammary tissue in women
with breast cancer).
Nonmonotonic dose–response curves result
from multiple mechanisms. Hormones and
hormone-mimicking chemicals act through
receptors in target cells. Very low doses can
stimulate the production of more recep-
tors (receptor up-regulation), resulting in an
increase in responses, whereas higher doses
(within the typical toxicologic range of chem-
ical testing) can inhibit receptors (receptor
down-regulation), resulting in a decrease in
responses (Welshons et al. 2003). The con-
sequence for gene activity, which is regulated
by hormone-mimicking chemicals binding
to receptors that amplify very small expo-
sures into very large responses, is that very
Address correspondence to J.P. Myers, Environmental
Health Sciences, 421 Park St., Charlottesville, VA
22902 USA. Telephone: (434) 220-0348. Fax: (434)
220-0347. E-mail: email@example.com
We thank L. Birnbaum, P. Ehrlich, D. Epel,
P. Hunt, D. Kennedy, P. Lee, and S. Vogel for com-
ments on the manuscript.
J.P.M. is CEO/chief scientist for Environmental
Health Sciences (EHS), a not-for-profit organization
that receives support from several private founda-
tions (listed at http://www.environmentalhealthnews.
org/about.html) to support EHS’s mission to
advance public understanding of environmental
health sciences. In addition to serving on the fac-
ulty of the University of Missouri, F.v.S. is CEO of
XenoAnalytical LLC, a small private laboratory that
performs assays of xenobiotic compounds. R.T.Z.
declares he has no competing financial interests.
Received 10 April 2009; accepted 29 July 2009.
A Clash of Old and New Scientific Concepts in Toxicity, with Important
Implications for Public Health
John Peterson Myers,1 R. Thomas Zoeller,2 and Frederick S. vom Saal3
1Environmental Health Sciences, Charlottesville, Virginia, USA; 2Biology Department, University of Massachusetts, Amherst,
Massachusetts, USA; 3Division of Biological Sciences, University of Missouri, Columbia, Missouri, USA
Background: A core assumption of current toxicologic procedures used to establish health
standards for chemical exposures is that testing the safety of chemicals at high doses can be used
to predict the effects of low-dose exposures, such as those common in the general population.
This assumption is based on the precept that “the dose makes the poison”: higher doses will cause
oBjectives: We challenge the validity of assuming that high-dose testing can be used to predict
low-dose effects for contaminants that behave like hormones. We review data from endocrinology
and toxicology that falsify this assumption and summarize current mechanistic understanding of
how low doses can lead to effects unpredictable from high-dose experiments.
discussion: Falsification of this assumption raises profound issues for regulatory toxicology. Many
exposure standards are based on this assumption. Rejecting the assumption will require that these
standards be reevaluated and that procedures employed to set health standards be changed. The
consequences of these changes may be significant for public health because of the range of health
conditions now plausibly linked to exposure to endocrine-disrupting contaminants.
conclusions: We recommend that procedures to establish acceptable exposure levels for
endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose
results. Setting acceptable levels of exposure must include testing for health consequences at preva-
lent levels of human exposure, not extrapolations from the effects observed in high-dose experi-
ments. Scientists trained in endocrinology must be engaged systematically in standard setting for
key words: biphasic, bisphenol A, dose–response curve, inverted U, low dose, nonmonotonic,
regulatory toxicology. Environ Health Perspect 117:1652–1655 (2009). doi:10.1289/ehp.0900887
available via http://dx.doi.org/ [Online 30 July 2009]
A clash of old and new concepts in toxicology
Environmental Health Perspectives • volume 117 | number 11 | November 2009
low doses of these chemicals (in the case of
a positively regulated gene) can up-regu late
gene expression, whereas at higher doses the
same chemicals down-regulate gene expres-
sion (Coser et al. 2003; Medlock et al. 1991;
Vandenberg et al. 2007).
If only one response is being measured,
a non monotonic dose–response curve is a
common finding for EDCs. An additional
complication, however, is that when multiple
outcomes are examined, qualitatively different
outcomes are commonly observed at low and
high doses of EDCs. One basis for this is that
the suite of genes whose expression is regu-
lated by low doses of endogenous hormones
and chemicals that mimic these hormones
can be completely different from the genes
affected by high doses (Coser et al. 2003). As
the dose increases, hormones and hormone-
mimicking chemicals can bind to receptors
for other hormones, referred to as recep-
tor cross-talk. For example, at high doses,
endogenous and man-made environmental
estrogens begin to inter act with androgen
and thyroid hormone receptors, producing
entirely different effects from those seen at
low doses, when only significant binding to
estrogen receptors occurs (Welshons et al.
2003). Furthermore, myriad hormonal feed-
back mechanisms among the brain, pituitary
gland, and hormone-producing organs (e.g.,
thyroid gland, adrenal glands, ovaries, testes)
contribute to the presence of non monotonic
dose–response curves and qualitatively differ-
ent responses at low and high doses of EDCs.
The consequence is that high doses and low
doses differ not just in quantitative effects but
also in qualitative impact, especially when
responses of whole organisms are considered.
Another consideration is that the effects
of EDCs classified as “xeno estrogens” are
not identical. As research has progressed into
identifying the molecular mechanisms medi-
ating responses, a consensus has emerged that
this class of EDCs should be categorized as
selective estrogen receptor modulators, to
highlight the fact that each can result in a
unique array of responses. However, conduct-
ing studies that involve comparing activities
of different xeno estrogens (or other chemi-
cals that act via simi lar mechanisms) requires
understanding the importance of the doses
being used (Shioda et al. 2006).
EDCs may also act by mechanisms that
do not require direct mediation by classi-
cal hormone receptors. Nonspecific (non–
receptor-mediated) toxicity can occur at high
but not low doses. EDCs also exert actions
upon synthesis or function of enzymes that
may be responsible for the synthesis or
degrada tion of hormones and on coregulatory
proteins that interact with receptors and, in
the case of neuro logic actions, affect neuro-
transmitters and their receptors (Gore 2007).
For example, low doses of atrazine activate
aromatase gene activity in zebrafish embryos;
this activity can alter sex determination via a
rapid signaling system (Suzawa and Ingraham
2008). This concept is important because each
of these mechanisms may have a unique dose–
response relationship for a particular EDC,
adding to the complexity of the overall shape
of the dose–response curve for each response.
Of great importance, above the dose at
which a hormonally active chemical saturates
(occupies virtually all) receptors, any change
in response that occurs cannot be caused by a
receptor-mediated mechanism, which requires
a change in receptor occupancy. Receptors
for steroid hormones are ligand-activated
transcription factors that require a change in
ligand binding to affect the rate of gene tran-
scription. Thus, high-dose experiments cannot
be used to predict low-dose results mediated
by EDCs binding to hormone receptors and
altering receptor-mediated responses at low
doses. The current paradigm in regulatory
toxicology of only testing a few very high
doses of chemicals within a relatively nar-
row dose range (with the highest dose being
the maximum tolerated dose) thus does not
serve to predict the hazards posed by low-level
exposure to numerous EDCs found in most
people in biomonitoring studies conducted
in the United States and elsewhere (Calafat
et al. 2008).
Nonmonotonic dose–response curves
have been reported for adverse effects with a
number of EDCs (Myers and Hessler 2007),
including the polycarbonate plastic monomer
BPA (Figure 1) used in some baby bottles,
water bottles, and food can linings (Wetherill
et al. 2002); di(2-ethyl hexyl) phthalate
(DEHP), used in medical devices and other
products made with polyvinyl chloride plas-
tic (Takano et al. 2006); and the pesticides
dieldrin, endosulfan, and hexa chloro benzene
(Narita et al. 2007). For example, exposure to
DEHP at a concentration 1,000-fold less than
the current safety standard, which is based
on high-dose liver toxicity, exacerbated aller-
gic reactions (Takano et al. 2006). Similarly,
exposure to extremely low (picomolar, parts
per trillion) levels of several persistent organic
pollutants increased allergic responses (Narita
et al. 2007). None of these effects was pre-
dicted by studies that examined only high
doses of these chemicals.
In an experiment explicitly designed to test
the adequacy of high-dose testing of DEHP
in rats, Andrade et al. (2006) found that a
high dose increased estrogen-synthesizing
(aromatase) enzyme activity in the brains of
neonatal male rats; a dose 100-fold lower
appeared to be the “no effect dose,” which
is used to estimate the dose deemed safe for
human exposure (the aromatase enzyme is
involved in determining sex differences in
brain function). Only because the scientists
broke with tradition and also tested lower
doses did they find significant down-regulation
of aromatase at a dose 37 times lower than the
putative no effect dose, an effect opposite to
and unpredicted from results of testing only
very high doses.
Other experiments have documented
nonmonotonicity in rat pituitary and cere-
bellar cortex cells exposed to pico molar
through micro molar levels of BPA (Wozniak
et al. 2005; Zsarnovszky et al. 2005). Acting
Figure 1. BPA induces cell proliferation in androgen-independent LNCaP prostate cancer cells. LNCaP cells
were propagated for 72 hr in 5% charcoal-/dextran-treated fetal bovine serum supplemented with 0.1%
ethanol vehicle and increasing BPA concentrations (0.1–100 nM). Cells were then labeled with bromode-
oxyuridine (BrdU), and BrdU incorporation was detected via indirect immuno fluorescence. Data shown are
mean ± SD of three independent experiments in which at least 250 cells/experiment were analyzed. The
shaded region indicates typical concentrations found in humans (Vandenbergh et al. 2007). The response
to 100 nM BPA did not differ from control. A standard toxicity test, working down the dose–response curve
from high doses, would have shown no difference between controls and exposed animals at a dose at that
level or above and would have used it to identify the “apparent no observed adverse effect level (NOAEL),”
indicated by the arrow. Testing at lower doses would not have been conducted, and the stimulatory effect
of BPA at 1 nM and 10 nM would never have been observed. Figure modified from Wetherill et al. (2002).
Range of serum concentrations
commonly observed in people
Cell proliferation (% BrdU positive)
Myers et al.
volume 117 | number 11 | November 2009 • Environmental Health Perspectives
through a relatively recently discovered non-
classical estrogen response system, very low
picomolar concentrations of BPA increased
calcium influx and activation of enzyme cas-
cades that dramatically amplify a very low-
dose signal into a large cellular response.
The dose–response curve followed a non-
monotonic inverted-U shape, with the stron-
gest response at picomolar to low nano molar
levels. The bioactive concentrations of BPA
in these experiments were below the range
found ubiqui tously in human blood and urine.
Other end points that follow a non monotonic
pattern for BPA are human prostate cancer cell
proliferation (Figure 1) (Wetherill et al. 2002),
promotion of human seminoma cell prolifera-
tion (Bouskine et al. 2009), and production
of the insulin-response–regulating hormone
adiponectin by human adipocytes (Hugo
et al. 2008). These specific responses to BPA
occurred within the range of human expo-
sure to BPA based on biomonitoring stud-
ies (Calafat et al. 2008; Richter et al. 2007;
Schonfelder et al. 2002) but were not observed
at much higher doses.
Research over the past 20 years has iden-
tified multiple EDCs that mimic or dis-
rupt hormone function at low doses in ways
that are not predicted by high-dose studies.
Biomonitoring studies have established that
many of these contaminants are widespread
in people. Yet classical regulatory toxicology
ignores nonmonotonicity despite the fact that,
similar to hormones, EDCs would be expected
to display non monotonic dose–response pat-
terns for many responses. This disconnect with
current science pervades virtually all regula-
tory agencies responsible for chemical safety
around the world, and it means that many
regulatory decisions are highly likely to have
under estimated risks.
If the health implications of these decisions
were inconsequential, the clash between regu-
latory toxicology and endocrinology would
appropriately remain buried in academia. But
the range of health conditions now plausi-
bly linked to EDCs—including, but not lim-
ited to, prostate cancer (Chamie et al. 2008),
breast cancer (Soto et al. 2008), attention
defi cit hyperactivity disorder (Ishido et al
2004), infertility and male and female repro-
ductive dis orders (Hauser and Sokol 2008;
Swan 2008), miscarriage, and most recently,
hyper allergic diseases, asthma (Bornehag et al.
2004), obesity (Hugo et al. 2008), and heart
disease and type 2 diabetes (Lang et al. 2008;
vom Saal and Myers 2008)—makes it impera-
tive that the clash between endocrinology and
regu latory toxicology be resolved in ways that
reflect modern scientific understanding.
These chronic diseases are major contribu-
tors to the steadily increasing human disease
burden and to the escalating cost of health
care throughout the world. Extensive, careful,
and replicable animal research suggests that
numerous common man-made chemicals to
which people are exposed every day, but that
have not been adequately studied for health
effects in humans, may be significant contribu-
tors to these adverse health trends. Because the
endocrine system is highly conserved between
animals used as models in biomedical research
and humans, the default assumption should be
that nonmonotonic dose–responses of EDCs
observed in laboratory animals and in vitro,
including with human cells and tissues, are
applicable to human health (Hugo et al. 2008;
Wetherill et al. 2007). Modernizing relevant
health standards by incorporating endocrino-
logic principles could help reduce a significant
portion of the human disease burden, but this
will require regulatory decision makers to fun-
damentally change the paradigm commonly
used to assess the risk to human health posed
We recommend the following:
• Animal testing protocols used to establish
regulatory safety standards must include
experiments that examine effects of chemi-
cals over a wide dose range that at their low
end overlap with typical human exposures,
particularly those experienced by vulnerable
populations based on biomonitoring data,
or modeling if actual data do not exist.
• Current scientific knowledge obtained
through studies on the endocrine system
and its disruption by exogenous chemicals
should be applied systematically when regu-
latory standards on EDCs are to be estab-
lished. For the best interest of public safety,
cooperation of chemical manufacturers in
reevaluating safety of their products under
the new criteria is critical. Their acceptance
of the endocrinology-derived concept that
high-dose experiments are insufficient to
establish safety standards for EDCs is essen-
tial. Continued denial of the reality that
nonmonotonic dose–response curves are
predicted to occur for EDCs is no longer
tenable (Bird 2005; vom Saal 2005).
The soaring health care crisis unfolding in
countries around the world demands that the
regulatory apparatus of governments move
into the 21st century. Blind obedience to
16th-century dogma will not solve the prob-
lem. Unless and until regulatory agencies
incorporate modern endocrinologic principles
into their risk assessment paradigms, they
will continue to provide false assurances of
“safety” and fail to recognize the actual health
risks posed by chronic low-level exposure to
an increasing number of chemicals found in
commonly used products.
Andrade AJ, Grande SW, Talsness CE, Grote K, Chahoud I.
2006. A dose-response study following in utero and lacta-
tional exposure to di-(2-ethylhexyl)-phthalate (DEHP): non-
monotonic dose-response and low dose effects on rat brain
aromatase activity. Toxicol 227(3):185–192.
Bird J. 2005. Hyperbole or commonsense. Chem Ind 5:14–15.
Bornehag CG, Sundell J, Weschler CJ, Sigsgaard T, Lundgren B,
Hasselgren M, et al. 2004. The association between asthma
and allergic symptoms in children and phthalates in house
dust: a nested case–control study. Environ Health Perspect
Bouskine A, Nebout M, Brucker-Davis F, Benahmed M, Fenichel
P. 2009. Low doses of bisphenol A promote human semi-
noma cell proliferation by activating PKA and PKG via a
membrane G-protein-coupled estrogen receptor. Environ
Health Perspect 117:1053–1058.
Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. 2008.
Exposure of the U.S. population to bisphenol A and 4-tertiary-
octylphenol: 2003–2004. Environ Health Perspect 116:39–44.
Chamie K, DeVere White RW, Lee D, Ok JH, Ellison LM. 2008.
Agent Orange exposure, Vietnam War veterans, and the
risk of prostate cancer. Cancer 113(9):2464–2470.
Coser KR, Chesnes J, Hur J, Ray S, Isselbacher KJ, Shioda T.
2003. Global analysis of ligand sensitivity of estrogen
inducible and suppressible genes in MCF7/BUS breast
cancer cells by DNA microarray. Proc Natl Acad Sci USA
Gallo MA. 1996. History and scope of toxicology. In: Casarett
and Doull’s Toxicology: The Basic Science of Poisons
(Klaassen CD, ed). 5th ed. New York: McGraw-Hill, 3–10.
Garner C. 1994. Uses of GnRH agonists. J Obstet Gynecol
Neonatal Nurs 23(7):563–570.
Gore AC, ed. 2007. Introduction to endocrine-disrupting chemicals.
In: Endocrine-Disrupting Chemicals: From Basic Research to
Clinical Practice. Totowa, NJ:Humana Press, 3–8.
Hauser R, Sokol R. 2008. Science linking environmental con-
taminant exposures with fertility and reproductive health
impacts in the adult male. Fertil Steril 89(2 suppl):e59–e65.
Hugo ER, Borcherding DC, Gersin KS, Loftus J, Ben-Jonathan N.
2008. Prolactin release by adipose explants, primary
adipo cytes, and LS14 adipocytes. J Clin Endocrinol Metab
Ishido M, Masuo Y, Kunimoto M, Oka S, Morita M. 2004.
Bisphenol A causes hyperactivity in the rat concomitantly
with impairment of tyrosine hydroxylase immunoreactivity.
J Neurosci Res 76:423–433.
Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M,
Wallace RB, et al. 2008. Association of urinary bisphenol
A concentration with medical disorders and laboratory
abnormalities in adults. JAMA 300(11):1303–1310.
Layton L. 2008. Studies on chemical in plastics questioned.
Washington Post (Washington DC) 27 April:A1. Available:
21 September 2009].
Medlock KL, Lyttle CR, Kelepouris N, Newman ED, Sheehan DM.
1991. Estradiol down-regulation of the rat uterine estrogen
receptor. Proc Soc Exp Biol Med 196(3):293–300.
Mortimer JE, Dehdashti F, Siegel BA, Trinkaus K,
Katzenellenbogen JA, Welch MJ. 2001. Metabolic flare:
indicator of hormone responsiveness in advanced breast
cancer. J Clin Oncol 19(11):2797–2803.
Myers JP, Hessler W. 2007. Does ‘the dose make the poi-
son?’ Environ Health News. Available: http://www.
2007/2007-0415nmdrc.html [accessed 9 April 2009].
Myers JP, vom Saal FS, Akingbemi BT, Arizono K, Belcher S,
Colborn T, et al. 2009. Why public health agencies cannot
depend on Good Laboratory Practices as a criterion for
selecting data: the case of bisphenol A. Environ Health
Narita S, Goldblum RM, Watson CS, Brooks EG, Estes DM,
Curran EM, et al. 2007. Environmental estrogens induce
mast cell degranulation and enhance IgE-mediated release
of allergic mediators. Environ Health Perspect 115:48–52.
Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS,
Talsness CE, et al. 2007. In vivo effects of bisphenol A in
laboratory rodent studies. Reprod Toxicol 24(2):199–224.
Schonfelder G, Wittfoht W, Hopp H, Talsness CE, Paul M,
Chahoud I. 2002. Parent bisphenol A accumulation in human
maternal–fetal–placental unit. Environ Health Perspect
A clash of old and new concepts in toxicology
Environmental Health Perspectives • volume 117 | number 11 | November 2009
Shioda T, Chesnes J, Coser KR, Zou L, Hur J, Dean KL, et al.
2006. Importance of dosage standardization for inter-
preting transcriptomal signature profiles: evidence
from studies of xenoestrogens. Proc Natl Acad Sci USA
Soto AM, Vandenberg LN, Maffini MV, Sonnenschein C.
2008. Does breast cancer start in the womb? Basic Clin
Pharmacol Toxicol 102(2):125–133.
Suzawa M, Ingraham HA. 2008. The herbicide atrazine
activates endocrine gene networks via non-steroidal
NR5A nuclear receptors in fish and mammalian cells.
PLoS ONE 3(5):e2117; doi:10.1371/journal.pone.0002117
[Online 7 May 2008].
Swan SH. 2008. Environmental phthalate exposure in relation
to reproductive outcomes and other health endpoints in
humans. Environ Res 108:177–184.
Takano H, Yanagisawa R, Inoue K, Ichinose T, Sadakane K,
Yoshikawa T. 2006. Di-(2-ethylhexyl) phthalate enhances
atopic dermatitis-like skin lesions in mice. Environ Health
Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV.
2007. Human exposure to bisphenol A (BPA). Reprod
vom Saal FS. 2005. Low-dose BPA: confirmed by extensive
literature. Chem Ind 7:14–15.
vom Saal FS, Myers JP. 2008. Bisphenol A and risk of metabolic
disorders. JAMA 300(11):1353–1355.
Welshons WV, Thayer KA, Judy BM, Taylor JA, Curran EM,
vom Saal FS. 2003. Large effects from small exposures.
I. Mechanisms for endocrine-disrupting chemicals with
estrogenic activity. Environ Health Perspect 111:994–1006.
Wetherill YB, Akingbemi BT, Kanno J, McLachlan JA, Nadal A,
Sonnenschein C, et al. 2007. In vitro molecular mecha-
nisms of bisphenol A action. Reprod Toxicol 24(2):178–198.
Wetherill YB, Petra CE, Monk KR, Puga A, Knudsen KE. 2002.
The xenoestrogen bisphenol A induces inappropriate
androgen receptor activation and mitogenesis in prostate
adenocarcinoma cells. Mol Cancer Ther 7:515–524.
White RH, Cote I, Zeise L, Fox M, Dominici F, Burke TA, et al.
2009. State-of-the-science workshop report: issues and
approaches in low-dose-response extrapolation for
environmental health risk assessment. Environ Health
Wozniak AL, Bulayeva NN, Watson CS. 2005. Xenoestrogens at
picomolar to nanomolar concentrations trigger membrane
estrogen receptor-α-mediated Ca2+ fluxes and prolactin
release in GH3/B6 pituitary tumor cells. Environ Health
Zsarnovszky A, Le HH, Wang HS, Belcher SM. 2005. Ontogeny
of rapid estrogen-mediated extracellular signal-regulated
kinase signaling in the rat cerebellar cortex: potent non-
genomic agonist and endocrine disrupting activity of the
xenoestrogen bisphenol A. Endocrinology 146(12):5388–5396.